Oncology

This article is a based on a video essay. The transcript has been edited for clarity.

I’d like to discuss what I think is a very interesting analysis that we need to see much more of. It’s perhaps not surprising, but the data, I think, are sobering. The paper was published in JAMA Network Open, entitled, “Trends and Disparities in Next-Generation Sequencing in Metastatic Prostate and Urothelial Cancers.”

As I think most of the listening audience is aware, we are in the midst of an ongoing — I would argue, accelerating — revolution in our understanding of cancer, its development and treatments, based upon our characterization at the molecular level of individual cancers.

This, of course, is changing the treatment paradigms and the drugs that we might have available in the first-, second-, and third-line settings. The question to be asked is, how are we, at a clinical level, keeping up with all of these changes, like those approved by the US Food and Drug Administration, and new diagnostic testing with a variety of molecular platforms?

This particular analysis looked at that specific question in metastatic prostate cancer and urothelial malignancies, obviously including bladder cancer. With the new approvals — including tumor agnostic testing, very specific testing, and very molecularly based drugs that are approved for particular abnormalities — they looked at the percentages of patients and the potential disparities in terms of the testing that has been performed.

There were 11,927 patients with prostate cancer. There were 6490 patients with advanced urothelial malignancies; the majority of these were male, but there were females included in this group.

The researchers looked at 2015 vs 2022 data. It’s not 2024 data, but it goes all the way to the end of 2022, so, not that long ago. In the metastatic prostate cancer group, 19% of patients had undergone molecular testing or next-generation sequencing in 2015.

By 2022, that number had increased, but only to 27%. Three out of four patients with metastatic prostate cancer had not undergone testing to know whether they were potential candidates for specific therapies. I won’t even get into the question of potential germline abnormalities that might be observed that are relevant for other discussions.

Among patients with urothelial cancer, in 2015, 14% had undergone such testing. By 2022, this number was substantially increased to 46.6%, but still, that’s less than 1 out of 2 patients. More than 50% of patients had not undergone the testing, and yet we have therapy that might be available for these populations based on such testing.

I should add that the population of Black, African American, and Hispanic patients was actually considerably lower, percentage-wise, than the numbers that I’ve quoted.

Clearly, there are explanations. There are socioeconomic explanations and insurance coverage explanations. However, the bottom line is that we have therapies available today, and we’ll have more in the future, that are based on knowledge of this testing.

Based on these data, which most recently included 2022 — we’ll see where we are in 2024 and 2025, and with other types — more than half of patients are not getting the testing to know if this is relevant for them and their care.

These are major questions that need to be addressed. Hopefully, answers will be forthcoming and we will see in the future that these percentages will be much higher for the benefit of our patients.

Dr Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed the following relevant financial relationships with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This article is a based on a video essay. The transcript has been edited for clarity.

I’d like to discuss what I think is a very interesting analysis that we need to see much more of. It’s perhaps not surprising, but the data, I think, are sobering. The paper was published in JAMA Network Open, entitled, “Trends and Disparities in Next-Generation Sequencing in Metastatic Prostate and Urothelial Cancers.”

As I think most of the listening audience is aware, we are in the midst of an ongoing — I would argue, accelerating — revolution in our understanding of cancer, its development and treatments, based upon our characterization at the molecular level of individual cancers.

This, of course, is changing the treatment paradigms and the drugs that we might have available in the first-, second-, and third-line settings. The question to be asked is, how are we, at a clinical level, keeping up with all of these changes, like those approved by the US Food and Drug Administration, and new diagnostic testing with a variety of molecular platforms?

This particular analysis looked at that specific question in metastatic prostate cancer and urothelial malignancies, obviously including bladder cancer. With the new approvals — including tumor agnostic testing, very specific testing, and very molecularly based drugs that are approved for particular abnormalities — they looked at the percentages of patients and the potential disparities in terms of the testing that has been performed.

There were 11,927 patients with prostate cancer. There were 6490 patients with advanced urothelial malignancies; the majority of these were male, but there were females included in this group.

The researchers looked at 2015 vs 2022 data. It’s not 2024 data, but it goes all the way to the end of 2022, so, not that long ago. In the metastatic prostate cancer group, 19% of patients had undergone molecular testing or next-generation sequencing in 2015.

By 2022, that number had increased, but only to 27%. Three out of four patients with metastatic prostate cancer had not undergone testing to know whether they were potential candidates for specific therapies. I won’t even get into the question of potential germline abnormalities that might be observed that are relevant for other discussions.

Among patients with urothelial cancer, in 2015, 14% had undergone such testing. By 2022, this number was substantially increased to 46.6%, but still, that’s less than 1 out of 2 patients. More than 50% of patients had not undergone the testing, and yet we have therapy that might be available for these populations based on such testing.

I should add that the population of Black, African American, and Hispanic patients was actually considerably lower, percentage-wise, than the numbers that I’ve quoted.

Clearly, there are explanations. There are socioeconomic explanations and insurance coverage explanations. However, the bottom line is that we have therapies available today, and we’ll have more in the future, that are based on knowledge of this testing.

Based on these data, which most recently included 2022 — we’ll see where we are in 2024 and 2025, and with other types — more than half of patients are not getting the testing to know if this is relevant for them and their care.

These are major questions that need to be addressed. Hopefully, answers will be forthcoming and we will see in the future that these percentages will be much higher for the benefit of our patients.

Dr Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed the following relevant financial relationships with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This article is a based on a video essay. The transcript has been edited for clarity.

I’d like to discuss what I think is a very interesting analysis that we need to see much more of. It’s perhaps not surprising, but the data, I think, are sobering. The paper was published in JAMA Network Open, entitled, “Trends and Disparities in Next-Generation Sequencing in Metastatic Prostate and Urothelial Cancers.”

As I think most of the listening audience is aware, we are in the midst of an ongoing — I would argue, accelerating — revolution in our understanding of cancer, its development and treatments, based upon our characterization at the molecular level of individual cancers.

This, of course, is changing the treatment paradigms and the drugs that we might have available in the first-, second-, and third-line settings. The question to be asked is, how are we, at a clinical level, keeping up with all of these changes, like those approved by the US Food and Drug Administration, and new diagnostic testing with a variety of molecular platforms?

This particular analysis looked at that specific question in metastatic prostate cancer and urothelial malignancies, obviously including bladder cancer. With the new approvals — including tumor agnostic testing, very specific testing, and very molecularly based drugs that are approved for particular abnormalities — they looked at the percentages of patients and the potential disparities in terms of the testing that has been performed.

There were 11,927 patients with prostate cancer. There were 6490 patients with advanced urothelial malignancies; the majority of these were male, but there were females included in this group.

The researchers looked at 2015 vs 2022 data. It’s not 2024 data, but it goes all the way to the end of 2022, so, not that long ago. In the metastatic prostate cancer group, 19% of patients had undergone molecular testing or next-generation sequencing in 2015.

By 2022, that number had increased, but only to 27%. Three out of four patients with metastatic prostate cancer had not undergone testing to know whether they were potential candidates for specific therapies. I won’t even get into the question of potential germline abnormalities that might be observed that are relevant for other discussions.

Among patients with urothelial cancer, in 2015, 14% had undergone such testing. By 2022, this number was substantially increased to 46.6%, but still, that’s less than 1 out of 2 patients. More than 50% of patients had not undergone the testing, and yet we have therapy that might be available for these populations based on such testing.

I should add that the population of Black, African American, and Hispanic patients was actually considerably lower, percentage-wise, than the numbers that I’ve quoted.

Clearly, there are explanations. There are socioeconomic explanations and insurance coverage explanations. However, the bottom line is that we have therapies available today, and we’ll have more in the future, that are based on knowledge of this testing.

Based on these data, which most recently included 2022 — we’ll see where we are in 2024 and 2025, and with other types — more than half of patients are not getting the testing to know if this is relevant for them and their care.

These are major questions that need to be addressed. Hopefully, answers will be forthcoming and we will see in the future that these percentages will be much higher for the benefit of our patients.

Dr Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed the following relevant financial relationships with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

TOPLINE:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in blood cancers — with six CAR T-cell products now approved by the Food and Drug Administration (FDA) to treat six hematologic malignancies.

For solid tumors, however, the efficacy of CAR T-cell treatments has been limited and progress “more incremental,” Christian Hinrichs, MD, with Rutgers Cancer Institute in New Brunswick, New Jersey, told this news organization. Currently, there are no CAR T-cell therapies approved in the United States to treat solid tumors.

Why have CAR T-cell therapies been less effective against solid tumors?

Perhaps the biggest hurdle is the ability to identify and selectively target specific molecular structures in cancer cells without causing severe toxicity by injuring healthy cells, Hinrichs and coauthors wrote in a recent JAMA review.

CAR T-cells are made up of “T cells genetically engineered to express a synthetic receptor that recognizes a tumor cell-surface protein,” Hinrichs and colleagues explained. But identifying cell surface antigens that are exclusive to solid tumor cells has been a challenge, which means CAR T-cell therapies end up affecting both tumor and healthy tissues.

“This makes it difficult to target and kill all the tumor cells without causing severe toxicity from injury to healthy cells,” Hinrichs explained.

Other common obstacles include challenges penetrating the dense extracellular matrix of solid tumors and the need to overcome inhibitory cells and molecules in the tumor microenvironment.

Despite the challenges and slow progress, some “promising results” have begun to emerge in the solid tumor, CAR T-cell space, Hinrichs said.

A recent phase 1-2 study, for instance, found that 63% (17 of 27) of pediatric patients with heavily pretreated neuroblastoma achieved an overall response with an investigational CAR T-cell therapy, GD2-CART01.

In a recent phase 1 trial, 38 of 98 patients with gastrointestinal cancers (39%) achieved partial or complete responses after receiving an investigational CAR T-cell treatment directed at Claudin18.2. However, the responses were short overall and could have been related to the chemotherapy given before the CAR T-cell infusion.

Another phase 1 trial found that a GPC3-targeted CAR T-cell therapy led to an objective response rate in half (12 of 24) of heavily treated patients with advanced hepatocellular carcinoma, with a disease control rate of almost 91%.

Outside of CAR-T cell therapies, other cell-based treatments have shown promise against solid tumors, including two T-cell therapies recently approved by the FDA.

Last February, the FDA approved the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (Amtagvi) for advanced melanoma. In August, the agency approved the T-cell receptor (TCR) therapy afamitresgene autoleucel for advanced synovial sarcoma.

“Response rates for these cellular therapies are in the 30% range, but already there is clear data that there’s durability for some patients, which is very exciting because previously treated patients really have very few treatment options,” Jennifer Brudno, MD, with the National Cancer Institute and coauthor of the JAMA review, said in a journal podcast.

Several cell-based agents are in early trials to treat a range of solid tumors.

Hinrichs and colleagues previously reported findings from a phase 2 clinical trial of TIL therapy for human papillomavirus (HPV) — associated cancers including cervical, oropharyngeal, and anal cancers. Responses occurred in 5 of 18 patients with cervical cancer and 2 of 11 patients with noncervical cancers. “Two of the patients with cervical cancer had complete responses that are ongoing years after a single infusion of cells,” Hinrichs told this news organization.

Hinrichs was also involved in a phase 1 trial of gene-engineered TCR T-cells targeting HPV E7 for HPV-associated cancers reported tumor responses in 6 of 12 patients, including 4 of 8 with tumors refractory to checkpoint blockade immunotherapy. A phase 2 trial is now open at Rutgers Cancer Institute, as is an early trial testing a new TCR T-cell therapy targeting Kita-Kyushu Lung Cancer Antigen-1 to treat metastatic gastric, lung, breast, and cervical cancers.

Despite the encouraging findings, for CAR T-cell and other cell-based therapies to be successful against solid tumors, “we need to develop more treatments directed against antigens that are expressed by most or all the cells in a tumor but not by critical healthy tissues,” Hinrichs said.

“It may also be important to increase the potency of therapeutic cells and develop more sophisticated methods of antigen targeting that can better distinguish between tumors and healthy tissues,” he noted.

Brudno reported being an unpaid scientific advisory board member for and receiving travel expenses from Kyverna Therapeutics. Hinrichs reported receiving personal fees from Neogene Therapeutics, Capstan Therapeutics, GlaxoSmithKline, Vir Biotechnology, and PACT Pharma; equity from Scarlet TCR (company officer); and sponsored research agreements from T-Cure Biosciences and Neogene Therapeutics outside the submitted work. He also holds several patents related to cellular therapies.

A version of this article first appeared on Medscape.com.

Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in blood cancers — with six CAR T-cell products now approved by the Food and Drug Administration (FDA) to treat six hematologic malignancies.

For solid tumors, however, the efficacy of CAR T-cell treatments has been limited and progress “more incremental,” Christian Hinrichs, MD, with Rutgers Cancer Institute in New Brunswick, New Jersey, told this news organization. Currently, there are no CAR T-cell therapies approved in the United States to treat solid tumors.

Why have CAR T-cell therapies been less effective against solid tumors?

