AVAHO

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

[email protected]

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

Fewer than one in five oncologic phase 3 randomized controlled trials (RCTs) had female corresponding authors, but the proportion of women in this authorship role appears to be gradually increasing, investigators report.

“Through identification of the factors associated with gender disparities in RCT leadership, we hope that the academic oncology community will work to better understand and address the underlying reasons for such imbalances,” wrote Ethan B. Ludmir, MD, of the University of Texas MD Anderson Cancer Center, Houston, and associates. The report is in JAMA Oncology.

The authors searched ClinicalTrials.gov in late 2017 for all oncologic phase 3 RCTs. Of the 1,239 they initially turned up, the authors narrowed them down to the 598 that used multiple arms to test a therapeutic intervention, underwent peer review, and published results of primary endpoints. Among the trials, all published between 2003 and 2018, 17.9% had female corresponding authors.

Industry-funded trials, which comprised 77.8% of the sample, had half as many female corresponding authors (14.4%) as those not funded by industry (30.1%) (P less than .001), “possibly reflecting gender biases that are enhanced in the context of industry relationships with academic medicine,” the authors wrote. The opposite trend appeared in cooperative group trials, a quarter of which (25.9%) had female corresponding authors, compared with 14.3% of noncooperative trials (P = .001).

Trials for breast cancer and head and neck cancer were most likely to have female corresponding authors, while the trials with the lowest rates were those for gastrointestinal, genitourinary, and hematologic cancers (P less than .001). The researchers also found gender disparities in the type of intervention tested: Radiotherapy and supportive care studies were more likely to have female corresponding authors, yet none of the surgical trials had any (P less than .001).

In addition, female corresponding authorship was more likely when the institutions were based in the United States (n = 329) than when they were overseas (P = .001). Women were corresponding authors in 22.5% of U.S. studies and 20% of Canadian studies but only 12% of European trials and 2.3% of Asian trials (P = .001).

Within the United States, more than a third of studies from institutions in the Southeast had female corresponding authors (34.1%), followed by those in the Midwest (27.5%) and West (25.9%). Southwestern institutions were least likely to have female corresponding authors (8.7%). Approximately twice as many studies came from Northeastern institutions as from other regions (n = 112), but only 18.8% of these had female corresponding authors (P = .03).

The frequency of female corresponding authors has been increasing, however: The authors calculated a 1.2% increase each year, “echoing data showing an approximate 1.0% annual increase in the number of female academic hematologist-oncologists,” they noted. “However, the absolute female corresponding author rate for these trials is still lower than the percentage of female academic oncologists in this general study period, ranging from 27% in 2000 to 39% in 2015.”

SOURCE: Ludmir EB et al. JAMA Oncology. 8 Aug 2019. doi: 10.1001/jamaoncol.2019.2196.

Fewer than one in five oncologic phase 3 randomized controlled trials (RCTs) had female corresponding authors, but the proportion of women in this authorship role appears to be gradually increasing, investigators report.

“Through identification of the factors associated with gender disparities in RCT leadership, we hope that the academic oncology community will work to better understand and address the underlying reasons for such imbalances,” wrote Ethan B. Ludmir, MD, of the University of Texas MD Anderson Cancer Center, Houston, and associates. The report is in JAMA Oncology.

The authors searched ClinicalTrials.gov in late 2017 for all oncologic phase 3 RCTs. Of the 1,239 they initially turned up, the authors narrowed them down to the 598 that used multiple arms to test a therapeutic intervention, underwent peer review, and published results of primary endpoints. Among the trials, all published between 2003 and 2018, 17.9% had female corresponding authors.

Industry-funded trials, which comprised 77.8% of the sample, had half as many female corresponding authors (14.4%) as those not funded by industry (30.1%) (P less than .001), “possibly reflecting gender biases that are enhanced in the context of industry relationships with academic medicine,” the authors wrote. The opposite trend appeared in cooperative group trials, a quarter of which (25.9%) had female corresponding authors, compared with 14.3% of noncooperative trials (P = .001).

Trials for breast cancer and head and neck cancer were most likely to have female corresponding authors, while the trials with the lowest rates were those for gastrointestinal, genitourinary, and hematologic cancers (P less than .001). The researchers also found gender disparities in the type of intervention tested: Radiotherapy and supportive care studies were more likely to have female corresponding authors, yet none of the surgical trials had any (P less than .001).

In addition, female corresponding authorship was more likely when the institutions were based in the United States (n = 329) than when they were overseas (P = .001). Women were corresponding authors in 22.5% of U.S. studies and 20% of Canadian studies but only 12% of European trials and 2.3% of Asian trials (P = .001).

Within the United States, more than a third of studies from institutions in the Southeast had female corresponding authors (34.1%), followed by those in the Midwest (27.5%) and West (25.9%). Southwestern institutions were least likely to have female corresponding authors (8.7%). Approximately twice as many studies came from Northeastern institutions as from other regions (n = 112), but only 18.8% of these had female corresponding authors (P = .03).

The frequency of female corresponding authors has been increasing, however: The authors calculated a 1.2% increase each year, “echoing data showing an approximate 1.0% annual increase in the number of female academic hematologist-oncologists,” they noted. “However, the absolute female corresponding author rate for these trials is still lower than the percentage of female academic oncologists in this general study period, ranging from 27% in 2000 to 39% in 2015.”

SOURCE: Ludmir EB et al. JAMA Oncology. 8 Aug 2019. doi: 10.1001/jamaoncol.2019.2196.

Fewer than one in five oncologic phase 3 randomized controlled trials (RCTs) had female corresponding authors, but the proportion of women in this authorship role appears to be gradually increasing, investigators report.

“Through identification of the factors associated with gender disparities in RCT leadership, we hope that the academic oncology community will work to better understand and address the underlying reasons for such imbalances,” wrote Ethan B. Ludmir, MD, of the University of Texas MD Anderson Cancer Center, Houston, and associates. The report is in JAMA Oncology.

The authors searched ClinicalTrials.gov in late 2017 for all oncologic phase 3 RCTs. Of the 1,239 they initially turned up, the authors narrowed them down to the 598 that used multiple arms to test a therapeutic intervention, underwent peer review, and published results of primary endpoints. Among the trials, all published between 2003 and 2018, 17.9% had female corresponding authors.

Industry-funded trials, which comprised 77.8% of the sample, had half as many female corresponding authors (14.4%) as those not funded by industry (30.1%) (P less than .001), “possibly reflecting gender biases that are enhanced in the context of industry relationships with academic medicine,” the authors wrote. The opposite trend appeared in cooperative group trials, a quarter of which (25.9%) had female corresponding authors, compared with 14.3% of noncooperative trials (P = .001).

Trials for breast cancer and head and neck cancer were most likely to have female corresponding authors, while the trials with the lowest rates were those for gastrointestinal, genitourinary, and hematologic cancers (P less than .001). The researchers also found gender disparities in the type of intervention tested: Radiotherapy and supportive care studies were more likely to have female corresponding authors, yet none of the surgical trials had any (P less than .001).

In addition, female corresponding authorship was more likely when the institutions were based in the United States (n = 329) than when they were overseas (P = .001). Women were corresponding authors in 22.5% of U.S. studies and 20% of Canadian studies but only 12% of European trials and 2.3% of Asian trials (P = .001).

Within the United States, more than a third of studies from institutions in the Southeast had female corresponding authors (34.1%), followed by those in the Midwest (27.5%) and West (25.9%). Southwestern institutions were least likely to have female corresponding authors (8.7%). Approximately twice as many studies came from Northeastern institutions as from other regions (n = 112), but only 18.8% of these had female corresponding authors (P = .03).

The frequency of female corresponding authors has been increasing, however: The authors calculated a 1.2% increase each year, “echoing data showing an approximate 1.0% annual increase in the number of female academic hematologist-oncologists,” they noted. “However, the absolute female corresponding author rate for these trials is still lower than the percentage of female academic oncologists in this general study period, ranging from 27% in 2000 to 39% in 2015.”

SOURCE: Ludmir EB et al. JAMA Oncology. 8 Aug 2019. doi: 10.1001/jamaoncol.2019.2196.

