sábado, 29 de julio de 2017
Dark Hair Dye and Chemical Relaxers Linked to Breast Cancer
News & Perspective > Reuters Health Information
Dark Hair Dye and Chemical Relaxers Linked to Breast Cancer
By Ronnie Cohen
July 13, 2017
(Reuters Health) - African-American and white women who regularly chemically straighten their hair or dye it dark brown or black have an elevated risk of breast cancer, new research suggests.
“I would be concerned about darker hair dye and hair straighteners,” epidemiologist Tamarra James-Todd said after reviewing the report online now in the journal Carcinogenesis. “We should really think about using things in moderation and really try to think about being more natural."
“Just because something is on the market does not necessarily mean it’s safe for us,” she said in a phone interview. James-Todd, a professor at the Harvard T.H. Chan School of Public Health in Boston, was not involved with the new research.
The study of 4,285 African-American and white women was the first to find a significant increase in breast cancer risk among black women who used dark shades of hair dye and white women who used chemical relaxers.
Black women who reported using dark hair dye had a 51 percent increased risk of breast cancer compared to black women who did not, while white women who reported using chemical relaxers had a 74 percent increased risk of breast cancer, the study found.
The risk of breast cancer was even higher for white women who regularly dyed their hair dark shades and also used chemical relaxers, and it more than doubled for white dual users compared to white women who used neither dark dye nor chemical straighteners.
The association between relaxers and breast cancer in white women surprised lead author Adana Llanos, an epidemiologist at the Rutgers School of Public Health in Piscataway, New Jersey, although she worried enough about the safety of hair relaxers in African-American women like herself to stop using them years ago.
“A lot of people have asked me if I’m telling women not to dye their hair or not to use relaxers,” she said in a phone interview. “I’m not saying that. What I think is really important is we need to be more aware of the types of exposures in the products we use.”
The study included adult women from New York and New Jersey, surveyed from 2002 through 2008, who had been diagnosed with breast cancer, plus women of similar age and race but without a history of cancer.
Women were asked if they had ever used permanent hair dye at least twice a year for at least a year. They were also asked if they had ever chemically relaxed or straightened their hair for at least a year.
While the vast majority - 88 percent - of blacks had used chemicals to relax their hair, only 5 percent of whites reported using relaxers.
For dark hair dye, the numbers flipped, though the differences were not as dramatic. While 58 percent of whites said they regularly dyed their hair dark shades, only 30 percent of blacks did.
The most striking results showed increased risk in the minority of black women who used dark hair dye and white women who used chemical relaxers.
Black women who used chemical straighteners and white women who used dark hair dyes were also at higher risk for breast cancer, but that might have been due to chance. James-Todd said that because so many of the black women used chemical relaxers and so many of the white women used dark hair dye, links would have been hard to detect.
There’s no reason to believe that chemical relaxers and hair dyes would increase the risk for women of one race and not of another, she said. She believes the association stems not from genetics but from cultural norms.
It could also boil down to products, and women from different cultures might use different straighteners and dyes. But the study did not ask women to specify the products they used.
The study included the largest population of African-American women thus far examined for breast cancer risk and dark hair dye, according to the research team.
Previous studies have shown that long-term users of dark dyes have a four-fold increased risk of fatal non-Hodgkin’s lymphoma and fatal multiple myeloma, the authors write. Prior research also has associated dark hair dye use with an increased risk of bladder cancer.
A 2016 report from the U.S. Centers for Disease Control and Prevention found that breast cancer rates are generally similar for black and white women, at around 122 new cases for every 100,000 women per year, although black women with the disease are more likely to die from it.
SOURCE: http://bit.ly/2ujsWXd
Carcinogenesis 2017.
Reuters Health Information © 2017
Cite this article: Dark Hair Dye and Chemical Relaxers Linked to Breast Cancer - Medscape - Jul 12, 2017.
viernes, 28 de julio de 2017
Checkpoint Immunotherapy for Cancer and Endocrinopathies
Medscape Coverage from the
American Association of Clinical Endocrinologists (AACE) 2017
Endocrinopathies Common With Checkpoint Immunotherapy for Cancer
Miriam E Tucker
May 09, 2017
AUSTIN, Texas — Cancer patients receiving treatment with recently approved immune checkpoint inhibitors are increasingly developing endocrine disorders that are mostly mild, but in some cases can be serious, new research suggests.
These agents — the first of which was approved in 2011 — generate immune responses to tumors, causing them to be rejected, and break tumor-induced immune tolerance.
They have been hailed as breakthrough treatments for advanced neoplasias, including metastatic melanoma, non–small-cell lung cancer, and advanced renal-cell carcinoma. However, their mechanism of action can lead to a variety of inflammatory toxicities, including those involving the thyroid, adrenal, and other glands, attendees were told here at the American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress.