Perhaps the biggest hurdle is the ability to identify and selectively target specific molecular structures in cancer cells without causing severe toxicity by injuring healthy cells, Hinrichs and coauthors wrote in a recent JAMA review.

CAR T-cells are made up of “T cells genetically engineered to express a synthetic receptor that recognizes a tumor cell-surface protein,” Hinrichs and colleagues explained. But identifying cell surface antigens that are exclusive to solid tumor cells has been a challenge, which means CAR T-cell therapies end up affecting both tumor and healthy tissues.

“This makes it difficult to target and kill all the tumor cells without causing severe toxicity from injury to healthy cells,” Hinrichs explained.

Other common obstacles include challenges penetrating the dense extracellular matrix of solid tumors and the need to overcome inhibitory cells and molecules in the tumor microenvironment.

Despite the challenges and slow progress, some “promising results” have begun to emerge in the solid tumor, CAR T-cell space, Hinrichs said.

A recent phase 1-2 study, for instance, found that 63% (17 of 27) of pediatric patients with heavily pretreated neuroblastoma achieved an overall response with an investigational CAR T-cell therapy, GD2-CART01.

In a recent phase 1 trial, 38 of 98 patients with gastrointestinal cancers (39%) achieved partial or complete responses after receiving an investigational CAR T-cell treatment directed at Claudin18.2. However, the responses were short overall and could have been related to the chemotherapy given before the CAR T-cell infusion.

Another phase 1 trial found that a GPC3-targeted CAR T-cell therapy led to an objective response rate in half (12 of 24) of heavily treated patients with advanced hepatocellular carcinoma, with a disease control rate of almost 91%.

Outside of CAR-T cell therapies, other cell-based treatments have shown promise against solid tumors, including two T-cell therapies recently approved by the FDA.

Last February, the FDA approved the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (Amtagvi) for advanced melanoma. In August, the agency approved the T-cell receptor (TCR) therapy afamitresgene autoleucel for advanced synovial sarcoma.

“Response rates for these cellular therapies are in the 30% range, but already there is clear data that there’s durability for some patients, which is very exciting because previously treated patients really have very few treatment options,” Jennifer Brudno, MD, with the National Cancer Institute and coauthor of the JAMA review, said in a journal podcast.

Several cell-based agents are in early trials to treat a range of solid tumors.

Hinrichs and colleagues previously reported findings from a phase 2 clinical trial of TIL therapy for human papillomavirus (HPV) — associated cancers including cervical, oropharyngeal, and anal cancers. Responses occurred in 5 of 18 patients with cervical cancer and 2 of 11 patients with noncervical cancers. “Two of the patients with cervical cancer had complete responses that are ongoing years after a single infusion of cells,” Hinrichs told this news organization.

Hinrichs was also involved in a phase 1 trial of gene-engineered TCR T-cells targeting HPV E7 for HPV-associated cancers reported tumor responses in 6 of 12 patients, including 4 of 8 with tumors refractory to checkpoint blockade immunotherapy. A phase 2 trial is now open at Rutgers Cancer Institute, as is an early trial testing a new TCR T-cell therapy targeting Kita-Kyushu Lung Cancer Antigen-1 to treat metastatic gastric, lung, breast, and cervical cancers.

Despite the encouraging findings, for CAR T-cell and other cell-based therapies to be successful against solid tumors, “we need to develop more treatments directed against antigens that are expressed by most or all the cells in a tumor but not by critical healthy tissues,” Hinrichs said.

“It may also be important to increase the potency of therapeutic cells and develop more sophisticated methods of antigen targeting that can better distinguish between tumors and healthy tissues,” he noted.

Brudno reported being an unpaid scientific advisory board member for and receiving travel expenses from Kyverna Therapeutics. Hinrichs reported receiving personal fees from Neogene Therapeutics, Capstan Therapeutics, GlaxoSmithKline, Vir Biotechnology, and PACT Pharma; equity from Scarlet TCR (company officer); and sponsored research agreements from T-Cure Biosciences and Neogene Therapeutics outside the submitted work. He also holds several patents related to cellular therapies.

A version of this article first appeared on Medscape.com.

Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in blood cancers — with six CAR T-cell products now approved by the Food and Drug Administration (FDA) to treat six hematologic malignancies.

For solid tumors, however, the efficacy of CAR T-cell treatments has been limited and progress “more incremental,” Christian Hinrichs, MD, with Rutgers Cancer Institute in New Brunswick, New Jersey, told this news organization. Currently, there are no CAR T-cell therapies approved in the United States to treat solid tumors.

Why have CAR T-cell therapies been less effective against solid tumors?

Perhaps the biggest hurdle is the ability to identify and selectively target specific molecular structures in cancer cells without causing severe toxicity by injuring healthy cells, Hinrichs and coauthors wrote in a recent JAMA review.

CAR T-cells are made up of “T cells genetically engineered to express a synthetic receptor that recognizes a tumor cell-surface protein,” Hinrichs and colleagues explained. But identifying cell surface antigens that are exclusive to solid tumor cells has been a challenge, which means CAR T-cell therapies end up affecting both tumor and healthy tissues.

“This makes it difficult to target and kill all the tumor cells without causing severe toxicity from injury to healthy cells,” Hinrichs explained.

Other common obstacles include challenges penetrating the dense extracellular matrix of solid tumors and the need to overcome inhibitory cells and molecules in the tumor microenvironment.

Despite the challenges and slow progress, some “promising results” have begun to emerge in the solid tumor, CAR T-cell space, Hinrichs said.

A recent phase 1-2 study, for instance, found that 63% (17 of 27) of pediatric patients with heavily pretreated neuroblastoma achieved an overall response with an investigational CAR T-cell therapy, GD2-CART01.

In a recent phase 1 trial, 38 of 98 patients with gastrointestinal cancers (39%) achieved partial or complete responses after receiving an investigational CAR T-cell treatment directed at Claudin18.2. However, the responses were short overall and could have been related to the chemotherapy given before the CAR T-cell infusion.

Another phase 1 trial found that a GPC3-targeted CAR T-cell therapy led to an objective response rate in half (12 of 24) of heavily treated patients with advanced hepatocellular carcinoma, with a disease control rate of almost 91%.

Outside of CAR-T cell therapies, other cell-based treatments have shown promise against solid tumors, including two T-cell therapies recently approved by the FDA.

Last February, the FDA approved the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (Amtagvi) for advanced melanoma. In August, the agency approved the T-cell receptor (TCR) therapy afamitresgene autoleucel for advanced synovial sarcoma.

“Response rates for these cellular therapies are in the 30% range, but already there is clear data that there’s durability for some patients, which is very exciting because previously treated patients really have very few treatment options,” Jennifer Brudno, MD, with the National Cancer Institute and coauthor of the JAMA review, said in a journal podcast.

Several cell-based agents are in early trials to treat a range of solid tumors.

Hinrichs and colleagues previously reported findings from a phase 2 clinical trial of TIL therapy for human papillomavirus (HPV) — associated cancers including cervical, oropharyngeal, and anal cancers. Responses occurred in 5 of 18 patients with cervical cancer and 2 of 11 patients with noncervical cancers. “Two of the patients with cervical cancer had complete responses that are ongoing years after a single infusion of cells,” Hinrichs told this news organization.

Hinrichs was also involved in a phase 1 trial of gene-engineered TCR T-cells targeting HPV E7 for HPV-associated cancers reported tumor responses in 6 of 12 patients, including 4 of 8 with tumors refractory to checkpoint blockade immunotherapy. A phase 2 trial is now open at Rutgers Cancer Institute, as is an early trial testing a new TCR T-cell therapy targeting Kita-Kyushu Lung Cancer Antigen-1 to treat metastatic gastric, lung, breast, and cervical cancers.

Despite the encouraging findings, for CAR T-cell and other cell-based therapies to be successful against solid tumors, “we need to develop more treatments directed against antigens that are expressed by most or all the cells in a tumor but not by critical healthy tissues,” Hinrichs said.

“It may also be important to increase the potency of therapeutic cells and develop more sophisticated methods of antigen targeting that can better distinguish between tumors and healthy tissues,” he noted.

Brudno reported being an unpaid scientific advisory board member for and receiving travel expenses from Kyverna Therapeutics. Hinrichs reported receiving personal fees from Neogene Therapeutics, Capstan Therapeutics, GlaxoSmithKline, Vir Biotechnology, and PACT Pharma; equity from Scarlet TCR (company officer); and sponsored research agreements from T-Cure Biosciences and Neogene Therapeutics outside the submitted work. He also holds several patents related to cellular therapies.

A version of this article first appeared on Medscape.com.

It is the best possible news after an advanced melanoma diagnosis: A clean 10-year scan. This, in all likelihood, means the patient is cured and can leave the office free from their annual ‘scanxiety.’ 

But even in the best-case scenarios, oncologists may dodge the word cure, searching for others such as “remission,” “no evidence of disease,” and “most likely cured” to communicate the good news. Using these more open-ended terms can give patients reassurance without providing false hope that the cancer won’t ever return.

The “risk of future recurrence — even when very small — makes oncologists reluctant to use the word cure, fearing it will be interpreted as a promise, and particularly one that might be broken,” Belinda E. Kiely, MD, and Martin R. Stockler, MD, medical oncologists from the University of Sydney in Australia, wrote in a recent editorial.

Is it ever safe for oncologists to use the word cure? Might doing so backfire? Or does a patient’s underlying fear of recurrence transcend the word?

 

A Word’s Heavy Impact

Part of clinicians’ hesitance to use the word cure may stem from a lack of accepted definition for the term in oncology.

For some experts, a cure means patients will have a normal life expectancy not affected by cancer. Being able to confidently tell a patient that “requires very long-term follow-up,” said James Larkin, PhD, a medical oncologist at The Royal Marsden Hospital, London, England.

The National Cancer Institute (NCI) has a similar definition: “Cure means that there are no traces of your cancer after treatment and the cancer will never come back,” the NCI website says.

The American Society of Clinical Oncology, however, defines cure much more narrowly, as “when a person’s cancer has not returned for at least 5 years after treatment.” 

Not having a standard definition of cure in oncology makes it even more challenging for an oncologist to know how to communicate that a cancer very likely won’t return, without overpromising.

Some of the hesitance in framing good news comes from nuances in prognoses that depend on the type and stage of cancer, explained Marleen Kok, MD, PhD, a breast cancer specialist from the Netherlands Cancer Institute in Amsterdam.

Patients with localized early-stage breast cancer, for instance, have a 5-year survival rate of nearly 100%, and most live 2 decades or longer but, for some, the cancer will return.

“If you talk about early disease, indeed, we cure 80% of breast cancer patients,” Kok said during a press conference at the annual 2024 European Society of Medical Oncology meeting. But sub-dividing breast cancer into tumor type adds complexity. “With triple negative breast cancer, if they relapse, they relapse during the first 2 or 3 years so, at 5 years, the majority are disease free. But that’s different for estrogen receptor positive breast cancer,” in which recurrences can come much later.

In advanced cancers, oncologists may, understandably, be more hesitant to use the word cure. However, ongoing progress in cancer treatments is making the prospect of a cure more likely for some patients.

Take recent findings in melanoma. The landmark CheckMate 067 study in advanced disease revealed that patients receiving the immunotherapy combination of nivolumab plus ipilimumab had a median melanoma-specific survival > 10 years and a median overall survival of about 6 years.

The findings from the trial suggest that “many patients may die from causes unrelated to melanoma — or, in essence, they are cured,” outside expert Elisa Funck-Brentano, MD, PhD, from Ambroise-Paré Hospital in Paris, France, explained to Medscape Medical News.

With CheckMate 067, “what we’re talking about here is potential cure of metastatic solid tumors, which in general is something that’s new,” said senior author Larkin. In fact, late relapses after the 2- to 3-year mark in immunotherapy-treated melanoma are extremely rare.

CheckMate 067 “really made people tempted to use the word cure, and I will say some people in our field do,” said Pauline Funchain, MD, a medical oncologist at Stanford Cancer Institute, and associate professor at Stanford University, Palo Alto, California. “The rest of us really, really want to, but are hesitant because of what we know about melanoma.”

Because the reality is late relapse is still possible.

The cancer can show up decades later and I think, as oncologists, that experience has sort of shaken us,” Funchain told this news organization.

“Oncologists are scarred by those examples,” agreed Evan Hall, MD, a medical oncologist at Fred Hutch Cancer Center and assistant professor at the University of Washington School of Medicine, both in Seattle.

Clinical trials also don’t typically frame patient outcomes in terms of being cured. A recent analysis, which examined the use of “cure” and “hope” in 13,363 oncology articles published between 2000 and 2019 in JAMA Oncology and the Journal of Clinical Oncology, found that both words were used infrequently, especially in primary research articles, and their use decreased significantly over time, even as survival rates in oncology improved. The word cure, for instance, appeared in about 0.1% of sentences in primary research papers published in either journal, though the context of its use was not identified.

Outcomes in cancer clinical trials, which may assess hundreds even thousands of patients, are largely framed in terms of risks and rates of survival — 85% of patients who received treatment X are alive at 5 years or patients receiving treatment Y have a 20% risk for recurrence, for instance.