A considerable proportion of patients treated with immune checkpoint inhibitors were hospitalized for immune-related toxicities, according to a retrospective cohort study.

In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.

“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.

The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.

The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.

In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.

Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.

“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.

The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.

“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.

Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.

SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.

A considerable proportion of patients treated with immune checkpoint inhibitors were hospitalized for immune-related toxicities, according to a retrospective cohort study.

In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.

“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.

The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.

The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.

In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.

Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.

“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.

The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.

“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.

Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.

SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.

A considerable proportion of patients treated with immune checkpoint inhibitors were hospitalized for immune-related toxicities, according to a retrospective cohort study.

In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.

“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.

The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.

The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.

In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.

Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.

“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.

The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.

“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.

Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.

SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.

Click here to access August 2019 Advances in Hematology and Oncology

Table of Contents

• Partners in Oncology Care: Coordinated Follicular Lymphoma Management
• Accuracy of Endoscopic Ultrasound in Staging of Early Rectal Cancer
• Treatment Facility: An Important Prognostic Factor for Dedifferentiated Liposarcoma Survival
• Review of Radiologic Considerations in an Immunocompetent Patient With Primary Central Nervous System Lymphoma
• Use of Mobile Messaging System for Self-Management of Chemotherapy Symptoms
• Timely Diagnosis of Lung Cancer in a Dedicated VA Referral Unit With Endobronchial Ultrasound
• Research News: Darolutamide Approved for Nonmetastatic CRPC
• Roundtable: Genomic Medicine and Genetic Counseling in the VA and DoD

Click here to access August 2019 Advances in Hematology and Oncology

Table of Contents

• Partners in Oncology Care: Coordinated Follicular Lymphoma Management
• Accuracy of Endoscopic Ultrasound in Staging of Early Rectal Cancer
• Treatment Facility: An Important Prognostic Factor for Dedifferentiated Liposarcoma Survival
• Review of Radiologic Considerations in an Immunocompetent Patient With Primary Central Nervous System Lymphoma
• Use of Mobile Messaging System for Self-Management of Chemotherapy Symptoms
• Timely Diagnosis of Lung Cancer in a Dedicated VA Referral Unit With Endobronchial Ultrasound
• Research News: Darolutamide Approved for Nonmetastatic CRPC
• Roundtable: Genomic Medicine and Genetic Counseling in the VA and DoD

Click here to access August 2019 Advances in Hematology and Oncology

Table of Contents

• Partners in Oncology Care: Coordinated Follicular Lymphoma Management
• Accuracy of Endoscopic Ultrasound in Staging of Early Rectal Cancer
• Treatment Facility: An Important Prognostic Factor for Dedifferentiated Liposarcoma Survival
• Review of Radiologic Considerations in an Immunocompetent Patient With Primary Central Nervous System Lymphoma
• Use of Mobile Messaging System for Self-Management of Chemotherapy Symptoms
• Timely Diagnosis of Lung Cancer in a Dedicated VA Referral Unit With Endobronchial Ultrasound
• Research News: Darolutamide Approved for Nonmetastatic CRPC
• Roundtable: Genomic Medicine and Genetic Counseling in the VA and DoD

Approximately 17% to 25% of all softtissue sarcomas (STS) are liposarcomas, making liposarcoma the most common type of STS.¹ The 2013 World Health Organization (WHO) classification separates liposarcoma into 4 histologic subtypes: atypical lipomatous tumor/well-differentiated (ALT/ WDLPS), dedifferentiated (DDLPS), myxoid, and pleomorphic.² Each subtype has unique histology, morphology, and natural history. WDLPS and DDLPS are the most common histologic subtypes, comprising approximately 50% of all sarcomas that arise in the retroperitoneum.³ DDLPS represents 18% of all liposarcomas, making it the second most common subtype of liposarcoma.⁴

In 1979, DDLPS was first characterized.⁵ Most (90%) cases of DDLPS present de novo, whereas the other 10% transform from preexisting low-grade WDLPS.² DDLPSs are formed by an amplification of 12q14-15 involving the MDM2 gene.⁴ These malignancies most commonly present in the retroperitoneum as a large painless mass, consisting of both fatty and nonfatty components.² Primary site has been previously reported as a major prognostic factor for DDLPSs, with retroperitoneal DDLPSs demonstrating the worst prognosis.6 DDLPSs have a high risk of local recurrence, with some reports estimating recurrence rates approaching 40%.² Overall mortality at 5 years for DDLPS is estimated to be between 30% and 40%.⁴

Previous literature has determined that median income, race, health insurance, and facility type are related to survival outcomes for patients with DDLPS.7-9 When comparing the most common types of cancers, residents of poorer US counties consistently had a higher risk of mortality than residents in affluent US counties, and all racial minorities showed worse survival outcomes when compared with white patients.⁷ Differences in survival outcomes have been reported in patients attending different treatment facilities for other cancers including pancreatic cancers, glioblastomas, and oral cancers, with multiple studies concluding that academic and research programs are associated with the longest survival outcomes.^10-12 For many cancers, insurance status has been shown to be a significant prognostic factor, with private insurance typically resulting in the best prognosis.^8,9

The goal of this retrospective study was to assess the prognostic effects of socioeconomic variables on the overall survival (OS) probabilities in a large cohort of DDLPS patients in order to inform clinicians about a potentially at-risk population.

Method

The National Cancer Database (NCDB) was created by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The NCDB is the largest cancer database in the US and includes data on almost 70% of US patients with cancer. CoC-accredited cancer programs add data on patients with cancer to the NCDB. The authors accessed the NCDB data through the use of the NCDB Participant Use File program.

Patients’ data from 2004 through 2015 were abstracted. Only patients with the International Classification of Diseases for Oncology histology code 8858, corresponding to DDLPS, were analyzed. Patients with other comorbid malignant tumors were excluded to accurately capture the true survival rates for DDLPS. Variables analyzed included age, sex, race, insurance status, treatment facility type, median household income by zip code, and percentage of adults in the patient’s zip code with no high school (HS) education.

Median survival, 5- and 10-year OS probabilities, and Kaplan-Meier survival curves were calculated for multiple variables, specifically race, insurance status, treatment facility type, median family income, and percentage of adults without a HS degree. Both 5- and 10-year OS probabilities were determined by race with the patients separated into white, African American, Asian, American Indian/Alaska Native (AI/AN), and Asian Indian or Pakistani groups. Our study categorized Chinese, Japanese, Filipino, Hmong, Korean, Vietnamese, Thai, Guamanian, Asian not otherwise specified, and other Asian ethnicity patients together into one collective Asian group. Insurance status was classified into Medicare, Medicaid, other government insurance, and private insurance groups. Other government insurance consisted of US Department of Veterans Affairs, Indian Health Service, Public Health Service, and other government health care programs. Further analysis could not be performed into the distribution of the other government insurance variable.

Facility types were divided into 4 groups: community, comprehensive community, academic/ research, and integrated network cancer treatment facilities. Median income quartiles and the percentage of adults with no high school degree were estimated by comparison of the patient’s zip code with US Census Bureau data. Median household income was separated into 4 groups, including lowest level of household income (< $38,000), low level of household income ($38,000 to $47,999), moderate level of household income ($48,000 to $62,999), and highest level of household income (≥ $63,000). The percentages of adults with no high school degree were divided into 4 groups: lowest level of HS education (≥ 21% ), low level of HS education (13.0% to 20.9%), moderate level of HS education (7.0% to 12.9%), and highest level of HS education (≤ 7%). The 5- and 10-year survival probabilities were calculated using the number of months between the date of diagnosis and the date of death or last known contact.

Continuous variables are presented as median and interquartile range (IQR) whereas categorical variables are presented as frequencies and proportion. IBM SPSS version 25.0 was used to produce Kaplan-Meier survival curves and descriptive statistics. This study used Kaplan- Meier survival tables and log-rank tests to analyze both the 5- and 10-year OS rates for the 5 variables listed above. This study also used a multivariable Cox regression model that accommodated the correlative nature of outcomes within facilities to study the association of the treatment facility type and other socioeconomic factors, while controlling for age, race (which was collapsed into 3 categories), sex, primary site, tumor stage, and treatment approaches. The proportional hazards assumption was individually checked for all pertinent variables. Any patient records that were missing data were excluded from the multivariable Cox regression model, which was analyzed with SAS version 9.4 (Cary, NC). P < 0.05 was used to indicate statistical significance for all analyses.

