Genitourinary Cancer

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Erdafitinib, an oral pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, is efficacious when used to treat urothelial cancer harboring FGFR genetic alterations, although dose adjustments are commonly needed, suggests a multicenter phase 2 trial.

“Mutations and fusions in FGFR2/3 are common in patients with urothelial carcinoma, particularly in the luminal I subtype, and can cause constitutive FGFR signaling that may contribute to carcinogenesis,” write Yohann Loriot, MD, of Gustave Roussy, Université Paris-Sud and Université Paris-Saclay, in Villejuif, France, and coinvestigators. Up to 20% of patients with advanced disease and fully 37% of those with upper-tract tumors have alterations in these genes. “ Thus, FGFR inhibition may be particularly appropriate in patients with luminal I subtype disease, in which immunotherapeutic approaches may be less effective,” they noted.

In the trial, 99 patients with pretreated locally advanced and unresectable or metastatic urothelial carcinoma having FGFR alterations were given single-agent, open-label erdafitinib (Balversa) for a median of five cycles. The drug was recently granted accelerated approval by the Food and Drug Administration for this indication.

The rate of confirmed response according to investigator assessment was 40% (3% of patients had a complete response and 37% had a partial response), based on trial results reported in the New England Journal of Medicine. The response rate was 59% among the subset who had previously received immunotherapy.

With a median follow-up of 11.0 months, the median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months.

Fully 46% of patients experienced a grade 3 or higher treatment-related adverse event, most commonly hyponatremia (11%), stomatitis (10%), and asthenia (7%). Nearly 56% of the trial population as a whole required a dose reduction. However, only 13% of patients stopped treatment because of an adverse event, and there were no treatment-related deaths.

“This study met its primary objective,” Dr. Loriot and coinvestigators concluded. “These findings showed that among patients with locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR alterations, erdafitinib had promising antitumor activity.”

“The response to erdafitinib was rapid and independent of the number of previous courses and types of therapy, the presence of visceral metastasis, or tumor location,” they wrote. In addition, the efficacy appears to be better than that achieved previously with chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates.

The trial was funded by Janssen Research and Development. Dr. Loriot reports grants and personal fees from Janssen, during the conduct of the study.

SOURCE: Loriot Y et al. N Engl J Med. 2019;381:338-348. doi: 10.1056/NEJMoa1817323.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The safety profile of combination abiraterone acetate (Zytiga) and glucocorticoid therapy in men with metastatic castration-resistant prostate cancer (mCRPC) hinged on the specific steroid regimen, according to a phase 2 open-label randomized controlled trial.

alexdans/Thinkstock

Glucocorticoids are added to abiraterone in part to prevent mineralocorticoid excess, but can also have adverse effects of their own, noted lead investigator Gerhardt Attard, MD, of the University College London Cancer Institute, London, and colleagues. Understanding of the comparative physiologic effects of various regimens is limited.

In the trial, the investigators randomized 164 men with mCRPC from 22 centers in 5 countries (median age 70 years) to 4 glucocorticoid regimens, each combined with abiraterone acetate, 1,000 mg, daily: prednisone, 5 mg, twice daily; prednisone, 5 mg, once daily; prednisone, 2.5 mg, twice daily; and dexamethasone, 0.5 mg, once daily.

Results reported in JAMA Oncology showed that the proportion of patients who had not developed toxicity (hypotension or hypokalemia) from mineralocorticoid excess during the first 24 weeks of treatment was highest, at about 70%, with prednisone, 5 mg, twice daily, and with dexamethasone, and only these regimens had confidence intervals excluding occurrence of this toxicity in at least half of patients. However, patients in the dexamethasone group had significantly heightened risks of insulin resistance and bone mineral density loss at the end of follow-up.

The median radiographic progression-free survival was 18.5 months in the group given prednisone, 5 mg, twice daily; 15.3 months in the group given prednisone, 5 mg, once daily; 12.8 months in the group given prednisone, 2.5 mg, twice daily; and 26.6 months in the group given dexamethasone, 0.5 mg, once daily.

“Different glucocorticoid regimens make distinct compromises on control of mineralocorticoid excess, changes in body composition, and development of insulin resistance,” Dr. Attard and coinvestigators summarized. “This trial provides results consistent with the approved use of abiraterone acetate with prednisone, 5 mg, twice daily for the treatment of mCRPC. Long-term adverse metabolic and musculoskeletal changes are small and do not appear to have a detrimental effect on patient-reported quality of life.”

