Renal Cell Carcinoma

In advanced renal cell carcinoma, four out of five immuno-oncology drug-based combination treatments are showing impressive results in trials, a new review finds. Based on initial data, all appear to show advantages over the standard first-line treatment with the older targeted-therapy drug sunitinib.

However, the review, published in the International Journal of Urology, cautions that uncertainty remains because of the “absence of long-term prognostic as well as safety data regarding these combination therapies.”

The review, led by Ken-ichi Harada MD, PhD, of Kobe (Japan) University, notes that the introduction of targeted therapies and immuno-oncology drugs over the last 2 decades has revolutionized the treatment of advanced renal cell carcinoma. Multiple combination therapies based on immuno-oncology drugs are now recommended by treatment guidelines.

However, the lack of head-to-head data means that “it is still challenging for physicians to make the best decision on first-line therapy,” the authors wrote.

In the review, the authors recapped the evidence regarding several combination therapies:

• Ipilimumab plus nivolumab, a combination of two monoclonal antibodies, has shown higher overall survival than sunitinib in multiple studies. Treatment-related adverse events are common, however, with one trial reporting that they led 69% of patients to discontinue treatment. Even so, “ipilimumab plus nivolumab therapy continues to demonstrate durable efficacy benefits over sunitinib in advanced renal cell carcinoma patients classified into intermediate or poor risk group after long-term follow-up.”
• Avelumab, a monoclonal antibody, plus the tyrosine kinase inhibitor (TKI) axitinib has not shown better overall survival rates versus sunitinib in a single trial, although there are signs of better progression-free survival. “Accordingly, avelumab plus axitinib is either not or discreetly recommended as a standard first-line therapy for advanced renal cell carcinoma patients by major clinical guidelines.”
• Pembrolizumab, a monoclonal antibody, plus axitinib has shown better progression-free survival and overall survival than sunitinib in a single trial. “Accordingly, pembrolizumab plus axitinib could be expected to have a powerful impact on favorable long-term cancer control with less frequent occurrence of severe adverse events, considering almost equivalent landmark overall survival to ipilimumab plus nivolumab.”
• Nivolumab plus cabozantinib, a TKI, beat sunitinib in a single trial in terms of progression-free survival and overall survival. “Nivolumab plus cabozantinib could be regarded as an efficacious therapeutic option for untreated advanced renal cell carcinoma patients with manageable safety.”
• Pembrolizumab plus lenvatinib, a TKI, showed better overall survival versus sunitinib in a single trial.

“These findings suggest that pembrolizumab plus lenvatinib could provide marked benefits with regard to cancer control in treatment-naive advanced renal cell carcinoma patients, and that caution should be exercised regarding the safety profile, considering the initial introduction of lenvatinib in the field of urological malignancies,” the authors wrote.

When compared against each other, most of these treatments appear to perform similarly, the authors wrote. With the exception of avelumab plus axitinib, all “showed almost similar advantages for the improvement of overall survival compared with sunitinib, judging from hazard ratios, and all five immuno-oncology drug-based combination therapies, particularly pembrolizumab plus lenvatinib, significantly prolonged progression-free survival, compared with sunitinib.”

No study funding was reported. The authors report various disclosures including relationships to Novartis, Pfizer, Ono, Takeda, MSD, Merck, and Bristol-Myers Squibb.

In advanced renal cell carcinoma, four out of five immuno-oncology drug-based combination treatments are showing impressive results in trials, a new review finds. Based on initial data, all appear to show advantages over the standard first-line treatment with the older targeted-therapy drug sunitinib.

However, the review, published in the International Journal of Urology, cautions that uncertainty remains because of the “absence of long-term prognostic as well as safety data regarding these combination therapies.”

The review, led by Ken-ichi Harada MD, PhD, of Kobe (Japan) University, notes that the introduction of targeted therapies and immuno-oncology drugs over the last 2 decades has revolutionized the treatment of advanced renal cell carcinoma. Multiple combination therapies based on immuno-oncology drugs are now recommended by treatment guidelines.

However, the lack of head-to-head data means that “it is still challenging for physicians to make the best decision on first-line therapy,” the authors wrote.