Results

Table 1 provides descriptive analysis for demographic characteristics of the 3573 patients including age, sex, and race. The median age at diagnosis was 64 years. There were 1073 more men (65%) than women (35%) in this analysis. Whites were the predominant racial category, comprising 87.7% of the patient population, followed by African Americans (6.5%) and Asians (2.5%).

Socioeconomic Variables

The largest proportion of the patient population (45.5%) had private insurance (Table 2). Medicare came in a close second covering almost 42.2% of the population, followed by Medicaid (5.0%), uninsured (2.8%), and other government insurance (1.5%). About half (53.7%) of the patients were treated at academic or research facilities, while the fewest number of patients (5.2%) underwent treatment at community cancer facilities. The largest percentage (36.6%) of patients lived in zip codes with the highest level of median household income, while 26.0% and 22.3% had moderate and low levels of income, respectively. About 14% of patients lived within an area of the lowest level of income. Similarly, almost 15% of patients lived in an area of lowest level of HS education. The greatest percentage of the patient population (34.5%) lived in a zip code with moderate level of HS education. Surgery was the most common treatment modality with 90.8% of the cohort undergoing surgery, while 35.4% and 16.5% were treated with radiation and chemotherapy, respectively (some patients received more than one type of treatment modality).

Survival Data

Survival data were available for 3112 patients. Kaplan-Meier survival curves were used to analyze OS according to insurance status, racial background, treatment facility type, median family income, and percentage of adults with no high school education. Overall 5- and 10- year OS probabilities were 51.5% and 34.8%, respectively, while the median OS (SD) was 63.57 (2.8) months (Table 3).

Private insurance showed significantly higher 5- and 10-year OS probabilities and median OS: 5-year OS was 61.2%, 10-year OS was 47.2%, and median survival (SD) was 101.2 (8.2) months compared with that of all other insurance groups (Medicare, Medicaid, other government insurance, and uninsured) (Figure 1). These other insurance types were fairly similar in their 5-year and median OS, but surprisingly, patients with no insurance had the second longest 10-year OS. The difference between the 5-year OS probabilities of private insurance compared with an average of the other insurances was 15.1%, which had almost doubled to 28.5% at 10 years, with a median OS difference of almost 5 years (56 months; data not shown).

Using the Kaplan-Meier survival curve, Asian Indians had the longest 5-year OS probability of 77.9% and African Americans had the longest 10-year OS probability of 40.6%. However, Asians as a group demonstrated the longest median (SD) OS outcome with 119.8 (47.8) months (Figure 2).

Overall, academic/research programs had the longest median OS and 5-year OS probability (SD) of 66.6 (4.5) months and 52.6%, respectively (Figure 3). Comprehensive community cancer programs and integrated network cancer programs had nearly identical 10-year OS rates (35.2% vs 35.1%, respectively). Community cancer programs had the worst 5- and 10-year OS probabilities (41.1% and 21.8%, respectively).

The top 2 income quartiles combined to demonstrate the longest median, 5-year, and 10-year OS probabilities and were very similar. Patients living in a zip code with the highest income level had the longest 5-year OS rates of 54.3%, while patients living in zip codes with a moderate income level had the longest 10-year OS at 39.3% and the longest median OS of about 71 months. Patients with the lowest level of median household income had the worst 5-year OS rates (48.3%) and a median (SD) OS of 53.4 (5.4) months (Figure 4).

A Kaplan-Meier curve for percentage of adults without a HS degree is displayed in Figure 5. Zip codes with the highest level of education had the longest 5-year OS rates and median (SD) OS of 55.3% and 70.9 (4.8) months, respectively. The longest 10-year OS outcomes at 38.1% were found in patients who lived in areas of low-education levels. The worst 5- and 10- year OS outcomes and median OS were found in the least educated zip codes.

Results from the Cox regression model of OS are displayed in Table 4. Race and ethnicity, zip code-level median household income, and zip code-level education were not associated with OS. Patients with no insurance had an increased risk of death (hazard ratio [HR], 1.84; 95% CI, 1.17-2.88; P < .01) when compared with patients with private insurance. Patients with other government insurance also had an increased risk of death (HR, 2.12; 95% CI, 1.27-3.54; P < .01) when compared with patients with private insurance while controlling for all other variables. Patients with Medicare had a decreased risk of death when compared with patients with other government insurance and no insurance (HR, 0.53; 95% CI, 0.31-0.92; P = .02 and HR, 0.62; 95% CI, 0.38-0.99; P = .05, respectively). Patients treated at academic centers had better OS when compared with patients treated at comprehensive treatment centers (HR, 0.77; 95% CI, 0.65-0.92;P < .01) and community treatment centers (HR, 0.62; 95% CI, 0.44-0.86; P < .01).

Discussion

This study is the largest study to date that specifically studies the type of treatment facilities and socioeconomic factors, including insurance status, race, income, and education, and how they affect survival of DDLPS. The overall 5- and 10-year OS probabilities for DDLPS in this study were 51.5% and 34.8%, respectively, with median OS of 63.6 months. These results were more encouraging than previous reports, which found a 5-year survival probability of 36.5% and a median OS of 45 months.^13,14

The largest age grouping was aged 61 to 80 years (48.9% of the cohort), and the median age at diagnosis was 64 years. DDLPSs most typically present between the ages of 50 and 70 years.¹⁵ Our cohort was 65% male. Previous studies have indicated that DDLPSs affect the sexes equally; however, another study showed a similar male predominance (68.8%) at the MD Anderson Cancer Center in Houston, Texas.^13,16

In our study, approximately 88% of patients were white, 6.5% were African American, and 2.5% were Asian, which differed from a previous study of 84 patients that had a 78.6% white, 4.8% Asian, and 1.2% African American patient population.¹⁴

Asian Indian or Pakistani patients had the best 5-year OS probability at 77.9%, followed by African American (57.2%), Asian (51.6%), AI/AN (51.4%), and white patients (50.9%). This trend had disappeared by 10 years and Asian, AI/AN, African American, and Asian Indian or Pakistani groups all demonstrated longer median OS than did white patients. In fact, Asian patients had the longest median OS at 119.8 months, which was almost double that of white patients with the lowest median OS of 61.2 months. This finding is contrary to previous studies, which reported that racial minorities typically had worse OS outcomes when compared with white patients in different types of cancer.^7,17 Notably, these findings were not statistically significant in our current study in the log-rank or multivariable analyses.

Private insurance was the most common form of insurance followed in decreasing order by Medicare, Medicaid, uninsured, and other government insurance. About 42% of the cohort had Medicare, which is a federally funded US insurance program designated for patients aged ≥ 65 years and certain younger patients with disabilities.

Patients with private insurance demonstrated the longest OS, essentially twice the median OS of all other insured groups at 101 months. Medicare had the worst 5-year OS probability and median OS of all groups. A previous study of 77 patients with DDLPS reported that patients aged > 65 years had reduced OS.13 Medicare patients in this study were older, with a mean and median age at DDLPS diagnosis of 71 and 72 years, respectively, while private insurance had a mean and median age at diagnosis of 56 and 57 years, respectively. Medicare inherently covers older patients and this age difference could account for the decrease in overall survival.

Improved OS for privately insured patients was most notable compared with the uninsured or patients with other government insurance. Uninsured patients had an 83.7% increased risk of mortality when compared with patients with private insurance. When compared with patients with private insurance, patients with other government insurance had an 111.5% increased risk of mortality. Comparing patients with Medicare vs patients with no insurance or other government insurance, there was a decreased risk of mortality of 38.5% and 46.6%, respectively. This decreased OS in patients with other government insurance could be related to the choice of treatment facility, because only 31% of the patients with other government insurance went to academic or research centers when compared with the 58.4% and 50.8% of patients with private and Medicare insurance treated there (data not shown). Such centers often have access to more advanced technology and protocols that may not be available at other treatment facilities.

