User login
Concurrent fibromyalgia intensifies ankylosing spondylitis symptoms
DENVER – Fibromyalgia syndrome commonly occurred in patients with ankylosing spondylitis who were reviewed at one U.S. center, and when the two coexisted ankylosing spondylitis disease severity significantly increased.
In the study’s 62 patients with confirmed ankylosing spondylitis (AS), 27 (44%) also met the 2010 American College of Rheumatology diagnostic criteria for fibromyalgia syndrome, Sherilyn Diomampo, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network. The fibromyalgia rate in these AS patients was substantially above prior reports of fibromyalgia prevalence rates in the range of 10%-15%, said Dr. Diomampo, a rheumatologist at MetroHealth Medical Center in Cleveland.
Patients with both disorders also had substantially higher scores across the board for all the measures of AS severity that Dr. Diomampo and her associates evaluated. For example, scores on the Bath AS Disease Activity Index averaged 6.8 in the patients with fibromyalgia and 3.8 in those without fibromyalgia. (A BASDAI score of 4.0 or higher generally suggests suboptimal disease control.) The average score of the AS Disease Activity Score using C-reactive protein (CRP) as the serum marker of inflammation was 4.2 in the subgroup with fibromyalgia and 2.8 in those without. (An ASDAS score of 3.5 or higher denotes high or very high disease activity. A score reduced by at least 1.1 indicates a clinically important improvement.) All these between-group differences were statistically significant.
Other measures of AS severity that were significantly higher with fibromyalgia included patient global self assessment, physician global assessment, average serum levels of CRP, and the average erythrocyte sedimentation rate.
The 2010 ACR diagnostic criteria for fibromyalgia syndrome used by Dr. Diomampo and her associates in their analysis require a patient to have a widespread pain index of at least 7 and symptom severity of at least 5, or alternatively, a widespread pain index of 3-6 and symptom severity of at least 9 (Arthritis Care Res. 2010 May;62[5]:600-10). In addition, for this study, the researchers stipulated that diagnosis of concomitant fibromyalgia meant patients had their fibromyalgia symptoms in place for at least 3 months, and the examining clinician could not attribute the patient’s pain to AS.
Using linear regression models with the widespread pain index and the symptom severity as the dependent variables, the researchers failed to see any statistically significant relationship between either of these two determinants of fibromyalgia severity and five different measures of AS severity, including the BASDAI and the ASDAS. In short, the assessment tools used to measure AS severity showed no ability to also measure the core characteristics of fibromyalgia, Dr. Diomampo said.
Overall, patients in the study averaged about 49 years old. The analysis showed a significantly higher rate of African-American patients in the fibromyalgia group, 63%, compared with a 37% rate of African Americans in those with AS and no fibromyalgia. The presence of acute, anterior uveitis was 27% among those with fibromyalgia and 73% of those with AS and no fibromyalgia. One notable similarity between the two subgroups was the percentage on treatment with a tumor necrosis factor inhibitor: 52% among those with concurrent fibromyalgia and 49% among those with AS alone.
Dr. Diomampo had no disclosures.
On Twitter @mitchelzoler
DENVER – Fibromyalgia syndrome commonly occurred in patients with ankylosing spondylitis who were reviewed at one U.S. center, and when the two coexisted ankylosing spondylitis disease severity significantly increased.
In the study’s 62 patients with confirmed ankylosing spondylitis (AS), 27 (44%) also met the 2010 American College of Rheumatology diagnostic criteria for fibromyalgia syndrome, Sherilyn Diomampo, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network. The fibromyalgia rate in these AS patients was substantially above prior reports of fibromyalgia prevalence rates in the range of 10%-15%, said Dr. Diomampo, a rheumatologist at MetroHealth Medical Center in Cleveland.
Patients with both disorders also had substantially higher scores across the board for all the measures of AS severity that Dr. Diomampo and her associates evaluated. For example, scores on the Bath AS Disease Activity Index averaged 6.8 in the patients with fibromyalgia and 3.8 in those without fibromyalgia. (A BASDAI score of 4.0 or higher generally suggests suboptimal disease control.) The average score of the AS Disease Activity Score using C-reactive protein (CRP) as the serum marker of inflammation was 4.2 in the subgroup with fibromyalgia and 2.8 in those without. (An ASDAS score of 3.5 or higher denotes high or very high disease activity. A score reduced by at least 1.1 indicates a clinically important improvement.) All these between-group differences were statistically significant.
Other measures of AS severity that were significantly higher with fibromyalgia included patient global self assessment, physician global assessment, average serum levels of CRP, and the average erythrocyte sedimentation rate.
The 2010 ACR diagnostic criteria for fibromyalgia syndrome used by Dr. Diomampo and her associates in their analysis require a patient to have a widespread pain index of at least 7 and symptom severity of at least 5, or alternatively, a widespread pain index of 3-6 and symptom severity of at least 9 (Arthritis Care Res. 2010 May;62[5]:600-10). In addition, for this study, the researchers stipulated that diagnosis of concomitant fibromyalgia meant patients had their fibromyalgia symptoms in place for at least 3 months, and the examining clinician could not attribute the patient’s pain to AS.
Using linear regression models with the widespread pain index and the symptom severity as the dependent variables, the researchers failed to see any statistically significant relationship between either of these two determinants of fibromyalgia severity and five different measures of AS severity, including the BASDAI and the ASDAS. In short, the assessment tools used to measure AS severity showed no ability to also measure the core characteristics of fibromyalgia, Dr. Diomampo said.
Overall, patients in the study averaged about 49 years old. The analysis showed a significantly higher rate of African-American patients in the fibromyalgia group, 63%, compared with a 37% rate of African Americans in those with AS and no fibromyalgia. The presence of acute, anterior uveitis was 27% among those with fibromyalgia and 73% of those with AS and no fibromyalgia. One notable similarity between the two subgroups was the percentage on treatment with a tumor necrosis factor inhibitor: 52% among those with concurrent fibromyalgia and 49% among those with AS alone.
Dr. Diomampo had no disclosures.
On Twitter @mitchelzoler
DENVER – Fibromyalgia syndrome commonly occurred in patients with ankylosing spondylitis who were reviewed at one U.S. center, and when the two coexisted ankylosing spondylitis disease severity significantly increased.
In the study’s 62 patients with confirmed ankylosing spondylitis (AS), 27 (44%) also met the 2010 American College of Rheumatology diagnostic criteria for fibromyalgia syndrome, Sherilyn Diomampo, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network. The fibromyalgia rate in these AS patients was substantially above prior reports of fibromyalgia prevalence rates in the range of 10%-15%, said Dr. Diomampo, a rheumatologist at MetroHealth Medical Center in Cleveland.
Patients with both disorders also had substantially higher scores across the board for all the measures of AS severity that Dr. Diomampo and her associates evaluated. For example, scores on the Bath AS Disease Activity Index averaged 6.8 in the patients with fibromyalgia and 3.8 in those without fibromyalgia. (A BASDAI score of 4.0 or higher generally suggests suboptimal disease control.) The average score of the AS Disease Activity Score using C-reactive protein (CRP) as the serum marker of inflammation was 4.2 in the subgroup with fibromyalgia and 2.8 in those without. (An ASDAS score of 3.5 or higher denotes high or very high disease activity. A score reduced by at least 1.1 indicates a clinically important improvement.) All these between-group differences were statistically significant.
Other measures of AS severity that were significantly higher with fibromyalgia included patient global self assessment, physician global assessment, average serum levels of CRP, and the average erythrocyte sedimentation rate.
The 2010 ACR diagnostic criteria for fibromyalgia syndrome used by Dr. Diomampo and her associates in their analysis require a patient to have a widespread pain index of at least 7 and symptom severity of at least 5, or alternatively, a widespread pain index of 3-6 and symptom severity of at least 9 (Arthritis Care Res. 2010 May;62[5]:600-10). In addition, for this study, the researchers stipulated that diagnosis of concomitant fibromyalgia meant patients had their fibromyalgia symptoms in place for at least 3 months, and the examining clinician could not attribute the patient’s pain to AS.
Using linear regression models with the widespread pain index and the symptom severity as the dependent variables, the researchers failed to see any statistically significant relationship between either of these two determinants of fibromyalgia severity and five different measures of AS severity, including the BASDAI and the ASDAS. In short, the assessment tools used to measure AS severity showed no ability to also measure the core characteristics of fibromyalgia, Dr. Diomampo said.
Overall, patients in the study averaged about 49 years old. The analysis showed a significantly higher rate of African-American patients in the fibromyalgia group, 63%, compared with a 37% rate of African Americans in those with AS and no fibromyalgia. The presence of acute, anterior uveitis was 27% among those with fibromyalgia and 73% of those with AS and no fibromyalgia. One notable similarity between the two subgroups was the percentage on treatment with a tumor necrosis factor inhibitor: 52% among those with concurrent fibromyalgia and 49% among those with AS alone.
Dr. Diomampo had no disclosures.
On Twitter @mitchelzoler
AT THE 2016 SPARTAN ANNUAL MEETING
Key clinical point: Nearly half of patients with ankylosing spondylitis had concurrent fibromyalgia at one U.S. center, and patients with both had much greater AS severity.
Major finding: The average BASDAI was 6.8 in patients with ankylosing spondylitis and fibromyalgia and 3.8 in patients with AS only.
Data source: Observational data collected on 62 adults with ankylosing spondylitis at one U.S. center.
Disclosures: Dr. Diomampo had no disclosures.
CDC warns pregnant women to avoid Miami neighborhood due to Zika risk
Health officials in Florida have identified 10 new cases of locally transmitted Zika virus infections in the neighborhood just north of downtown Miami where four other cases were reported earlier.
Persistent mosquito populations in southern Florida are the leading cause of the disease’s growing incursion into the continental United States, according to Tom Frieden, MD, MPH, director of the Centers for Disease Control and Prevention.
“This suggests that there is a risk of continued, active transmission of Zika in that area,” Dr. Frieden said Aug. 1 during a press call regarding the discovery of new cases by Florida officials.
The CDC is issuing new recommendations for people who either have visited, are currently visiting, or plan to visit this Miami neighborhood at any point after June 15, the earliest known date on which the infected individuals could have been exposed to the virus.
Women who are pregnant or planning to become pregnant are advised to stay away from the neighborhood north of downtown Miami. Women who live in or around Miami, and who either are or plan to become pregnant, should take steps to protect themselves from mosquitoes. Individuals living in Miami should take precautions to prevent transmitting the disease sexually.
Additionally, the CDC is sending an Emergency Response Team to Florida to assist with efforts to quell the mosquito population and spread awareness about Zika virus prevention.
“These experts include individuals with extensive experience in Zika, in addressing pregnancy and birth defects, in mosquito control, in laboratory science, and community engagement,” Dr. Frieden said.
Dr. Frieden reiterated that controlling the local mosquito population is one of the most effective ways to stop ongoing Zika virus transmission. However, current efforts are being hampered by several factors, including small bodies of standing water near which mosquitoes are breeding, the inherent difficulty in killing this species of mosquito, and the possibility that the Aedes aegypti mosquito is resistant to the insecticides being used.
Vector control experts will work with health officials on the ground in Miami to conduct resistance testing on local mosquitoes, in order to confirm whether the insecticides are working. These tests could be done after just 1 week, but may take 3 or more weeks. Further discussion is also ongoing to determine other ways of bringing down the mosquito population.
“What we know about Zika is scary [but] in some ways, what we don’t know about Zika is even more unsettling,” said Dr. Frieden, who added that “at CDC, more than 1,600 of our experts have been working since January to learn more about Zika and protect the health of pregnant women and others.”
Health officials in Florida have identified 10 new cases of locally transmitted Zika virus infections in the neighborhood just north of downtown Miami where four other cases were reported earlier.
Persistent mosquito populations in southern Florida are the leading cause of the disease’s growing incursion into the continental United States, according to Tom Frieden, MD, MPH, director of the Centers for Disease Control and Prevention.
“This suggests that there is a risk of continued, active transmission of Zika in that area,” Dr. Frieden said Aug. 1 during a press call regarding the discovery of new cases by Florida officials.
The CDC is issuing new recommendations for people who either have visited, are currently visiting, or plan to visit this Miami neighborhood at any point after June 15, the earliest known date on which the infected individuals could have been exposed to the virus.
Women who are pregnant or planning to become pregnant are advised to stay away from the neighborhood north of downtown Miami. Women who live in or around Miami, and who either are or plan to become pregnant, should take steps to protect themselves from mosquitoes. Individuals living in Miami should take precautions to prevent transmitting the disease sexually.
Additionally, the CDC is sending an Emergency Response Team to Florida to assist with efforts to quell the mosquito population and spread awareness about Zika virus prevention.
“These experts include individuals with extensive experience in Zika, in addressing pregnancy and birth defects, in mosquito control, in laboratory science, and community engagement,” Dr. Frieden said.
Dr. Frieden reiterated that controlling the local mosquito population is one of the most effective ways to stop ongoing Zika virus transmission. However, current efforts are being hampered by several factors, including small bodies of standing water near which mosquitoes are breeding, the inherent difficulty in killing this species of mosquito, and the possibility that the Aedes aegypti mosquito is resistant to the insecticides being used.
Vector control experts will work with health officials on the ground in Miami to conduct resistance testing on local mosquitoes, in order to confirm whether the insecticides are working. These tests could be done after just 1 week, but may take 3 or more weeks. Further discussion is also ongoing to determine other ways of bringing down the mosquito population.
“What we know about Zika is scary [but] in some ways, what we don’t know about Zika is even more unsettling,” said Dr. Frieden, who added that “at CDC, more than 1,600 of our experts have been working since January to learn more about Zika and protect the health of pregnant women and others.”