These risks and rates can’t tell an oncologist whether the patient sitting in front of them can close the cancer chapter of their lives for good.

“I just saw a patient the other day who was 30 years out from their melanoma diagnosis, and they had a recurrence,” Hall recalled. That’s why, “ultimately, it’s a hard thing to tell somebody they’re cured,” he said. “I personally don’t really like using that term.”

While the literature on using the word cure in oncology is limited, one older survey of oncology clinicians supports this view that many feel reluctant to use the term. Of 117 oncology clinicians who responded, 81% said they were “hesitant to tell a patient that they are cured,” and 63% said that they “would never tell a patient that they are cured,” while just 36% said they were comfortable saying the word, with most respondents waiting at least 6-10 years before doing so.

A more recent Italian survey, however, revealed a more favorable view of the word cure in oncology. The survey, which included 224 clinicians and 249 patients, reported that > 90% of cancer physicians, which included surgeons, radiotherapists, and medical oncologists, agreed that it’s possible for a patient to be cured, while about 84% of patients believed this. And > 80% of respondents said using the word cure would be “beneficial” to patients.

Still, even for those hearing the word cure and feeling comforted by an oncologist’s reassurance, it may only provide short-term relief. Fear that the cancer will come slinking, even roaring, back eventually may loom. And this lingering worry can haunt cancer survivors for years.

In a recent cross-sectional study of 229 adults who survived childhood cancer and had lived cancer-free for decades, researchers found that one third reported experiencing clinically significant elevated fear that their primary cancer would recur or a subsequent malignant neoplasm would develop. Similar anxiety has been documented in long-term survivors of adult-onset cancers.

To some degree, every survivor will experience fear and anxiety that their cancer will come back and, at a certain level, that is normal, the study’s senior author Nicole Alberts, PhD, a psychologist, associate professor, and Canada research chair in Behavioural Health Intervention at Concordia University, Montréal, Quebec, Canada, told this news organization.

Although an oncologist’s words do matter and clinicians may wrestle with the right words for patients in the moment, it can take more than words to quell patients’ fear, she said.

“What we know about that kind of anxiety is that there’s this cycle where reassurance doesn’t really help in the long-term,” Alberts said. In other words, hearing the word cure from their oncologist initially makes people feel better, but the anxiety may eventually come back.

Alberts tries to help patients acknowledge and accept uncertainty while also calming residual or lingering anxiety about a cancer recurrence. Ultimately, Alberts’ goal is to help cancer survivors “find the sweet spot to live again.”

A version of this article first appeared on Medscape.com. 

It is the best possible news after an advanced melanoma diagnosis: A clean 10-year scan. This, in all likelihood, means the patient is cured and can leave the office free from their annual ‘scanxiety.’ 

But even in the best-case scenarios, oncologists may dodge the word cure, searching for others such as “remission,” “no evidence of disease,” and “most likely cured” to communicate the good news. Using these more open-ended terms can give patients reassurance without providing false hope that the cancer won’t ever return.

The “risk of future recurrence — even when very small — makes oncologists reluctant to use the word cure, fearing it will be interpreted as a promise, and particularly one that might be broken,” Belinda E. Kiely, MD, and Martin R. Stockler, MD, medical oncologists from the University of Sydney in Australia, wrote in a recent editorial.

Is it ever safe for oncologists to use the word cure? Might doing so backfire? Or does a patient’s underlying fear of recurrence transcend the word?

 

A Word’s Heavy Impact

Part of clinicians’ hesitance to use the word cure may stem from a lack of accepted definition for the term in oncology.

For some experts, a cure means patients will have a normal life expectancy not affected by cancer. Being able to confidently tell a patient that “requires very long-term follow-up,” said James Larkin, PhD, a medical oncologist at The Royal Marsden Hospital, London, England.

The National Cancer Institute (NCI) has a similar definition: “Cure means that there are no traces of your cancer after treatment and the cancer will never come back,” the NCI website says.

The American Society of Clinical Oncology, however, defines cure much more narrowly, as “when a person’s cancer has not returned for at least 5 years after treatment.” 

Not having a standard definition of cure in oncology makes it even more challenging for an oncologist to know how to communicate that a cancer very likely won’t return, without overpromising.

Some of the hesitance in framing good news comes from nuances in prognoses that depend on the type and stage of cancer, explained Marleen Kok, MD, PhD, a breast cancer specialist from the Netherlands Cancer Institute in Amsterdam.

Patients with localized early-stage breast cancer, for instance, have a 5-year survival rate of nearly 100%, and most live 2 decades or longer but, for some, the cancer will return.

“If you talk about early disease, indeed, we cure 80% of breast cancer patients,” Kok said during a press conference at the annual 2024 European Society of Medical Oncology meeting. But sub-dividing breast cancer into tumor type adds complexity. “With triple negative breast cancer, if they relapse, they relapse during the first 2 or 3 years so, at 5 years, the majority are disease free. But that’s different for estrogen receptor positive breast cancer,” in which recurrences can come much later.

In advanced cancers, oncologists may, understandably, be more hesitant to use the word cure. However, ongoing progress in cancer treatments is making the prospect of a cure more likely for some patients.

Take recent findings in melanoma. The landmark CheckMate 067 study in advanced disease revealed that patients receiving the immunotherapy combination of nivolumab plus ipilimumab had a median melanoma-specific survival > 10 years and a median overall survival of about 6 years.

The findings from the trial suggest that “many patients may die from causes unrelated to melanoma — or, in essence, they are cured,” outside expert Elisa Funck-Brentano, MD, PhD, from Ambroise-Paré Hospital in Paris, France, explained to Medscape Medical News.

With CheckMate 067, “what we’re talking about here is potential cure of metastatic solid tumors, which in general is something that’s new,” said senior author Larkin. In fact, late relapses after the 2- to 3-year mark in immunotherapy-treated melanoma are extremely rare.

CheckMate 067 “really made people tempted to use the word cure, and I will say some people in our field do,” said Pauline Funchain, MD, a medical oncologist at Stanford Cancer Institute, and associate professor at Stanford University, Palo Alto, California. “The rest of us really, really want to, but are hesitant because of what we know about melanoma.”

Because the reality is late relapse is still possible.

The cancer can show up decades later and I think, as oncologists, that experience has sort of shaken us,” Funchain told this news organization.

“Oncologists are scarred by those examples,” agreed Evan Hall, MD, a medical oncologist at Fred Hutch Cancer Center and assistant professor at the University of Washington School of Medicine, both in Seattle.

Clinical trials also don’t typically frame patient outcomes in terms of being cured. A recent analysis, which examined the use of “cure” and “hope” in 13,363 oncology articles published between 2000 and 2019 in JAMA Oncology and the Journal of Clinical Oncology, found that both words were used infrequently, especially in primary research articles, and their use decreased significantly over time, even as survival rates in oncology improved. The word cure, for instance, appeared in about 0.1% of sentences in primary research papers published in either journal, though the context of its use was not identified.

Outcomes in cancer clinical trials, which may assess hundreds even thousands of patients, are largely framed in terms of risks and rates of survival — 85% of patients who received treatment X are alive at 5 years or patients receiving treatment Y have a 20% risk for recurrence, for instance.

These risks and rates can’t tell an oncologist whether the patient sitting in front of them can close the cancer chapter of their lives for good.

“I just saw a patient the other day who was 30 years out from their melanoma diagnosis, and they had a recurrence,” Hall recalled. That’s why, “ultimately, it’s a hard thing to tell somebody they’re cured,” he said. “I personally don’t really like using that term.”

While the literature on using the word cure in oncology is limited, one older survey of oncology clinicians supports this view that many feel reluctant to use the term. Of 117 oncology clinicians who responded, 81% said they were “hesitant to tell a patient that they are cured,” and 63% said that they “would never tell a patient that they are cured,” while just 36% said they were comfortable saying the word, with most respondents waiting at least 6-10 years before doing so.

A more recent Italian survey, however, revealed a more favorable view of the word cure in oncology. The survey, which included 224 clinicians and 249 patients, reported that > 90% of cancer physicians, which included surgeons, radiotherapists, and medical oncologists, agreed that it’s possible for a patient to be cured, while about 84% of patients believed this. And > 80% of respondents said using the word cure would be “beneficial” to patients.

Still, even for those hearing the word cure and feeling comforted by an oncologist’s reassurance, it may only provide short-term relief. Fear that the cancer will come slinking, even roaring, back eventually may loom. And this lingering worry can haunt cancer survivors for years.

In a recent cross-sectional study of 229 adults who survived childhood cancer and had lived cancer-free for decades, researchers found that one third reported experiencing clinically significant elevated fear that their primary cancer would recur or a subsequent malignant neoplasm would develop. Similar anxiety has been documented in long-term survivors of adult-onset cancers.

To some degree, every survivor will experience fear and anxiety that their cancer will come back and, at a certain level, that is normal, the study’s senior author Nicole Alberts, PhD, a psychologist, associate professor, and Canada research chair in Behavioural Health Intervention at Concordia University, Montréal, Quebec, Canada, told this news organization.

Although an oncologist’s words do matter and clinicians may wrestle with the right words for patients in the moment, it can take more than words to quell patients’ fear, she said.

“What we know about that kind of anxiety is that there’s this cycle where reassurance doesn’t really help in the long-term,” Alberts said. In other words, hearing the word cure from their oncologist initially makes people feel better, but the anxiety may eventually come back.

Alberts tries to help patients acknowledge and accept uncertainty while also calming residual or lingering anxiety about a cancer recurrence. Ultimately, Alberts’ goal is to help cancer survivors “find the sweet spot to live again.”

A version of this article first appeared on Medscape.com. 

It is the best possible news after an advanced melanoma diagnosis: A clean 10-year scan. This, in all likelihood, means the patient is cured and can leave the office free from their annual ‘scanxiety.’ 

But even in the best-case scenarios, oncologists may dodge the word cure, searching for others such as “remission,” “no evidence of disease,” and “most likely cured” to communicate the good news. Using these more open-ended terms can give patients reassurance without providing false hope that the cancer won’t ever return.

The “risk of future recurrence — even when very small — makes oncologists reluctant to use the word cure, fearing it will be interpreted as a promise, and particularly one that might be broken,” Belinda E. Kiely, MD, and Martin R. Stockler, MD, medical oncologists from the University of Sydney in Australia, wrote in a recent editorial.

Is it ever safe for oncologists to use the word cure? Might doing so backfire? Or does a patient’s underlying fear of recurrence transcend the word?

 

A Word’s Heavy Impact

Part of clinicians’ hesitance to use the word cure may stem from a lack of accepted definition for the term in oncology.

For some experts, a cure means patients will have a normal life expectancy not affected by cancer. Being able to confidently tell a patient that “requires very long-term follow-up,” said James Larkin, PhD, a medical oncologist at The Royal Marsden Hospital, London, England.

The National Cancer Institute (NCI) has a similar definition: “Cure means that there are no traces of your cancer after treatment and the cancer will never come back,” the NCI website says.

The American Society of Clinical Oncology, however, defines cure much more narrowly, as “when a person’s cancer has not returned for at least 5 years after treatment.” 

Not having a standard definition of cure in oncology makes it even more challenging for an oncologist to know how to communicate that a cancer very likely won’t return, without overpromising.

Some of the hesitance in framing good news comes from nuances in prognoses that depend on the type and stage of cancer, explained Marleen Kok, MD, PhD, a breast cancer specialist from the Netherlands Cancer Institute in Amsterdam.

Patients with localized early-stage breast cancer, for instance, have a 5-year survival rate of nearly 100%, and most live 2 decades or longer but, for some, the cancer will return.

“If you talk about early disease, indeed, we cure 80% of breast cancer patients,” Kok said during a press conference at the annual 2024 European Society of Medical Oncology meeting. But sub-dividing breast cancer into tumor type adds complexity. “With triple negative breast cancer, if they relapse, they relapse during the first 2 or 3 years so, at 5 years, the majority are disease free. But that’s different for estrogen receptor positive breast cancer,” in which recurrences can come much later.

In advanced cancers, oncologists may, understandably, be more hesitant to use the word cure. However, ongoing progress in cancer treatments is making the prospect of a cure more likely for some patients.

Take recent findings in melanoma. The landmark CheckMate 067 study in advanced disease revealed that patients receiving the immunotherapy combination of nivolumab plus ipilimumab had a median melanoma-specific survival > 10 years and a median overall survival of about 6 years.

The findings from the trial suggest that “many patients may die from causes unrelated to melanoma — or, in essence, they are cured,” outside expert Elisa Funck-Brentano, MD, PhD, from Ambroise-Paré Hospital in Paris, France, explained to Medscape Medical News.

With CheckMate 067, “what we’re talking about here is potential cure of metastatic solid tumors, which in general is something that’s new,” said senior author Larkin. In fact, late relapses after the 2- to 3-year mark in immunotherapy-treated melanoma are extremely rare.

CheckMate 067 “really made people tempted to use the word cure, and I will say some people in our field do,” said Pauline Funchain, MD, a medical oncologist at Stanford Cancer Institute, and associate professor at Stanford University, Palo Alto, California. “The rest of us really, really want to, but are hesitant because of what we know about melanoma.”