In the review, the authors recapped the evidence regarding several combination therapies:

• Ipilimumab plus nivolumab, a combination of two monoclonal antibodies, has shown higher overall survival than sunitinib in multiple studies. Treatment-related adverse events are common, however, with one trial reporting that they led 69% of patients to discontinue treatment. Even so, “ipilimumab plus nivolumab therapy continues to demonstrate durable efficacy benefits over sunitinib in advanced renal cell carcinoma patients classified into intermediate or poor risk group after long-term follow-up.”
• Avelumab, a monoclonal antibody, plus the tyrosine kinase inhibitor (TKI) axitinib has not shown better overall survival rates versus sunitinib in a single trial, although there are signs of better progression-free survival. “Accordingly, avelumab plus axitinib is either not or discreetly recommended as a standard first-line therapy for advanced renal cell carcinoma patients by major clinical guidelines.”
• Pembrolizumab, a monoclonal antibody, plus axitinib has shown better progression-free survival and overall survival than sunitinib in a single trial. “Accordingly, pembrolizumab plus axitinib could be expected to have a powerful impact on favorable long-term cancer control with less frequent occurrence of severe adverse events, considering almost equivalent landmark overall survival to ipilimumab plus nivolumab.”
• Nivolumab plus cabozantinib, a TKI, beat sunitinib in a single trial in terms of progression-free survival and overall survival. “Nivolumab plus cabozantinib could be regarded as an efficacious therapeutic option for untreated advanced renal cell carcinoma patients with manageable safety.”
• Pembrolizumab plus lenvatinib, a TKI, showed better overall survival versus sunitinib in a single trial.

“These findings suggest that pembrolizumab plus lenvatinib could provide marked benefits with regard to cancer control in treatment-naive advanced renal cell carcinoma patients, and that caution should be exercised regarding the safety profile, considering the initial introduction of lenvatinib in the field of urological malignancies,” the authors wrote.

When compared against each other, most of these treatments appear to perform similarly, the authors wrote. With the exception of avelumab plus axitinib, all “showed almost similar advantages for the improvement of overall survival compared with sunitinib, judging from hazard ratios, and all five immuno-oncology drug-based combination therapies, particularly pembrolizumab plus lenvatinib, significantly prolonged progression-free survival, compared with sunitinib.”

No study funding was reported. The authors report various disclosures including relationships to Novartis, Pfizer, Ono, Takeda, MSD, Merck, and Bristol-Myers Squibb.

In advanced renal cell carcinoma, four out of five immuno-oncology drug-based combination treatments are showing impressive results in trials, a new review finds. Based on initial data, all appear to show advantages over the standard first-line treatment with the older targeted-therapy drug sunitinib.

However, the review, published in the International Journal of Urology, cautions that uncertainty remains because of the “absence of long-term prognostic as well as safety data regarding these combination therapies.”

The review, led by Ken-ichi Harada MD, PhD, of Kobe (Japan) University, notes that the introduction of targeted therapies and immuno-oncology drugs over the last 2 decades has revolutionized the treatment of advanced renal cell carcinoma. Multiple combination therapies based on immuno-oncology drugs are now recommended by treatment guidelines.

However, the lack of head-to-head data means that “it is still challenging for physicians to make the best decision on first-line therapy,” the authors wrote.

In the review, the authors recapped the evidence regarding several combination therapies:

• Ipilimumab plus nivolumab, a combination of two monoclonal antibodies, has shown higher overall survival than sunitinib in multiple studies. Treatment-related adverse events are common, however, with one trial reporting that they led 69% of patients to discontinue treatment. Even so, “ipilimumab plus nivolumab therapy continues to demonstrate durable efficacy benefits over sunitinib in advanced renal cell carcinoma patients classified into intermediate or poor risk group after long-term follow-up.”
• Avelumab, a monoclonal antibody, plus the tyrosine kinase inhibitor (TKI) axitinib has not shown better overall survival rates versus sunitinib in a single trial, although there are signs of better progression-free survival. “Accordingly, avelumab plus axitinib is either not or discreetly recommended as a standard first-line therapy for advanced renal cell carcinoma patients by major clinical guidelines.”
• Pembrolizumab, a monoclonal antibody, plus axitinib has shown better progression-free survival and overall survival than sunitinib in a single trial. “Accordingly, pembrolizumab plus axitinib could be expected to have a powerful impact on favorable long-term cancer control with less frequent occurrence of severe adverse events, considering almost equivalent landmark overall survival to ipilimumab plus nivolumab.”
• Nivolumab plus cabozantinib, a TKI, beat sunitinib in a single trial in terms of progression-free survival and overall survival. “Nivolumab plus cabozantinib could be regarded as an efficacious therapeutic option for untreated advanced renal cell carcinoma patients with manageable safety.”
• Pembrolizumab plus lenvatinib, a TKI, showed better overall survival versus sunitinib in a single trial.

“These findings suggest that pembrolizumab plus lenvatinib could provide marked benefits with regard to cancer control in treatment-naive advanced renal cell carcinoma patients, and that caution should be exercised regarding the safety profile, considering the initial introduction of lenvatinib in the field of urological malignancies,” the authors wrote.

When compared against each other, most of these treatments appear to perform similarly, the authors wrote. With the exception of avelumab plus axitinib, all “showed almost similar advantages for the improvement of overall survival compared with sunitinib, judging from hazard ratios, and all five immuno-oncology drug-based combination therapies, particularly pembrolizumab plus lenvatinib, significantly prolonged progression-free survival, compared with sunitinib.”

