Melanoma

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

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In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. Two recent phase 1 studies of anti-PD-1 antibodies indicate that these agents exhibit considerable antitumor activity alone or in combination with ipilimumab in patients with advanced melanoma.

*Click on the links to the left for PDFs of the full article and related Commentary.

The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. Two recent phase 1 studies of anti-PD-1 antibodies indicate that these agents exhibit considerable antitumor activity alone or in combination with ipilimumab in patients with advanced melanoma.

*Click on the links to the left for PDFs of the full article and related Commentary.

The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. Two recent phase 1 studies of anti-PD-1 antibodies indicate that these agents exhibit considerable antitumor activity alone or in combination with ipilimumab in patients with advanced melanoma.

*Click on the links to the left for PDFs of the full article and related Commentary.

I have taken beta-blockers for nearly 30 years to combat a non–life-threatening but very disconcerting supraventricular arrhythmia. Also being fair skinned and having suffered through many a blistering sunburn in my youth, I was excited to read the most recent publication regarding the relationship between beta-blocker ingestion and survival from melanoma by De Giorgi et al (Mayo Clin Proc. 2013;88:1196-1203). The Italian investigators collected data from all melanoma patients diagnosed in the dermatology department at the University of Florence (1993-2009). After excluding patients who presented with metastatic disease, they then compared the courses of the remaining patients based on whether or not they had been prescribed beta-blockers for at least 1 year before or after their cutaneous melanoma diagnosis. Of 741 consecutive patients who fit the retrospective study criteria, 79 (11%) had been taking beta-blockers and the remaining 662 (89%) had not been taking beta-blockers.

An analysis based on the multivariate Cox model indicated that the beta-blocker group had improved overall survival after a median follow-up of 4.2 years (P=.005). Looked at in another way, significantly more patients in the untreated group (8%) than the beta-blocker group (3%) experienced disease progression or death (P<.001). The “protective” effect of beta-blockers was so striking that it could be quantified; for each year of beta-blocker use, the risk for death was reduced by 38%. More notable was the fact that the beneficial effect of beta-blocker administration was consistent, even among patients with inherently unfavorable prognostic factors, such as advanced age, thicker lesions, higher frequency of mitoses and ulceration, and nodular melanoma subtype. This large study confirms the results of a much smaller study (N=121) published by the same group in 2011 (Arch Intern Med. 2011;171:779-781).

What’s the issue?

Why might this phenomenon occur? Perhaps blocking sympathetic nervous system neurotransmitters might help avoid the suspected immunosuppression that accompanies stress. Sympathetic neurotransmitters also are known to interact with molecular pathways implicated in abnormal cellular replication, such as the p38/MAPK pathway. Thus, blunting the effects of epinephrine and norepinephrine by blocking some of their receptors might produce a salutatory benefit in the cancer (in this case, melanoma) patient.

Before we all rush out and give all our melanoma patients daily doses of metoprolol, however, De Giorgi et al noted in the most recent study that about two-thirds of the patients were already taking a beta-blocker when their melanoma was diagnosed. Although this study suggests that beta-blockers reduce the risk for recurrence and disease-specific mortality, these drugs clearly do not prevent melanoma in the first place. Furthermore, it should be noted that the number of melanoma patients receiving beta-blockers was small, and conclusions should always be tempered in a retrospective study. The authors duly admit that their investigation indicates the strong need for a truly randomized prospective clinical trial. Of course, administration of beta-blockers is not a totally benign endeavor, as serious hypotension and/or bradycardia may occur, leading to syncope or even worse problems. Finally, the evidence of beta-blocker benefit in melanoma patients is contradictory! A Dutch cohort of 709 melanoma patients recently was studied (Eur J Cancer. 2013;49:3863-3871); this set of investigators found that exposure to beta-blockers did not impact overall melanoma survival regardless of the timing, duration, or dosage of beta-blocker use. In summary, therefore, we still need to determine many things about the relationship between beta-blockers and melanoma survival. That is, if there is a relationship at all. What do you think?

We want to know your views! Tell us what you think.

I have taken beta-blockers for nearly 30 years to combat a non–life-threatening but very disconcerting supraventricular arrhythmia. Also being fair skinned and having suffered through many a blistering sunburn in my youth, I was excited to read the most recent publication regarding the relationship between beta-blocker ingestion and survival from melanoma by De Giorgi et al (Mayo Clin Proc. 2013;88:1196-1203). The Italian investigators collected data from all melanoma patients diagnosed in the dermatology department at the University of Florence (1993-2009). After excluding patients who presented with metastatic disease, they then compared the courses of the remaining patients based on whether or not they had been prescribed beta-blockers for at least 1 year before or after their cutaneous melanoma diagnosis. Of 741 consecutive patients who fit the retrospective study criteria, 79 (11%) had been taking beta-blockers and the remaining 662 (89%) had not been taking beta-blockers.

An analysis based on the multivariate Cox model indicated that the beta-blocker group had improved overall survival after a median follow-up of 4.2 years (P=.005). Looked at in another way, significantly more patients in the untreated group (8%) than the beta-blocker group (3%) experienced disease progression or death (P<.001). The “protective” effect of beta-blockers was so striking that it could be quantified; for each year of beta-blocker use, the risk for death was reduced by 38%. More notable was the fact that the beneficial effect of beta-blocker administration was consistent, even among patients with inherently unfavorable prognostic factors, such as advanced age, thicker lesions, higher frequency of mitoses and ulceration, and nodular melanoma subtype. This large study confirms the results of a much smaller study (N=121) published by the same group in 2011 (Arch Intern Med. 2011;171:779-781).