At the same time, lower-dose prednisone regimens – with their more modest long-term risks of insulin resistance, increased body fat, and bone mineral density loss – can still be used, with caution. “With careful monitoring, the risk of hypokalemia with lower glucocorticoid doses can be mitigated, as demonstrated in the LATITUDE and STAMPEDE trials where no major safety concerns were raised,” they elaborated.

Dr. Attard disclosed personal fees, research support, and travel support from Janssen during the conduct of the study; as well as personal fees research, and/or travel support from numerous other pharmaceutical companies. The study was funded by Janssen EMEA.

SOURCE: Attard G et al. JAMA Oncol. Published online June 27, 2019. doi:10.1001/jamaoncol.2019.1011.

The safety profile of combination abiraterone acetate (Zytiga) and glucocorticoid therapy in men with metastatic castration-resistant prostate cancer (mCRPC) hinged on the specific steroid regimen, according to a phase 2 open-label randomized controlled trial.

alexdans/Thinkstock

Glucocorticoids are added to abiraterone in part to prevent mineralocorticoid excess, but can also have adverse effects of their own, noted lead investigator Gerhardt Attard, MD, of the University College London Cancer Institute, London, and colleagues. Understanding of the comparative physiologic effects of various regimens is limited.

In the trial, the investigators randomized 164 men with mCRPC from 22 centers in 5 countries (median age 70 years) to 4 glucocorticoid regimens, each combined with abiraterone acetate, 1,000 mg, daily: prednisone, 5 mg, twice daily; prednisone, 5 mg, once daily; prednisone, 2.5 mg, twice daily; and dexamethasone, 0.5 mg, once daily.

Results reported in JAMA Oncology showed that the proportion of patients who had not developed toxicity (hypotension or hypokalemia) from mineralocorticoid excess during the first 24 weeks of treatment was highest, at about 70%, with prednisone, 5 mg, twice daily, and with dexamethasone, and only these regimens had confidence intervals excluding occurrence of this toxicity in at least half of patients. However, patients in the dexamethasone group had significantly heightened risks of insulin resistance and bone mineral density loss at the end of follow-up.

The median radiographic progression-free survival was 18.5 months in the group given prednisone, 5 mg, twice daily; 15.3 months in the group given prednisone, 5 mg, once daily; 12.8 months in the group given prednisone, 2.5 mg, twice daily; and 26.6 months in the group given dexamethasone, 0.5 mg, once daily.

“Different glucocorticoid regimens make distinct compromises on control of mineralocorticoid excess, changes in body composition, and development of insulin resistance,” Dr. Attard and coinvestigators summarized. “This trial provides results consistent with the approved use of abiraterone acetate with prednisone, 5 mg, twice daily for the treatment of mCRPC. Long-term adverse metabolic and musculoskeletal changes are small and do not appear to have a detrimental effect on patient-reported quality of life.”

At the same time, lower-dose prednisone regimens – with their more modest long-term risks of insulin resistance, increased body fat, and bone mineral density loss – can still be used, with caution. “With careful monitoring, the risk of hypokalemia with lower glucocorticoid doses can be mitigated, as demonstrated in the LATITUDE and STAMPEDE trials where no major safety concerns were raised,” they elaborated.

Dr. Attard disclosed personal fees, research support, and travel support from Janssen during the conduct of the study; as well as personal fees research, and/or travel support from numerous other pharmaceutical companies. The study was funded by Janssen EMEA.

SOURCE: Attard G et al. JAMA Oncol. Published online June 27, 2019. doi:10.1001/jamaoncol.2019.1011.

The safety profile of combination abiraterone acetate (Zytiga) and glucocorticoid therapy in men with metastatic castration-resistant prostate cancer (mCRPC) hinged on the specific steroid regimen, according to a phase 2 open-label randomized controlled trial.

alexdans/Thinkstock

Glucocorticoids are added to abiraterone in part to prevent mineralocorticoid excess, but can also have adverse effects of their own, noted lead investigator Gerhardt Attard, MD, of the University College London Cancer Institute, London, and colleagues. Understanding of the comparative physiologic effects of various regimens is limited.

In the trial, the investigators randomized 164 men with mCRPC from 22 centers in 5 countries (median age 70 years) to 4 glucocorticoid regimens, each combined with abiraterone acetate, 1,000 mg, daily: prednisone, 5 mg, twice daily; prednisone, 5 mg, once daily; prednisone, 2.5 mg, twice daily; and dexamethasone, 0.5 mg, once daily.