Single-center data presented on May 6 showed that not only are these endocrine disorders quite common — occurring in about one in three patients receiving the agents — but some are serious and life-threatening.
Moreover, the timing of their occurrence suggests that monitoring should be more frequent and of longer duration than has recently been proposed, endocrinology fellow Lauren Clarine, DO, said in presenting chart review findings from Scripps Health in San Diego.
"These drugs are showing a lot of promise, and more and more are being developed," Dr Clarine told Medscape Medical News, so, as endocrinologists, "if you haven't already seen one of these disorders, you probably will," she noted.
And previous research suggests that the patients who develop adverse events from immune checkpoint inhibitors are the ones whose cancers are most likely to respond to them.
So "it's important to maintain a high degree of suspicion and treat early so patients don't have to discontinue cancer treatment because of an endocrine disorder that we should be able to manage," Dr Clarine noted.
Greater Coordination of Care Needed Between Specialties
The phenomenon calls for greater coordination of care between specialists, session moderator David Lieb, MD, associate professor of internal medicine and program director of the endocrinology fellowship program at Eastern Virginia Medical School, Norfolk, Virginia, told Medscape Medical News.
"I think the key things are education for endocrinologists and oncologists and collaborating together. We need to follow these patients long term to get a good understanding of what types of endocrinopathies they develop and when. We're still at an early stage....It's not a small niche thing."
Thyroid dysfunction was the most common endocrinopathy reported by Dr Clarine's group, followed by inflammation of the pituitary gland (hypophysitis).
Speaking with Medscape Medical News prior to the AACE meeting, oncologist Jonathan Powell, MD, PhD, associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore, Maryland, said he and his colleagues have become "very much attuned to" this phenomenon, and that "the good news is that a lot of times we can inhibit the autoimmune response."
But when that's not possible they refer patients to the relevant specialists — at Johns Hopkins, both endocrinologists and rheumatologists are beginning to specialize in the autoimmune consequences of the new cancer therapies.
"We have people at Hopkins who had seen a couple of cases, so now we send them all our cases."
Dr Powell, who is also professor of oncology and of pharmacology and molecular sciences at Hopkins, added: "Coming from my end, the percentage of patients who have suffered these problems is relatively low. Given that cancer is going to kill them, I think the risk is well worth it."
Of course, Dr Lieb pointed out, untreated adrenal insufficiency and thyroid dysfunction can also be life-threatening.
A Variety of Endocrinopathies Seen
Dr Clarine and colleagues identified a total of 117 Scripps patients — 66% men and 34% women — who had received immune checkpoint inhibitors from January 2015 through December 2016. Of those, 26 had received the anti-CTLA4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb), 83 were treated with the anti-PD1 antibody nivolimumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck), while the other eight patients had received a combination of the two inhibitor types.
Of the 26 receiving ipilimumab, seven (27%) developed hypophysitis, four (16%) hypothyroidism, and one thyroiditis. Of those with hypophysitis, six had central adrenal insufficiency and two had central hypothyroidism.
Among those receiving nivolimumab or pembrolizumab, 21 (25%) became hypothyroid and two (4%) developed type 1 diabetes (both of whom were on nivolimumab).
And of the eight on combination immune checkpoint inhibitor treatment, one developed hypophysitis — with both central adrenal insufficiency and central hypothyroidism — while another developed thyroiditis.
Gender did not appear to be a factor, as 32% of the women and 27% of the men receiving the immune checkpoint inhibitors developed an endocrinopathy. And, in contrast to previous reports, the incidence of hypophysitis was not associated with higher ipilimumab doses, Dr Clarine noted.
The patients who developed hypophysitis and type 1 diabetes were hospitalized and immunotherapy eventually discontinued. At 9 months, none of the seven hypophysitis patients with central adrenal insufficiency had recovery of function despite high-dose glucocorticoid therapy.
Moreover, three of three cases of central hypothyroidism in the hypophysitis patients had not resolved completely, although the thyroid-hormone–replacement dose requirement decreased significantly in one.
"While other hormone axes may recover, development of central adrenal insufficiency is likely to be permanent," Dr Clarine commented.
How Should These Cases Be Screened and Managed?
Even at their single institution, Dr Clarine and colleagues found a great deal of variability in obtaining baseline and subsequent thyroid-function and pituitary-hormone testing.
One published protocol, from Joshi et al in Clinical Endocrinology, suggests baseline biochemistry prior to the start of immune checkpoint treatment, checking for clinical features prior to each treatment cycle, and further screening bloodwork at weeks 8 and 16. If normal, no further testing is advised.
However, the current findings suggest that more laboratory testing than that is necessary, given that most of the endocrinologic adverse events occurred between the second and fifth infusion, with one occurring after the first infusion and another after 14 infusions.