Because the reality is late relapse is still possible.

The cancer can show up decades later and I think, as oncologists, that experience has sort of shaken us,” Funchain told this news organization.

“Oncologists are scarred by those examples,” agreed Evan Hall, MD, a medical oncologist at Fred Hutch Cancer Center and assistant professor at the University of Washington School of Medicine, both in Seattle.

Clinical trials also don’t typically frame patient outcomes in terms of being cured. A recent analysis, which examined the use of “cure” and “hope” in 13,363 oncology articles published between 2000 and 2019 in JAMA Oncology and the Journal of Clinical Oncology, found that both words were used infrequently, especially in primary research articles, and their use decreased significantly over time, even as survival rates in oncology improved. The word cure, for instance, appeared in about 0.1% of sentences in primary research papers published in either journal, though the context of its use was not identified.

Outcomes in cancer clinical trials, which may assess hundreds even thousands of patients, are largely framed in terms of risks and rates of survival — 85% of patients who received treatment X are alive at 5 years or patients receiving treatment Y have a 20% risk for recurrence, for instance.

These risks and rates can’t tell an oncologist whether the patient sitting in front of them can close the cancer chapter of their lives for good.

“I just saw a patient the other day who was 30 years out from their melanoma diagnosis, and they had a recurrence,” Hall recalled. That’s why, “ultimately, it’s a hard thing to tell somebody they’re cured,” he said. “I personally don’t really like using that term.”

While the literature on using the word cure in oncology is limited, one older survey of oncology clinicians supports this view that many feel reluctant to use the term. Of 117 oncology clinicians who responded, 81% said they were “hesitant to tell a patient that they are cured,” and 63% said that they “would never tell a patient that they are cured,” while just 36% said they were comfortable saying the word, with most respondents waiting at least 6-10 years before doing so.

A more recent Italian survey, however, revealed a more favorable view of the word cure in oncology. The survey, which included 224 clinicians and 249 patients, reported that > 90% of cancer physicians, which included surgeons, radiotherapists, and medical oncologists, agreed that it’s possible for a patient to be cured, while about 84% of patients believed this. And > 80% of respondents said using the word cure would be “beneficial” to patients.

Still, even for those hearing the word cure and feeling comforted by an oncologist’s reassurance, it may only provide short-term relief. Fear that the cancer will come slinking, even roaring, back eventually may loom. And this lingering worry can haunt cancer survivors for years.

In a recent cross-sectional study of 229 adults who survived childhood cancer and had lived cancer-free for decades, researchers found that one third reported experiencing clinically significant elevated fear that their primary cancer would recur or a subsequent malignant neoplasm would develop. Similar anxiety has been documented in long-term survivors of adult-onset cancers.

To some degree, every survivor will experience fear and anxiety that their cancer will come back and, at a certain level, that is normal, the study’s senior author Nicole Alberts, PhD, a psychologist, associate professor, and Canada research chair in Behavioural Health Intervention at Concordia University, Montréal, Quebec, Canada, told this news organization.

Although an oncologist’s words do matter and clinicians may wrestle with the right words for patients in the moment, it can take more than words to quell patients’ fear, she said.

“What we know about that kind of anxiety is that there’s this cycle where reassurance doesn’t really help in the long-term,” Alberts said. In other words, hearing the word cure from their oncologist initially makes people feel better, but the anxiety may eventually come back.

Alberts tries to help patients acknowledge and accept uncertainty while also calming residual or lingering anxiety about a cancer recurrence. Ultimately, Alberts’ goal is to help cancer survivors “find the sweet spot to live again.”

A version of this article first appeared on Medscape.com. 

TOPLINE:

Adding cetuximab (C) to postoperative radiotherapy (RT) improves disease-free survival (DFS) but not overall survival (OS) in intermediate-risk squamous cell carcinoma of the head and neck. Benefits were specifically observed in human papillomavirus–negative patients, who represented 80.2% of the study participants.

METHODOLOGY:

• Previous research showed that adding high-dose cisplatin to postoperative RT in patients with squamous cell carcinoma of the head and neck (SCCHN) improved outcomes in those with positive margins and nodal extracapsular extension of the tumor.
• The new phase 3 randomized trial, which enrolled patients from November 2009 to March 2018 included 577 individuals with resected SCCHN of the oral cavity, oropharynx, or larynx, specifically.
• Participants were randomly assigned 1:1 to receive either intensity-modulated RT (60-66 Gy) with weekly C (400 mg/m² loading dose, followed by 250 mg/m² weekly) or RT alone.
• The primary endpoint was OS in randomly assigned eligible patients, with DFS and toxicity as secondary endpoints.
• Analysis included stratified log-rank test for OS and DFS, while toxicity was compared using Fisher’s exact test.

TAKEAWAY:

• OS was not significantly improved with RT plus C vs RT alone (hazard ratio [HR], 0.81; 95% CI, 0.60-1.08; P = .0747), though 5-year OS rates were 76.5% vs 68.7%.
• DFS showed significant improvement with combined therapy (HR, 0.75; 95% CI, 0.57-0.98; P = .0168), with 5-year rates of 71.7% vs 63.6%.
• Grade 3-4 acute toxicity rates were significantly higher with combination therapy (70.3% vs 39.7%; P < .0001), primarily affecting skin and mucosa, though late toxicity rates were similar (33.2% vs 29.0%; P = .3101).
• The benefit of RT plus C was only observed in those patients who were human papillomavirus–negative, which comprised 80.2% of trial participants.

IN PRACTICE:

RT plus C “significantly improved DFS, but not OS, with no increase in long-term toxicity, compared with RT alone for resected, intermediate-risk SCCHN. RT plus C is an appropriate option for carefully selected patients with HPV-negative disease,” the authors of the study wrote.

SOURCE:

This study was led by Mitchell Machtay, MD, Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania. It was published online  in Journal of Clinical Oncology.

LIMITATIONS:

According to the researchers, the OS in the control group was higher than predicted, resulting in the trial being underpowered to detect the initial targeted HR. The authors noted that the better-than-expected survival rates could be attributed to improvements in surgical and radiotherapeutic techniques, including mandatory intensity-modulated RT for all patients. Additionally, the researchers pointed out that patient selection may have influenced outcomes, as only 30% of study participants had more than two risk factors.

DISCLOSURES:

This study was supported by grants from the US National Cancer Institute and Eli Lilly Inc. Machtay received grants from Lilly/ImClone, AstraZeneca, and Merck Sharp & Dohme. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Adding cetuximab (C) to postoperative radiotherapy (RT) improves disease-free survival (DFS) but not overall survival (OS) in intermediate-risk squamous cell carcinoma of the head and neck. Benefits were specifically observed in human papillomavirus–negative patients, who represented 80.2% of the study participants.

METHODOLOGY:

• Previous research showed that adding high-dose cisplatin to postoperative RT in patients with squamous cell carcinoma of the head and neck (SCCHN) improved outcomes in those with positive margins and nodal extracapsular extension of the tumor.
• The new phase 3 randomized trial, which enrolled patients from November 2009 to March 2018 included 577 individuals with resected SCCHN of the oral cavity, oropharynx, or larynx, specifically.
• Participants were randomly assigned 1:1 to receive either intensity-modulated RT (60-66 Gy) with weekly C (400 mg/m² loading dose, followed by 250 mg/m² weekly) or RT alone.
• The primary endpoint was OS in randomly assigned eligible patients, with DFS and toxicity as secondary endpoints.
• Analysis included stratified log-rank test for OS and DFS, while toxicity was compared using Fisher’s exact test.

TAKEAWAY:

• OS was not significantly improved with RT plus C vs RT alone (hazard ratio [HR], 0.81; 95% CI, 0.60-1.08; P = .0747), though 5-year OS rates were 76.5% vs 68.7%.
• DFS showed significant improvement with combined therapy (HR, 0.75; 95% CI, 0.57-0.98; P = .0168), with 5-year rates of 71.7% vs 63.6%.
• Grade 3-4 acute toxicity rates were significantly higher with combination therapy (70.3% vs 39.7%; P < .0001), primarily affecting skin and mucosa, though late toxicity rates were similar (33.2% vs 29.0%; P = .3101).
• The benefit of RT plus C was only observed in those patients who were human papillomavirus–negative, which comprised 80.2% of trial participants.

IN PRACTICE:

RT plus C “significantly improved DFS, but not OS, with no increase in long-term toxicity, compared with RT alone for resected, intermediate-risk SCCHN. RT plus C is an appropriate option for carefully selected patients with HPV-negative disease,” the authors of the study wrote.

SOURCE:

This study was led by Mitchell Machtay, MD, Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania. It was published online  in Journal of Clinical Oncology.

LIMITATIONS:

According to the researchers, the OS in the control group was higher than predicted, resulting in the trial being underpowered to detect the initial targeted HR. The authors noted that the better-than-expected survival rates could be attributed to improvements in surgical and radiotherapeutic techniques, including mandatory intensity-modulated RT for all patients. Additionally, the researchers pointed out that patient selection may have influenced outcomes, as only 30% of study participants had more than two risk factors.

DISCLOSURES:

This study was supported by grants from the US National Cancer Institute and Eli Lilly Inc. Machtay received grants from Lilly/ImClone, AstraZeneca, and Merck Sharp & Dohme. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Adding cetuximab (C) to postoperative radiotherapy (RT) improves disease-free survival (DFS) but not overall survival (OS) in intermediate-risk squamous cell carcinoma of the head and neck. Benefits were specifically observed in human papillomavirus–negative patients, who represented 80.2% of the study participants.

METHODOLOGY:

• Previous research showed that adding high-dose cisplatin to postoperative RT in patients with squamous cell carcinoma of the head and neck (SCCHN) improved outcomes in those with positive margins and nodal extracapsular extension of the tumor.
• The new phase 3 randomized trial, which enrolled patients from November 2009 to March 2018 included 577 individuals with resected SCCHN of the oral cavity, oropharynx, or larynx, specifically.
• Participants were randomly assigned 1:1 to receive either intensity-modulated RT (60-66 Gy) with weekly C (400 mg/m² loading dose, followed by 250 mg/m² weekly) or RT alone.
• The primary endpoint was OS in randomly assigned eligible patients, with DFS and toxicity as secondary endpoints.
• Analysis included stratified log-rank test for OS and DFS, while toxicity was compared using Fisher’s exact test.

TAKEAWAY:

• OS was not significantly improved with RT plus C vs RT alone (hazard ratio [HR], 0.81; 95% CI, 0.60-1.08; P = .0747), though 5-year OS rates were 76.5% vs 68.7%.
• DFS showed significant improvement with combined therapy (HR, 0.75; 95% CI, 0.57-0.98; P = .0168), with 5-year rates of 71.7% vs 63.6%.
• Grade 3-4 acute toxicity rates were significantly higher with combination therapy (70.3% vs 39.7%; P < .0001), primarily affecting skin and mucosa, though late toxicity rates were similar (33.2% vs 29.0%; P = .3101).
• The benefit of RT plus C was only observed in those patients who were human papillomavirus–negative, which comprised 80.2% of trial participants.

IN PRACTICE:

RT plus C “significantly improved DFS, but not OS, with no increase in long-term toxicity, compared with RT alone for resected, intermediate-risk SCCHN. RT plus C is an appropriate option for carefully selected patients with HPV-negative disease,” the authors of the study wrote.

SOURCE:

This study was led by Mitchell Machtay, MD, Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania. It was published online  in Journal of Clinical Oncology.

LIMITATIONS:

According to the researchers, the OS in the control group was higher than predicted, resulting in the trial being underpowered to detect the initial targeted HR. The authors noted that the better-than-expected survival rates could be attributed to improvements in surgical and radiotherapeutic techniques, including mandatory intensity-modulated RT for all patients. Additionally, the researchers pointed out that patient selection may have influenced outcomes, as only 30% of study participants had more than two risk factors.

DISCLOSURES:

This study was supported by grants from the US National Cancer Institute and Eli Lilly Inc. Machtay received grants from Lilly/ImClone, AstraZeneca, and Merck Sharp & Dohme. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A cross-sectional survey of patients preparing for their first radiation therapy consultation found that many patients worried about the physical effects of radiation therapy, including pain, memory loss, and nausea, and more than 60% said they were concerned about their ability to perform daily activities. Respondents reported a range of other worries, including the financial cost of treatment, transportation to treatment sessions, and the ability to continue working, as well as misconceptions about radiation therapy, such as concerns about emitting radiation to others.

METHODOLOGY:

• Toxicities from cancer therapies can significantly affect patients’ quality of life and may contribute to their apprehensions before starting a new treatment. Some studies have indicated that patients may have misconceptions about chemotherapy, but less is known about patients’ perceptions of radiation therapy.
• Researchers conducted a cross-sectional survey of patients presenting for initial radiation therapy consultation at a single academic institution and analyzed responses from 214 patients (52% men; 51% White individuals) with no prior radiation therapy experience.
• The patients completed a 30-question electronic survey about radiation therapy perceptions and fears or concerns prior to their initial radiation consultation.
• Cancer diagnoses spanned 18 disease sites, with hematologic malignancies (21%), breast cancer (18%), and lung cancer (15%) being the most common.