Health officials in Florida have identified 10 new cases of locally transmitted Zika virus infections in the neighborhood just north of downtown Miami where four other cases were reported earlier.
Persistent mosquito populations in southern Florida are the leading cause of the disease’s growing incursion into the continental United States, according to Tom Frieden, MD, MPH, director of the Centers for Disease Control and Prevention.
“This suggests that there is a risk of continued, active transmission of Zika in that area,” Dr. Frieden said Aug. 1 during a press call regarding the discovery of new cases by Florida officials.
The CDC is issuing new recommendations for people who either have visited, are currently visiting, or plan to visit this Miami neighborhood at any point after June 15, the earliest known date on which the infected individuals could have been exposed to the virus.
Women who are pregnant or planning to become pregnant are advised to stay away from the neighborhood north of downtown Miami. Women who live in or around Miami, and who either are or plan to become pregnant, should take steps to protect themselves from mosquitoes. Individuals living in Miami should take precautions to prevent transmitting the disease sexually.
Additionally, the CDC is sending an Emergency Response Team to Florida to assist with efforts to quell the mosquito population and spread awareness about Zika virus prevention.
“These experts include individuals with extensive experience in Zika, in addressing pregnancy and birth defects, in mosquito control, in laboratory science, and community engagement,” Dr. Frieden said.
Dr. Frieden reiterated that controlling the local mosquito population is one of the most effective ways to stop ongoing Zika virus transmission. However, current efforts are being hampered by several factors, including small bodies of standing water near which mosquitoes are breeding, the inherent difficulty in killing this species of mosquito, and the possibility that the Aedes aegypti mosquito is resistant to the insecticides being used.
Vector control experts will work with health officials on the ground in Miami to conduct resistance testing on local mosquitoes, in order to confirm whether the insecticides are working. These tests could be done after just 1 week, but may take 3 or more weeks. Further discussion is also ongoing to determine other ways of bringing down the mosquito population.
“What we know about Zika is scary [but] in some ways, what we don’t know about Zika is even more unsettling,” said Dr. Frieden, who added that “at CDC, more than 1,600 of our experts have been working since January to learn more about Zika and protect the health of pregnant women and others.”
Current Therapeutic Approaches to Renal Cell Carcinoma
From the Department of Medicine, Carole and Ray Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (Dr. Namakydoust and Dr. Clement) and the UConn School of Pharmacy, Storrs, CT (Dr. Holle).
Abstract
- Objective: To review therapeutic options for the treatment of renal cell carcinoma (RCC).
- Methods: Review of the literature in the context of a clinical case.
- Results: RCC accounts for 90% of all renal tumors. For RCC patients with nondistant metastases, preferred treatment is curative-intent radical nephrectomy or partial nephrectomy; oncologic outcomes for the 2 procedures are similar. For patients who are deemed not to be surgical candidates, ablative techniques such as cryoablation and radiofrequency ablation may be considered. Systemic therapy for metastatic RCC is based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. First-line treatment options for patients with metastatic clear-cell RCC include biologic agents such as high-dose interleukin-2 immune therapy, as well as targeted therapies including tyrosine kinase inhibitors (TKIs) and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis. Second-line therapies in this setting include TKIs and nivolumab (PD-1 inhibitor). If TKIs were used as first-line therapy, mTOR inhibitors can be used in the second line. In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options. Best supportive care should always be provided along with initial and subsequent therapies.
- Conclusion: Multiple treatment options are now available for patients with metastatic or unresectable RCC. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors [1]. Approximately 55,000 new RCC cases are diagnosed each year [1]. Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured sur-gically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [2]. Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.
Epidemiology and Classification
Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs [2]. Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure [3]. Longer duration of tobacco use is associated with a more aggressive course.
The 2004 World Health Organization classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics [2]. Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%) [2]. Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis.
Familial Syndromes
Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs [4].
VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS) [4]. Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common [5]. VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models [6–8]. HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease [4–8].
Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome [9]. In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.
Case Study
Initial Presentation
A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further workup is recommended.
• What are common clinical presentations of RCC?
Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes [10]. Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease [11]. Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.
• What is the approach to initial evaluation for a patient with suspected RCC?
Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion [12]. Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.
• What are the therapeutic options for limited-stage disease?
For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.
Surgical Intervention
Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.
A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8% [14]. Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as either an open or laparoscopic procedure, the latter of which may be performed robotically [15]. Oncologic outcomes appear to be comparable between the 2 approaches, with equivalent 5-year cancer-specific survival (91% with laparoscopic versus 93% with open approach) and recurrence-free survival (91% with laparoscopic versus 93% with open approach) [16]. The approach ultimately is selected based on provider- and patient-specific input, though in all cases the goal is to remove the specimen intact [16,17].
Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma [15].
In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events [18]. Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC [19].
Adjuvant Therapy
Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy [20]. Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection [21]. Therefore, observation remains the standard of care after nephrectomy.
Renal Tumor Ablation
For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.
Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.
Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates [22]. There have been no studies performed directly comparing the modalities.
Cryoablation. Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high-pressure gas (argon, nitrogen) is passed through the probe and it cools once it enters a lower pressure region. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor [23,24].
RFA. Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) from a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum [24].
Microwave ablation. Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA [24]. The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years [25]. However, a study by Castle and colleagues [26] demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.
Irreversible electroporation. Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe [27]. Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings [24].
Active Surveillance
Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter [28,29]. The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance [30]. The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews [31–33].
• What is the approach to follow-up after treatment of localized RCC?
After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen with bone and brain metastases, and thus bone scans and brain imaging are not listed as part of routine surveillance protocols in asymptomatic patients. Although there is inconclusive evidence that surveillance protocols improve outcomes in RCC, many professional associations have outlined recommendations based on expert opinion [34]. The American Urological Association released guidelines in 2013 and the National Comprehensive Cancer Network (NCCN) released their most recent set of guidelines in 2016 [21,35]. These guidelines use TNM staging to risk-stratify patients and recommend follow up.
Case Continued
CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.
• How is prognosis defined for metastatic RCC?
Prognostic Models
Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [13]. Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse [36,37]. Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.
Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa [38]. The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors) [39]. Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively [40].
Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy [41]. This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients were not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level [42].
The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant medial survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively) [43]. The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available [44,45]. Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.
Case Continued
Based on the MSKCC prognostic factor model, the patient is deemed to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.
• What is the appropriate first-line therapy in managing this patient’s metastatic disease?
Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology [57,58]. In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus [59]. Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option [21].
Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features [60]. Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response [61]. A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient [62].
Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients [63].
Biologics
Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology [64]. Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients [65].
Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study [66,67]. However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.
VEGF Monoclonal Antibodies
Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo [68]. In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SQ] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001) [47,48]. Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.
Tyrosine Kinase Inhibitors
TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.
Sunitinib. Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues [52,53] compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SQ 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy [69–71].
Pazopanib. Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4% [72]. This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy [50]. In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.
Sorafenib. Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy [73]. A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029) [51]. Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.
Axitinib. Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving one prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted [74]. In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2) [46]. The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.
Cabozantinib
Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a randomized, open label, phase 3 trial of cabozantinib versus everolimus in advanced RCC, Choueiri and colleagues [75] compared the efficacy of cabozantinib with everolimus in patients with metastatic RCC who had progressed on previous VEGFR-targeted therapies. In this study, 658 patients were randomly assigned to receive cabozantinib (60 mg orally daily) or everolimus (10 mg orally daily). Results of the study found that PFS was longer with cabozantinib in patients who had previously been treated with other TKIs (median PFS of 7.4 months versus 3.8 months; HR 0.58), corresponding to a 42% reduction in the rate of disease progression or death. The most common grade 3 and 4 toxicities seen with cabozantinib were similar to its class effect and consisted of hypertension, diarrhea, and fatigue. In the final analysis of the data, the median overall survival was 21.4 months (95% CI 18.7–not estimable) with cabozantinib and 16.5 months (95% CI 14.7 to 18.8) with everolimus (HR 0.66; 95% CI 0.53 to 0.83; P = 0.00026). The median follow-up for overall survival and safety was 18.7 months. These results highlight the importance of cabozantinib as a first line option in treatment of previously treated patients with advanced RCC [76].
mTOR Inhibitors
The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis [77]. Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.
Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model) [54]. The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SQ 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SQ 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hypercholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.
Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval [78]. The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.
TKI + mTOR Inhibitor
Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor, everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40; 95% CI 0.24 to 0.68; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66, 95% CI 0.30 to 1.10, P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61; 95% CI 0.38 to 0.98; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC [55].
Case Continued
The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.
• What is the appropriate next step in treatment?
PD1 Blockade
Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized anti-bodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy [79]. Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC [80]. Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues [81] demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.
Case Conclusion
Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.
Future Directions
With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Corresponding author: Jessica Clement, MD, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, [email protected].
Financial disclosures: None.
1. Siegel R, Miller, K, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin 2015;65:5–29.
2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics. Tumors of the urinary system and male genital organs. Lyon: IARC Press; 2004.
3. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000;343:1305–11.
4. Cohen H, McGovern F. Renal-cell carcinoma. N Engl J Med 2005;353:2477–90
5. Yao M, Yoshida M, Kishida T, et al. VHL tumor suppres sor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 2002;94:1569–75.
6. Iliopoulos O, Kibel A, Gray S, Kaelin WG Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1995;1:822–6
7. Chen F, Kishida T, Duh FM, et al. Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 1995;55:4804–7.
8. Iliopoulos O, Levy AP, Jiang C, et al. Negative regulation of hypoxia-inducible genes by the von Hippel Lindau protein. Proc Natl Acad Sci U S A 1996;93:10595–9.
9. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Bir- Hogg-Dube syndrome. Cancer Cell 2002;2:157–64
10. Shuch B, Vorganit S, Ricketts CJ, et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 2014;32:431–7.
11. Bukowski RM. Immunotherapy in renal cell carcinoma. Oncology 1999;13:801–10.
12. Mueller-Lisse UG, Mueller-Lisse UL. Imaging of advanced renal cell carcinoma. World J Urol 2010;28:253–61.
13. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC cancer staging manual, 7th ed. New York: Springer Science and Business Media LLC; 2010.
14. O’Malley RL, Godoy G, Kanofsky JA, Taneja SS. The necessity of adrenalectomy at the time of radical nephrectomy: a systematic review. J Urol 2009;181:2009–17.
15. McDougal S, Wein AJ, Kavoussi LR, et al. Campbell-Walsh Urology. 10th ed. Philadelphia (PA): Saunders; 2012.
16. Colombo JR Jr, Haber GP, Kelovsek JE, et al. Seven years after laparoscopic radical nephrectomy: oncologic and renal functional outcomes. Urology 2008:71:1149–54.
17. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Ca 2013;49:1374–403.
18. Weight CJ, Larson BT, Fergany AF, et al. Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183:1317–23.
19. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543–52.
20. Smaldone MC, Fung C, Uzzo RG, Hass NB. Adjuvant and neoadjuvant therapies in high-risk renal cell carcioma. Hematol Oncol Clin North Am 2011;25:765–91.
21. NCCN clinical practice guidelines in oncology. Version 3.2016. www.nccn.org. Accessed July 13, 2016
22. El Dib R, Touma NJ, Kapoor A. Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-amalysis of case series studies. BJU Int 2012;110:510–6.
23. Theodorescu D. Cancer cryotherapy: evolution and biology. Rev Urol 2004;6 Suppl 4:S9–S19.
24. Khiatani V, Dixon RG. Renal ablation update. Sem Intervent Radiol 2014;31:157–66.
25. Yu J, Liang P, Yu XL, et al. US-guided percutaneous microwave ablation of renal cell carcinoma: intermediate-term results. Radiol 2012;263:900–8.
26. Castle SM, Salas N, Leveillee RJ. Initial experience using microwave ablation therapy for renal tumor treatment: 18- month follow-up. Urology 2011;77:792–7.
27. Pech M, Janitzky A, Wendler JJ, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Intervent Radiol 2011;34:132–8.
28. Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628–31.
29. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998;51:203–5.
30. Pierorazio PM, Johnson MH, Ball MW, et al. Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry. Eur Urol 2015;68:408–15.
31. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 2011;60:39–44.
32. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006;175:425–31.
33. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer 2012;118:997–1006.
34. Williamson TJ, Pearson JR, Ischia J, et al.Guideline of guidelines: follow-up after nephrectomy for renal cell carcinoma. BJU Int 2016;117:555–62.
35. Donat S, Diaz M, Bishoff JT, et al. Follow-up for clinically localized renal neoplasms: AUA Guideline. J Urol 2013;190:407–16.
36. Janzen NK, Kim HL, Figlin RA, Bell-degrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003:30:843–52.
37. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socio-economic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008;34:193–205.
38. Mekhail T, Abou-Jawde R, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering Prognostic Factors Model for Survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2005;23: 832–41.
39. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289–96.
40. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530–40.
41. Heng DY, Xie W, Regan MM. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794–9.
42. Leibovich BC, Han KR, Bui MH, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: A stratification tool for prospective clinical trials. Cancer 2003;98:2566–77.
43. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071–6.
44. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol 2011;185:60–6.
45. Chapin BF, Delacroix SE Jr, Culp SH, et al. Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma. Eur Urol 2011;60:964–71.
46. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol 2013;14:1287–94.
47. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metatastic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 2007;370:2103–11.
48. Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144–50.
49. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8.
50. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–31.
51. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cell global evaluation trial. J Clin Oncol 2009;27:3312–8.
52. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24.
53. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–90.
54. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81.
55. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus and the combination in patients with metastatic renal cell carcinoma: a randomized, phase 2, open label, multicenter trial. Lancet Oncology 2015;16:1473–82.
56. Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Drugs version 2.3.3. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.
57. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008;26:127–31.
58. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Ann Oncol 2012;23:2108–14.
59. Armstrong AJ, Broderick S, Eisen T, et al. Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN). ASCO Meeting Abstracts 2015;33:4507.
60. Chowdhury S, Matrana MR, Tsang C, et al. Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions. Hematol Oncol Clin North Am 2011;25:853–69.
61. Escudier B, Droz JP, Rolland F, et al. Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 2002; 168–71
62. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004;101:1545–51.
63. Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435–43.
64. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8
65. Cho DC, Puzanov I, Regan MM, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009;32:181–5.
66. Pyrhönen S, Salminen E, Ruutu M, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999;17:2859–67.
67. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353:14–7.
68. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34.
69. Atkinson BJ, Kalra S, Wang X, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014;191:611–8.
70. Kollmannsberger C, Bjarnason G, Burnett P, et al. Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities. Oncologist 2011;16:543–53.
71. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9.
72. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–8.
73. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34
74. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9.
75. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–23.
76. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR) final results from a randomized, open-label, phase 3 trial. Lancet Oncology 2016;17:917–27.
77. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.
78. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–56.
79. Brahmer J, Tykodi S, Chow L, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65.
80. Thomson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow up. Cancer Res 2006;66: 3381–5.
81. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.
From the Department of Medicine, Carole and Ray Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (Dr. Namakydoust and Dr. Clement) and the UConn School of Pharmacy, Storrs, CT (Dr. Holle).
Abstract
- Objective: To review therapeutic options for the treatment of renal cell carcinoma (RCC).
- Methods: Review of the literature in the context of a clinical case.
- Results: RCC accounts for 90% of all renal tumors. For RCC patients with nondistant metastases, preferred treatment is curative-intent radical nephrectomy or partial nephrectomy; oncologic outcomes for the 2 procedures are similar. For patients who are deemed not to be surgical candidates, ablative techniques such as cryoablation and radiofrequency ablation may be considered. Systemic therapy for metastatic RCC is based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. First-line treatment options for patients with metastatic clear-cell RCC include biologic agents such as high-dose interleukin-2 immune therapy, as well as targeted therapies including tyrosine kinase inhibitors (TKIs) and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis. Second-line therapies in this setting include TKIs and nivolumab (PD-1 inhibitor). If TKIs were used as first-line therapy, mTOR inhibitors can be used in the second line. In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options. Best supportive care should always be provided along with initial and subsequent therapies.
- Conclusion: Multiple treatment options are now available for patients with metastatic or unresectable RCC. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors [1]. Approximately 55,000 new RCC cases are diagnosed each year [1]. Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured sur-gically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [2]. Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.
Epidemiology and Classification
Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs [2]. Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure [3]. Longer duration of tobacco use is associated with a more aggressive course.
The 2004 World Health Organization classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics [2]. Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%) [2]. Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis.
Familial Syndromes
Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs [4].
VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS) [4]. Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common [5]. VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models [6–8]. HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease [4–8].
Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome [9]. In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.
Case Study
Initial Presentation
A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further workup is recommended.
• What are common clinical presentations of RCC?
Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes [10]. Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease [11]. Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.
• What is the approach to initial evaluation for a patient with suspected RCC?
Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion [12]. Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.
• What are the therapeutic options for limited-stage disease?
For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.
Surgical Intervention
Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.
A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8% [14]. Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as either an open or laparoscopic procedure, the latter of which may be performed robotically [15]. Oncologic outcomes appear to be comparable between the 2 approaches, with equivalent 5-year cancer-specific survival (91% with laparoscopic versus 93% with open approach) and recurrence-free survival (91% with laparoscopic versus 93% with open approach) [16]. The approach ultimately is selected based on provider- and patient-specific input, though in all cases the goal is to remove the specimen intact [16,17].
Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma [15].
In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events [18]. Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC [19].
Adjuvant Therapy
Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy [20]. Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection [21]. Therefore, observation remains the standard of care after nephrectomy.
Renal Tumor Ablation
For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.
Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.
Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates [22]. There have been no studies performed directly comparing the modalities.
Cryoablation. Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high-pressure gas (argon, nitrogen) is passed through the probe and it cools once it enters a lower pressure region. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor [23,24].
RFA. Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) from a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum [24].
Microwave ablation. Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA [24]. The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years [25]. However, a study by Castle and colleagues [26] demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.
Irreversible electroporation. Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe [27]. Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings [24].
Active Surveillance
Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter [28,29]. The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance [30]. The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews [31–33].
• What is the approach to follow-up after treatment of localized RCC?
After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen with bone and brain metastases, and thus bone scans and brain imaging are not listed as part of routine surveillance protocols in asymptomatic patients. Although there is inconclusive evidence that surveillance protocols improve outcomes in RCC, many professional associations have outlined recommendations based on expert opinion [34]. The American Urological Association released guidelines in 2013 and the National Comprehensive Cancer Network (NCCN) released their most recent set of guidelines in 2016 [21,35]. These guidelines use TNM staging to risk-stratify patients and recommend follow up.
Case Continued
CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.
• How is prognosis defined for metastatic RCC?
Prognostic Models
Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [13]. Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse [36,37]. Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.
Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa [38]. The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors) [39]. Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively [40].
Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy [41]. This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients were not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level [42].
The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant medial survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively) [43]. The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available [44,45]. Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.
Case Continued
Based on the MSKCC prognostic factor model, the patient is deemed to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.
• What is the appropriate first-line therapy in managing this patient’s metastatic disease?
Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology [57,58]. In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus [59]. Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option [21].
Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features [60]. Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response [61]. A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient [62].
Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients [63].
Biologics
Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology [64]. Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients [65].
Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study [66,67]. However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.
VEGF Monoclonal Antibodies
Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo [68]. In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SQ] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001) [47,48]. Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.
Tyrosine Kinase Inhibitors
TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.
Sunitinib. Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues [52,53] compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SQ 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy [69–71].
Pazopanib. Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4% [72]. This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy [50]. In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.
Sorafenib. Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy [73]. A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029) [51]. Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.
Axitinib. Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving one prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted [74]. In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2) [46]. The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.
Cabozantinib
Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a randomized, open label, phase 3 trial of cabozantinib versus everolimus in advanced RCC, Choueiri and colleagues [75] compared the efficacy of cabozantinib with everolimus in patients with metastatic RCC who had progressed on previous VEGFR-targeted therapies. In this study, 658 patients were randomly assigned to receive cabozantinib (60 mg orally daily) or everolimus (10 mg orally daily). Results of the study found that PFS was longer with cabozantinib in patients who had previously been treated with other TKIs (median PFS of 7.4 months versus 3.8 months; HR 0.58), corresponding to a 42% reduction in the rate of disease progression or death. The most common grade 3 and 4 toxicities seen with cabozantinib were similar to its class effect and consisted of hypertension, diarrhea, and fatigue. In the final analysis of the data, the median overall survival was 21.4 months (95% CI 18.7–not estimable) with cabozantinib and 16.5 months (95% CI 14.7 to 18.8) with everolimus (HR 0.66; 95% CI 0.53 to 0.83; P = 0.00026). The median follow-up for overall survival and safety was 18.7 months. These results highlight the importance of cabozantinib as a first line option in treatment of previously treated patients with advanced RCC [76].
mTOR Inhibitors
The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis [77]. Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.
Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model) [54]. The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SQ 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SQ 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hypercholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.
Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval [78]. The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.
TKI + mTOR Inhibitor
Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor, everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40; 95% CI 0.24 to 0.68; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66, 95% CI 0.30 to 1.10, P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61; 95% CI 0.38 to 0.98; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC [55].
Case Continued
The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.
• What is the appropriate next step in treatment?
PD1 Blockade
Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized anti-bodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy [79]. Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC [80]. Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues [81] demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.
Case Conclusion
Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.
Future Directions
With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Corresponding author: Jessica Clement, MD, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, [email protected].
Financial disclosures: None.
From the Department of Medicine, Carole and Ray Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (Dr. Namakydoust and Dr. Clement) and the UConn School of Pharmacy, Storrs, CT (Dr. Holle).
Abstract
- Objective: To review therapeutic options for the treatment of renal cell carcinoma (RCC).
- Methods: Review of the literature in the context of a clinical case.
- Results: RCC accounts for 90% of all renal tumors. For RCC patients with nondistant metastases, preferred treatment is curative-intent radical nephrectomy or partial nephrectomy; oncologic outcomes for the 2 procedures are similar. For patients who are deemed not to be surgical candidates, ablative techniques such as cryoablation and radiofrequency ablation may be considered. Systemic therapy for metastatic RCC is based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. First-line treatment options for patients with metastatic clear-cell RCC include biologic agents such as high-dose interleukin-2 immune therapy, as well as targeted therapies including tyrosine kinase inhibitors (TKIs) and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis. Second-line therapies in this setting include TKIs and nivolumab (PD-1 inhibitor). If TKIs were used as first-line therapy, mTOR inhibitors can be used in the second line. In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options. Best supportive care should always be provided along with initial and subsequent therapies.
- Conclusion: Multiple treatment options are now available for patients with metastatic or unresectable RCC. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors [1]. Approximately 55,000 new RCC cases are diagnosed each year [1]. Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured sur-gically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [2]. Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.
Epidemiology and Classification
Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs [2]. Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure [3]. Longer duration of tobacco use is associated with a more aggressive course.
The 2004 World Health Organization classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics [2]. Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%) [2]. Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis.
Familial Syndromes
Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs [4].
VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS) [4]. Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common [5]. VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models [6–8]. HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease [4–8].
Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome [9]. In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.
Case Study
Initial Presentation
A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further workup is recommended.
• What are common clinical presentations of RCC?
Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes [10]. Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease [11]. Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.
• What is the approach to initial evaluation for a patient with suspected RCC?
Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion [12]. Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.
• What are the therapeutic options for limited-stage disease?
For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.
Surgical Intervention
Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.
A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8% [14]. Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as either an open or laparoscopic procedure, the latter of which may be performed robotically [15]. Oncologic outcomes appear to be comparable between the 2 approaches, with equivalent 5-year cancer-specific survival (91% with laparoscopic versus 93% with open approach) and recurrence-free survival (91% with laparoscopic versus 93% with open approach) [16]. The approach ultimately is selected based on provider- and patient-specific input, though in all cases the goal is to remove the specimen intact [16,17].
Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma [15].
In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events [18]. Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC [19].
Adjuvant Therapy
Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy [20]. Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection [21]. Therefore, observation remains the standard of care after nephrectomy.
Renal Tumor Ablation
For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.
Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.
Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates [22]. There have been no studies performed directly comparing the modalities.
Cryoablation. Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high-pressure gas (argon, nitrogen) is passed through the probe and it cools once it enters a lower pressure region. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor [23,24].
RFA. Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) from a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum [24].
Microwave ablation. Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA [24]. The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years [25]. However, a study by Castle and colleagues [26] demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.
Irreversible electroporation. Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe [27]. Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings [24].
Active Surveillance
Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter [28,29]. The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance [30]. The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews [31–33].
• What is the approach to follow-up after treatment of localized RCC?
After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen with bone and brain metastases, and thus bone scans and brain imaging are not listed as part of routine surveillance protocols in asymptomatic patients. Although there is inconclusive evidence that surveillance protocols improve outcomes in RCC, many professional associations have outlined recommendations based on expert opinion [34]. The American Urological Association released guidelines in 2013 and the National Comprehensive Cancer Network (NCCN) released their most recent set of guidelines in 2016 [21,35]. These guidelines use TNM staging to risk-stratify patients and recommend follow up.
Case Continued
CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.
• How is prognosis defined for metastatic RCC?
Prognostic Models
Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [13]. Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse [36,37]. Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.
Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa [38]. The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors) [39]. Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively [40].
Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy [41]. This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients were not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level [42].
The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant medial survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively) [43]. The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available [44,45]. Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.
Case Continued
Based on the MSKCC prognostic factor model, the patient is deemed to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.
• What is the appropriate first-line therapy in managing this patient’s metastatic disease?
Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology [57,58]. In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus [59]. Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option [21].
Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features [60]. Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response [61]. A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient [62].
Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients [63].
Biologics
Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology [64]. Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients [65].
Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study [66,67]. However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.
VEGF Monoclonal Antibodies
Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo [68]. In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SQ] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001) [47,48]. Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.
Tyrosine Kinase Inhibitors
TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.
Sunitinib. Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues [52,53] compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SQ 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy [69–71].
Pazopanib. Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4% [72]. This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy [50]. In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.
Sorafenib. Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy [73]. A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029) [51]. Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.
Axitinib. Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving one prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted [74]. In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2) [46]. The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.
Cabozantinib
Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a randomized, open label, phase 3 trial of cabozantinib versus everolimus in advanced RCC, Choueiri and colleagues [75] compared the efficacy of cabozantinib with everolimus in patients with metastatic RCC who had progressed on previous VEGFR-targeted therapies. In this study, 658 patients were randomly assigned to receive cabozantinib (60 mg orally daily) or everolimus (10 mg orally daily). Results of the study found that PFS was longer with cabozantinib in patients who had previously been treated with other TKIs (median PFS of 7.4 months versus 3.8 months; HR 0.58), corresponding to a 42% reduction in the rate of disease progression or death. The most common grade 3 and 4 toxicities seen with cabozantinib were similar to its class effect and consisted of hypertension, diarrhea, and fatigue. In the final analysis of the data, the median overall survival was 21.4 months (95% CI 18.7–not estimable) with cabozantinib and 16.5 months (95% CI 14.7 to 18.8) with everolimus (HR 0.66; 95% CI 0.53 to 0.83; P = 0.00026). The median follow-up for overall survival and safety was 18.7 months. These results highlight the importance of cabozantinib as a first line option in treatment of previously treated patients with advanced RCC [76].
mTOR Inhibitors
The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis [77]. Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.
Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model) [54]. The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SQ 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SQ 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hypercholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.
Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval [78]. The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.
TKI + mTOR Inhibitor
Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor, everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40; 95% CI 0.24 to 0.68; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66, 95% CI 0.30 to 1.10, P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61; 95% CI 0.38 to 0.98; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC [55].
Case Continued
The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.
• What is the appropriate next step in treatment?
PD1 Blockade
Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized anti-bodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy [79]. Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC [80]. Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues [81] demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.
Case Conclusion
Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.
Future Directions
With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.
Corresponding author: Jessica Clement, MD, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, [email protected].
Financial disclosures: None.
1. Siegel R, Miller, K, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin 2015;65:5–29.
2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics. Tumors of the urinary system and male genital organs. Lyon: IARC Press; 2004.
3. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000;343:1305–11.
4. Cohen H, McGovern F. Renal-cell carcinoma. N Engl J Med 2005;353:2477–90
5. Yao M, Yoshida M, Kishida T, et al. VHL tumor suppres sor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 2002;94:1569–75.
6. Iliopoulos O, Kibel A, Gray S, Kaelin WG Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1995;1:822–6
7. Chen F, Kishida T, Duh FM, et al. Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 1995;55:4804–7.
8. Iliopoulos O, Levy AP, Jiang C, et al. Negative regulation of hypoxia-inducible genes by the von Hippel Lindau protein. Proc Natl Acad Sci U S A 1996;93:10595–9.
9. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Bir- Hogg-Dube syndrome. Cancer Cell 2002;2:157–64
10. Shuch B, Vorganit S, Ricketts CJ, et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 2014;32:431–7.
11. Bukowski RM. Immunotherapy in renal cell carcinoma. Oncology 1999;13:801–10.
12. Mueller-Lisse UG, Mueller-Lisse UL. Imaging of advanced renal cell carcinoma. World J Urol 2010;28:253–61.
13. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC cancer staging manual, 7th ed. New York: Springer Science and Business Media LLC; 2010.
14. O’Malley RL, Godoy G, Kanofsky JA, Taneja SS. The necessity of adrenalectomy at the time of radical nephrectomy: a systematic review. J Urol 2009;181:2009–17.
15. McDougal S, Wein AJ, Kavoussi LR, et al. Campbell-Walsh Urology. 10th ed. Philadelphia (PA): Saunders; 2012.
16. Colombo JR Jr, Haber GP, Kelovsek JE, et al. Seven years after laparoscopic radical nephrectomy: oncologic and renal functional outcomes. Urology 2008:71:1149–54.
17. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Ca 2013;49:1374–403.
18. Weight CJ, Larson BT, Fergany AF, et al. Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183:1317–23.
19. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543–52.
20. Smaldone MC, Fung C, Uzzo RG, Hass NB. Adjuvant and neoadjuvant therapies in high-risk renal cell carcioma. Hematol Oncol Clin North Am 2011;25:765–91.
21. NCCN clinical practice guidelines in oncology. Version 3.2016. www.nccn.org. Accessed July 13, 2016
22. El Dib R, Touma NJ, Kapoor A. Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-amalysis of case series studies. BJU Int 2012;110:510–6.
23. Theodorescu D. Cancer cryotherapy: evolution and biology. Rev Urol 2004;6 Suppl 4:S9–S19.
24. Khiatani V, Dixon RG. Renal ablation update. Sem Intervent Radiol 2014;31:157–66.
25. Yu J, Liang P, Yu XL, et al. US-guided percutaneous microwave ablation of renal cell carcinoma: intermediate-term results. Radiol 2012;263:900–8.
26. Castle SM, Salas N, Leveillee RJ. Initial experience using microwave ablation therapy for renal tumor treatment: 18- month follow-up. Urology 2011;77:792–7.
27. Pech M, Janitzky A, Wendler JJ, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Intervent Radiol 2011;34:132–8.
28. Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628–31.
29. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998;51:203–5.
30. Pierorazio PM, Johnson MH, Ball MW, et al. Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry. Eur Urol 2015;68:408–15.
31. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 2011;60:39–44.
32. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006;175:425–31.
33. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer 2012;118:997–1006.
34. Williamson TJ, Pearson JR, Ischia J, et al.Guideline of guidelines: follow-up after nephrectomy for renal cell carcinoma. BJU Int 2016;117:555–62.
35. Donat S, Diaz M, Bishoff JT, et al. Follow-up for clinically localized renal neoplasms: AUA Guideline. J Urol 2013;190:407–16.
36. Janzen NK, Kim HL, Figlin RA, Bell-degrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003:30:843–52.
37. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socio-economic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008;34:193–205.
38. Mekhail T, Abou-Jawde R, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering Prognostic Factors Model for Survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2005;23: 832–41.
39. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289–96.
40. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530–40.
41. Heng DY, Xie W, Regan MM. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794–9.
42. Leibovich BC, Han KR, Bui MH, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: A stratification tool for prospective clinical trials. Cancer 2003;98:2566–77.
43. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071–6.
44. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol 2011;185:60–6.
45. Chapin BF, Delacroix SE Jr, Culp SH, et al. Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma. Eur Urol 2011;60:964–71.
46. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol 2013;14:1287–94.
47. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metatastic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 2007;370:2103–11.
48. Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144–50.
49. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8.
50. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–31.
51. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cell global evaluation trial. J Clin Oncol 2009;27:3312–8.
52. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24.
53. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–90.
54. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81.
55. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus and the combination in patients with metastatic renal cell carcinoma: a randomized, phase 2, open label, multicenter trial. Lancet Oncology 2015;16:1473–82.
56. Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Drugs version 2.3.3. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.
57. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008;26:127–31.
58. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Ann Oncol 2012;23:2108–14.
59. Armstrong AJ, Broderick S, Eisen T, et al. Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN). ASCO Meeting Abstracts 2015;33:4507.
60. Chowdhury S, Matrana MR, Tsang C, et al. Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions. Hematol Oncol Clin North Am 2011;25:853–69.
61. Escudier B, Droz JP, Rolland F, et al. Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 2002; 168–71
62. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004;101:1545–51.
63. Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435–43.
64. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8
65. Cho DC, Puzanov I, Regan MM, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009;32:181–5.
66. Pyrhönen S, Salminen E, Ruutu M, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999;17:2859–67.
67. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353:14–7.
68. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34.
69. Atkinson BJ, Kalra S, Wang X, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014;191:611–8.
70. Kollmannsberger C, Bjarnason G, Burnett P, et al. Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities. Oncologist 2011;16:543–53.
71. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9.
72. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–8.
73. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34
74. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9.
75. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–23.
76. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR) final results from a randomized, open-label, phase 3 trial. Lancet Oncology 2016;17:917–27.
77. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.
78. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–56.
79. Brahmer J, Tykodi S, Chow L, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65.
80. Thomson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow up. Cancer Res 2006;66: 3381–5.
81. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.
1. Siegel R, Miller, K, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin 2015;65:5–29.
2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics. Tumors of the urinary system and male genital organs. Lyon: IARC Press; 2004.
3. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000;343:1305–11.
4. Cohen H, McGovern F. Renal-cell carcinoma. N Engl J Med 2005;353:2477–90
5. Yao M, Yoshida M, Kishida T, et al. VHL tumor suppres sor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 2002;94:1569–75.
6. Iliopoulos O, Kibel A, Gray S, Kaelin WG Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1995;1:822–6
7. Chen F, Kishida T, Duh FM, et al. Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 1995;55:4804–7.
8. Iliopoulos O, Levy AP, Jiang C, et al. Negative regulation of hypoxia-inducible genes by the von Hippel Lindau protein. Proc Natl Acad Sci U S A 1996;93:10595–9.
9. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Bir- Hogg-Dube syndrome. Cancer Cell 2002;2:157–64
10. Shuch B, Vorganit S, Ricketts CJ, et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 2014;32:431–7.
11. Bukowski RM. Immunotherapy in renal cell carcinoma. Oncology 1999;13:801–10.
12. Mueller-Lisse UG, Mueller-Lisse UL. Imaging of advanced renal cell carcinoma. World J Urol 2010;28:253–61.
13. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC cancer staging manual, 7th ed. New York: Springer Science and Business Media LLC; 2010.
14. O’Malley RL, Godoy G, Kanofsky JA, Taneja SS. The necessity of adrenalectomy at the time of radical nephrectomy: a systematic review. J Urol 2009;181:2009–17.
15. McDougal S, Wein AJ, Kavoussi LR, et al. Campbell-Walsh Urology. 10th ed. Philadelphia (PA): Saunders; 2012.
16. Colombo JR Jr, Haber GP, Kelovsek JE, et al. Seven years after laparoscopic radical nephrectomy: oncologic and renal functional outcomes. Urology 2008:71:1149–54.
17. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Ca 2013;49:1374–403.
18. Weight CJ, Larson BT, Fergany AF, et al. Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183:1317–23.
19. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543–52.
20. Smaldone MC, Fung C, Uzzo RG, Hass NB. Adjuvant and neoadjuvant therapies in high-risk renal cell carcioma. Hematol Oncol Clin North Am 2011;25:765–91.
21. NCCN clinical practice guidelines in oncology. Version 3.2016. www.nccn.org. Accessed July 13, 2016
22. El Dib R, Touma NJ, Kapoor A. Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-amalysis of case series studies. BJU Int 2012;110:510–6.
23. Theodorescu D. Cancer cryotherapy: evolution and biology. Rev Urol 2004;6 Suppl 4:S9–S19.
24. Khiatani V, Dixon RG. Renal ablation update. Sem Intervent Radiol 2014;31:157–66.
25. Yu J, Liang P, Yu XL, et al. US-guided percutaneous microwave ablation of renal cell carcinoma: intermediate-term results. Radiol 2012;263:900–8.
26. Castle SM, Salas N, Leveillee RJ. Initial experience using microwave ablation therapy for renal tumor treatment: 18- month follow-up. Urology 2011;77:792–7.
27. Pech M, Janitzky A, Wendler JJ, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Intervent Radiol 2011;34:132–8.
28. Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628–31.
29. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998;51:203–5.
30. Pierorazio PM, Johnson MH, Ball MW, et al. Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry. Eur Urol 2015;68:408–15.
31. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 2011;60:39–44.
32. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006;175:425–31.
33. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer 2012;118:997–1006.
34. Williamson TJ, Pearson JR, Ischia J, et al.Guideline of guidelines: follow-up after nephrectomy for renal cell carcinoma. BJU Int 2016;117:555–62.
35. Donat S, Diaz M, Bishoff JT, et al. Follow-up for clinically localized renal neoplasms: AUA Guideline. J Urol 2013;190:407–16.
36. Janzen NK, Kim HL, Figlin RA, Bell-degrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003:30:843–52.
37. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socio-economic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008;34:193–205.
38. Mekhail T, Abou-Jawde R, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering Prognostic Factors Model for Survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2005;23: 832–41.
39. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289–96.
40. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530–40.
41. Heng DY, Xie W, Regan MM. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794–9.
42. Leibovich BC, Han KR, Bui MH, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: A stratification tool for prospective clinical trials. Cancer 2003;98:2566–77.
43. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071–6.
44. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol 2011;185:60–6.
45. Chapin BF, Delacroix SE Jr, Culp SH, et al. Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma. Eur Urol 2011;60:964–71.
46. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol 2013;14:1287–94.
47. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metatastic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 2007;370:2103–11.
48. Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144–50.
49. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8.
50. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–31.
51. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cell global evaluation trial. J Clin Oncol 2009;27:3312–8.
52. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24.
53. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–90.
54. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81.
55. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus and the combination in patients with metastatic renal cell carcinoma: a randomized, phase 2, open label, multicenter trial. Lancet Oncology 2015;16:1473–82.
56. Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Drugs version 2.3.3. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.
57. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008;26:127–31.
58. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Ann Oncol 2012;23:2108–14.
59. Armstrong AJ, Broderick S, Eisen T, et al. Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN). ASCO Meeting Abstracts 2015;33:4507.
60. Chowdhury S, Matrana MR, Tsang C, et al. Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions. Hematol Oncol Clin North Am 2011;25:853–69.
61. Escudier B, Droz JP, Rolland F, et al. Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 2002; 168–71
62. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004;101:1545–51.
63. Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435–43.
64. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select”trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561–8
65. Cho DC, Puzanov I, Regan MM, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009;32:181–5.
66. Pyrhönen S, Salminen E, Ruutu M, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999;17:2859–67.
67. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353:14–7.
68. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34.
69. Atkinson BJ, Kalra S, Wang X, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014;191:611–8.
70. Kollmannsberger C, Bjarnason G, Burnett P, et al. Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities. Oncologist 2011;16:543–53.
71. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9.
72. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–8.
73. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34
74. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9.
75. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–23.
76. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR) final results from a randomized, open-label, phase 3 trial. Lancet Oncology 2016;17:917–27.
77. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.
78. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–56.
79. Brahmer J, Tykodi S, Chow L, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65.
80. Thomson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow up. Cancer Res 2006;66: 3381–5.
81. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.
Oxaliplatin boosts pCR in patients with locally advanced rectal cancer
Adding oxaliplatin to perioperative fluorouracil and radiotherapy was associated with a higher rate of pathologic complete response (pCR) in advanced rectal cancer patients, compared with single-agent fluorouracil plus radiotherapy, investigators report in the Journal of Clinical Oncology.