A little more than half of the patients in the cohort went to an academic or research center for treatment (53.7%); comprehensive community cancer programs were the second most common treatment facility at 28%. Patients treated at academic or research centers demonstrated the best outcomes with a 5-year OS of 52.6%, followed in decreasing order by comprehensive community cancer programs (49.7%), integrated network cancer programs (48.8%), and community cancer programs (41.1%). In our patient cocohort, patients treated at an academic/research center had slightly decreased 10-year OS rates compared with those patients treated at a comprehensive community cancer program, although the median OS for the academic/research centers were still the highest of all treatment facilities.

Treatment options varied significantly by facility, and the number of patients treated surgically followed a similar trend, with 92% undergoing surgery as the primary treatment at academic or research programs compared with 89% at comprehensive cancer programs and 82.7% at community cancer programs (data not shown). Another potential explaination for differing OS outcomes across facilities is the surgical margin outcome. Surgeries performed at community cancer programs or comprehensive cancer programs resulted with no residual tumor in 36% and 40% of cases, respectively, whereas cases performed at academic or research programs resulted with no residual tumor in 47% of cases (data not shown). Regardless, multivariate analysis demonstrated a marked decrease in the chance of mortality when comparing treatment received at academic facility centers with that received at comprehensive cancer centers (22.9%) and community cancer centers (38.3%) (data not shown).

A recent study demonstrated improved outcomes for patients with retroperitoneal or extremity STS treated at high-volume treatment centers.¹⁸ Patients treated at high-volume centers were found to have an 8% decreased risk of death compared with patients treated at low-volume centers. Notably, they found highvolume academic centers demonstrated the strongest improvement in survival, while highvolume community centers showed decreased survival.¹⁸ Similarly, we found that patients treated at academic/research institutions had improved 5-year OS and greater median OS than did patients treated at community cancer programs or comprehensive community cancer programs.

The top 2 income quartiles (≥ $48,000) combined to demonstrate the longest median, 5-year, and 10-year OS and were fairly similar between the quartiles. Patients living in zip codes with a median income of $38,000 to $47,999 had the worst 5-year OS and median OS. The log-rank analysis showed statistical evidence of differences in survival associated with income, but within the context of the multivariable analysis, there was no remaining evidence of a difference.

The longest 5-year OS outcomes were seen in patients living in zip codes with the highest level of education (55.3%). However, the difference in OS was not statistically significant using either the log-rank analysis or multivariate analysis.

Limitations

This study has certain inherent limitations in using a retrospective design and a large database such as the NCDB. Many different pathologists at CoC-accredited cancer programs perform the pathology that contributes to the data in the NCDB. There was no pathological review of these findings, which could potentially introduce error into the findings of this study. With the NCDB, potential selection bias is possible because patients in the database are added only from CoC-accredited cancer programs. This risk is minimized because NCDB contains data on most newly diagnosed cancer patients in the US. Further potential risks, which are unable to be controlled for, include potential interobserver error and data that may be incompletely, improperly, or inaccurately recorded from the patients’ charts. Without patient-specific information regarding income and education, it is challenging to utilize zip codes to estimate socioeconomic status and educational level. Even though a patient may live in a zip code identified with specific economic and educational characteristics, that patient may not share those characteristics. Furthermore, patients with Medicare tend to be older than patients with other forms of insurance, which limits the significance of comparisons across insurance groups. A future SEER (Surveillance, Epidemiology, and End Results) program study to confirm this study’s results and the effects of socioeconomic variables on DDLPS would be an excellent followup study.

Conclusion

This study used a large cohort of patients with DDLPS to study the effects of treatment facility, insurance status, and socioeconomic variables on survival outcomes. Although insurance status, median household income, and treatment facility were associated with differences in median OS and 5- and 10-year OS probabilities, evidence for a difference remained for only insurance status and facility type within the context of a multivariable analysis irrespective of age, race, sex, insurance status, education, and median income. Patients with private insurance and Medicaid had a decreased risk of mortality compared with other government insurance and no insurance. Patients receiving treatment at academic research programs had the highest median and 5-year OS of 66.6 months and 52.6%, respectively. Patients receiving treatment at academic centers had improved survival outcomes with a decrease in mortality of 23% and 38% compared to comprehensive or community cancer programs.

Approximately 17% to 25% of all softtissue sarcomas (STS) are liposarcomas, making liposarcoma the most common type of STS.¹ The 2013 World Health Organization (WHO) classification separates liposarcoma into 4 histologic subtypes: atypical lipomatous tumor/well-differentiated (ALT/ WDLPS), dedifferentiated (DDLPS), myxoid, and pleomorphic.² Each subtype has unique histology, morphology, and natural history. WDLPS and DDLPS are the most common histologic subtypes, comprising approximately 50% of all sarcomas that arise in the retroperitoneum.³ DDLPS represents 18% of all liposarcomas, making it the second most common subtype of liposarcoma.⁴

In 1979, DDLPS was first characterized.⁵ Most (90%) cases of DDLPS present de novo, whereas the other 10% transform from preexisting low-grade WDLPS.² DDLPSs are formed by an amplification of 12q14-15 involving the MDM2 gene.⁴ These malignancies most commonly present in the retroperitoneum as a large painless mass, consisting of both fatty and nonfatty components.² Primary site has been previously reported as a major prognostic factor for DDLPSs, with retroperitoneal DDLPSs demonstrating the worst prognosis.6 DDLPSs have a high risk of local recurrence, with some reports estimating recurrence rates approaching 40%.² Overall mortality at 5 years for DDLPS is estimated to be between 30% and 40%.⁴

Previous literature has determined that median income, race, health insurance, and facility type are related to survival outcomes for patients with DDLPS.7-9 When comparing the most common types of cancers, residents of poorer US counties consistently had a higher risk of mortality than residents in affluent US counties, and all racial minorities showed worse survival outcomes when compared with white patients.⁷ Differences in survival outcomes have been reported in patients attending different treatment facilities for other cancers including pancreatic cancers, glioblastomas, and oral cancers, with multiple studies concluding that academic and research programs are associated with the longest survival outcomes.^10-12 For many cancers, insurance status has been shown to be a significant prognostic factor, with private insurance typically resulting in the best prognosis.^8,9

The goal of this retrospective study was to assess the prognostic effects of socioeconomic variables on the overall survival (OS) probabilities in a large cohort of DDLPS patients in order to inform clinicians about a potentially at-risk population.

Method

The National Cancer Database (NCDB) was created by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The NCDB is the largest cancer database in the US and includes data on almost 70% of US patients with cancer. CoC-accredited cancer programs add data on patients with cancer to the NCDB. The authors accessed the NCDB data through the use of the NCDB Participant Use File program.

Patients’ data from 2004 through 2015 were abstracted. Only patients with the International Classification of Diseases for Oncology histology code 8858, corresponding to DDLPS, were analyzed. Patients with other comorbid malignant tumors were excluded to accurately capture the true survival rates for DDLPS. Variables analyzed included age, sex, race, insurance status, treatment facility type, median household income by zip code, and percentage of adults in the patient’s zip code with no high school (HS) education.

Median survival, 5- and 10-year OS probabilities, and Kaplan-Meier survival curves were calculated for multiple variables, specifically race, insurance status, treatment facility type, median family income, and percentage of adults without a HS degree. Both 5- and 10-year OS probabilities were determined by race with the patients separated into white, African American, Asian, American Indian/Alaska Native (AI/AN), and Asian Indian or Pakistani groups. Our study categorized Chinese, Japanese, Filipino, Hmong, Korean, Vietnamese, Thai, Guamanian, Asian not otherwise specified, and other Asian ethnicity patients together into one collective Asian group. Insurance status was classified into Medicare, Medicaid, other government insurance, and private insurance groups. Other government insurance consisted of US Department of Veterans Affairs, Indian Health Service, Public Health Service, and other government health care programs. Further analysis could not be performed into the distribution of the other government insurance variable.