TAKEAWAY:

• Physical adverse effects were the top concern for patients. These included radiation-induced pain (67%), memory loss (62%), nausea/vomiting (60%), and skin reactions (58%).
• Patients expressed concerns about the impact radiation therapy would have on daily activities, with 62% reporting being moderately or very concerned about their ability to perform daily activities and 37% worried about their ability to continue working. Other concerns included the ability to exercise (over half of respondents), financial cost (36%), and transportation to treatment sessions (26%).
• Misconceptions among patients were also common, with 48% expressing concerns about emitting radiation to others and 45% worrying about excreting radioactive urine or stool.
• Patients had varied levels of prior understanding of radiation therapy. Half of patients reported a complete lack of knowledge about radiation therapy, and 35% said they had read or heard stories about bad adverse effects.

IN PRACTICE:

“Our study suggests that a survey administered prior to radiation oncology consultation can reveal patients’ primary concerns which could promote a more patient-centered discussion that addresses specific concerns and involves appropriate services to help the patient,” the authors wrote.

SOURCE:

This study, led by Jennifer Novak, MD, MS, Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California, was published online in Advances in Radiation Oncology.

LIMITATIONS:

Limitations included response bias and time constraints, which prevented many eligible patients from completing the survey. The single-institution design limits the generalizability of the findings. The survey results also showed a disproportionate focus on physical effects over the social impacts of radiation therapy, which could have limited the comprehensiveness of the findings.

DISCLOSURES:

The authors reported no specific funding for this work and no relevant competing financial interests or personal relationships that could have influenced the work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A cross-sectional survey of patients preparing for their first radiation therapy consultation found that many patients worried about the physical effects of radiation therapy, including pain, memory loss, and nausea, and more than 60% said they were concerned about their ability to perform daily activities. Respondents reported a range of other worries, including the financial cost of treatment, transportation to treatment sessions, and the ability to continue working, as well as misconceptions about radiation therapy, such as concerns about emitting radiation to others.

METHODOLOGY:

• Toxicities from cancer therapies can significantly affect patients’ quality of life and may contribute to their apprehensions before starting a new treatment. Some studies have indicated that patients may have misconceptions about chemotherapy, but less is known about patients’ perceptions of radiation therapy.
• Researchers conducted a cross-sectional survey of patients presenting for initial radiation therapy consultation at a single academic institution and analyzed responses from 214 patients (52% men; 51% White individuals) with no prior radiation therapy experience.
• The patients completed a 30-question electronic survey about radiation therapy perceptions and fears or concerns prior to their initial radiation consultation.
• Cancer diagnoses spanned 18 disease sites, with hematologic malignancies (21%), breast cancer (18%), and lung cancer (15%) being the most common.

TAKEAWAY:

• Physical adverse effects were the top concern for patients. These included radiation-induced pain (67%), memory loss (62%), nausea/vomiting (60%), and skin reactions (58%).
• Patients expressed concerns about the impact radiation therapy would have on daily activities, with 62% reporting being moderately or very concerned about their ability to perform daily activities and 37% worried about their ability to continue working. Other concerns included the ability to exercise (over half of respondents), financial cost (36%), and transportation to treatment sessions (26%).
• Misconceptions among patients were also common, with 48% expressing concerns about emitting radiation to others and 45% worrying about excreting radioactive urine or stool.
• Patients had varied levels of prior understanding of radiation therapy. Half of patients reported a complete lack of knowledge about radiation therapy, and 35% said they had read or heard stories about bad adverse effects.

IN PRACTICE:

“Our study suggests that a survey administered prior to radiation oncology consultation can reveal patients’ primary concerns which could promote a more patient-centered discussion that addresses specific concerns and involves appropriate services to help the patient,” the authors wrote.

SOURCE:

This study, led by Jennifer Novak, MD, MS, Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California, was published online in Advances in Radiation Oncology.

LIMITATIONS:

Limitations included response bias and time constraints, which prevented many eligible patients from completing the survey. The single-institution design limits the generalizability of the findings. The survey results also showed a disproportionate focus on physical effects over the social impacts of radiation therapy, which could have limited the comprehensiveness of the findings.

DISCLOSURES:

The authors reported no specific funding for this work and no relevant competing financial interests or personal relationships that could have influenced the work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A cross-sectional survey of patients preparing for their first radiation therapy consultation found that many patients worried about the physical effects of radiation therapy, including pain, memory loss, and nausea, and more than 60% said they were concerned about their ability to perform daily activities. Respondents reported a range of other worries, including the financial cost of treatment, transportation to treatment sessions, and the ability to continue working, as well as misconceptions about radiation therapy, such as concerns about emitting radiation to others.

METHODOLOGY:

• Toxicities from cancer therapies can significantly affect patients’ quality of life and may contribute to their apprehensions before starting a new treatment. Some studies have indicated that patients may have misconceptions about chemotherapy, but less is known about patients’ perceptions of radiation therapy.
• Researchers conducted a cross-sectional survey of patients presenting for initial radiation therapy consultation at a single academic institution and analyzed responses from 214 patients (52% men; 51% White individuals) with no prior radiation therapy experience.
• The patients completed a 30-question electronic survey about radiation therapy perceptions and fears or concerns prior to their initial radiation consultation.
• Cancer diagnoses spanned 18 disease sites, with hematologic malignancies (21%), breast cancer (18%), and lung cancer (15%) being the most common.

TAKEAWAY:

• Physical adverse effects were the top concern for patients. These included radiation-induced pain (67%), memory loss (62%), nausea/vomiting (60%), and skin reactions (58%).
• Patients expressed concerns about the impact radiation therapy would have on daily activities, with 62% reporting being moderately or very concerned about their ability to perform daily activities and 37% worried about their ability to continue working. Other concerns included the ability to exercise (over half of respondents), financial cost (36%), and transportation to treatment sessions (26%).
• Misconceptions among patients were also common, with 48% expressing concerns about emitting radiation to others and 45% worrying about excreting radioactive urine or stool.
• Patients had varied levels of prior understanding of radiation therapy. Half of patients reported a complete lack of knowledge about radiation therapy, and 35% said they had read or heard stories about bad adverse effects.

IN PRACTICE:

“Our study suggests that a survey administered prior to radiation oncology consultation can reveal patients’ primary concerns which could promote a more patient-centered discussion that addresses specific concerns and involves appropriate services to help the patient,” the authors wrote.

SOURCE:

This study, led by Jennifer Novak, MD, MS, Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California, was published online in Advances in Radiation Oncology.

LIMITATIONS:

Limitations included response bias and time constraints, which prevented many eligible patients from completing the survey. The single-institution design limits the generalizability of the findings. The survey results also showed a disproportionate focus on physical effects over the social impacts of radiation therapy, which could have limited the comprehensiveness of the findings.

DISCLOSURES:

The authors reported no specific funding for this work and no relevant competing financial interests or personal relationships that could have influenced the work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Last year, Eric Singhi, MD, a thoracic medical oncologist at MD Anderson Cancer Center in Houston, noticed a shift in his team. The small band of four clinicians, once motivated and enthusiastic, were now withdrawn and distant.

“We had to take a break from clinic one day. We went out, got food and…acknowledged something was off,” Singhi recalled.

That something: Intense emotional exhaustion.

No thoracic oncology team has it easy. Lung cancer remains the leading cause of cancer deaths. But over the last 12 months Singhi’s team had taken on more and more cases in younger patients. Watching patients so close to their own age struggle and ultimately be consumed by this disease took its toll, Singhi said. And the toll was showing up in the lives of his colleagues.

Singhi’s team was suffering from compassion fatigue — the mental, physical, or emotional exhaustion brought on by prolonged exposure to the trauma of people in one’s care. Also referred to secondary trauma, compassion fatigue “leaves someone feeling numb, detached, or like they don’t have emotional resources to keep on giving,” Singhi said.

This fatigue is common among people who work in high-stress caretaking professions. Those involved in cancer care, who frequently find themselves navigating life and death conversations and experiences with patients, are particularly at risk, experts told this news organization.

“I think anyone in medical oncology or hematology who has practiced long enough will feel this,” said Alfred Lee, MD, PhD, burnout researcher and director of the hematology/oncology fellowship at Yale School of Medicine in New Haven, Connecticut. “It’s par for the course, even in training.”

Still, compassion fatigue can be hard to detect without help. Left unaddressed, compassion fatigue can undermine good patient care, even lead to burnout.

“I’ve absolutely treated people leaving the field who think they shouldn’t be a doctor anymore,” said Jennifer Bickel, MD, recently named MD Anderson’s inaugural vice president and chief wellness officer. Those are preventable losses the field can’t afford in a provider shortage, she said.

 

Recognizing the Signs

Compassion is an essential part of patient care as is empathy. Expressing compassion or feeling empathy toward patients can foster the doctor-patient bond and help both navigate challenging conversations and decisions.

“Compassion and being able to empathize are so important — it’s how you gain trust,” Singhi said. This is especially true for patients who may be underrepresented. “That’s how they become a partner in their care, how they agree to listen about a clinical trial or agree to adhere to their treatment plan,” Singhi noted.

But there’s a risk when clinicians start to give too much.

Overtime, repeated exposure to patients’ trauma can create a sense of heaviness and fatigue, and ultimately cause caregivers to detach, Lee said.

A case study of compassion fatigue, based on the experience of one oncologist, highlighted that the condition parallels posttraumatic stress disorder, aligning on three main symptoms: Feeling hyperarousal, notably hypervigilance or irritability, avoiding stressful situations, and reliving traumatic events.

The initial phases of compassion fatigue, however, can be subtle and easily dismissed. An oncologist may begin to feel a creeping sense of detachment — a divide slowly growing with their patients, a buzz of dissatisfaction on the job, unusual mood changes.

While it’s normal for healthcare workers to experience moments of irritability, dissatisfaction, exhaustion or avoidance, when these experiences become pervasive, compassion fatigue could be the culprit, according to Marra Ackerman, MD, a psychiatrist at NYU Langone Health in New York City.

Compassion fatigue is “a form of coping more than anything,” Ackerman explained. Most of the time, it’s not a conscious choice, she said. When a brain experiences repeated distressing inputs it can shift into self-protection mode. The tipping point is different for everyone, but eventually the brain tries to detach and distance itself from the stressor, Ackerman said. And, in oncology, that stressor is often very sick patients.

If not addressed, the emotional exhaustion can limit a doctor’s efficacy at work. Clinicians suffering from compassion fatigue may find themselves calling in sick more often, making more mistakes, avoiding very sick patients, or having panic attacks at work, said Ackerman.

Clinicians also might use food, drugs, or alcohol to feel better, or detach from their patients, Lee added. “We find if you detach, you can’t provide the care patients need,” he said.

When trying to identify the issue, it’s important to understand that compassion fatigue is not burnout. The two issues can look similar, sharing symptoms like emotional detachment or disillusionment, and may co-exist, but the phenomena stem from different root causes.

While compassion fatigue is rooted in emotions and isn’t necessarily tied to work, burnout is a product of work-related stress. It’s often caused by system-level problems that leave clinicians feeling their work has lost its meaning. Inefficient technology or excessive data entry, for instance, could be drivers of burnout for oncologists because these tasks can pull the doctor away from the meaningful work of treating patients.

 

What Can Be Done

Oncology comes with its own set of risks and traumas, but for a long time, doctors weren’t equipped or encouraged to see the constant life-or-death tension of the job as a risk factor to their well-being, said Bickel.

“It’s not something we are inherently taught to identify and it’s not something we can identify without time for self-reflection,” Bickel told this news organization. In fact, many people don’t see their own compassion fatigue until a colleague points it out or they’re already past it and have some distance.

Although common among oncology clinicians, compassion fatigue is not inevitable. Oncologists can learn strategies to help manage their exposures to suffering and stave off reverting to coping mechanisms that only perpetuate the problem.

The key, Bickel said, is creating environments where people can feel safe and share their vulnerabilities. Formal peer support check-ins are a good example because they normalize regular communication about day-to-day difficulties as they happen and create space to experience grief. In these groups, no one has to worry that they’re complaining, she said.

Formalized groups also serve as a training ground where staff can learn to be better listeners. Healthcare providers are more likely to reach out to peers because so few people outside their field can relate to the challenges, Bickel explained. That’s why Moffitt Cancer Center, where Bickel recently worked before moving to MD Anderson, offers trainings to help staff learn to listen more effectively. Thirty doctors, nurses and health professionals have received the training so far and serve as a point of contact for colleagues who might be struggling, Bickel said. They can offer their peers an empathic ear, without providing unsolicited advice or commentary.

NYU Langone has a similar offering, Ackerman said. Providers can reach out to fellow nurses or doctors who have more mental health training. The conversation isn’t recorded like an appointment with a therapist may be. It’s more like mentorship where doctors can be open about what they are facing and find some comradery from someone who understands, without fear of stigma.