For the Neoadjuvant FOLFOX6 Chemotherapy With or Without Radiation in Rectal Cancer (FOWARC) study, 495 patients with locally advanced rectal cancer (LARC) who were undergoing total mesorectal excision were randomly assigned to one of three preoperative treatment arms: neoadjuvant therapy with fluorouracil plus radiotherapy (fluorouracil-radiotherapy group), fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin plus radiotherapy (mFOLFOX6-radiotherapy group), or fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin without radiotherapy (mFOLFOX6 group).The rates of pCR were 14.0%, 27.5%, and 6.6% for patients in the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively, Dr. Yanhong Deng of the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou City, China, and her associates reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.66.6198).
No patients died during neoadjuvant treatment. Grade 3 or 4 toxicities occurred in 55.5% (n = 86), 88% (n = 139), and 24.5% (n = 40) of patients in the fluorouracil-radiotherapy group, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively. The most common grade 3 to 4 toxicities were leukopenia, radiodermatitis, and radiation proctitis.
Initial analysis of this study showed that “compared with the single-agent fluorouracil, mFOLFOX6 concurrent with radiotherapy preoperatively results in a higher rate of pCR (14.0% vs. 27.5%), a higher good response rate, good compliance, and acceptable toxicity for patients with stage II/III rectal cancer,” the investigators wrote.
“These preliminary results suggest that a strategy of combining full-dose chemotherapy with radiation over chemosensitizing radiation may be a new option for neoadjuvant treatment in LARC,” they added.
Sun Yat-sen University funded this study. Dr. Deng and her associates did not have any disclosures to report.
On Twitter @jessnicolecraig
Adding oxaliplatin to perioperative fluorouracil and radiotherapy was associated with a higher rate of pathologic complete response (pCR) in advanced rectal cancer patients, compared with single-agent fluorouracil plus radiotherapy, investigators report in the Journal of Clinical Oncology.
For the Neoadjuvant FOLFOX6 Chemotherapy With or Without Radiation in Rectal Cancer (FOWARC) study, 495 patients with locally advanced rectal cancer (LARC) who were undergoing total mesorectal excision were randomly assigned to one of three preoperative treatment arms: neoadjuvant therapy with fluorouracil plus radiotherapy (fluorouracil-radiotherapy group), fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin plus radiotherapy (mFOLFOX6-radiotherapy group), or fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin without radiotherapy (mFOLFOX6 group).The rates of pCR were 14.0%, 27.5%, and 6.6% for patients in the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively, Dr. Yanhong Deng of the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou City, China, and her associates reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.66.6198).
No patients died during neoadjuvant treatment. Grade 3 or 4 toxicities occurred in 55.5% (n = 86), 88% (n = 139), and 24.5% (n = 40) of patients in the fluorouracil-radiotherapy group, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively. The most common grade 3 to 4 toxicities were leukopenia, radiodermatitis, and radiation proctitis.
Initial analysis of this study showed that “compared with the single-agent fluorouracil, mFOLFOX6 concurrent with radiotherapy preoperatively results in a higher rate of pCR (14.0% vs. 27.5%), a higher good response rate, good compliance, and acceptable toxicity for patients with stage II/III rectal cancer,” the investigators wrote.
“These preliminary results suggest that a strategy of combining full-dose chemotherapy with radiation over chemosensitizing radiation may be a new option for neoadjuvant treatment in LARC,” they added.
Sun Yat-sen University funded this study. Dr. Deng and her associates did not have any disclosures to report.
On Twitter @jessnicolecraig
Adding oxaliplatin to perioperative fluorouracil and radiotherapy was associated with a higher rate of pathologic complete response (pCR) in advanced rectal cancer patients, compared with single-agent fluorouracil plus radiotherapy, investigators report in the Journal of Clinical Oncology.
For the Neoadjuvant FOLFOX6 Chemotherapy With or Without Radiation in Rectal Cancer (FOWARC) study, 495 patients with locally advanced rectal cancer (LARC) who were undergoing total mesorectal excision were randomly assigned to one of three preoperative treatment arms: neoadjuvant therapy with fluorouracil plus radiotherapy (fluorouracil-radiotherapy group), fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin plus radiotherapy (mFOLFOX6-radiotherapy group), or fluorouracil chemotherapy with perioperative fluorouracil and oxaliplatin without radiotherapy (mFOLFOX6 group).The rates of pCR were 14.0%, 27.5%, and 6.6% for patients in the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively, Dr. Yanhong Deng of the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou City, China, and her associates reported (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.66.6198).
No patients died during neoadjuvant treatment. Grade 3 or 4 toxicities occurred in 55.5% (n = 86), 88% (n = 139), and 24.5% (n = 40) of patients in the fluorouracil-radiotherapy group, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, respectively. The most common grade 3 to 4 toxicities were leukopenia, radiodermatitis, and radiation proctitis.
Initial analysis of this study showed that “compared with the single-agent fluorouracil, mFOLFOX6 concurrent with radiotherapy preoperatively results in a higher rate of pCR (14.0% vs. 27.5%), a higher good response rate, good compliance, and acceptable toxicity for patients with stage II/III rectal cancer,” the investigators wrote.
“These preliminary results suggest that a strategy of combining full-dose chemotherapy with radiation over chemosensitizing radiation may be a new option for neoadjuvant treatment in LARC,” they added.
Sun Yat-sen University funded this study. Dr. Deng and her associates did not have any disclosures to report.
On Twitter @jessnicolecraig
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Perioperative oxaliplatin administered in combination with fluorouracil and radiotherapy was associated with a higher rate of pathologic complete response in advanced rectal cancer patients compared with single-agent fluorouracil and radiotherapy.
Major finding: The rate of pathologic complete response was 27.5% for patients receiving oxaliplatin, fluorouracil, and radiotherapy vs. 14.0% for patients receiving single-agent fluorouracil and radiotherapy.
Data source: A multicenter, open-label, phase III trial involving 495 patients with locally advanced stage II/III rectal cancer.
Disclosures: Sun Yat-sen University funded this study. Dr. Deng and her associates did not have any disclosures to report.
Daily fish oil dose boosts healing after heart attack
A daily dose of omega-3 fatty acids from fish oil significantly improved heart function in adults after heart attacks, based on data from a randomized trial of 358 heart attack survivors. The findings were published online Aug. 1 in Circulation.
Patients who received 4 grams of omega-3 fatty acids from fish oil (O-3FA) for 6 months had significant reductions in left ventricular end-systolic volume index (–5.8%) and noninfarct myocardial fibrosis (–5.6%), compared with placebo patients, Bobak Heydari, MD, MPH, of Brigham and Women’s Hospital, Boston, and colleagues.
The effects remained significant after adjusting for factors including guideline-based standard post-heart attack medical therapies, they noted.
Treatment with omega-3 fatty acids (O-3FA) “also was associated with a significant reduction of both biomarkers of inflammation (myeloperoxidase, lipoprotein-associated phospholipase A2) and myocardial fibrosis (ST2),” the researchers wrote. “We therefore speculate that O-3FA treatment provides the aforementioned improvement in LV remodeling and noninfarct myocardial fibrosis through suppression of inflammation at both systemic and myocardial levels during the convalescent healing phase after acute MI,” they noted.
The results build on data from a previous study showing an association between daily doses of O-3FA and improved survival rates in heart attack patients, but the specific impact on heart structure and tissue has not been well studied, the researchers noted (Circulation. 2016;134:378-91 doi: 10.1161/circulationaha.115.019949).
The OMEGA-REMODEL trial (Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction) was designed to assess the impact of omega-3 fatty acids on heart healing after a heart attack. The average age of the patients was about 60 years. Demographic characteristics and cardiovascular disease histories were not significantly different between the groups.
Compliance for both treatment and placebo groups was 96% based on pill counts. Nausea was the most common side effect, reported by 5.9% of treatment patients and 5.4% of placebo patients. No serious adverse events associated with treatment were reported.
The findings were limited by several factors, including the possible use of over-the-counter fish oil supplementation by patients, the researchers noted. “However, dose-response relationship between O-3FA therapy and our main study endpoints strongly supported our intention-to-treat analysis,” they said.
The study was funded by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose.
A daily dose of omega-3 fatty acids from fish oil significantly improved heart function in adults after heart attacks, based on data from a randomized trial of 358 heart attack survivors. The findings were published online Aug. 1 in Circulation.
Patients who received 4 grams of omega-3 fatty acids from fish oil (O-3FA) for 6 months had significant reductions in left ventricular end-systolic volume index (–5.8%) and noninfarct myocardial fibrosis (–5.6%), compared with placebo patients, Bobak Heydari, MD, MPH, of Brigham and Women’s Hospital, Boston, and colleagues.
The effects remained significant after adjusting for factors including guideline-based standard post-heart attack medical therapies, they noted.
Treatment with omega-3 fatty acids (O-3FA) “also was associated with a significant reduction of both biomarkers of inflammation (myeloperoxidase, lipoprotein-associated phospholipase A2) and myocardial fibrosis (ST2),” the researchers wrote. “We therefore speculate that O-3FA treatment provides the aforementioned improvement in LV remodeling and noninfarct myocardial fibrosis through suppression of inflammation at both systemic and myocardial levels during the convalescent healing phase after acute MI,” they noted.
The results build on data from a previous study showing an association between daily doses of O-3FA and improved survival rates in heart attack patients, but the specific impact on heart structure and tissue has not been well studied, the researchers noted (Circulation. 2016;134:378-91 doi: 10.1161/circulationaha.115.019949).
The OMEGA-REMODEL trial (Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction) was designed to assess the impact of omega-3 fatty acids on heart healing after a heart attack. The average age of the patients was about 60 years. Demographic characteristics and cardiovascular disease histories were not significantly different between the groups.
Compliance for both treatment and placebo groups was 96% based on pill counts. Nausea was the most common side effect, reported by 5.9% of treatment patients and 5.4% of placebo patients. No serious adverse events associated with treatment were reported.
The findings were limited by several factors, including the possible use of over-the-counter fish oil supplementation by patients, the researchers noted. “However, dose-response relationship between O-3FA therapy and our main study endpoints strongly supported our intention-to-treat analysis,” they said.
The study was funded by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose.
A daily dose of omega-3 fatty acids from fish oil significantly improved heart function in adults after heart attacks, based on data from a randomized trial of 358 heart attack survivors. The findings were published online Aug. 1 in Circulation.
Patients who received 4 grams of omega-3 fatty acids from fish oil (O-3FA) for 6 months had significant reductions in left ventricular end-systolic volume index (–5.8%) and noninfarct myocardial fibrosis (–5.6%), compared with placebo patients, Bobak Heydari, MD, MPH, of Brigham and Women’s Hospital, Boston, and colleagues.
The effects remained significant after adjusting for factors including guideline-based standard post-heart attack medical therapies, they noted.
Treatment with omega-3 fatty acids (O-3FA) “also was associated with a significant reduction of both biomarkers of inflammation (myeloperoxidase, lipoprotein-associated phospholipase A2) and myocardial fibrosis (ST2),” the researchers wrote. “We therefore speculate that O-3FA treatment provides the aforementioned improvement in LV remodeling and noninfarct myocardial fibrosis through suppression of inflammation at both systemic and myocardial levels during the convalescent healing phase after acute MI,” they noted.
The results build on data from a previous study showing an association between daily doses of O-3FA and improved survival rates in heart attack patients, but the specific impact on heart structure and tissue has not been well studied, the researchers noted (Circulation. 2016;134:378-91 doi: 10.1161/circulationaha.115.019949).
The OMEGA-REMODEL trial (Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction) was designed to assess the impact of omega-3 fatty acids on heart healing after a heart attack. The average age of the patients was about 60 years. Demographic characteristics and cardiovascular disease histories were not significantly different between the groups.
Compliance for both treatment and placebo groups was 96% based on pill counts. Nausea was the most common side effect, reported by 5.9% of treatment patients and 5.4% of placebo patients. No serious adverse events associated with treatment were reported.
The findings were limited by several factors, including the possible use of over-the-counter fish oil supplementation by patients, the researchers noted. “However, dose-response relationship between O-3FA therapy and our main study endpoints strongly supported our intention-to-treat analysis,” they said.
The study was funded by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose.
FROM CIRCULATION
Key clinical point: A daily dose of omega-3 fatty acids for 6 months after a heart attack improved heart function and reduced scarring.
Major finding: Heart attack patients who received 4 grams of omega-3 fatty acids from fish oil daily had significant reductions in both left ventricular end-systolic volume index (-5.8%) and noninfarct myocardial fibrosis (-5.6%), compared with placebo patients after 6 months.
Data source: A randomized trial of 360 heart attack survivors.
Disclosures: The study was funded by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose.
Young age, tumor subtype linked in breast cancer survival
Younger age at diagnosis of breast cancer predicts poor survival only with certain molecular subtypes of tumor, according to a report published online Aug. 1 in the Journal of Clinical Oncology.
An age of 40 years or younger “has long been considered a poor prognostic factor, because young women, on average, have an increased risk of disease recurrence and decreased survival. In recent years, however, with improved understanding of tumor biology, this assertion has been challenged with increased recognition of the prognostic and predictive role of tumor subtype and awareness that young women are more likely to develop more aggressive phenotypes,” said Ann H. Partridge, MD, of the Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, both in Boston, and her associates.
To examine the relationships among patient age, tumor subtypes, and outcomes, they analyzed data for 17,575 women treated at eight U.S. cancer centers in 2000-2007 and enrolled in a National Comprehensive Cancer Network registry. The study participants (mean age, 35 years) all had newly diagnosed unilateral stage I, II, or III breast cancer and were followed for a median of 6.4 years. Their data were stratified by age at diagnosis: 40 years or younger, 41-50 years, 51-60 years, 61-70 years, or over 70 years.