Facility types were divided into 4 groups: community, comprehensive community, academic/ research, and integrated network cancer treatment facilities. Median income quartiles and the percentage of adults with no high school degree were estimated by comparison of the patient’s zip code with US Census Bureau data. Median household income was separated into 4 groups, including lowest level of household income (< $38,000), low level of household income ($38,000 to $47,999), moderate level of household income ($48,000 to $62,999), and highest level of household income (≥ $63,000). The percentages of adults with no high school degree were divided into 4 groups: lowest level of HS education (≥ 21% ), low level of HS education (13.0% to 20.9%), moderate level of HS education (7.0% to 12.9%), and highest level of HS education (≤ 7%). The 5- and 10-year survival probabilities were calculated using the number of months between the date of diagnosis and the date of death or last known contact.

Continuous variables are presented as median and interquartile range (IQR) whereas categorical variables are presented as frequencies and proportion. IBM SPSS version 25.0 was used to produce Kaplan-Meier survival curves and descriptive statistics. This study used Kaplan- Meier survival tables and log-rank tests to analyze both the 5- and 10-year OS rates for the 5 variables listed above. This study also used a multivariable Cox regression model that accommodated the correlative nature of outcomes within facilities to study the association of the treatment facility type and other socioeconomic factors, while controlling for age, race (which was collapsed into 3 categories), sex, primary site, tumor stage, and treatment approaches. The proportional hazards assumption was individually checked for all pertinent variables. Any patient records that were missing data were excluded from the multivariable Cox regression model, which was analyzed with SAS version 9.4 (Cary, NC). P < 0.05 was used to indicate statistical significance for all analyses.

Results

Table 1 provides descriptive analysis for demographic characteristics of the 3573 patients including age, sex, and race. The median age at diagnosis was 64 years. There were 1073 more men (65%) than women (35%) in this analysis. Whites were the predominant racial category, comprising 87.7% of the patient population, followed by African Americans (6.5%) and Asians (2.5%).

Socioeconomic Variables

The largest proportion of the patient population (45.5%) had private insurance (Table 2). Medicare came in a close second covering almost 42.2% of the population, followed by Medicaid (5.0%), uninsured (2.8%), and other government insurance (1.5%). About half (53.7%) of the patients were treated at academic or research facilities, while the fewest number of patients (5.2%) underwent treatment at community cancer facilities. The largest percentage (36.6%) of patients lived in zip codes with the highest level of median household income, while 26.0% and 22.3% had moderate and low levels of income, respectively. About 14% of patients lived within an area of the lowest level of income. Similarly, almost 15% of patients lived in an area of lowest level of HS education. The greatest percentage of the patient population (34.5%) lived in a zip code with moderate level of HS education. Surgery was the most common treatment modality with 90.8% of the cohort undergoing surgery, while 35.4% and 16.5% were treated with radiation and chemotherapy, respectively (some patients received more than one type of treatment modality).

Survival Data

Survival data were available for 3112 patients. Kaplan-Meier survival curves were used to analyze OS according to insurance status, racial background, treatment facility type, median family income, and percentage of adults with no high school education. Overall 5- and 10- year OS probabilities were 51.5% and 34.8%, respectively, while the median OS (SD) was 63.57 (2.8) months (Table 3).

Private insurance showed significantly higher 5- and 10-year OS probabilities and median OS: 5-year OS was 61.2%, 10-year OS was 47.2%, and median survival (SD) was 101.2 (8.2) months compared with that of all other insurance groups (Medicare, Medicaid, other government insurance, and uninsured) (Figure 1). These other insurance types were fairly similar in their 5-year and median OS, but surprisingly, patients with no insurance had the second longest 10-year OS. The difference between the 5-year OS probabilities of private insurance compared with an average of the other insurances was 15.1%, which had almost doubled to 28.5% at 10 years, with a median OS difference of almost 5 years (56 months; data not shown).

Using the Kaplan-Meier survival curve, Asian Indians had the longest 5-year OS probability of 77.9% and African Americans had the longest 10-year OS probability of 40.6%. However, Asians as a group demonstrated the longest median (SD) OS outcome with 119.8 (47.8) months (Figure 2).

Overall, academic/research programs had the longest median OS and 5-year OS probability (SD) of 66.6 (4.5) months and 52.6%, respectively (Figure 3). Comprehensive community cancer programs and integrated network cancer programs had nearly identical 10-year OS rates (35.2% vs 35.1%, respectively). Community cancer programs had the worst 5- and 10-year OS probabilities (41.1% and 21.8%, respectively).

The top 2 income quartiles combined to demonstrate the longest median, 5-year, and 10-year OS probabilities and were very similar. Patients living in a zip code with the highest income level had the longest 5-year OS rates of 54.3%, while patients living in zip codes with a moderate income level had the longest 10-year OS at 39.3% and the longest median OS of about 71 months. Patients with the lowest level of median household income had the worst 5-year OS rates (48.3%) and a median (SD) OS of 53.4 (5.4) months (Figure 4).

A Kaplan-Meier curve for percentage of adults without a HS degree is displayed in Figure 5. Zip codes with the highest level of education had the longest 5-year OS rates and median (SD) OS of 55.3% and 70.9 (4.8) months, respectively. The longest 10-year OS outcomes at 38.1% were found in patients who lived in areas of low-education levels. The worst 5- and 10- year OS outcomes and median OS were found in the least educated zip codes.

Results from the Cox regression model of OS are displayed in Table 4. Race and ethnicity, zip code-level median household income, and zip code-level education were not associated with OS. Patients with no insurance had an increased risk of death (hazard ratio [HR], 1.84; 95% CI, 1.17-2.88; P < .01) when compared with patients with private insurance. Patients with other government insurance also had an increased risk of death (HR, 2.12; 95% CI, 1.27-3.54; P < .01) when compared with patients with private insurance while controlling for all other variables. Patients with Medicare had a decreased risk of death when compared with patients with other government insurance and no insurance (HR, 0.53; 95% CI, 0.31-0.92; P = .02 and HR, 0.62; 95% CI, 0.38-0.99; P = .05, respectively). Patients treated at academic centers had better OS when compared with patients treated at comprehensive treatment centers (HR, 0.77; 95% CI, 0.65-0.92;P < .01) and community treatment centers (HR, 0.62; 95% CI, 0.44-0.86; P < .01).

Discussion

This study is the largest study to date that specifically studies the type of treatment facilities and socioeconomic factors, including insurance status, race, income, and education, and how they affect survival of DDLPS. The overall 5- and 10-year OS probabilities for DDLPS in this study were 51.5% and 34.8%, respectively, with median OS of 63.6 months. These results were more encouraging than previous reports, which found a 5-year survival probability of 36.5% and a median OS of 45 months.^13,14

The largest age grouping was aged 61 to 80 years (48.9% of the cohort), and the median age at diagnosis was 64 years. DDLPSs most typically present between the ages of 50 and 70 years.¹⁵ Our cohort was 65% male. Previous studies have indicated that DDLPSs affect the sexes equally; however, another study showed a similar male predominance (68.8%) at the MD Anderson Cancer Center in Houston, Texas.^13,16

In our study, approximately 88% of patients were white, 6.5% were African American, and 2.5% were Asian, which differed from a previous study of 84 patients that had a 78.6% white, 4.8% Asian, and 1.2% African American patient population.¹⁴

Asian Indian or Pakistani patients had the best 5-year OS probability at 77.9%, followed by African American (57.2%), Asian (51.6%), AI/AN (51.4%), and white patients (50.9%). This trend had disappeared by 10 years and Asian, AI/AN, African American, and Asian Indian or Pakistani groups all demonstrated longer median OS than did white patients. In fact, Asian patients had the longest median OS at 119.8 months, which was almost double that of white patients with the lowest median OS of 61.2 months. This finding is contrary to previous studies, which reported that racial minorities typically had worse OS outcomes when compared with white patients in different types of cancer.^7,17 Notably, these findings were not statistically significant in our current study in the log-rank or multivariable analyses.