The average number of doses of immunotherapy given prior to the development of the endocrinopathy was 3 for hypophysitis, 5.5 for hypothyroidism, and 2 for thyroiditis.
"It is important to monitor closely for development of immune-related adverse events throughout therapy given the variable onset," Dr Clarine observed, adding that the current recommendation to stop at 16 weeks "could be problematic," because it could lead to some of these conditions being missed.
Instead, she suggests monthly thyroid-function testing during treatment and continuation of testing beyond the recommended 16 weeks.
Dr Lieb noted that the thyroid disorders associated with these agents can take the form of thyroiditis, primary hypothyroidism, or Graves' hyperthyroidism, and in the setting of thyrotoxicosis "treatment might be symptomatic control with a beta-blocker and then watching them over time.
"The key thing is going to be following them. Understanding the types of thyroid conditions that arise is going to be very important."
Dr Clarine and Dr Lieb have no relevant financial relationships. Dr Powell is founder of Dracen Pharmaceuticals and consultant for/shareholder in Corvus.
For more diabetes and endocrinology news, follow us on Twitter and on Facebook.
American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress. May 6, 2017; Austin, Texas. Abstract 716.
American Association of Clinical Endocrinologists (AACE) 2017
Endocrinopathies Common With Checkpoint Immunotherapy for Cancer
Miriam E Tucker
May 09, 2017
AUSTIN, Texas — Cancer patients receiving treatment with recently approved immune checkpoint inhibitors are increasingly developing endocrine disorders that are mostly mild, but in some cases can be serious, new research suggests.
These agents — the first of which was approved in 2011 — generate immune responses to tumors, causing them to be rejected, and break tumor-induced immune tolerance.
They have been hailed as breakthrough treatments for advanced neoplasias, including metastatic melanoma, non–small-cell lung cancer, and advanced renal-cell carcinoma. However, their mechanism of action can lead to a variety of inflammatory toxicities, including those involving the thyroid, adrenal, and other glands, attendees were told here at the American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress.
Single-center data presented on May 6 showed that not only are these endocrine disorders quite common — occurring in about one in three patients receiving the agents — but some are serious and life-threatening.
Moreover, the timing of their occurrence suggests that monitoring should be more frequent and of longer duration than has recently been proposed, endocrinology fellow Lauren Clarine, DO, said in presenting chart review findings from Scripps Health in San Diego.
"These drugs are showing a lot of promise, and more and more are being developed," Dr Clarine told Medscape Medical News, so, as endocrinologists, "if you haven't already seen one of these disorders, you probably will," she noted.
And previous research suggests that the patients who develop adverse events from immune checkpoint inhibitors are the ones whose cancers are most likely to respond to them.
So "it's important to maintain a high degree of suspicion and treat early so patients don't have to discontinue cancer treatment because of an endocrine disorder that we should be able to manage," Dr Clarine noted.
Greater Coordination of Care Needed Between Specialties
The phenomenon calls for greater coordination of care between specialists, session moderator David Lieb, MD, associate professor of internal medicine and program director of the endocrinology fellowship program at Eastern Virginia Medical School, Norfolk, Virginia, told Medscape Medical News.
"I think the key things are education for endocrinologists and oncologists and collaborating together. We need to follow these patients long term to get a good understanding of what types of endocrinopathies they develop and when. We're still at an early stage....It's not a small niche thing."
Thyroid dysfunction was the most common endocrinopathy reported by Dr Clarine's group, followed by inflammation of the pituitary gland (hypophysitis).
Speaking with Medscape Medical News prior to the AACE meeting, oncologist Jonathan Powell, MD, PhD, associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore, Maryland, said he and his colleagues have become "very much attuned to" this phenomenon, and that "the good news is that a lot of times we can inhibit the autoimmune response."
But when that's not possible they refer patients to the relevant specialists — at Johns Hopkins, both endocrinologists and rheumatologists are beginning to specialize in the autoimmune consequences of the new cancer therapies.
"We have people at Hopkins who had seen a couple of cases, so now we send them all our cases."
Dr Powell, who is also professor of oncology and of pharmacology and molecular sciences at Hopkins, added: "Coming from my end, the percentage of patients who have suffered these problems is relatively low. Given that cancer is going to kill them, I think the risk is well worth it."
Of course, Dr Lieb pointed out, untreated adrenal insufficiency and thyroid dysfunction can also be life-threatening.
A Variety of Endocrinopathies Seen
Dr Clarine and colleagues identified a total of 117 Scripps patients — 66% men and 34% women — who had received immune checkpoint inhibitors from January 2015 through December 2016. Of those, 26 had received the anti-CTLA4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb), 83 were treated with the anti-PD1 antibody nivolimumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck), while the other eight patients had received a combination of the two inhibitor types.