In the initial analysis, younger women were 90% more likely to die of breast cancer than older women. This probability decreased to 50% when the data were adjusted to control for treatment, stage at diagnosis, and tumor grade, then decreased further to 30% when the data were further adjusted to control for tumor molecular subtype and method of detection, the investigators said (J Clin Oncol. 2016 Aug 1; doi:10.1200/JCO.2015.65.8013).
However, when the data were analyzed according to tumor subtype, women who had luminal A breast cancer (7,738 participants) were more than twice as likely to die of their disease if they were aged 40 or younger at diagnosis than if they were older (hazard ratio, 2.1). The age-related increase in risk was slightly lower for luminal B breast cancer (HR, 1.4), and appeared to be largely confined to those with HER2-negative luminal B tumors.
There also was a borderline increased risk of death in younger women who had triple-negative breast cancer (HR, 1.4), compared with older women who had that tumor subtype. In contrast, younger age did not correlate with increased breast cancer mortality among women with HER2-positive disease.
These findings “support the growing evidence that the relationship between age at diagnosis and breast-cancer-specific survival varies by tumor subtype, which has implications for both treatment decisions and future research directions. ....In women with luminal disease, younger age does have a substantial prognostic role, which may reflect inadequate therapy, including lower treatment efficacy and less therapeutic adherence and persistence, as well as residual differences in tumor biology,” Dr. Partridge and her associates said.
No specific source of funding was identified for this study. Dr. Partridge reported serving as a consultant for Pfizer; her associates reported ties to Pfizer, Tokai, Bristol-Myers Squibb, Carevive Systems, Oncothyreon, Amgen, and BeyondSpring Pharmaceuticals.
Younger age at diagnosis of breast cancer predicts poor survival only with certain molecular subtypes of tumor, according to a report published online Aug. 1 in the Journal of Clinical Oncology.
An age of 40 years or younger “has long been considered a poor prognostic factor, because young women, on average, have an increased risk of disease recurrence and decreased survival. In recent years, however, with improved understanding of tumor biology, this assertion has been challenged with increased recognition of the prognostic and predictive role of tumor subtype and awareness that young women are more likely to develop more aggressive phenotypes,” said Ann H. Partridge, MD, of the Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, both in Boston, and her associates.
To examine the relationships among patient age, tumor subtypes, and outcomes, they analyzed data for 17,575 women treated at eight U.S. cancer centers in 2000-2007 and enrolled in a National Comprehensive Cancer Network registry. The study participants (mean age, 35 years) all had newly diagnosed unilateral stage I, II, or III breast cancer and were followed for a median of 6.4 years. Their data were stratified by age at diagnosis: 40 years or younger, 41-50 years, 51-60 years, 61-70 years, or over 70 years.
In the initial analysis, younger women were 90% more likely to die of breast cancer than older women. This probability decreased to 50% when the data were adjusted to control for treatment, stage at diagnosis, and tumor grade, then decreased further to 30% when the data were further adjusted to control for tumor molecular subtype and method of detection, the investigators said (J Clin Oncol. 2016 Aug 1; doi:10.1200/JCO.2015.65.8013).
However, when the data were analyzed according to tumor subtype, women who had luminal A breast cancer (7,738 participants) were more than twice as likely to die of their disease if they were aged 40 or younger at diagnosis than if they were older (hazard ratio, 2.1). The age-related increase in risk was slightly lower for luminal B breast cancer (HR, 1.4), and appeared to be largely confined to those with HER2-negative luminal B tumors.
There also was a borderline increased risk of death in younger women who had triple-negative breast cancer (HR, 1.4), compared with older women who had that tumor subtype. In contrast, younger age did not correlate with increased breast cancer mortality among women with HER2-positive disease.
These findings “support the growing evidence that the relationship between age at diagnosis and breast-cancer-specific survival varies by tumor subtype, which has implications for both treatment decisions and future research directions. ....In women with luminal disease, younger age does have a substantial prognostic role, which may reflect inadequate therapy, including lower treatment efficacy and less therapeutic adherence and persistence, as well as residual differences in tumor biology,” Dr. Partridge and her associates said.
No specific source of funding was identified for this study. Dr. Partridge reported serving as a consultant for Pfizer; her associates reported ties to Pfizer, Tokai, Bristol-Myers Squibb, Carevive Systems, Oncothyreon, Amgen, and BeyondSpring Pharmaceuticals.
Younger age at diagnosis of breast cancer predicts poor survival only with certain molecular subtypes of tumor, according to a report published online Aug. 1 in the Journal of Clinical Oncology.
An age of 40 years or younger “has long been considered a poor prognostic factor, because young women, on average, have an increased risk of disease recurrence and decreased survival. In recent years, however, with improved understanding of tumor biology, this assertion has been challenged with increased recognition of the prognostic and predictive role of tumor subtype and awareness that young women are more likely to develop more aggressive phenotypes,” said Ann H. Partridge, MD, of the Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, both in Boston, and her associates.
To examine the relationships among patient age, tumor subtypes, and outcomes, they analyzed data for 17,575 women treated at eight U.S. cancer centers in 2000-2007 and enrolled in a National Comprehensive Cancer Network registry. The study participants (mean age, 35 years) all had newly diagnosed unilateral stage I, II, or III breast cancer and were followed for a median of 6.4 years. Their data were stratified by age at diagnosis: 40 years or younger, 41-50 years, 51-60 years, 61-70 years, or over 70 years.
In the initial analysis, younger women were 90% more likely to die of breast cancer than older women. This probability decreased to 50% when the data were adjusted to control for treatment, stage at diagnosis, and tumor grade, then decreased further to 30% when the data were further adjusted to control for tumor molecular subtype and method of detection, the investigators said (J Clin Oncol. 2016 Aug 1; doi:10.1200/JCO.2015.65.8013).
However, when the data were analyzed according to tumor subtype, women who had luminal A breast cancer (7,738 participants) were more than twice as likely to die of their disease if they were aged 40 or younger at diagnosis than if they were older (hazard ratio, 2.1). The age-related increase in risk was slightly lower for luminal B breast cancer (HR, 1.4), and appeared to be largely confined to those with HER2-negative luminal B tumors.
There also was a borderline increased risk of death in younger women who had triple-negative breast cancer (HR, 1.4), compared with older women who had that tumor subtype. In contrast, younger age did not correlate with increased breast cancer mortality among women with HER2-positive disease.
These findings “support the growing evidence that the relationship between age at diagnosis and breast-cancer-specific survival varies by tumor subtype, which has implications for both treatment decisions and future research directions. ....In women with luminal disease, younger age does have a substantial prognostic role, which may reflect inadequate therapy, including lower treatment efficacy and less therapeutic adherence and persistence, as well as residual differences in tumor biology,” Dr. Partridge and her associates said.
No specific source of funding was identified for this study. Dr. Partridge reported serving as a consultant for Pfizer; her associates reported ties to Pfizer, Tokai, Bristol-Myers Squibb, Carevive Systems, Oncothyreon, Amgen, and BeyondSpring Pharmaceuticals.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Younger age at diagnosis of breast cancer predicts poor survival only with certain molecular subtypes of tumor.
Major finding: Women who had luminal A breast cancer (7,738 participants) were more than twice as likely to die of their disease if they were aged 40 or younger at diagnosis than if they were older (HR, 2.1).
Data source: A longitudinal cohort study assessing the role of age, tumor subtype, and survival among 17,575 breast cancer patients treated in 2000-2007 and followed for 6 years.
Disclosures: No specific source of funding was identified for this study. Dr. Partridge reported serving as a consultant for Pfizer; her associates reported ties to Pfizer, Tokai, Bristol-Myers Squibb, Carevive Systems, Oncothyreon, Amgen, and BeyondSpring Pharmaceuticals.
Biomarker-driven targeted therapy feasible for NSCLC
Biomarker-driven targeted therapy was found feasible for heavily pretreated, metastatic non–small-cell lung cancer in a phase II trial reported online Aug. 1 in the Journal of Clinical Oncology.
The open-label multicenter umbrella study under the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, called the BATTLE-2, involved 200 patients with advanced NSCLC refractory to platinum-based chemotherapy and multiple other treatments. All patients underwent tumor tissue biopsies for biomarker and gene expression analyses.
The results of those assessments were then used to perform “adaptive randomization” in which the patients were assigned to one of four treatment arms deemed most likely to control their particular malignancy, said Vassiliki Papadimitrakopoulou, MD, professor of medicine in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, and her associates.
One group of 22 patients received 150 mg erlotinib once daily; the second group (42 patients) received 150 mg erlotinib daily plus 135 mg of the AKT inhibitor MK-2206 once weekly; the third group (75 patients) received 100 mg per week of MK-2206 plus 100 mg of the MEK inhibitor AZD6244 once daily; and the fourth group (61 patients) received 400 mg of sorafenib twice daily. A total of 186 patients were evaluable at 8 weeks, and the overall rate of disease control was 48% at that time. After a median follow-up of 20 months, the median progression-free survival was 2.0 months, median overall survival was 6.5 months, and the 1-year survival was 28%.
The primary endpoint of the study – disease control rate at 8 weeks – was not significantly different among the four treatment groups. It was 32% in group 1, 50% in group 2, 53% in group 3, and 46% in group 4. There were no complete responses and only 6 partial responses: 3 patients in group 3 and 3 patients in group 4. However, the study demonstrated “the utility of real-time biopsies for broad profiling of tumors that serve as a discovery vehicle for better target selection,” the investigators said (J Clin Oncol. 2016 Aug 1. doi:10.1200/JCO.2015.66.0084).
“We are currently pursuing alternative strategies in targeting KRAS mut+ tumors by incorporating knowledge derived from BATTLE 2,” they added.
This study was supported by Merck, Bayer Healthcare Pharmaceuticals, and the National Cancer Institute. Dr. Papadimitrakopoulou and her associates reported ties to numerous industry sources.
“Notwithstanding the low bar of the relatively unconventional endpoint of 8-week [disease control rate], BATTLE-2 should be recognized as a valuable contribution to the field, despite it failing to demonstrate encouraging efficacy in any of the treatment arms or patient subsets,” Howard (Jack) West, MD, wrote in an accompanying editorial (J Clin Oncol. 2016 Aug 1. doi: 10.1200/JCO.2016.68.8226).
But the main result of this study was that all treatment arms produced a disappointing 8-week disease control rate averaging 48%, with no treatment proving to be more promising than the others, with no complete responses and only rare partial responses, and with a progression-free survival of only 2 months in every group, he wrote. However, molecular targeting sometimes benefits small subgroups of patients, such as when advanced squamous NSCLC responds to afatinib. In this study, a subgroup of 52 patients whose tumors showed KRAS mut+ mutations had a significantly longer progression-free survival if they did not receive erlotinib.
Dr. West is affiliated with the Swedish Cancer Institute, Seattle. He reported ties to numerous industry sources.
“Notwithstanding the low bar of the relatively unconventional endpoint of 8-week [disease control rate], BATTLE-2 should be recognized as a valuable contribution to the field, despite it failing to demonstrate encouraging efficacy in any of the treatment arms or patient subsets,” Howard (Jack) West, MD, wrote in an accompanying editorial (J Clin Oncol. 2016 Aug 1. doi: 10.1200/JCO.2016.68.8226).
But the main result of this study was that all treatment arms produced a disappointing 8-week disease control rate averaging 48%, with no treatment proving to be more promising than the others, with no complete responses and only rare partial responses, and with a progression-free survival of only 2 months in every group, he wrote. However, molecular targeting sometimes benefits small subgroups of patients, such as when advanced squamous NSCLC responds to afatinib. In this study, a subgroup of 52 patients whose tumors showed KRAS mut+ mutations had a significantly longer progression-free survival if they did not receive erlotinib.
Dr. West is affiliated with the Swedish Cancer Institute, Seattle. He reported ties to numerous industry sources.
“Notwithstanding the low bar of the relatively unconventional endpoint of 8-week [disease control rate], BATTLE-2 should be recognized as a valuable contribution to the field, despite it failing to demonstrate encouraging efficacy in any of the treatment arms or patient subsets,” Howard (Jack) West, MD, wrote in an accompanying editorial (J Clin Oncol. 2016 Aug 1. doi: 10.1200/JCO.2016.68.8226).
But the main result of this study was that all treatment arms produced a disappointing 8-week disease control rate averaging 48%, with no treatment proving to be more promising than the others, with no complete responses and only rare partial responses, and with a progression-free survival of only 2 months in every group, he wrote. However, molecular targeting sometimes benefits small subgroups of patients, such as when advanced squamous NSCLC responds to afatinib. In this study, a subgroup of 52 patients whose tumors showed KRAS mut+ mutations had a significantly longer progression-free survival if they did not receive erlotinib.
Dr. West is affiliated with the Swedish Cancer Institute, Seattle. He reported ties to numerous industry sources.
Biomarker-driven targeted therapy was found feasible for heavily pretreated, metastatic non–small-cell lung cancer in a phase II trial reported online Aug. 1 in the Journal of Clinical Oncology.
The open-label multicenter umbrella study under the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, called the BATTLE-2, involved 200 patients with advanced NSCLC refractory to platinum-based chemotherapy and multiple other treatments. All patients underwent tumor tissue biopsies for biomarker and gene expression analyses.
The results of those assessments were then used to perform “adaptive randomization” in which the patients were assigned to one of four treatment arms deemed most likely to control their particular malignancy, said Vassiliki Papadimitrakopoulou, MD, professor of medicine in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, and her associates.