Private insurance was the most common form of insurance followed in decreasing order by Medicare, Medicaid, uninsured, and other government insurance. About 42% of the cohort had Medicare, which is a federally funded US insurance program designated for patients aged ≥ 65 years and certain younger patients with disabilities.

Patients with private insurance demonstrated the longest OS, essentially twice the median OS of all other insured groups at 101 months. Medicare had the worst 5-year OS probability and median OS of all groups. A previous study of 77 patients with DDLPS reported that patients aged > 65 years had reduced OS.13 Medicare patients in this study were older, with a mean and median age at DDLPS diagnosis of 71 and 72 years, respectively, while private insurance had a mean and median age at diagnosis of 56 and 57 years, respectively. Medicare inherently covers older patients and this age difference could account for the decrease in overall survival.

Improved OS for privately insured patients was most notable compared with the uninsured or patients with other government insurance. Uninsured patients had an 83.7% increased risk of mortality when compared with patients with private insurance. When compared with patients with private insurance, patients with other government insurance had an 111.5% increased risk of mortality. Comparing patients with Medicare vs patients with no insurance or other government insurance, there was a decreased risk of mortality of 38.5% and 46.6%, respectively. This decreased OS in patients with other government insurance could be related to the choice of treatment facility, because only 31% of the patients with other government insurance went to academic or research centers when compared with the 58.4% and 50.8% of patients with private and Medicare insurance treated there (data not shown). Such centers often have access to more advanced technology and protocols that may not be available at other treatment facilities.

A little more than half of the patients in the cohort went to an academic or research center for treatment (53.7%); comprehensive community cancer programs were the second most common treatment facility at 28%. Patients treated at academic or research centers demonstrated the best outcomes with a 5-year OS of 52.6%, followed in decreasing order by comprehensive community cancer programs (49.7%), integrated network cancer programs (48.8%), and community cancer programs (41.1%). In our patient cocohort, patients treated at an academic/research center had slightly decreased 10-year OS rates compared with those patients treated at a comprehensive community cancer program, although the median OS for the academic/research centers were still the highest of all treatment facilities.

Treatment options varied significantly by facility, and the number of patients treated surgically followed a similar trend, with 92% undergoing surgery as the primary treatment at academic or research programs compared with 89% at comprehensive cancer programs and 82.7% at community cancer programs (data not shown). Another potential explaination for differing OS outcomes across facilities is the surgical margin outcome. Surgeries performed at community cancer programs or comprehensive cancer programs resulted with no residual tumor in 36% and 40% of cases, respectively, whereas cases performed at academic or research programs resulted with no residual tumor in 47% of cases (data not shown). Regardless, multivariate analysis demonstrated a marked decrease in the chance of mortality when comparing treatment received at academic facility centers with that received at comprehensive cancer centers (22.9%) and community cancer centers (38.3%) (data not shown).

A recent study demonstrated improved outcomes for patients with retroperitoneal or extremity STS treated at high-volume treatment centers.¹⁸ Patients treated at high-volume centers were found to have an 8% decreased risk of death compared with patients treated at low-volume centers. Notably, they found highvolume academic centers demonstrated the strongest improvement in survival, while highvolume community centers showed decreased survival.¹⁸ Similarly, we found that patients treated at academic/research institutions had improved 5-year OS and greater median OS than did patients treated at community cancer programs or comprehensive community cancer programs.

The top 2 income quartiles (≥ $48,000) combined to demonstrate the longest median, 5-year, and 10-year OS and were fairly similar between the quartiles. Patients living in zip codes with a median income of $38,000 to $47,999 had the worst 5-year OS and median OS. The log-rank analysis showed statistical evidence of differences in survival associated with income, but within the context of the multivariable analysis, there was no remaining evidence of a difference.

The longest 5-year OS outcomes were seen in patients living in zip codes with the highest level of education (55.3%). However, the difference in OS was not statistically significant using either the log-rank analysis or multivariate analysis.

Limitations

This study has certain inherent limitations in using a retrospective design and a large database such as the NCDB. Many different pathologists at CoC-accredited cancer programs perform the pathology that contributes to the data in the NCDB. There was no pathological review of these findings, which could potentially introduce error into the findings of this study. With the NCDB, potential selection bias is possible because patients in the database are added only from CoC-accredited cancer programs. This risk is minimized because NCDB contains data on most newly diagnosed cancer patients in the US. Further potential risks, which are unable to be controlled for, include potential interobserver error and data that may be incompletely, improperly, or inaccurately recorded from the patients’ charts. Without patient-specific information regarding income and education, it is challenging to utilize zip codes to estimate socioeconomic status and educational level. Even though a patient may live in a zip code identified with specific economic and educational characteristics, that patient may not share those characteristics. Furthermore, patients with Medicare tend to be older than patients with other forms of insurance, which limits the significance of comparisons across insurance groups. A future SEER (Surveillance, Epidemiology, and End Results) program study to confirm this study’s results and the effects of socioeconomic variables on DDLPS would be an excellent followup study.

Conclusion

This study used a large cohort of patients with DDLPS to study the effects of treatment facility, insurance status, and socioeconomic variables on survival outcomes. Although insurance status, median household income, and treatment facility were associated with differences in median OS and 5- and 10-year OS probabilities, evidence for a difference remained for only insurance status and facility type within the context of a multivariable analysis irrespective of age, race, sex, insurance status, education, and median income. Patients with private insurance and Medicaid had a decreased risk of mortality compared with other government insurance and no insurance. Patients receiving treatment at academic research programs had the highest median and 5-year OS of 66.6 months and 52.6%, respectively. Patients receiving treatment at academic centers had improved survival outcomes with a decrease in mortality of 23% and 38% compared to comprehensive or community cancer programs.

Approximately 17% to 25% of all softtissue sarcomas (STS) are liposarcomas, making liposarcoma the most common type of STS.¹ The 2013 World Health Organization (WHO) classification separates liposarcoma into 4 histologic subtypes: atypical lipomatous tumor/well-differentiated (ALT/ WDLPS), dedifferentiated (DDLPS), myxoid, and pleomorphic.² Each subtype has unique histology, morphology, and natural history. WDLPS and DDLPS are the most common histologic subtypes, comprising approximately 50% of all sarcomas that arise in the retroperitoneum.³ DDLPS represents 18% of all liposarcomas, making it the second most common subtype of liposarcoma.⁴

In 1979, DDLPS was first characterized.⁵ Most (90%) cases of DDLPS present de novo, whereas the other 10% transform from preexisting low-grade WDLPS.² DDLPSs are formed by an amplification of 12q14-15 involving the MDM2 gene.⁴ These malignancies most commonly present in the retroperitoneum as a large painless mass, consisting of both fatty and nonfatty components.² Primary site has been previously reported as a major prognostic factor for DDLPSs, with retroperitoneal DDLPSs demonstrating the worst prognosis.6 DDLPSs have a high risk of local recurrence, with some reports estimating recurrence rates approaching 40%.² Overall mortality at 5 years for DDLPS is estimated to be between 30% and 40%.⁴

Previous literature has determined that median income, race, health insurance, and facility type are related to survival outcomes for patients with DDLPS.7-9 When comparing the most common types of cancers, residents of poorer US counties consistently had a higher risk of mortality than residents in affluent US counties, and all racial minorities showed worse survival outcomes when compared with white patients.⁷ Differences in survival outcomes have been reported in patients attending different treatment facilities for other cancers including pancreatic cancers, glioblastomas, and oral cancers, with multiple studies concluding that academic and research programs are associated with the longest survival outcomes.^10-12 For many cancers, insurance status has been shown to be a significant prognostic factor, with private insurance typically resulting in the best prognosis.^8,9

The goal of this retrospective study was to assess the prognostic effects of socioeconomic variables on the overall survival (OS) probabilities in a large cohort of DDLPS patients in order to inform clinicians about a potentially at-risk population.

Method

The National Cancer Database (NCDB) was created by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The NCDB is the largest cancer database in the US and includes data on almost 70% of US patients with cancer. CoC-accredited cancer programs add data on patients with cancer to the NCDB. The authors accessed the NCDB data through the use of the NCDB Participant Use File program.