No study funding was reported. The authors report various disclosures including relationships to Novartis, Pfizer, Ono, Takeda, MSD, Merck, and Bristol-Myers Squibb.

New research offers more evidence linking targeted therapies for patients with advanced renal cell carcinoma to higher risks for major adverse cardiovascular events.

Patients on targeted therapy were more likely to develop conditions such as heart attacks and stroke than were those who took cytokine therapy (adjusted hazard ratio, 1.80; 95% confidence interval [CI] 1.19-2.74), according to a retrospective Taiwanese study reports.

“These findings may inform the evaluation of cardiovascular risk when considering targeted cancer therapies for patients with advanced renal cell carcinoma in real-world clinical practice,” wrote the authors of the report, which appeared in JACC: CardioOncology.

The study notes that one kind of targeted therapy – tyrosine kinase inhibitors with anti–vascular endothelial growth factor (VEGFR-TKI) have been linked to higher rates of major adverse cardiovascular events (1.38-22.7). There have also been reports linking another kind of targeted therapy, mechanistic target of rapamycin inhibitors (mTOR), to major adverse cardiovascular events.

In the new study, Dong-Yi Chen, MD, of Chang Gung University, Taiwan, and colleagues, tracked patients with renal cell carcinoma who underwent treatment with targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus, (n = 2,257, 81%) or cytokine therapy (interleukin-2 or interferon gamma, n = 528, 19%) from 2007 to 2018.

The two groups had similar gender, age and socioeconomic levels. Combined, the groups were 74% male, the median age was 63, and 68% had hypertension.

After stabilized inverse probability of treatment weighting, the adjusted incidence rates of major cardiovascular events were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively. “The higher cardiovascular risk of the targeted group was driven primarily by the VEGFR TKI–treated patients,” the authors wrote.

Two drugs were linked to statistically significant higher rates of major cardiovascular adverse events compared with the reference drug sunitinib: the VEGFR TKI sorafenib (univariable HR, 1.94, 95% CI, 1.11-3.39), P = .021) and the mTOR temsirolimus (univariable HR, 2.11, 95% CI, 1.24-3.59, P = .006). Sunitinib was by far the most commonly used targeted therapy drug.

Among patients on targeted therapy, several factors were linked to higher rates of major cardiovascular events, such as baseline history of heart failure (HR, 3.88, 95% CI, 2.25-6.71), atrial fibrillation (HR, 3.60, 95% CI, 2.16-5.99), venous thromboembolism (HR, 2.50, 95% CI, 1.27-4.92), ischemic stroke (HR, 1.88, 95% CI, 1.14-3.11), and age at least 65 years (HR, 1.81, 95% CI, 1.27-2.58).

According to the authors, there are several theories about why targeted therapy may boost the risk of major adverse cardiovascular risk. “VEGF signaling inhibitors have been associated with hypertension,” which is a risk factor for cardiac death, they noted. Also, “multi-receptor TKIs, including VEGFR and platelet-derived growth factor receptor inhibitors, could destabilize the coronary microvascular endothelial network and reduce coronary flow reserve, leading to an increased risk for thrombosis and arterial ischemic events, including myocardial infarction and ischemic stroke.”

The study was funded by Chang Gung Memorial Hospital.

New research offers more evidence linking targeted therapies for patients with advanced renal cell carcinoma to higher risks for major adverse cardiovascular events.

Patients on targeted therapy were more likely to develop conditions such as heart attacks and stroke than were those who took cytokine therapy (adjusted hazard ratio, 1.80; 95% confidence interval [CI] 1.19-2.74), according to a retrospective Taiwanese study reports.

“These findings may inform the evaluation of cardiovascular risk when considering targeted cancer therapies for patients with advanced renal cell carcinoma in real-world clinical practice,” wrote the authors of the report, which appeared in JACC: CardioOncology.

The study notes that one kind of targeted therapy – tyrosine kinase inhibitors with anti–vascular endothelial growth factor (VEGFR-TKI) have been linked to higher rates of major adverse cardiovascular events (1.38-22.7). There have also been reports linking another kind of targeted therapy, mechanistic target of rapamycin inhibitors (mTOR), to major adverse cardiovascular events.

In the new study, Dong-Yi Chen, MD, of Chang Gung University, Taiwan, and colleagues, tracked patients with renal cell carcinoma who underwent treatment with targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus, (n = 2,257, 81%) or cytokine therapy (interleukin-2 or interferon gamma, n = 528, 19%) from 2007 to 2018.

The two groups had similar gender, age and socioeconomic levels. Combined, the groups were 74% male, the median age was 63, and 68% had hypertension.