What’s the issue?

Why might this phenomenon occur? Perhaps blocking sympathetic nervous system neurotransmitters might help avoid the suspected immunosuppression that accompanies stress. Sympathetic neurotransmitters also are known to interact with molecular pathways implicated in abnormal cellular replication, such as the p38/MAPK pathway. Thus, blunting the effects of epinephrine and norepinephrine by blocking some of their receptors might produce a salutatory benefit in the cancer (in this case, melanoma) patient.

Before we all rush out and give all our melanoma patients daily doses of metoprolol, however, De Giorgi et al noted in the most recent study that about two-thirds of the patients were already taking a beta-blocker when their melanoma was diagnosed. Although this study suggests that beta-blockers reduce the risk for recurrence and disease-specific mortality, these drugs clearly do not prevent melanoma in the first place. Furthermore, it should be noted that the number of melanoma patients receiving beta-blockers was small, and conclusions should always be tempered in a retrospective study. The authors duly admit that their investigation indicates the strong need for a truly randomized prospective clinical trial. Of course, administration of beta-blockers is not a totally benign endeavor, as serious hypotension and/or bradycardia may occur, leading to syncope or even worse problems. Finally, the evidence of beta-blocker benefit in melanoma patients is contradictory! A Dutch cohort of 709 melanoma patients recently was studied (Eur J Cancer. 2013;49:3863-3871); this set of investigators found that exposure to beta-blockers did not impact overall melanoma survival regardless of the timing, duration, or dosage of beta-blocker use. In summary, therefore, we still need to determine many things about the relationship between beta-blockers and melanoma survival. That is, if there is a relationship at all. What do you think?

We want to know your views! Tell us what you think.

I have taken beta-blockers for nearly 30 years to combat a non–life-threatening but very disconcerting supraventricular arrhythmia. Also being fair skinned and having suffered through many a blistering sunburn in my youth, I was excited to read the most recent publication regarding the relationship between beta-blocker ingestion and survival from melanoma by De Giorgi et al (Mayo Clin Proc. 2013;88:1196-1203). The Italian investigators collected data from all melanoma patients diagnosed in the dermatology department at the University of Florence (1993-2009). After excluding patients who presented with metastatic disease, they then compared the courses of the remaining patients based on whether or not they had been prescribed beta-blockers for at least 1 year before or after their cutaneous melanoma diagnosis. Of 741 consecutive patients who fit the retrospective study criteria, 79 (11%) had been taking beta-blockers and the remaining 662 (89%) had not been taking beta-blockers.

An analysis based on the multivariate Cox model indicated that the beta-blocker group had improved overall survival after a median follow-up of 4.2 years (P=.005). Looked at in another way, significantly more patients in the untreated group (8%) than the beta-blocker group (3%) experienced disease progression or death (P<.001). The “protective” effect of beta-blockers was so striking that it could be quantified; for each year of beta-blocker use, the risk for death was reduced by 38%. More notable was the fact that the beneficial effect of beta-blocker administration was consistent, even among patients with inherently unfavorable prognostic factors, such as advanced age, thicker lesions, higher frequency of mitoses and ulceration, and nodular melanoma subtype. This large study confirms the results of a much smaller study (N=121) published by the same group in 2011 (Arch Intern Med. 2011;171:779-781).

What’s the issue?

Why might this phenomenon occur? Perhaps blocking sympathetic nervous system neurotransmitters might help avoid the suspected immunosuppression that accompanies stress. Sympathetic neurotransmitters also are known to interact with molecular pathways implicated in abnormal cellular replication, such as the p38/MAPK pathway. Thus, blunting the effects of epinephrine and norepinephrine by blocking some of their receptors might produce a salutatory benefit in the cancer (in this case, melanoma) patient.

Before we all rush out and give all our melanoma patients daily doses of metoprolol, however, De Giorgi et al noted in the most recent study that about two-thirds of the patients were already taking a beta-blocker when their melanoma was diagnosed. Although this study suggests that beta-blockers reduce the risk for recurrence and disease-specific mortality, these drugs clearly do not prevent melanoma in the first place. Furthermore, it should be noted that the number of melanoma patients receiving beta-blockers was small, and conclusions should always be tempered in a retrospective study. The authors duly admit that their investigation indicates the strong need for a truly randomized prospective clinical trial. Of course, administration of beta-blockers is not a totally benign endeavor, as serious hypotension and/or bradycardia may occur, leading to syncope or even worse problems. Finally, the evidence of beta-blocker benefit in melanoma patients is contradictory! A Dutch cohort of 709 melanoma patients recently was studied (Eur J Cancer. 2013;49:3863-3871); this set of investigators found that exposure to beta-blockers did not impact overall melanoma survival regardless of the timing, duration, or dosage of beta-blocker use. In summary, therefore, we still need to determine many things about the relationship between beta-blockers and melanoma survival. That is, if there is a relationship at all. What do you think?

We want to know your views! Tell us what you think.