Patients’ data from 2004 through 2015 were abstracted. Only patients with the International Classification of Diseases for Oncology histology code 8858, corresponding to DDLPS, were analyzed. Patients with other comorbid malignant tumors were excluded to accurately capture the true survival rates for DDLPS. Variables analyzed included age, sex, race, insurance status, treatment facility type, median household income by zip code, and percentage of adults in the patient’s zip code with no high school (HS) education.

Median survival, 5- and 10-year OS probabilities, and Kaplan-Meier survival curves were calculated for multiple variables, specifically race, insurance status, treatment facility type, median family income, and percentage of adults without a HS degree. Both 5- and 10-year OS probabilities were determined by race with the patients separated into white, African American, Asian, American Indian/Alaska Native (AI/AN), and Asian Indian or Pakistani groups. Our study categorized Chinese, Japanese, Filipino, Hmong, Korean, Vietnamese, Thai, Guamanian, Asian not otherwise specified, and other Asian ethnicity patients together into one collective Asian group. Insurance status was classified into Medicare, Medicaid, other government insurance, and private insurance groups. Other government insurance consisted of US Department of Veterans Affairs, Indian Health Service, Public Health Service, and other government health care programs. Further analysis could not be performed into the distribution of the other government insurance variable.

Facility types were divided into 4 groups: community, comprehensive community, academic/ research, and integrated network cancer treatment facilities. Median income quartiles and the percentage of adults with no high school degree were estimated by comparison of the patient’s zip code with US Census Bureau data. Median household income was separated into 4 groups, including lowest level of household income (< $38,000), low level of household income ($38,000 to $47,999), moderate level of household income ($48,000 to $62,999), and highest level of household income (≥ $63,000). The percentages of adults with no high school degree were divided into 4 groups: lowest level of HS education (≥ 21% ), low level of HS education (13.0% to 20.9%), moderate level of HS education (7.0% to 12.9%), and highest level of HS education (≤ 7%). The 5- and 10-year survival probabilities were calculated using the number of months between the date of diagnosis and the date of death or last known contact.

Continuous variables are presented as median and interquartile range (IQR) whereas categorical variables are presented as frequencies and proportion. IBM SPSS version 25.0 was used to produce Kaplan-Meier survival curves and descriptive statistics. This study used Kaplan- Meier survival tables and log-rank tests to analyze both the 5- and 10-year OS rates for the 5 variables listed above. This study also used a multivariable Cox regression model that accommodated the correlative nature of outcomes within facilities to study the association of the treatment facility type and other socioeconomic factors, while controlling for age, race (which was collapsed into 3 categories), sex, primary site, tumor stage, and treatment approaches. The proportional hazards assumption was individually checked for all pertinent variables. Any patient records that were missing data were excluded from the multivariable Cox regression model, which was analyzed with SAS version 9.4 (Cary, NC). P < 0.05 was used to indicate statistical significance for all analyses.

Results

Table 1 provides descriptive analysis for demographic characteristics of the 3573 patients including age, sex, and race. The median age at diagnosis was 64 years. There were 1073 more men (65%) than women (35%) in this analysis. Whites were the predominant racial category, comprising 87.7% of the patient population, followed by African Americans (6.5%) and Asians (2.5%).

Socioeconomic Variables

The largest proportion of the patient population (45.5%) had private insurance (Table 2). Medicare came in a close second covering almost 42.2% of the population, followed by Medicaid (5.0%), uninsured (2.8%), and other government insurance (1.5%). About half (53.7%) of the patients were treated at academic or research facilities, while the fewest number of patients (5.2%) underwent treatment at community cancer facilities. The largest percentage (36.6%) of patients lived in zip codes with the highest level of median household income, while 26.0% and 22.3% had moderate and low levels of income, respectively. About 14% of patients lived within an area of the lowest level of income. Similarly, almost 15% of patients lived in an area of lowest level of HS education. The greatest percentage of the patient population (34.5%) lived in a zip code with moderate level of HS education. Surgery was the most common treatment modality with 90.8% of the cohort undergoing surgery, while 35.4% and 16.5% were treated with radiation and chemotherapy, respectively (some patients received more than one type of treatment modality).

Survival Data

Survival data were available for 3112 patients. Kaplan-Meier survival curves were used to analyze OS according to insurance status, racial background, treatment facility type, median family income, and percentage of adults with no high school education. Overall 5- and 10- year OS probabilities were 51.5% and 34.8%, respectively, while the median OS (SD) was 63.57 (2.8) months (Table 3).

Private insurance showed significantly higher 5- and 10-year OS probabilities and median OS: 5-year OS was 61.2%, 10-year OS was 47.2%, and median survival (SD) was 101.2 (8.2) months compared with that of all other insurance groups (Medicare, Medicaid, other government insurance, and uninsured) (Figure 1). These other insurance types were fairly similar in their 5-year and median OS, but surprisingly, patients with no insurance had the second longest 10-year OS. The difference between the 5-year OS probabilities of private insurance compared with an average of the other insurances was 15.1%, which had almost doubled to 28.5% at 10 years, with a median OS difference of almost 5 years (56 months; data not shown).

Using the Kaplan-Meier survival curve, Asian Indians had the longest 5-year OS probability of 77.9% and African Americans had the longest 10-year OS probability of 40.6%. However, Asians as a group demonstrated the longest median (SD) OS outcome with 119.8 (47.8) months (Figure 2).

Overall, academic/research programs had the longest median OS and 5-year OS probability (SD) of 66.6 (4.5) months and 52.6%, respectively (Figure 3). Comprehensive community cancer programs and integrated network cancer programs had nearly identical 10-year OS rates (35.2% vs 35.1%, respectively). Community cancer programs had the worst 5- and 10-year OS probabilities (41.1% and 21.8%, respectively).

The top 2 income quartiles combined to demonstrate the longest median, 5-year, and 10-year OS probabilities and were very similar. Patients living in a zip code with the highest income level had the longest 5-year OS rates of 54.3%, while patients living in zip codes with a moderate income level had the longest 10-year OS at 39.3% and the longest median OS of about 71 months. Patients with the lowest level of median household income had the worst 5-year OS rates (48.3%) and a median (SD) OS of 53.4 (5.4) months (Figure 4).

A Kaplan-Meier curve for percentage of adults without a HS degree is displayed in Figure 5. Zip codes with the highest level of education had the longest 5-year OS rates and median (SD) OS of 55.3% and 70.9 (4.8) months, respectively. The longest 10-year OS outcomes at 38.1% were found in patients who lived in areas of low-education levels. The worst 5- and 10- year OS outcomes and median OS were found in the least educated zip codes.

Results from the Cox regression model of OS are displayed in Table 4. Race and ethnicity, zip code-level median household income, and zip code-level education were not associated with OS. Patients with no insurance had an increased risk of death (hazard ratio [HR], 1.84; 95% CI, 1.17-2.88; P < .01) when compared with patients with private insurance. Patients with other government insurance also had an increased risk of death (HR, 2.12; 95% CI, 1.27-3.54; P < .01) when compared with patients with private insurance while controlling for all other variables. Patients with Medicare had a decreased risk of death when compared with patients with other government insurance and no insurance (HR, 0.53; 95% CI, 0.31-0.92; P = .02 and HR, 0.62; 95% CI, 0.38-0.99; P = .05, respectively). Patients treated at academic centers had better OS when compared with patients treated at comprehensive treatment centers (HR, 0.77; 95% CI, 0.65-0.92;P < .01) and community treatment centers (HR, 0.62; 95% CI, 0.44-0.86; P < .01).