After stabilized inverse probability of treatment weighting, the adjusted incidence rates of major cardiovascular events were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively. “The higher cardiovascular risk of the targeted group was driven primarily by the VEGFR TKI–treated patients,” the authors wrote.

Two drugs were linked to statistically significant higher rates of major cardiovascular adverse events compared with the reference drug sunitinib: the VEGFR TKI sorafenib (univariable HR, 1.94, 95% CI, 1.11-3.39), P = .021) and the mTOR temsirolimus (univariable HR, 2.11, 95% CI, 1.24-3.59, P = .006). Sunitinib was by far the most commonly used targeted therapy drug.

Among patients on targeted therapy, several factors were linked to higher rates of major cardiovascular events, such as baseline history of heart failure (HR, 3.88, 95% CI, 2.25-6.71), atrial fibrillation (HR, 3.60, 95% CI, 2.16-5.99), venous thromboembolism (HR, 2.50, 95% CI, 1.27-4.92), ischemic stroke (HR, 1.88, 95% CI, 1.14-3.11), and age at least 65 years (HR, 1.81, 95% CI, 1.27-2.58).

According to the authors, there are several theories about why targeted therapy may boost the risk of major adverse cardiovascular risk. “VEGF signaling inhibitors have been associated with hypertension,” which is a risk factor for cardiac death, they noted. Also, “multi-receptor TKIs, including VEGFR and platelet-derived growth factor receptor inhibitors, could destabilize the coronary microvascular endothelial network and reduce coronary flow reserve, leading to an increased risk for thrombosis and arterial ischemic events, including myocardial infarction and ischemic stroke.”

The study was funded by Chang Gung Memorial Hospital.

New research offers more evidence linking targeted therapies for patients with advanced renal cell carcinoma to higher risks for major adverse cardiovascular events.

Patients on targeted therapy were more likely to develop conditions such as heart attacks and stroke than were those who took cytokine therapy (adjusted hazard ratio, 1.80; 95% confidence interval [CI] 1.19-2.74), according to a retrospective Taiwanese study reports.

“These findings may inform the evaluation of cardiovascular risk when considering targeted cancer therapies for patients with advanced renal cell carcinoma in real-world clinical practice,” wrote the authors of the report, which appeared in JACC: CardioOncology.

The study notes that one kind of targeted therapy – tyrosine kinase inhibitors with anti–vascular endothelial growth factor (VEGFR-TKI) have been linked to higher rates of major adverse cardiovascular events (1.38-22.7). There have also been reports linking another kind of targeted therapy, mechanistic target of rapamycin inhibitors (mTOR), to major adverse cardiovascular events.

In the new study, Dong-Yi Chen, MD, of Chang Gung University, Taiwan, and colleagues, tracked patients with renal cell carcinoma who underwent treatment with targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus, (n = 2,257, 81%) or cytokine therapy (interleukin-2 or interferon gamma, n = 528, 19%) from 2007 to 2018.

The two groups had similar gender, age and socioeconomic levels. Combined, the groups were 74% male, the median age was 63, and 68% had hypertension.

After stabilized inverse probability of treatment weighting, the adjusted incidence rates of major cardiovascular events were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively. “The higher cardiovascular risk of the targeted group was driven primarily by the VEGFR TKI–treated patients,” the authors wrote.

Two drugs were linked to statistically significant higher rates of major cardiovascular adverse events compared with the reference drug sunitinib: the VEGFR TKI sorafenib (univariable HR, 1.94, 95% CI, 1.11-3.39), P = .021) and the mTOR temsirolimus (univariable HR, 2.11, 95% CI, 1.24-3.59, P = .006). Sunitinib was by far the most commonly used targeted therapy drug.

Among patients on targeted therapy, several factors were linked to higher rates of major cardiovascular events, such as baseline history of heart failure (HR, 3.88, 95% CI, 2.25-6.71), atrial fibrillation (HR, 3.60, 95% CI, 2.16-5.99), venous thromboembolism (HR, 2.50, 95% CI, 1.27-4.92), ischemic stroke (HR, 1.88, 95% CI, 1.14-3.11), and age at least 65 years (HR, 1.81, 95% CI, 1.27-2.58).

According to the authors, there are several theories about why targeted therapy may boost the risk of major adverse cardiovascular risk. “VEGF signaling inhibitors have been associated with hypertension,” which is a risk factor for cardiac death, they noted. Also, “multi-receptor TKIs, including VEGFR and platelet-derived growth factor receptor inhibitors, could destabilize the coronary microvascular endothelial network and reduce coronary flow reserve, leading to an increased risk for thrombosis and arterial ischemic events, including myocardial infarction and ischemic stroke.”

The study was funded by Chang Gung Memorial Hospital.

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.