Results reported in JAMA Oncology showed that the proportion of patients who had not developed toxicity (hypotension or hypokalemia) from mineralocorticoid excess during the first 24 weeks of treatment was highest, at about 70%, with prednisone, 5 mg, twice daily, and with dexamethasone, and only these regimens had confidence intervals excluding occurrence of this toxicity in at least half of patients. However, patients in the dexamethasone group had significantly heightened risks of insulin resistance and bone mineral density loss at the end of follow-up.

The median radiographic progression-free survival was 18.5 months in the group given prednisone, 5 mg, twice daily; 15.3 months in the group given prednisone, 5 mg, once daily; 12.8 months in the group given prednisone, 2.5 mg, twice daily; and 26.6 months in the group given dexamethasone, 0.5 mg, once daily.

“Different glucocorticoid regimens make distinct compromises on control of mineralocorticoid excess, changes in body composition, and development of insulin resistance,” Dr. Attard and coinvestigators summarized. “This trial provides results consistent with the approved use of abiraterone acetate with prednisone, 5 mg, twice daily for the treatment of mCRPC. Long-term adverse metabolic and musculoskeletal changes are small and do not appear to have a detrimental effect on patient-reported quality of life.”

At the same time, lower-dose prednisone regimens – with their more modest long-term risks of insulin resistance, increased body fat, and bone mineral density loss – can still be used, with caution. “With careful monitoring, the risk of hypokalemia with lower glucocorticoid doses can be mitigated, as demonstrated in the LATITUDE and STAMPEDE trials where no major safety concerns were raised,” they elaborated.

Dr. Attard disclosed personal fees, research support, and travel support from Janssen during the conduct of the study; as well as personal fees research, and/or travel support from numerous other pharmaceutical companies. The study was funded by Janssen EMEA.

SOURCE: Attard G et al. JAMA Oncol. Published online June 27, 2019. doi:10.1001/jamaoncol.2019.1011.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.

Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.

Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.

By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.

In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.

Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”

In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.

While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.

“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.

The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.

With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).

Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.

SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding short-term androgen deprivation therapy (ADT) to radiotherapy as salvage treatment after radical prostatectomy was associated with significantly better metastasis-free survival at nearly 10 years compared with salvage radiation alone, long-term results of a randomized phase 3 trial show.

Neil Osterweil/MDedge News

After a median follow-up of 112 months (9.3 years), the metastasis-free survival (MFS) rate for 369 patients assigned to receive salvage radiation and short-term goserelin was 75%, compared with 69% for 374 patients randomized to radiation alone (P = .034), reported Nicolas Magné, MD, from Jean Monnet Saint Etienne University in Saint-Priest en Jarez, France.

“We can conclude and do believe that short ADT, only two injections at 3-month intervals, could increase MFS at 10 years compared to radiation alone in patients with rising PSA after initial prostatectomy,“ he said at the annual meeting of the American Society of Clinical Oncology.

There was no significant difference, however, in the secondary endpoint of overall survival at 10 years.

Dr. Magné and co-investigators in the GETUG-AFU 16 trial had previously reported that after a median follow-up of 5.3 years, patients assigned to radiation plus goserelin were significantly more likely to be free of biochemical or clinical progression at 5 years than patients assigned to radiotherapy alone (80% vs, 62%, hazard ratio [HR] 0.50, P less than .0001).

The open-label trial enrolled men 18 or older from 43 French centers who had been treated for a histologically confirmed adenocarcinoma of the prostate but had not received prior androgen deprivation therapy (ADT) or pelvic radiation. The patients had either stage pT2 or pT3 cancers, or stage pT4a with invasive disease limited to the bladder neck. The patients all had biochemical failure, defined as a rising prostate-specific antigen (PSA) of 0.2 to 2.0 mcg/L following radical prostatectomy, with no clinically evident disease.

The patients were randomly assigned to receive standard salvage radiotherapy either alone or with hormonal therapy. Randomization was stratified by investigational site, radiotherapy modality, and prognosis.

Radiotherapy consisted of either 3-D conformal radiotherapy or intensity modulated radiotherapy, delivered in 66 Gy doses divided into 33 fractions of 2 Gy each 5 days a week for 7 weeks.

Patients assigned to hormonal therapy in addition to radiation received one subcutaneous injection of goserelin 10.8 mg on the first day of radiation, and a second injection 3 months later.

Progression-free survival (PFS), the primary endpoint, was significantly better with the combination than with radiation alone for both low-risk patients (HR 0.47, 95% confidence interval [CI] 0.28-0.80), and high-risk patients (HR 0.56, CI 0.44-0.83).

As noted before, metastasis-free survival was also significantly better in the combination arm ( HR, 0.73, P = .034) at 10 years.