Discussion

This study is the largest study to date that specifically studies the type of treatment facilities and socioeconomic factors, including insurance status, race, income, and education, and how they affect survival of DDLPS. The overall 5- and 10-year OS probabilities for DDLPS in this study were 51.5% and 34.8%, respectively, with median OS of 63.6 months. These results were more encouraging than previous reports, which found a 5-year survival probability of 36.5% and a median OS of 45 months.^13,14

The largest age grouping was aged 61 to 80 years (48.9% of the cohort), and the median age at diagnosis was 64 years. DDLPSs most typically present between the ages of 50 and 70 years.¹⁵ Our cohort was 65% male. Previous studies have indicated that DDLPSs affect the sexes equally; however, another study showed a similar male predominance (68.8%) at the MD Anderson Cancer Center in Houston, Texas.^13,16

In our study, approximately 88% of patients were white, 6.5% were African American, and 2.5% were Asian, which differed from a previous study of 84 patients that had a 78.6% white, 4.8% Asian, and 1.2% African American patient population.¹⁴

Asian Indian or Pakistani patients had the best 5-year OS probability at 77.9%, followed by African American (57.2%), Asian (51.6%), AI/AN (51.4%), and white patients (50.9%). This trend had disappeared by 10 years and Asian, AI/AN, African American, and Asian Indian or Pakistani groups all demonstrated longer median OS than did white patients. In fact, Asian patients had the longest median OS at 119.8 months, which was almost double that of white patients with the lowest median OS of 61.2 months. This finding is contrary to previous studies, which reported that racial minorities typically had worse OS outcomes when compared with white patients in different types of cancer.^7,17 Notably, these findings were not statistically significant in our current study in the log-rank or multivariable analyses.

Private insurance was the most common form of insurance followed in decreasing order by Medicare, Medicaid, uninsured, and other government insurance. About 42% of the cohort had Medicare, which is a federally funded US insurance program designated for patients aged ≥ 65 years and certain younger patients with disabilities.

Patients with private insurance demonstrated the longest OS, essentially twice the median OS of all other insured groups at 101 months. Medicare had the worst 5-year OS probability and median OS of all groups. A previous study of 77 patients with DDLPS reported that patients aged > 65 years had reduced OS.13 Medicare patients in this study were older, with a mean and median age at DDLPS diagnosis of 71 and 72 years, respectively, while private insurance had a mean and median age at diagnosis of 56 and 57 years, respectively. Medicare inherently covers older patients and this age difference could account for the decrease in overall survival.

Improved OS for privately insured patients was most notable compared with the uninsured or patients with other government insurance. Uninsured patients had an 83.7% increased risk of mortality when compared with patients with private insurance. When compared with patients with private insurance, patients with other government insurance had an 111.5% increased risk of mortality. Comparing patients with Medicare vs patients with no insurance or other government insurance, there was a decreased risk of mortality of 38.5% and 46.6%, respectively. This decreased OS in patients with other government insurance could be related to the choice of treatment facility, because only 31% of the patients with other government insurance went to academic or research centers when compared with the 58.4% and 50.8% of patients with private and Medicare insurance treated there (data not shown). Such centers often have access to more advanced technology and protocols that may not be available at other treatment facilities.

A little more than half of the patients in the cohort went to an academic or research center for treatment (53.7%); comprehensive community cancer programs were the second most common treatment facility at 28%. Patients treated at academic or research centers demonstrated the best outcomes with a 5-year OS of 52.6%, followed in decreasing order by comprehensive community cancer programs (49.7%), integrated network cancer programs (48.8%), and community cancer programs (41.1%). In our patient cocohort, patients treated at an academic/research center had slightly decreased 10-year OS rates compared with those patients treated at a comprehensive community cancer program, although the median OS for the academic/research centers were still the highest of all treatment facilities.

Treatment options varied significantly by facility, and the number of patients treated surgically followed a similar trend, with 92% undergoing surgery as the primary treatment at academic or research programs compared with 89% at comprehensive cancer programs and 82.7% at community cancer programs (data not shown). Another potential explaination for differing OS outcomes across facilities is the surgical margin outcome. Surgeries performed at community cancer programs or comprehensive cancer programs resulted with no residual tumor in 36% and 40% of cases, respectively, whereas cases performed at academic or research programs resulted with no residual tumor in 47% of cases (data not shown). Regardless, multivariate analysis demonstrated a marked decrease in the chance of mortality when comparing treatment received at academic facility centers with that received at comprehensive cancer centers (22.9%) and community cancer centers (38.3%) (data not shown).

A recent study demonstrated improved outcomes for patients with retroperitoneal or extremity STS treated at high-volume treatment centers.¹⁸ Patients treated at high-volume centers were found to have an 8% decreased risk of death compared with patients treated at low-volume centers. Notably, they found highvolume academic centers demonstrated the strongest improvement in survival, while highvolume community centers showed decreased survival.¹⁸ Similarly, we found that patients treated at academic/research institutions had improved 5-year OS and greater median OS than did patients treated at community cancer programs or comprehensive community cancer programs.

The top 2 income quartiles (≥ $48,000) combined to demonstrate the longest median, 5-year, and 10-year OS and were fairly similar between the quartiles. Patients living in zip codes with a median income of $38,000 to $47,999 had the worst 5-year OS and median OS. The log-rank analysis showed statistical evidence of differences in survival associated with income, but within the context of the multivariable analysis, there was no remaining evidence of a difference.

The longest 5-year OS outcomes were seen in patients living in zip codes with the highest level of education (55.3%). However, the difference in OS was not statistically significant using either the log-rank analysis or multivariate analysis.

Limitations

This study has certain inherent limitations in using a retrospective design and a large database such as the NCDB. Many different pathologists at CoC-accredited cancer programs perform the pathology that contributes to the data in the NCDB. There was no pathological review of these findings, which could potentially introduce error into the findings of this study. With the NCDB, potential selection bias is possible because patients in the database are added only from CoC-accredited cancer programs. This risk is minimized because NCDB contains data on most newly diagnosed cancer patients in the US. Further potential risks, which are unable to be controlled for, include potential interobserver error and data that may be incompletely, improperly, or inaccurately recorded from the patients’ charts. Without patient-specific information regarding income and education, it is challenging to utilize zip codes to estimate socioeconomic status and educational level. Even though a patient may live in a zip code identified with specific economic and educational characteristics, that patient may not share those characteristics. Furthermore, patients with Medicare tend to be older than patients with other forms of insurance, which limits the significance of comparisons across insurance groups. A future SEER (Surveillance, Epidemiology, and End Results) program study to confirm this study’s results and the effects of socioeconomic variables on DDLPS would be an excellent followup study.

Conclusion

This study used a large cohort of patients with DDLPS to study the effects of treatment facility, insurance status, and socioeconomic variables on survival outcomes. Although insurance status, median household income, and treatment facility were associated with differences in median OS and 5- and 10-year OS probabilities, evidence for a difference remained for only insurance status and facility type within the context of a multivariable analysis irrespective of age, race, sex, insurance status, education, and median income. Patients with private insurance and Medicaid had a decreased risk of mortality compared with other government insurance and no insurance. Patients receiving treatment at academic research programs had the highest median and 5-year OS of 66.6 months and 52.6%, respectively. Patients receiving treatment at academic centers had improved survival outcomes with a decrease in mortality of 23% and 38% compared to comprehensive or community cancer programs.

NEW YORK – Sunscreens remain the front-line strategy for preventing skin cancers of all types, but there is a growing array of chemopreventive agents for keratinocyte carcinomas (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.

In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.

Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.

In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.

However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.

“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .

Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.

When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.

“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.

There are other options for chemoprevention of KCs, but they are less attractive.

For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.

Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.

Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.

Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.

“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.

“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.

Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).

Dr. Hartman reported no financial relationships relevant to her presentation.

 

NEW YORK – Sunscreens remain the front-line strategy for preventing skin cancers of all types, but there is a growing array of chemopreventive agents for keratinocyte carcinomas (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.

In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.

Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.

In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.

However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.

“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .

Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.

When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.

“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.

There are other options for chemoprevention of KCs, but they are less attractive.

For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.

Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.

Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.

Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.

“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.

“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.

Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).

Dr. Hartman reported no financial relationships relevant to her presentation.

 

NEW YORK – Sunscreens remain the front-line strategy for preventing skin cancers of all types, but there is a growing array of chemopreventive agents for keratinocyte carcinomas (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.

In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.

Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.

In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.

However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.

“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .

Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.

When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.

“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.

There are other options for chemoprevention of KCs, but they are less attractive.

For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.

Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.

Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.

Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.

“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.

“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.

Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).

Dr. Hartman reported no financial relationships relevant to her presentation.