One group of 22 patients received 150 mg erlotinib once daily; the second group (42 patients) received 150 mg erlotinib daily plus 135 mg of the AKT inhibitor MK-2206 once weekly; the third group (75 patients) received 100 mg per week of MK-2206 plus 100 mg of the MEK inhibitor AZD6244 once daily; and the fourth group (61 patients) received 400 mg of sorafenib twice daily. A total of 186 patients were evaluable at 8 weeks, and the overall rate of disease control was 48% at that time. After a median follow-up of 20 months, the median progression-free survival was 2.0 months, median overall survival was 6.5 months, and the 1-year survival was 28%.
The primary endpoint of the study – disease control rate at 8 weeks – was not significantly different among the four treatment groups. It was 32% in group 1, 50% in group 2, 53% in group 3, and 46% in group 4. There were no complete responses and only 6 partial responses: 3 patients in group 3 and 3 patients in group 4. However, the study demonstrated “the utility of real-time biopsies for broad profiling of tumors that serve as a discovery vehicle for better target selection,” the investigators said (J Clin Oncol. 2016 Aug 1. doi:10.1200/JCO.2015.66.0084).
“We are currently pursuing alternative strategies in targeting KRAS mut+ tumors by incorporating knowledge derived from BATTLE 2,” they added.
This study was supported by Merck, Bayer Healthcare Pharmaceuticals, and the National Cancer Institute. Dr. Papadimitrakopoulou and her associates reported ties to numerous industry sources.
Biomarker-driven targeted therapy was found feasible for heavily pretreated, metastatic non–small-cell lung cancer in a phase II trial reported online Aug. 1 in the Journal of Clinical Oncology.
The open-label multicenter umbrella study under the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, called the BATTLE-2, involved 200 patients with advanced NSCLC refractory to platinum-based chemotherapy and multiple other treatments. All patients underwent tumor tissue biopsies for biomarker and gene expression analyses.
The results of those assessments were then used to perform “adaptive randomization” in which the patients were assigned to one of four treatment arms deemed most likely to control their particular malignancy, said Vassiliki Papadimitrakopoulou, MD, professor of medicine in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston, and her associates.
One group of 22 patients received 150 mg erlotinib once daily; the second group (42 patients) received 150 mg erlotinib daily plus 135 mg of the AKT inhibitor MK-2206 once weekly; the third group (75 patients) received 100 mg per week of MK-2206 plus 100 mg of the MEK inhibitor AZD6244 once daily; and the fourth group (61 patients) received 400 mg of sorafenib twice daily. A total of 186 patients were evaluable at 8 weeks, and the overall rate of disease control was 48% at that time. After a median follow-up of 20 months, the median progression-free survival was 2.0 months, median overall survival was 6.5 months, and the 1-year survival was 28%.
The primary endpoint of the study – disease control rate at 8 weeks – was not significantly different among the four treatment groups. It was 32% in group 1, 50% in group 2, 53% in group 3, and 46% in group 4. There were no complete responses and only 6 partial responses: 3 patients in group 3 and 3 patients in group 4. However, the study demonstrated “the utility of real-time biopsies for broad profiling of tumors that serve as a discovery vehicle for better target selection,” the investigators said (J Clin Oncol. 2016 Aug 1. doi:10.1200/JCO.2015.66.0084).
“We are currently pursuing alternative strategies in targeting KRAS mut+ tumors by incorporating knowledge derived from BATTLE 2,” they added.
This study was supported by Merck, Bayer Healthcare Pharmaceuticals, and the National Cancer Institute. Dr. Papadimitrakopoulou and her associates reported ties to numerous industry sources.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Biomarker-driven targeted therapy was found feasible for heavily pretreated, metastatic NSCLC.
Major finding: The primary endpoint – disease control rate at 8 weeks – was 32% in group 1, 50% in group 2, 53% in group 3, and 46% in group 4.
Data source: A randomized open-label phase II study involving 200 patients with heavily pretreated, metastatic NSCLC.
Disclosures: This study was supported by Merck, Bayer Healthcare Pharmaceuticals, and the National Cancer Institute. Dr. Papadimitrakopoulou and her associates reported ties to numerous industry sources.
Statins in Chronic Kidney Disease: When and When Not to Use Them
2016 Obstetric code changes that could affect your reimbursement (very soon)
By now the upheaval of changing to the new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) diagnostic coding system has settled. The code freeze that was initiated in 2012 has ended, and the new and revised codes that will go into effect on October 1, 2016, are being revealed. Good documentation will lead to more accurate diagnostic coding, which in turn assists decision makers in their quest to report the health of our population and to make good decisions for resource allocation. You are in the unique position to assist in this process, so keep up the good work.
In this article, I focus on ICD-10 diagnostic coding for obstetric services. I will cover diagnostic coding for gynecologic services in the September issue of OBG Management.
Code revisions for uterine scar and more changes to note
With the upcoming edition of ICD-10, the code Z3A, Weeks’ gestation, will be changed from mandatory reporting to reporting if known. This means that if the patient is no longer pregnant, a Z3A code no longer needs to be reported, and if at the time of service the provider does not know the weeks’ gestation, Z3A would not be required. However, this information should be readily available during the antepartum period and should still be considered important to record and report. And it would still be reported for hospitalization for delivery.
If the code O09.81, Supervision of pregnancy resulting from assisted reproductive technology, is reported, the code Z33.3, Gestational carrier status, may be reported in addition for informational purposes.
When the code O34.29, Maternal care due to uterine scar from other previous surgery, is reported, the tabular index clarifies that this refers to a uterine scar from a transmural uterine incision other than that used for cesarean delivery. This would include incision into the uterine wall to remove fibroids.
The O42 code category, relating to Premature rupture of membranes, should now be interpreted to mean rupture of membranes at or after 37 completed weeks of gestation, rather than after 37 completed weeks.
The code category O99.6, Diseases of the digestive system complicating pregnancy, childbirth, and the puerperium, has been clarified: it does not include hemorrhoids in pregnancy. Therefore, a code from O22.4_ (a final digit of 0 [unspecified], 1, 2, or 3 is required for the trimester) also can be reported if hemorrhoids are present.
A note now clarifies that O99.82, Streptococcus B carrier state complicating pregnancy, childbirth, and the puerperium, cannot be reported with Z22.330, Carrier of streptococcus group B (GBS) in a nonpregnant woman.
New codes for specifying types of ectopic pregnancy
ICD-10 did not initially recognize ectopic pregnancy with and without intrauterine pregnancy, as was the case in ICD-9, but starting in October it will do so. In addition, a history of ectopic or molar pregnancy during a current pregnancy is now reported separately. Each of these codes will require a final digit to indicate the trimester (TABLE).
Codes added for complicating conditions of childbirth and the puerperium
Missing from the ICD-10 lineup last year were codes for conditions related to hypertension, edema, proteinuria, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and eclampsia that were complicating the pregnancy at the time of delivery or after delivery (TABLE).
Note that the “childbirth” code is reported only when a patient delivers at the current episode of care. Once a patient delivers and is discharged, the “puerperium” code should be selected.
Revised descriptions, new reporting instruction for diabetes
The code descriptions for preexisting type 1 and type 2 diabetes were revised, but this change does not impact reporting the codes. However, for type 2 diabetes, the instruction for reporting an additional code has changed. Now, in addition to reporting the code for current use of insulin (Z79.4), when appropriate, report the new added code for use of hypoglycemic agents (Z79.84), such as glyburide or metformin.
For gestational diabetes, new codes have been added for the use of hypoglycemic agents; therefore, no additional code is reported (TABLE).
Disproportion code includes numeric specifier for fetus
The disproportion code category was expanded to include a final digit for the fetus with the deformity (TABLE). The final digit of the code number denotes which fetus; for example, “0” means a singleton pregnancy, “1” means fetus 1 (number range from 1 to 5), and “9” denotes any fetus after the fifth.
Cesarean delivery scar codes expanded
The code for maternal care for a scar from a previous cesarean delivery has been expanded to 3 different codes (TABLE). Clinicians should make every effort to document and report the location of the previous cesarean as low transverse or vertical. From a coding standpoint, a vertical scar can also be referred to as a classical scar.
Changes to placenta previa codes
The code category for placenta previa has been expanded to capture the degree of previa as complete, partial, or low lying and with or without hemorrhage (TABLE). Going forward, it will be important to carefully document the circumstances so that the most specific code can be reported and tracked. Trimester specification is required as the final digit.
New subclassifications for perineal laceration
The code category for perineal laceration has been expanded with new codes to capture subclassifications for a third-degree laceration that can involve the external and internal anal sphincter (TABLE). Through its collaborative hub, the Women’s Health Registry Alliance (reVITALize) initiative, the American Congress of Obstetricians and Gynecologists (ACOG) worked on the current classification of third- and fourth-degree perineal lacerations, which has been adopted by the Royal College of Obstetricians and Gynaecologists.1
Under this subclassification, a 3a laceration would involve a tear of less than 50% of the external anal sphincter (EAS); 3b would involve a tear of more than 50% of the EAS; and 3c would mean that both the external and internal anal sphincter are torn. ACOG and its collaborative group encourage clinicians to use these subclassifications in documentation to allow for more robust data collection and complete repair information. From a payment standpoint, such information may go a long way to substantiating the severity of a tear, which may require more physician work.
Z code additions
Finally, the ever-popular diagnostic code for Rho(D) immunization is back, and 2 codes have been added for a gestational carrier and 1 for a family history of sudden infant death syndrome. The codes are:
- Z29.13 Encounter for prophylactic Rho(D) immune globulin
- Z31.7 Encounter for procreative management and counseling for gestational carrier
- Z33.3 Pregnant state, gestational carrier
- Z84.82 Family history of sudden infant death syndrome.
- Centers for Disease Control and Prevention. ICD-10 Coordination and Maintenance Committee meeting: diagnosis agenda. September 23-24, 2014;38, 39. http://www.cdc.gov/nchs/data/icd/topic_packet_09_23_2012.pdf. Accessed July 5, 2016.
Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.
The author reports no financial relationships relevant to this article.
Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.
The author reports no financial relationships relevant to this article.
Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.
The author reports no financial relationships relevant to this article.
By now the upheaval of changing to the new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) diagnostic coding system has settled. The code freeze that was initiated in 2012 has ended, and the new and revised codes that will go into effect on October 1, 2016, are being revealed. Good documentation will lead to more accurate diagnostic coding, which in turn assists decision makers in their quest to report the health of our population and to make good decisions for resource allocation. You are in the unique position to assist in this process, so keep up the good work.
In this article, I focus on ICD-10 diagnostic coding for obstetric services. I will cover diagnostic coding for gynecologic services in the September issue of OBG Management.
Code revisions for uterine scar and more changes to note
With the upcoming edition of ICD-10, the code Z3A, Weeks’ gestation, will be changed from mandatory reporting to reporting if known. This means that if the patient is no longer pregnant, a Z3A code no longer needs to be reported, and if at the time of service the provider does not know the weeks’ gestation, Z3A would not be required. However, this information should be readily available during the antepartum period and should still be considered important to record and report. And it would still be reported for hospitalization for delivery.
If the code O09.81, Supervision of pregnancy resulting from assisted reproductive technology, is reported, the code Z33.3, Gestational carrier status, may be reported in addition for informational purposes.
When the code O34.29, Maternal care due to uterine scar from other previous surgery, is reported, the tabular index clarifies that this refers to a uterine scar from a transmural uterine incision other than that used for cesarean delivery. This would include incision into the uterine wall to remove fibroids.
The O42 code category, relating to Premature rupture of membranes, should now be interpreted to mean rupture of membranes at or after 37 completed weeks of gestation, rather than after 37 completed weeks.
The code category O99.6, Diseases of the digestive system complicating pregnancy, childbirth, and the puerperium, has been clarified: it does not include hemorrhoids in pregnancy. Therefore, a code from O22.4_ (a final digit of 0 [unspecified], 1, 2, or 3 is required for the trimester) also can be reported if hemorrhoids are present.
A note now clarifies that O99.82, Streptococcus B carrier state complicating pregnancy, childbirth, and the puerperium, cannot be reported with Z22.330, Carrier of streptococcus group B (GBS) in a nonpregnant woman.
New codes for specifying types of ectopic pregnancy
ICD-10 did not initially recognize ectopic pregnancy with and without intrauterine pregnancy, as was the case in ICD-9, but starting in October it will do so. In addition, a history of ectopic or molar pregnancy during a current pregnancy is now reported separately. Each of these codes will require a final digit to indicate the trimester (TABLE).
Codes added for complicating conditions of childbirth and the puerperium
Missing from the ICD-10 lineup last year were codes for conditions related to hypertension, edema, proteinuria, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and eclampsia that were complicating the pregnancy at the time of delivery or after delivery (TABLE).
Note that the “childbirth” code is reported only when a patient delivers at the current episode of care. Once a patient delivers and is discharged, the “puerperium” code should be selected.
Revised descriptions, new reporting instruction for diabetes
The code descriptions for preexisting type 1 and type 2 diabetes were revised, but this change does not impact reporting the codes. However, for type 2 diabetes, the instruction for reporting an additional code has changed. Now, in addition to reporting the code for current use of insulin (Z79.4), when appropriate, report the new added code for use of hypoglycemic agents (Z79.84), such as glyburide or metformin.
For gestational diabetes, new codes have been added for the use of hypoglycemic agents; therefore, no additional code is reported (TABLE).