Invited discussant Daniel Spratt, MD, from the University of Michigan in Ann Arbor, commented that the study results “do show, just like they did in 2016, that bicochemical control is improved, which is linked to their primary endpoint of PFS, but I always caution that this alone will always be improved with testosterone suppression.”

Neil Osterweil/MDedge News

He noted that if you give ADT to patients with low-risk prostate cancer “that we don’t usually even treat today,” adding hormonal therapy will produce a nearly identical improvement in biochemical control, suggesting more of a signal than a clinical benefit.

The improvement in MFS, however, is indeed a clinical benefit, “but it is a small difference, and one thing to note is that when you give these patients about 6 months of hormonal therapy, depending on the age of the patient, it can be about 6 months until they recover testosterone, and at their median follow-up, you can see that the delay in MFS, which is usually the trigger to start hormone therapy, is about 12 months. So it’s important when you counsel these patients that [for] about potentially 6 months to a year of symptoms you may delay the need for hormone therapy by about 12 months,” he said.

The study was supported by UNICANCER and AstraZeneca. Dr. Magné reported no relevant disclosures. Dr. Spratt reported amconsulting or advisory role with Blue Earth Diagnostics and Janssen Oncology.

SOURCE: Magn é D et al. ASCO 2019. Abstract 5001.

CHICAGO – Adding short-term androgen deprivation therapy (ADT) to radiotherapy as salvage treatment after radical prostatectomy was associated with significantly better metastasis-free survival at nearly 10 years compared with salvage radiation alone, long-term results of a randomized phase 3 trial show.

Neil Osterweil/MDedge News

After a median follow-up of 112 months (9.3 years), the metastasis-free survival (MFS) rate for 369 patients assigned to receive salvage radiation and short-term goserelin was 75%, compared with 69% for 374 patients randomized to radiation alone (P = .034), reported Nicolas Magné, MD, from Jean Monnet Saint Etienne University in Saint-Priest en Jarez, France.

“We can conclude and do believe that short ADT, only two injections at 3-month intervals, could increase MFS at 10 years compared to radiation alone in patients with rising PSA after initial prostatectomy,“ he said at the annual meeting of the American Society of Clinical Oncology.

There was no significant difference, however, in the secondary endpoint of overall survival at 10 years.

Dr. Magné and co-investigators in the GETUG-AFU 16 trial had previously reported that after a median follow-up of 5.3 years, patients assigned to radiation plus goserelin were significantly more likely to be free of biochemical or clinical progression at 5 years than patients assigned to radiotherapy alone (80% vs, 62%, hazard ratio [HR] 0.50, P less than .0001).

The open-label trial enrolled men 18 or older from 43 French centers who had been treated for a histologically confirmed adenocarcinoma of the prostate but had not received prior androgen deprivation therapy (ADT) or pelvic radiation. The patients had either stage pT2 or pT3 cancers, or stage pT4a with invasive disease limited to the bladder neck. The patients all had biochemical failure, defined as a rising prostate-specific antigen (PSA) of 0.2 to 2.0 mcg/L following radical prostatectomy, with no clinically evident disease.

The patients were randomly assigned to receive standard salvage radiotherapy either alone or with hormonal therapy. Randomization was stratified by investigational site, radiotherapy modality, and prognosis.

Radiotherapy consisted of either 3-D conformal radiotherapy or intensity modulated radiotherapy, delivered in 66 Gy doses divided into 33 fractions of 2 Gy each 5 days a week for 7 weeks.

Patients assigned to hormonal therapy in addition to radiation received one subcutaneous injection of goserelin 10.8 mg on the first day of radiation, and a second injection 3 months later.

Progression-free survival (PFS), the primary endpoint, was significantly better with the combination than with radiation alone for both low-risk patients (HR 0.47, 95% confidence interval [CI] 0.28-0.80), and high-risk patients (HR 0.56, CI 0.44-0.83).

As noted before, metastasis-free survival was also significantly better in the combination arm ( HR, 0.73, P = .034) at 10 years.

Invited discussant Daniel Spratt, MD, from the University of Michigan in Ann Arbor, commented that the study results “do show, just like they did in 2016, that bicochemical control is improved, which is linked to their primary endpoint of PFS, but I always caution that this alone will always be improved with testosterone suppression.”

Neil Osterweil/MDedge News

He noted that if you give ADT to patients with low-risk prostate cancer “that we don’t usually even treat today,” adding hormonal therapy will produce a nearly identical improvement in biochemical control, suggesting more of a signal than a clinical benefit.