Talking to colleagues or having debriefs with your care team is critical because it eliminates the isolation that allows compassion fatigue to fester, Lee said. “Reflecting on positive encounters can help inspire us to keep going. Reflecting on the negative can be therapeutic and help find that sense of balance that everyone needs to find.”

As for Singhi’s team, “lots has changed since we’ve become more open,” he said. The team talks about hard patients early and often. These discussions have helped team members keep the challenges at work from seeping into their home life.

Experts agree that the threshold for seeking out help and guidance should be low. Waiting for depression or more severe symptoms to set in is not the best point of intervention, Bickel said. As soon as an oncologist begins to acknowledge a shift in how they connect with patients and the job, that’s enough to reach out.

“It’s not about what you can handle, it’s about how can you thrive and find joy,” she said.

A version of this article first appeared on Medscape.com.

Last year, Eric Singhi, MD, a thoracic medical oncologist at MD Anderson Cancer Center in Houston, noticed a shift in his team. The small band of four clinicians, once motivated and enthusiastic, were now withdrawn and distant.

“We had to take a break from clinic one day. We went out, got food and…acknowledged something was off,” Singhi recalled.

That something: Intense emotional exhaustion.

No thoracic oncology team has it easy. Lung cancer remains the leading cause of cancer deaths. But over the last 12 months Singhi’s team had taken on more and more cases in younger patients. Watching patients so close to their own age struggle and ultimately be consumed by this disease took its toll, Singhi said. And the toll was showing up in the lives of his colleagues.

Singhi’s team was suffering from compassion fatigue — the mental, physical, or emotional exhaustion brought on by prolonged exposure to the trauma of people in one’s care. Also referred to secondary trauma, compassion fatigue “leaves someone feeling numb, detached, or like they don’t have emotional resources to keep on giving,” Singhi said.

This fatigue is common among people who work in high-stress caretaking professions. Those involved in cancer care, who frequently find themselves navigating life and death conversations and experiences with patients, are particularly at risk, experts told this news organization.

“I think anyone in medical oncology or hematology who has practiced long enough will feel this,” said Alfred Lee, MD, PhD, burnout researcher and director of the hematology/oncology fellowship at Yale School of Medicine in New Haven, Connecticut. “It’s par for the course, even in training.”

Still, compassion fatigue can be hard to detect without help. Left unaddressed, compassion fatigue can undermine good patient care, even lead to burnout.

“I’ve absolutely treated people leaving the field who think they shouldn’t be a doctor anymore,” said Jennifer Bickel, MD, recently named MD Anderson’s inaugural vice president and chief wellness officer. Those are preventable losses the field can’t afford in a provider shortage, she said.

 

Recognizing the Signs

Compassion is an essential part of patient care as is empathy. Expressing compassion or feeling empathy toward patients can foster the doctor-patient bond and help both navigate challenging conversations and decisions.

“Compassion and being able to empathize are so important — it’s how you gain trust,” Singhi said. This is especially true for patients who may be underrepresented. “That’s how they become a partner in their care, how they agree to listen about a clinical trial or agree to adhere to their treatment plan,” Singhi noted.

But there’s a risk when clinicians start to give too much.

Overtime, repeated exposure to patients’ trauma can create a sense of heaviness and fatigue, and ultimately cause caregivers to detach, Lee said.

A case study of compassion fatigue, based on the experience of one oncologist, highlighted that the condition parallels posttraumatic stress disorder, aligning on three main symptoms: Feeling hyperarousal, notably hypervigilance or irritability, avoiding stressful situations, and reliving traumatic events.

The initial phases of compassion fatigue, however, can be subtle and easily dismissed. An oncologist may begin to feel a creeping sense of detachment — a divide slowly growing with their patients, a buzz of dissatisfaction on the job, unusual mood changes.

While it’s normal for healthcare workers to experience moments of irritability, dissatisfaction, exhaustion or avoidance, when these experiences become pervasive, compassion fatigue could be the culprit, according to Marra Ackerman, MD, a psychiatrist at NYU Langone Health in New York City.

Compassion fatigue is “a form of coping more than anything,” Ackerman explained. Most of the time, it’s not a conscious choice, she said. When a brain experiences repeated distressing inputs it can shift into self-protection mode. The tipping point is different for everyone, but eventually the brain tries to detach and distance itself from the stressor, Ackerman said. And, in oncology, that stressor is often very sick patients.

If not addressed, the emotional exhaustion can limit a doctor’s efficacy at work. Clinicians suffering from compassion fatigue may find themselves calling in sick more often, making more mistakes, avoiding very sick patients, or having panic attacks at work, said Ackerman.

Clinicians also might use food, drugs, or alcohol to feel better, or detach from their patients, Lee added. “We find if you detach, you can’t provide the care patients need,” he said.

When trying to identify the issue, it’s important to understand that compassion fatigue is not burnout. The two issues can look similar, sharing symptoms like emotional detachment or disillusionment, and may co-exist, but the phenomena stem from different root causes.

While compassion fatigue is rooted in emotions and isn’t necessarily tied to work, burnout is a product of work-related stress. It’s often caused by system-level problems that leave clinicians feeling their work has lost its meaning. Inefficient technology or excessive data entry, for instance, could be drivers of burnout for oncologists because these tasks can pull the doctor away from the meaningful work of treating patients.

 

What Can Be Done

Oncology comes with its own set of risks and traumas, but for a long time, doctors weren’t equipped or encouraged to see the constant life-or-death tension of the job as a risk factor to their well-being, said Bickel.

“It’s not something we are inherently taught to identify and it’s not something we can identify without time for self-reflection,” Bickel told this news organization. In fact, many people don’t see their own compassion fatigue until a colleague points it out or they’re already past it and have some distance.

Although common among oncology clinicians, compassion fatigue is not inevitable. Oncologists can learn strategies to help manage their exposures to suffering and stave off reverting to coping mechanisms that only perpetuate the problem.

The key, Bickel said, is creating environments where people can feel safe and share their vulnerabilities. Formal peer support check-ins are a good example because they normalize regular communication about day-to-day difficulties as they happen and create space to experience grief. In these groups, no one has to worry that they’re complaining, she said.

Formalized groups also serve as a training ground where staff can learn to be better listeners. Healthcare providers are more likely to reach out to peers because so few people outside their field can relate to the challenges, Bickel explained. That’s why Moffitt Cancer Center, where Bickel recently worked before moving to MD Anderson, offers trainings to help staff learn to listen more effectively. Thirty doctors, nurses and health professionals have received the training so far and serve as a point of contact for colleagues who might be struggling, Bickel said. They can offer their peers an empathic ear, without providing unsolicited advice or commentary.

NYU Langone has a similar offering, Ackerman said. Providers can reach out to fellow nurses or doctors who have more mental health training. The conversation isn’t recorded like an appointment with a therapist may be. It’s more like mentorship where doctors can be open about what they are facing and find some comradery from someone who understands, without fear of stigma.

Talking to colleagues or having debriefs with your care team is critical because it eliminates the isolation that allows compassion fatigue to fester, Lee said. “Reflecting on positive encounters can help inspire us to keep going. Reflecting on the negative can be therapeutic and help find that sense of balance that everyone needs to find.”

As for Singhi’s team, “lots has changed since we’ve become more open,” he said. The team talks about hard patients early and often. These discussions have helped team members keep the challenges at work from seeping into their home life.

Experts agree that the threshold for seeking out help and guidance should be low. Waiting for depression or more severe symptoms to set in is not the best point of intervention, Bickel said. As soon as an oncologist begins to acknowledge a shift in how they connect with patients and the job, that’s enough to reach out.

“It’s not about what you can handle, it’s about how can you thrive and find joy,” she said.

A version of this article first appeared on Medscape.com.

Last year, Eric Singhi, MD, a thoracic medical oncologist at MD Anderson Cancer Center in Houston, noticed a shift in his team. The small band of four clinicians, once motivated and enthusiastic, were now withdrawn and distant.

“We had to take a break from clinic one day. We went out, got food and…acknowledged something was off,” Singhi recalled.

That something: Intense emotional exhaustion.

No thoracic oncology team has it easy. Lung cancer remains the leading cause of cancer deaths. But over the last 12 months Singhi’s team had taken on more and more cases in younger patients. Watching patients so close to their own age struggle and ultimately be consumed by this disease took its toll, Singhi said. And the toll was showing up in the lives of his colleagues.

Singhi’s team was suffering from compassion fatigue — the mental, physical, or emotional exhaustion brought on by prolonged exposure to the trauma of people in one’s care. Also referred to secondary trauma, compassion fatigue “leaves someone feeling numb, detached, or like they don’t have emotional resources to keep on giving,” Singhi said.

This fatigue is common among people who work in high-stress caretaking professions. Those involved in cancer care, who frequently find themselves navigating life and death conversations and experiences with patients, are particularly at risk, experts told this news organization.

“I think anyone in medical oncology or hematology who has practiced long enough will feel this,” said Alfred Lee, MD, PhD, burnout researcher and director of the hematology/oncology fellowship at Yale School of Medicine in New Haven, Connecticut. “It’s par for the course, even in training.”

Still, compassion fatigue can be hard to detect without help. Left unaddressed, compassion fatigue can undermine good patient care, even lead to burnout.

“I’ve absolutely treated people leaving the field who think they shouldn’t be a doctor anymore,” said Jennifer Bickel, MD, recently named MD Anderson’s inaugural vice president and chief wellness officer. Those are preventable losses the field can’t afford in a provider shortage, she said.

 

Recognizing the Signs

Compassion is an essential part of patient care as is empathy. Expressing compassion or feeling empathy toward patients can foster the doctor-patient bond and help both navigate challenging conversations and decisions.

“Compassion and being able to empathize are so important — it’s how you gain trust,” Singhi said. This is especially true for patients who may be underrepresented. “That’s how they become a partner in their care, how they agree to listen about a clinical trial or agree to adhere to their treatment plan,” Singhi noted.

But there’s a risk when clinicians start to give too much.

Overtime, repeated exposure to patients’ trauma can create a sense of heaviness and fatigue, and ultimately cause caregivers to detach, Lee said.

A case study of compassion fatigue, based on the experience of one oncologist, highlighted that the condition parallels posttraumatic stress disorder, aligning on three main symptoms: Feeling hyperarousal, notably hypervigilance or irritability, avoiding stressful situations, and reliving traumatic events.

The initial phases of compassion fatigue, however, can be subtle and easily dismissed. An oncologist may begin to feel a creeping sense of detachment — a divide slowly growing with their patients, a buzz of dissatisfaction on the job, unusual mood changes.

While it’s normal for healthcare workers to experience moments of irritability, dissatisfaction, exhaustion or avoidance, when these experiences become pervasive, compassion fatigue could be the culprit, according to Marra Ackerman, MD, a psychiatrist at NYU Langone Health in New York City.

Compassion fatigue is “a form of coping more than anything,” Ackerman explained. Most of the time, it’s not a conscious choice, she said. When a brain experiences repeated distressing inputs it can shift into self-protection mode. The tipping point is different for everyone, but eventually the brain tries to detach and distance itself from the stressor, Ackerman said. And, in oncology, that stressor is often very sick patients.

If not addressed, the emotional exhaustion can limit a doctor’s efficacy at work. Clinicians suffering from compassion fatigue may find themselves calling in sick more often, making more mistakes, avoiding very sick patients, or having panic attacks at work, said Ackerman.

Clinicians also might use food, drugs, or alcohol to feel better, or detach from their patients, Lee added. “We find if you detach, you can’t provide the care patients need,” he said.

When trying to identify the issue, it’s important to understand that compassion fatigue is not burnout. The two issues can look similar, sharing symptoms like emotional detachment or disillusionment, and may co-exist, but the phenomena stem from different root causes.

While compassion fatigue is rooted in emotions and isn’t necessarily tied to work, burnout is a product of work-related stress. It’s often caused by system-level problems that leave clinicians feeling their work has lost its meaning. Inefficient technology or excessive data entry, for instance, could be drivers of burnout for oncologists because these tasks can pull the doctor away from the meaningful work of treating patients.

 

What Can Be Done

Oncology comes with its own set of risks and traumas, but for a long time, doctors weren’t equipped or encouraged to see the constant life-or-death tension of the job as a risk factor to their well-being, said Bickel.

“It’s not something we are inherently taught to identify and it’s not something we can identify without time for self-reflection,” Bickel told this news organization. In fact, many people don’t see their own compassion fatigue until a colleague points it out or they’re already past it and have some distance.

Although common among oncology clinicians, compassion fatigue is not inevitable. Oncologists can learn strategies to help manage their exposures to suffering and stave off reverting to coping mechanisms that only perpetuate the problem.

The key, Bickel said, is creating environments where people can feel safe and share their vulnerabilities. Formal peer support check-ins are a good example because they normalize regular communication about day-to-day difficulties as they happen and create space to experience grief. In these groups, no one has to worry that they’re complaining, she said.