Disproportion code includes numeric specifier for fetus
The disproportion code category was expanded to include a final digit for the fetus with the deformity (TABLE). The final digit of the code number denotes which fetus; for example, “0” means a singleton pregnancy, “1” means fetus 1 (number range from 1 to 5), and “9” denotes any fetus after the fifth.
Cesarean delivery scar codes expanded
The code for maternal care for a scar from a previous cesarean delivery has been expanded to 3 different codes (TABLE). Clinicians should make every effort to document and report the location of the previous cesarean as low transverse or vertical. From a coding standpoint, a vertical scar can also be referred to as a classical scar.
Changes to placenta previa codes
The code category for placenta previa has been expanded to capture the degree of previa as complete, partial, or low lying and with or without hemorrhage (TABLE). Going forward, it will be important to carefully document the circumstances so that the most specific code can be reported and tracked. Trimester specification is required as the final digit.
New subclassifications for perineal laceration
The code category for perineal laceration has been expanded with new codes to capture subclassifications for a third-degree laceration that can involve the external and internal anal sphincter (TABLE). Through its collaborative hub, the Women’s Health Registry Alliance (reVITALize) initiative, the American Congress of Obstetricians and Gynecologists (ACOG) worked on the current classification of third- and fourth-degree perineal lacerations, which has been adopted by the Royal College of Obstetricians and Gynaecologists.1
Under this subclassification, a 3a laceration would involve a tear of less than 50% of the external anal sphincter (EAS); 3b would involve a tear of more than 50% of the EAS; and 3c would mean that both the external and internal anal sphincter are torn. ACOG and its collaborative group encourage clinicians to use these subclassifications in documentation to allow for more robust data collection and complete repair information. From a payment standpoint, such information may go a long way to substantiating the severity of a tear, which may require more physician work.
Z code additions
Finally, the ever-popular diagnostic code for Rho(D) immunization is back, and 2 codes have been added for a gestational carrier and 1 for a family history of sudden infant death syndrome. The codes are:
- Z29.13 Encounter for prophylactic Rho(D) immune globulin
- Z31.7 Encounter for procreative management and counseling for gestational carrier
- Z33.3 Pregnant state, gestational carrier
- Z84.82 Family history of sudden infant death syndrome.
By now the upheaval of changing to the new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) diagnostic coding system has settled. The code freeze that was initiated in 2012 has ended, and the new and revised codes that will go into effect on October 1, 2016, are being revealed. Good documentation will lead to more accurate diagnostic coding, which in turn assists decision makers in their quest to report the health of our population and to make good decisions for resource allocation. You are in the unique position to assist in this process, so keep up the good work.
In this article, I focus on ICD-10 diagnostic coding for obstetric services. I will cover diagnostic coding for gynecologic services in the September issue of OBG Management.
Code revisions for uterine scar and more changes to note
With the upcoming edition of ICD-10, the code Z3A, Weeks’ gestation, will be changed from mandatory reporting to reporting if known. This means that if the patient is no longer pregnant, a Z3A code no longer needs to be reported, and if at the time of service the provider does not know the weeks’ gestation, Z3A would not be required. However, this information should be readily available during the antepartum period and should still be considered important to record and report. And it would still be reported for hospitalization for delivery.
If the code O09.81, Supervision of pregnancy resulting from assisted reproductive technology, is reported, the code Z33.3, Gestational carrier status, may be reported in addition for informational purposes.
When the code O34.29, Maternal care due to uterine scar from other previous surgery, is reported, the tabular index clarifies that this refers to a uterine scar from a transmural uterine incision other than that used for cesarean delivery. This would include incision into the uterine wall to remove fibroids.
The O42 code category, relating to Premature rupture of membranes, should now be interpreted to mean rupture of membranes at or after 37 completed weeks of gestation, rather than after 37 completed weeks.
The code category O99.6, Diseases of the digestive system complicating pregnancy, childbirth, and the puerperium, has been clarified: it does not include hemorrhoids in pregnancy. Therefore, a code from O22.4_ (a final digit of 0 [unspecified], 1, 2, or 3 is required for the trimester) also can be reported if hemorrhoids are present.
A note now clarifies that O99.82, Streptococcus B carrier state complicating pregnancy, childbirth, and the puerperium, cannot be reported with Z22.330, Carrier of streptococcus group B (GBS) in a nonpregnant woman.
New codes for specifying types of ectopic pregnancy
ICD-10 did not initially recognize ectopic pregnancy with and without intrauterine pregnancy, as was the case in ICD-9, but starting in October it will do so. In addition, a history of ectopic or molar pregnancy during a current pregnancy is now reported separately. Each of these codes will require a final digit to indicate the trimester (TABLE).
Codes added for complicating conditions of childbirth and the puerperium
Missing from the ICD-10 lineup last year were codes for conditions related to hypertension, edema, proteinuria, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and eclampsia that were complicating the pregnancy at the time of delivery or after delivery (TABLE).
Note that the “childbirth” code is reported only when a patient delivers at the current episode of care. Once a patient delivers and is discharged, the “puerperium” code should be selected.
Revised descriptions, new reporting instruction for diabetes
The code descriptions for preexisting type 1 and type 2 diabetes were revised, but this change does not impact reporting the codes. However, for type 2 diabetes, the instruction for reporting an additional code has changed. Now, in addition to reporting the code for current use of insulin (Z79.4), when appropriate, report the new added code for use of hypoglycemic agents (Z79.84), such as glyburide or metformin.
For gestational diabetes, new codes have been added for the use of hypoglycemic agents; therefore, no additional code is reported (TABLE).
Disproportion code includes numeric specifier for fetus
The disproportion code category was expanded to include a final digit for the fetus with the deformity (TABLE). The final digit of the code number denotes which fetus; for example, “0” means a singleton pregnancy, “1” means fetus 1 (number range from 1 to 5), and “9” denotes any fetus after the fifth.
Cesarean delivery scar codes expanded
The code for maternal care for a scar from a previous cesarean delivery has been expanded to 3 different codes (TABLE). Clinicians should make every effort to document and report the location of the previous cesarean as low transverse or vertical. From a coding standpoint, a vertical scar can also be referred to as a classical scar.
Changes to placenta previa codes
The code category for placenta previa has been expanded to capture the degree of previa as complete, partial, or low lying and with or without hemorrhage (TABLE). Going forward, it will be important to carefully document the circumstances so that the most specific code can be reported and tracked. Trimester specification is required as the final digit.
New subclassifications for perineal laceration
The code category for perineal laceration has been expanded with new codes to capture subclassifications for a third-degree laceration that can involve the external and internal anal sphincter (TABLE). Through its collaborative hub, the Women’s Health Registry Alliance (reVITALize) initiative, the American Congress of Obstetricians and Gynecologists (ACOG) worked on the current classification of third- and fourth-degree perineal lacerations, which has been adopted by the Royal College of Obstetricians and Gynaecologists.1
Under this subclassification, a 3a laceration would involve a tear of less than 50% of the external anal sphincter (EAS); 3b would involve a tear of more than 50% of the EAS; and 3c would mean that both the external and internal anal sphincter are torn. ACOG and its collaborative group encourage clinicians to use these subclassifications in documentation to allow for more robust data collection and complete repair information. From a payment standpoint, such information may go a long way to substantiating the severity of a tear, which may require more physician work.
Z code additions
Finally, the ever-popular diagnostic code for Rho(D) immunization is back, and 2 codes have been added for a gestational carrier and 1 for a family history of sudden infant death syndrome. The codes are:
- Z29.13 Encounter for prophylactic Rho(D) immune globulin
- Z31.7 Encounter for procreative management and counseling for gestational carrier
- Z33.3 Pregnant state, gestational carrier
- Z84.82 Family history of sudden infant death syndrome.
- Centers for Disease Control and Prevention. ICD-10 Coordination and Maintenance Committee meeting: diagnosis agenda. September 23-24, 2014;38, 39. http://www.cdc.gov/nchs/data/icd/topic_packet_09_23_2012.pdf. Accessed July 5, 2016.
- Centers for Disease Control and Prevention. ICD-10 Coordination and Maintenance Committee meeting: diagnosis agenda. September 23-24, 2014;38, 39. http://www.cdc.gov/nchs/data/icd/topic_packet_09_23_2012.pdf. Accessed July 5, 2016.
In this Article
- New and expanded codes
- Z code additions
- Table of codes
PHM16: Visual Clues Can Help Establish a Diagnosis
PHM16’s Visual Diagnosis: Signs and Why They Matter session led by Dr. Kenneth Roberts and guest presenters was a review of case presentations in which visual clues were vital to establishing a diagnosis. Though much of the content was presented with pictures, the emphasis was placed on the importance of correct diagnosis to avoid both misdiagnoses/over-diagnoses and the potential harm that may result from inappropriate treatment. This may also translate into poor utilization of resources and significant financial burden that can result from the unnecessary hospitalization of a patient.
Many of the presented cases (such as the Gianotti-Crosti toddler over-diagnosed as eczema herpeticum, a child with pseudochromhidrosis misdiagnosed as a cyanotic disease, the case of phytophotodermatitis mistaken as child abuse, and a teen treated for 2 years for JIA before diagnosis of hypertrophic osteoarthropathy was made) highlighted examples in which there was extensive workup, hospitalization, subspecialty evaluation, and even incorrect treatment of patients.
In other instances, such as Henoch-Schonlein purpura, Waardenburg syndrome, or McCune-Albright syndrome, the correct diagnosis is necessary to help guide management and future treatment, including subspecialty evaluation.
Many diseases with visual presentations also have a benign course and require no treatment, and acknowledging this is important in providing reassurance to a family that may be very anxious over the physical appearance of their child.
This session underscores the need for experience and exposure to various signs, not only with rare medical conditions, but also in common illnesses such as Kawasaki and scarlet fever that may present similarly.
Key Takeaway:
Providers should have a high index of suspicion and use visual clues to make the correct diagnosis in order to guide treatment, avoid harm in children, and ensure appropriate utilization of resources.
Chandani DeZure, MD, FAAP, is a pediatric Hospitalist at Children’s National Health System, Instruction of Pediatrics at George Washington University’s School of Medicine and Health Sciences in Washington, D.C.
PHM16’s Visual Diagnosis: Signs and Why They Matter session led by Dr. Kenneth Roberts and guest presenters was a review of case presentations in which visual clues were vital to establishing a diagnosis. Though much of the content was presented with pictures, the emphasis was placed on the importance of correct diagnosis to avoid both misdiagnoses/over-diagnoses and the potential harm that may result from inappropriate treatment. This may also translate into poor utilization of resources and significant financial burden that can result from the unnecessary hospitalization of a patient.
Many of the presented cases (such as the Gianotti-Crosti toddler over-diagnosed as eczema herpeticum, a child with pseudochromhidrosis misdiagnosed as a cyanotic disease, the case of phytophotodermatitis mistaken as child abuse, and a teen treated for 2 years for JIA before diagnosis of hypertrophic osteoarthropathy was made) highlighted examples in which there was extensive workup, hospitalization, subspecialty evaluation, and even incorrect treatment of patients.
In other instances, such as Henoch-Schonlein purpura, Waardenburg syndrome, or McCune-Albright syndrome, the correct diagnosis is necessary to help guide management and future treatment, including subspecialty evaluation.
Many diseases with visual presentations also have a benign course and require no treatment, and acknowledging this is important in providing reassurance to a family that may be very anxious over the physical appearance of their child.
This session underscores the need for experience and exposure to various signs, not only with rare medical conditions, but also in common illnesses such as Kawasaki and scarlet fever that may present similarly.
Key Takeaway:
Providers should have a high index of suspicion and use visual clues to make the correct diagnosis in order to guide treatment, avoid harm in children, and ensure appropriate utilization of resources.
Chandani DeZure, MD, FAAP, is a pediatric Hospitalist at Children’s National Health System, Instruction of Pediatrics at George Washington University’s School of Medicine and Health Sciences in Washington, D.C.
PHM16’s Visual Diagnosis: Signs and Why They Matter session led by Dr. Kenneth Roberts and guest presenters was a review of case presentations in which visual clues were vital to establishing a diagnosis. Though much of the content was presented with pictures, the emphasis was placed on the importance of correct diagnosis to avoid both misdiagnoses/over-diagnoses and the potential harm that may result from inappropriate treatment. This may also translate into poor utilization of resources and significant financial burden that can result from the unnecessary hospitalization of a patient.
Many of the presented cases (such as the Gianotti-Crosti toddler over-diagnosed as eczema herpeticum, a child with pseudochromhidrosis misdiagnosed as a cyanotic disease, the case of phytophotodermatitis mistaken as child abuse, and a teen treated for 2 years for JIA before diagnosis of hypertrophic osteoarthropathy was made) highlighted examples in which there was extensive workup, hospitalization, subspecialty evaluation, and even incorrect treatment of patients.
In other instances, such as Henoch-Schonlein purpura, Waardenburg syndrome, or McCune-Albright syndrome, the correct diagnosis is necessary to help guide management and future treatment, including subspecialty evaluation.
Many diseases with visual presentations also have a benign course and require no treatment, and acknowledging this is important in providing reassurance to a family that may be very anxious over the physical appearance of their child.
This session underscores the need for experience and exposure to various signs, not only with rare medical conditions, but also in common illnesses such as Kawasaki and scarlet fever that may present similarly.
Key Takeaway:
Providers should have a high index of suspicion and use visual clues to make the correct diagnosis in order to guide treatment, avoid harm in children, and ensure appropriate utilization of resources.
Chandani DeZure, MD, FAAP, is a pediatric Hospitalist at Children’s National Health System, Instruction of Pediatrics at George Washington University’s School of Medicine and Health Sciences in Washington, D.C.