The improvement in MFS, however, is indeed a clinical benefit, “but it is a small difference, and one thing to note is that when you give these patients about 6 months of hormonal therapy, depending on the age of the patient, it can be about 6 months until they recover testosterone, and at their median follow-up, you can see that the delay in MFS, which is usually the trigger to start hormone therapy, is about 12 months. So it’s important when you counsel these patients that [for] about potentially 6 months to a year of symptoms you may delay the need for hormone therapy by about 12 months,” he said.

The study was supported by UNICANCER and AstraZeneca. Dr. Magné reported no relevant disclosures. Dr. Spratt reported amconsulting or advisory role with Blue Earth Diagnostics and Janssen Oncology.

SOURCE: Magn é D et al. ASCO 2019. Abstract 5001.

CHICAGO – Adding short-term androgen deprivation therapy (ADT) to radiotherapy as salvage treatment after radical prostatectomy was associated with significantly better metastasis-free survival at nearly 10 years compared with salvage radiation alone, long-term results of a randomized phase 3 trial show.

Neil Osterweil/MDedge News

After a median follow-up of 112 months (9.3 years), the metastasis-free survival (MFS) rate for 369 patients assigned to receive salvage radiation and short-term goserelin was 75%, compared with 69% for 374 patients randomized to radiation alone (P = .034), reported Nicolas Magné, MD, from Jean Monnet Saint Etienne University in Saint-Priest en Jarez, France.

“We can conclude and do believe that short ADT, only two injections at 3-month intervals, could increase MFS at 10 years compared to radiation alone in patients with rising PSA after initial prostatectomy,“ he said at the annual meeting of the American Society of Clinical Oncology.

There was no significant difference, however, in the secondary endpoint of overall survival at 10 years.

Dr. Magné and co-investigators in the GETUG-AFU 16 trial had previously reported that after a median follow-up of 5.3 years, patients assigned to radiation plus goserelin were significantly more likely to be free of biochemical or clinical progression at 5 years than patients assigned to radiotherapy alone (80% vs, 62%, hazard ratio [HR] 0.50, P less than .0001).

The open-label trial enrolled men 18 or older from 43 French centers who had been treated for a histologically confirmed adenocarcinoma of the prostate but had not received prior androgen deprivation therapy (ADT) or pelvic radiation. The patients had either stage pT2 or pT3 cancers, or stage pT4a with invasive disease limited to the bladder neck. The patients all had biochemical failure, defined as a rising prostate-specific antigen (PSA) of 0.2 to 2.0 mcg/L following radical prostatectomy, with no clinically evident disease.

The patients were randomly assigned to receive standard salvage radiotherapy either alone or with hormonal therapy. Randomization was stratified by investigational site, radiotherapy modality, and prognosis.

Radiotherapy consisted of either 3-D conformal radiotherapy or intensity modulated radiotherapy, delivered in 66 Gy doses divided into 33 fractions of 2 Gy each 5 days a week for 7 weeks.

Patients assigned to hormonal therapy in addition to radiation received one subcutaneous injection of goserelin 10.8 mg on the first day of radiation, and a second injection 3 months later.

Progression-free survival (PFS), the primary endpoint, was significantly better with the combination than with radiation alone for both low-risk patients (HR 0.47, 95% confidence interval [CI] 0.28-0.80), and high-risk patients (HR 0.56, CI 0.44-0.83).

As noted before, metastasis-free survival was also significantly better in the combination arm ( HR, 0.73, P = .034) at 10 years.

Invited discussant Daniel Spratt, MD, from the University of Michigan in Ann Arbor, commented that the study results “do show, just like they did in 2016, that bicochemical control is improved, which is linked to their primary endpoint of PFS, but I always caution that this alone will always be improved with testosterone suppression.”

Neil Osterweil/MDedge News

He noted that if you give ADT to patients with low-risk prostate cancer “that we don’t usually even treat today,” adding hormonal therapy will produce a nearly identical improvement in biochemical control, suggesting more of a signal than a clinical benefit.

The improvement in MFS, however, is indeed a clinical benefit, “but it is a small difference, and one thing to note is that when you give these patients about 6 months of hormonal therapy, depending on the age of the patient, it can be about 6 months until they recover testosterone, and at their median follow-up, you can see that the delay in MFS, which is usually the trigger to start hormone therapy, is about 12 months. So it’s important when you counsel these patients that [for] about potentially 6 months to a year of symptoms you may delay the need for hormone therapy by about 12 months,” he said.

The study was supported by UNICANCER and AstraZeneca. Dr. Magné reported no relevant disclosures. Dr. Spratt reported amconsulting or advisory role with Blue Earth Diagnostics and Janssen Oncology.

SOURCE: Magn é D et al. ASCO 2019. Abstract 5001.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.