Formalized groups also serve as a training ground where staff can learn to be better listeners. Healthcare providers are more likely to reach out to peers because so few people outside their field can relate to the challenges, Bickel explained. That’s why Moffitt Cancer Center, where Bickel recently worked before moving to MD Anderson, offers trainings to help staff learn to listen more effectively. Thirty doctors, nurses and health professionals have received the training so far and serve as a point of contact for colleagues who might be struggling, Bickel said. They can offer their peers an empathic ear, without providing unsolicited advice or commentary.

NYU Langone has a similar offering, Ackerman said. Providers can reach out to fellow nurses or doctors who have more mental health training. The conversation isn’t recorded like an appointment with a therapist may be. It’s more like mentorship where doctors can be open about what they are facing and find some comradery from someone who understands, without fear of stigma.

Talking to colleagues or having debriefs with your care team is critical because it eliminates the isolation that allows compassion fatigue to fester, Lee said. “Reflecting on positive encounters can help inspire us to keep going. Reflecting on the negative can be therapeutic and help find that sense of balance that everyone needs to find.”

As for Singhi’s team, “lots has changed since we’ve become more open,” he said. The team talks about hard patients early and often. These discussions have helped team members keep the challenges at work from seeping into their home life.

Experts agree that the threshold for seeking out help and guidance should be low. Waiting for depression or more severe symptoms to set in is not the best point of intervention, Bickel said. As soon as an oncologist begins to acknowledge a shift in how they connect with patients and the job, that’s enough to reach out.

“It’s not about what you can handle, it’s about how can you thrive and find joy,” she said.

A version of this article first appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study of nearly 250,000 veterans.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said, in an interview.

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he commented.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

A version of this article first appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study of nearly 250,000 veterans.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said, in an interview.

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he commented.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

A version of this article first appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study of nearly 250,000 veterans.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said, in an interview.

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he commented.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

A version of this article first appeared on Medscape.com.

The use of surrogate endpoints to predict overall survival in oncology trials has been vigorously debated in the oncology community. 

In multiple studies, we have shown that the correlation of surrogate endpoints with overall survival has been weak and, in most cases, inadequate. However, others have made arguments against using overall survival as the gold standard endpoint for cancer drug trials. These arguments include claims that overall survival is not a feasible endpoint for pivotal cancer drug trials and that negative overall survival results may be unreliable.

In this column, we counter some of these arguments from the perspective of an oncologist who treats cancer and is engaged in oncology research and a patient advocate with lived experience of cancer.

Argument: Overall survival is not the only meaningful clinical endpoint. Response rates and progression-free survival also are important clinical endpoints because patients feel good when their tumor shrinks or they have more time without disease progression. Both situations can improve patients’ quality of life. 

Response: On the face of it, this argument sounds reasonable, but it treats response rates and progression-free survival as clinical endpoints rather than surrogate endpoints that need to be validated. A patient would surely welcome news that treatment has reduced the size of their tumor and would feel dismayed if the tumor is growing. However, these reactions rest on the belief that these changes signal recovery in the case of a shrinking tumor, or worsening symptoms in the case of a growing tumor, neither of which may be true. 

“Disease progression” and “progression-free survival” were developed as technical terms to signify whether a therapy in a phase 2 clinical trial was sufficiently promising to advance to phase 3. The terms were not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. In clinical trials, a progression event is defined as an increase in the sum of tumor diameters by more than 20%, or the appearance of a new lesion. These are both arbitrary benchmarks that in no way imply that a patient’s subjective experience of symptoms or their survival time would differ widely between a tumor growth of 19% vs 21%, or if a new, tiny lesion develops.

Of course, disease progression sometimes does affect a patient’s quality of life, but trials treat all progression events equally. An event in the brain that affects the patient’s ability to walk and an asymptomatic tumor growth in the lung from 1 cm to 1.3 cm are both considered disease progression in trials.

Patients care about progression-free survival because they mistakenly believe that an improvement will probably lead to improved overall survival or quality of life. But overall survival and quality of life can actually be affected detrimentally, despite progression-free survival gains, because the patient may experience treatment-related physical and financial toxicity without clinical benefit. Conversely, it is possible to have better overall survival and quality of life without any improvement in progression-free survival.

With response rates, the relationships to overall survival and quality of life are even weaker. Because progression-free survival and response rates do not represent clinical benefit, they cannot be considered clinical endpoints. They are surrogate endpoints that need to be validated.

A patient will reasonably welcome a treatment-related change that improves the prospect of living a longer life or enduring less suffering but should not be misled when these outcomes have not been demonstrated as being clinically beneficial.

Argument: It is not ethical to wait for overall survival when there is an unmet need.

Response: The phrase “unmet need” is used to represent the lack of effective treatment options for a particular condition. Regulators may expedite approval of a new drug that is intended to fulfil the need because waiting for overall survival may not seem ethical in these settings. 

In reality, however, the term is used inconsistently, both when the need is either questionable (the indication is indolent) or the need is real but one or more treatment options already exist. 

When the need for a drug with clinical benefit is genuinely unmet, presenting patients with just any drug is unethical; their need will continue to exist despite drug approvals if survival is not improved. In fact, approving ineffective drugs can impede the development of drugs that work.

Argument: Overall survival is not a practical endpoint for drug trials for rare cancers. 

Response: This argument has some practical validity because the low prevalence of a rare cancer may limit study recruitment opportunities. From an equity perspective, however, patients with rare cancers are no less deserving of treatments based on meaningful evidence of safety and efficacy than are patients with common cancers. Like any other patient with cancer, they should know those treatments have shown the potential for an overall survival or quality of life benefit before undergoing potentially toxic treatments. 

Several trials, such as FIRM-ACT, VIT-0910, AEWS0031, and rEECur, have shown that international collaboration makes randomized clinical trials with an endpoint of overall survival possible for most rare cancers. We support offering early access via accelerated approval when scientific evidence suggests a drug has potential benefit for patients, but the trial should be followed to confirm an overall survival benefit and the drug should be withdrawn if an overall survival benefit is lacking. 

Argument: The point of measuring overall survival is to ensure that the treatment does not worsen overall survival. 

Response: This argument is frequently made, even by regulators. However, unless a drug is tested in a justified noninferiority design trial where the aim is to determine whether it provides compensatory benefits — easier administration, lower cost, or fewer side effects than the alternative — the goal of new cancer drugs is to improve survival. Merely “not worsening survival” is incongruent with medicine’s fundamental goal of benevolence. All drugs have toxicities, some of which can be fatal. Recommending a treatment with toxicities because it did not worsen survival would harm patients and go against the Hippocratic Oath.

Argument: Overall survival in this trial was negative, but this was probably a false-negative finding. We expect future trials will be positive. 

Response: When a drug fails to improve overall survival, some experts will argue that it was a false-negative result and a future trial will be positive. For instance, to explain the negative overall survival findings in a 2020 confirmatory trial, the researchers cited a subgroup analysis in which the drug received accelerated approval based on early exploratory results. However, the subgroup analysis violated the statistical plan and raised the likelihood that the early trial’s favorable outcome was false-positive.

A second trend that increases the likelihood of false-positives is when the same anticancer medications are studied across multiple trials. If we run dozens of trials of the same drug, some of them will eventually be positive by chance alone. 

Dismissing a negative overall survival finding as a statistical artifact puts patients at risk because oncologists may continue to use the drug, despite it providing no discernable clinical benefit to patients. 

Argument: The overall survival was negative because of crossover so that patients in the control arm received the therapy at progression. 

Response: Highly effective drugs will continue to show overall survival gains despite crossover — that is, when patients in the control arm receive the experimental drug at the time of progression.

For example, a trial evaluating the addition of pertuzumab in first-line HER2-positive metastatic breast cancer allowed crossover and still showed a significant overall survival benefit. Another trial evaluating sunitinib vs placebo in advanced gastrointestinal stromal tumors showed a significant overall survival improvement despite 80% of patients in the placebo arm crossing over to sunitinib at progression.

However, in the SONIA trial, receiving cyclin-dependent kinase 4/6 inhibitors as first-line treatment of metastatic hormone receptor–positive breast cancer did not improve survival and added toxicities compared with receipt of the same agents as second-line treatment.

If crossover negates an overall survival benefit, this implies that patients in the experimental arm who received the drug upfront and patients in control arm who get the drug only at progression have no difference in survival times. If the survival outcomes in the groups are similar, that is evidence that the new drug should be given only to those who need treatment at the time of progression and not to everyone upfront. 

Giving patients the drug at the time of progression would spare patients toxicities, preserve efficacy, and save health systems costs.

Argument: Although overall survival is negative in the confirmatory trial, the clinical practice guidelines recommend using the drug, and the guidelines should be followed.

Response: We cannot ignore results of a confirmatory trial just because the drug is already in the guidelines. Guidelines should be updated on the basis of the latest evidence, rather than clinical practice being dictated by outdated guidelines. When a drug given accelerated approval appears in the guidelines, the confidence level of the evidence should be rated low until confirmatory results are available. If a confirmatory trial shows that overall survival does not improve, the guidelines should be quickly updated. However, even if they are not, physicians should not just blindly follow the guidelines.

Furthermore, practitioners should be aware that members of oncology guidelines committees often have financial conflicts of interest with pharmaceutical companies, which the literature shows can bias guideline recommendations.

 

The Bottom Line

We believe that despite arguments put forward against relying on or measuring overall survival, it continues to be the most patient-centric marker of clinical benefit. Patients deserve to know that the cancer drugs their oncologists recommend will contribute to a longer or better life.

Bishal Gyawali, Associate Professor, Department of Oncology and Department of Public Health Sciences; Scientist, Division of Cancer Care and Epidemiology, Queen’s University, Kingston, Ontario, Canada; Affiliated Faculty at the Program on Regulation, Therapeutics, and Law, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, has disclosed the financial relationship by receiving consulting fees from Vivio Health. Sharon Batt, Cancer survivor and patient advocate; Adjunct professor, Department of Bioethics and Department of Political Science, Dalhousie University, Halifax, Nova Scotia, Canada, has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The use of surrogate endpoints to predict overall survival in oncology trials has been vigorously debated in the oncology community. 

In multiple studies, we have shown that the correlation of surrogate endpoints with overall survival has been weak and, in most cases, inadequate. However, others have made arguments against using overall survival as the gold standard endpoint for cancer drug trials. These arguments include claims that overall survival is not a feasible endpoint for pivotal cancer drug trials and that negative overall survival results may be unreliable.

In this column, we counter some of these arguments from the perspective of an oncologist who treats cancer and is engaged in oncology research and a patient advocate with lived experience of cancer.

Argument: Overall survival is not the only meaningful clinical endpoint. Response rates and progression-free survival also are important clinical endpoints because patients feel good when their tumor shrinks or they have more time without disease progression. Both situations can improve patients’ quality of life. 

Response: On the face of it, this argument sounds reasonable, but it treats response rates and progression-free survival as clinical endpoints rather than surrogate endpoints that need to be validated. A patient would surely welcome news that treatment has reduced the size of their tumor and would feel dismayed if the tumor is growing. However, these reactions rest on the belief that these changes signal recovery in the case of a shrinking tumor, or worsening symptoms in the case of a growing tumor, neither of which may be true. 

“Disease progression” and “progression-free survival” were developed as technical terms to signify whether a therapy in a phase 2 clinical trial was sufficiently promising to advance to phase 3. The terms were not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. In clinical trials, a progression event is defined as an increase in the sum of tumor diameters by more than 20%, or the appearance of a new lesion. These are both arbitrary benchmarks that in no way imply that a patient’s subjective experience of symptoms or their survival time would differ widely between a tumor growth of 19% vs 21%, or if a new, tiny lesion develops.

Of course, disease progression sometimes does affect a patient’s quality of life, but trials treat all progression events equally. An event in the brain that affects the patient’s ability to walk and an asymptomatic tumor growth in the lung from 1 cm to 1.3 cm are both considered disease progression in trials.

Patients care about progression-free survival because they mistakenly believe that an improvement will probably lead to improved overall survival or quality of life. But overall survival and quality of life can actually be affected detrimentally, despite progression-free survival gains, because the patient may experience treatment-related physical and financial toxicity without clinical benefit. Conversely, it is possible to have better overall survival and quality of life without any improvement in progression-free survival.

With response rates, the relationships to overall survival and quality of life are even weaker. Because progression-free survival and response rates do not represent clinical benefit, they cannot be considered clinical endpoints. They are surrogate endpoints that need to be validated.

A patient will reasonably welcome a treatment-related change that improves the prospect of living a longer life or enduring less suffering but should not be misled when these outcomes have not been demonstrated as being clinically beneficial.

Argument: It is not ethical to wait for overall survival when there is an unmet need.

Response: The phrase “unmet need” is used to represent the lack of effective treatment options for a particular condition. Regulators may expedite approval of a new drug that is intended to fulfil the need because waiting for overall survival may not seem ethical in these settings. 

In reality, however, the term is used inconsistently, both when the need is either questionable (the indication is indolent) or the need is real but one or more treatment options already exist. 

When the need for a drug with clinical benefit is genuinely unmet, presenting patients with just any drug is unethical; their need will continue to exist despite drug approvals if survival is not improved. In fact, approving ineffective drugs can impede the development of drugs that work.

Argument: Overall survival is not a practical endpoint for drug trials for rare cancers. 

Response: This argument has some practical validity because the low prevalence of a rare cancer may limit study recruitment opportunities. From an equity perspective, however, patients with rare cancers are no less deserving of treatments based on meaningful evidence of safety and efficacy than are patients with common cancers. Like any other patient with cancer, they should know those treatments have shown the potential for an overall survival or quality of life benefit before undergoing potentially toxic treatments. 

Several trials, such as FIRM-ACT, VIT-0910, AEWS0031, and rEECur, have shown that international collaboration makes randomized clinical trials with an endpoint of overall survival possible for most rare cancers. We support offering early access via accelerated approval when scientific evidence suggests a drug has potential benefit for patients, but the trial should be followed to confirm an overall survival benefit and the drug should be withdrawn if an overall survival benefit is lacking. 

Argument: The point of measuring overall survival is to ensure that the treatment does not worsen overall survival. 

Response: This argument is frequently made, even by regulators. However, unless a drug is tested in a justified noninferiority design trial where the aim is to determine whether it provides compensatory benefits — easier administration, lower cost, or fewer side effects than the alternative — the goal of new cancer drugs is to improve survival. Merely “not worsening survival” is incongruent with medicine’s fundamental goal of benevolence. All drugs have toxicities, some of which can be fatal. Recommending a treatment with toxicities because it did not worsen survival would harm patients and go against the Hippocratic Oath.

Argument: Overall survival in this trial was negative, but this was probably a false-negative finding. We expect future trials will be positive. 

Response: When a drug fails to improve overall survival, some experts will argue that it was a false-negative result and a future trial will be positive. For instance, to explain the negative overall survival findings in a 2020 confirmatory trial, the researchers cited a subgroup analysis in which the drug received accelerated approval based on early exploratory results. However, the subgroup analysis violated the statistical plan and raised the likelihood that the early trial’s favorable outcome was false-positive.

A second trend that increases the likelihood of false-positives is when the same anticancer medications are studied across multiple trials. If we run dozens of trials of the same drug, some of them will eventually be positive by chance alone. 

Dismissing a negative overall survival finding as a statistical artifact puts patients at risk because oncologists may continue to use the drug, despite it providing no discernable clinical benefit to patients. 

Argument: The overall survival was negative because of crossover so that patients in the control arm received the therapy at progression. 

Response: Highly effective drugs will continue to show overall survival gains despite crossover — that is, when patients in the control arm receive the experimental drug at the time of progression.

For example, a trial evaluating the addition of pertuzumab in first-line HER2-positive metastatic breast cancer allowed crossover and still showed a significant overall survival benefit. Another trial evaluating sunitinib vs placebo in advanced gastrointestinal stromal tumors showed a significant overall survival improvement despite 80% of patients in the placebo arm crossing over to sunitinib at progression.

However, in the SONIA trial, receiving cyclin-dependent kinase 4/6 inhibitors as first-line treatment of metastatic hormone receptor–positive breast cancer did not improve survival and added toxicities compared with receipt of the same agents as second-line treatment.

If crossover negates an overall survival benefit, this implies that patients in the experimental arm who received the drug upfront and patients in control arm who get the drug only at progression have no difference in survival times. If the survival outcomes in the groups are similar, that is evidence that the new drug should be given only to those who need treatment at the time of progression and not to everyone upfront. 

Giving patients the drug at the time of progression would spare patients toxicities, preserve efficacy, and save health systems costs.

Argument: Although overall survival is negative in the confirmatory trial, the clinical practice guidelines recommend using the drug, and the guidelines should be followed.

Response: We cannot ignore results of a confirmatory trial just because the drug is already in the guidelines. Guidelines should be updated on the basis of the latest evidence, rather than clinical practice being dictated by outdated guidelines. When a drug given accelerated approval appears in the guidelines, the confidence level of the evidence should be rated low until confirmatory results are available. If a confirmatory trial shows that overall survival does not improve, the guidelines should be quickly updated. However, even if they are not, physicians should not just blindly follow the guidelines.

Furthermore, practitioners should be aware that members of oncology guidelines committees often have financial conflicts of interest with pharmaceutical companies, which the literature shows can bias guideline recommendations.

 

The Bottom Line

We believe that despite arguments put forward against relying on or measuring overall survival, it continues to be the most patient-centric marker of clinical benefit. Patients deserve to know that the cancer drugs their oncologists recommend will contribute to a longer or better life.

Bishal Gyawali, Associate Professor, Department of Oncology and Department of Public Health Sciences; Scientist, Division of Cancer Care and Epidemiology, Queen’s University, Kingston, Ontario, Canada; Affiliated Faculty at the Program on Regulation, Therapeutics, and Law, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, has disclosed the financial relationship by receiving consulting fees from Vivio Health. Sharon Batt, Cancer survivor and patient advocate; Adjunct professor, Department of Bioethics and Department of Political Science, Dalhousie University, Halifax, Nova Scotia, Canada, has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The use of surrogate endpoints to predict overall survival in oncology trials has been vigorously debated in the oncology community. 

In multiple studies, we have shown that the correlation of surrogate endpoints with overall survival has been weak and, in most cases, inadequate. However, others have made arguments against using overall survival as the gold standard endpoint for cancer drug trials. These arguments include claims that overall survival is not a feasible endpoint for pivotal cancer drug trials and that negative overall survival results may be unreliable.

In this column, we counter some of these arguments from the perspective of an oncologist who treats cancer and is engaged in oncology research and a patient advocate with lived experience of cancer.

Argument: Overall survival is not the only meaningful clinical endpoint. Response rates and progression-free survival also are important clinical endpoints because patients feel good when their tumor shrinks or they have more time without disease progression. Both situations can improve patients’ quality of life. 

Response: On the face of it, this argument sounds reasonable, but it treats response rates and progression-free survival as clinical endpoints rather than surrogate endpoints that need to be validated. A patient would surely welcome news that treatment has reduced the size of their tumor and would feel dismayed if the tumor is growing. However, these reactions rest on the belief that these changes signal recovery in the case of a shrinking tumor, or worsening symptoms in the case of a growing tumor, neither of which may be true. 

“Disease progression” and “progression-free survival” were developed as technical terms to signify whether a therapy in a phase 2 clinical trial was sufficiently promising to advance to phase 3. The terms were not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. In clinical trials, a progression event is defined as an increase in the sum of tumor diameters by more than 20%, or the appearance of a new lesion. These are both arbitrary benchmarks that in no way imply that a patient’s subjective experience of symptoms or their survival time would differ widely between a tumor growth of 19% vs 21%, or if a new, tiny lesion develops.

Of course, disease progression sometimes does affect a patient’s quality of life, but trials treat all progression events equally. An event in the brain that affects the patient’s ability to walk and an asymptomatic tumor growth in the lung from 1 cm to 1.3 cm are both considered disease progression in trials.

Patients care about progression-free survival because they mistakenly believe that an improvement will probably lead to improved overall survival or quality of life. But overall survival and quality of life can actually be affected detrimentally, despite progression-free survival gains, because the patient may experience treatment-related physical and financial toxicity without clinical benefit. Conversely, it is possible to have better overall survival and quality of life without any improvement in progression-free survival.

With response rates, the relationships to overall survival and quality of life are even weaker. Because progression-free survival and response rates do not represent clinical benefit, they cannot be considered clinical endpoints. They are surrogate endpoints that need to be validated.

A patient will reasonably welcome a treatment-related change that improves the prospect of living a longer life or enduring less suffering but should not be misled when these outcomes have not been demonstrated as being clinically beneficial.

Argument: It is not ethical to wait for overall survival when there is an unmet need.

Response: The phrase “unmet need” is used to represent the lack of effective treatment options for a particular condition. Regulators may expedite approval of a new drug that is intended to fulfil the need because waiting for overall survival may not seem ethical in these settings. 

In reality, however, the term is used inconsistently, both when the need is either questionable (the indication is indolent) or the need is real but one or more treatment options already exist. 

When the need for a drug with clinical benefit is genuinely unmet, presenting patients with just any drug is unethical; their need will continue to exist despite drug approvals if survival is not improved. In fact, approving ineffective drugs can impede the development of drugs that work.

Argument: Overall survival is not a practical endpoint for drug trials for rare cancers. 

Response: This argument has some practical validity because the low prevalence of a rare cancer may limit study recruitment opportunities. From an equity perspective, however, patients with rare cancers are no less deserving of treatments based on meaningful evidence of safety and efficacy than are patients with common cancers. Like any other patient with cancer, they should know those treatments have shown the potential for an overall survival or quality of life benefit before undergoing potentially toxic treatments. 

Several trials, such as FIRM-ACT, VIT-0910, AEWS0031, and rEECur, have shown that international collaboration makes randomized clinical trials with an endpoint of overall survival possible for most rare cancers. We support offering early access via accelerated approval when scientific evidence suggests a drug has potential benefit for patients, but the trial should be followed to confirm an overall survival benefit and the drug should be withdrawn if an overall survival benefit is lacking. 

Argument: The point of measuring overall survival is to ensure that the treatment does not worsen overall survival. 

Response: This argument is frequently made, even by regulators. However, unless a drug is tested in a justified noninferiority design trial where the aim is to determine whether it provides compensatory benefits — easier administration, lower cost, or fewer side effects than the alternative — the goal of new cancer drugs is to improve survival. Merely “not worsening survival” is incongruent with medicine’s fundamental goal of benevolence. All drugs have toxicities, some of which can be fatal. Recommending a treatment with toxicities because it did not worsen survival would harm patients and go against the Hippocratic Oath.

Argument: Overall survival in this trial was negative, but this was probably a false-negative finding. We expect future trials will be positive. 

Response: When a drug fails to improve overall survival, some experts will argue that it was a false-negative result and a future trial will be positive. For instance, to explain the negative overall survival findings in a 2020 confirmatory trial, the researchers cited a subgroup analysis in which the drug received accelerated approval based on early exploratory results. However, the subgroup analysis violated the statistical plan and raised the likelihood that the early trial’s favorable outcome was false-positive.

A second trend that increases the likelihood of false-positives is when the same anticancer medications are studied across multiple trials. If we run dozens of trials of the same drug, some of them will eventually be positive by chance alone. 

Dismissing a negative overall survival finding as a statistical artifact puts patients at risk because oncologists may continue to use the drug, despite it providing no discernable clinical benefit to patients. 

Argument: The overall survival was negative because of crossover so that patients in the control arm received the therapy at progression. 

Response: Highly effective drugs will continue to show overall survival gains despite crossover — that is, when patients in the control arm receive the experimental drug at the time of progression.

For example, a trial evaluating the addition of pertuzumab in first-line HER2-positive metastatic breast cancer allowed crossover and still showed a significant overall survival benefit. Another trial evaluating sunitinib vs placebo in advanced gastrointestinal stromal tumors showed a significant overall survival improvement despite 80% of patients in the placebo arm crossing over to sunitinib at progression.

However, in the SONIA trial, receiving cyclin-dependent kinase 4/6 inhibitors as first-line treatment of metastatic hormone receptor–positive breast cancer did not improve survival and added toxicities compared with receipt of the same agents as second-line treatment.

If crossover negates an overall survival benefit, this implies that patients in the experimental arm who received the drug upfront and patients in control arm who get the drug only at progression have no difference in survival times. If the survival outcomes in the groups are similar, that is evidence that the new drug should be given only to those who need treatment at the time of progression and not to everyone upfront. 

Giving patients the drug at the time of progression would spare patients toxicities, preserve efficacy, and save health systems costs.

Argument: Although overall survival is negative in the confirmatory trial, the clinical practice guidelines recommend using the drug, and the guidelines should be followed.

Response: We cannot ignore results of a confirmatory trial just because the drug is already in the guidelines. Guidelines should be updated on the basis of the latest evidence, rather than clinical practice being dictated by outdated guidelines. When a drug given accelerated approval appears in the guidelines, the confidence level of the evidence should be rated low until confirmatory results are available. If a confirmatory trial shows that overall survival does not improve, the guidelines should be quickly updated. However, even if they are not, physicians should not just blindly follow the guidelines.

Furthermore, practitioners should be aware that members of oncology guidelines committees often have financial conflicts of interest with pharmaceutical companies, which the literature shows can bias guideline recommendations.

 

The Bottom Line

We believe that despite arguments put forward against relying on or measuring overall survival, it continues to be the most patient-centric marker of clinical benefit. Patients deserve to know that the cancer drugs their oncologists recommend will contribute to a longer or better life.

Bishal Gyawali, Associate Professor, Department of Oncology and Department of Public Health Sciences; Scientist, Division of Cancer Care and Epidemiology, Queen’s University, Kingston, Ontario, Canada; Affiliated Faculty at the Program on Regulation, Therapeutics, and Law, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, has disclosed the financial relationship by receiving consulting fees from Vivio Health. Sharon Batt, Cancer survivor and patient advocate; Adjunct professor, Department of Bioethics and Department of Political Science, Dalhousie University, Halifax, Nova Scotia, Canada, has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.