Of the 26 receiving ipilimumab, seven (27%) developed hypophysitis, four (16%) hypothyroidism, and one thyroiditis. Of those with hypophysitis, six had central adrenal insufficiency and two had central hypothyroidism.
Among those receiving nivolimumab or pembrolizumab, 21 (25%) became hypothyroid and two (4%) developed type 1 diabetes (both of whom were on nivolimumab).
And of the eight on combination immune checkpoint inhibitor treatment, one developed hypophysitis — with both central adrenal insufficiency and central hypothyroidism — while another developed thyroiditis.
Gender did not appear to be a factor, as 32% of the women and 27% of the men receiving the immune checkpoint inhibitors developed an endocrinopathy. And, in contrast to previous reports, the incidence of hypophysitis was not associated with higher ipilimumab doses, Dr Clarine noted.
The patients who developed hypophysitis and type 1 diabetes were hospitalized and immunotherapy eventually discontinued. At 9 months, none of the seven hypophysitis patients with central adrenal insufficiency had recovery of function despite high-dose glucocorticoid therapy.
Moreover, three of three cases of central hypothyroidism in the hypophysitis patients had not resolved completely, although the thyroid-hormone–replacement dose requirement decreased significantly in one.
"While other hormone axes may recover, development of central adrenal insufficiency is likely to be permanent," Dr Clarine commented.
How Should These Cases Be Screened and Managed?
Even at their single institution, Dr Clarine and colleagues found a great deal of variability in obtaining baseline and subsequent thyroid-function and pituitary-hormone testing.
One published protocol, from Joshi et al in Clinical Endocrinology, suggests baseline biochemistry prior to the start of immune checkpoint treatment, checking for clinical features prior to each treatment cycle, and further screening bloodwork at weeks 8 and 16. If normal, no further testing is advised.
However, the current findings suggest that more laboratory testing than that is necessary, given that most of the endocrinologic adverse events occurred between the second and fifth infusion, with one occurring after the first infusion and another after 14 infusions.
The average number of doses of immunotherapy given prior to the development of the endocrinopathy was 3 for hypophysitis, 5.5 for hypothyroidism, and 2 for thyroiditis.
"It is important to monitor closely for development of immune-related adverse events throughout therapy given the variable onset," Dr Clarine observed, adding that the current recommendation to stop at 16 weeks "could be problematic," because it could lead to some of these conditions being missed.
Instead, she suggests monthly thyroid-function testing during treatment and continuation of testing beyond the recommended 16 weeks.
Dr Lieb noted that the thyroid disorders associated with these agents can take the form of thyroiditis, primary hypothyroidism, or Graves' hyperthyroidism, and in the setting of thyrotoxicosis "treatment might be symptomatic control with a beta-blocker and then watching them over time.
"The key thing is going to be following them. Understanding the types of thyroid conditions that arise is going to be very important."
Dr Clarine and Dr Lieb have no relevant financial relationships. Dr Powell is founder of Dracen Pharmaceuticals and consultant for/shareholder in Corvus.
For more diabetes and endocrinology news, follow us on Twitter and on Facebook.
American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress. May 6, 2017; Austin, Texas. Abstract 716.
jueves, 20 de julio de 2017
Prescribing Late Chemotherapy: Oncologists Explain
News & Perspective >
Journal of Oncology Practice
Paradox of Prescribing Late Chemotherapy: Oncologists Explain
Minnie Bluhm, PhD, MPH; Cathleen M. Connell, PhD; Raymond G. De Vries, PhD; Nancy K. Janz, PhD; Kathleen E. Bickel, MD, MPhil; Maria J. Silveira, MD, MA, MPH
DISCLOSURESJ Oncol Pract. 2016;12(12):e1006-e1015.
Abstract
Purpose
The value of chemotherapy for patients with cancer in the last weeks of life warrants examination.
Late chemotherapy may not improve survival or quality of life but typically precludes hospice enrollment and may result in additional symptoms, increased use of other aggressive treatments, and worsening quality of life.
Few studies have explored oncologists' rationales for administering chemotherapy near death. This study examines the self-reported factors that influence oncologists' decisions about late chemotherapy.
Methods
In-depth individual interviews were conducted with 17 oncologists through a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. Transcripts were coded and analyzed using conventional content analysis, a qualitative method that allows the detection and analysis of patterns in the data.
Results
Clinical factors take priority in determining late chemotherapy decisions when clear treatment choices exist. When clinical factors are ambiguous, emotion becomes a highly salient influence. Oncologists view late chemotherapy to be patient driven and use it to palliate emotional distress and maintain patient hope even when physical benefit is unexpected. Oncologists experience unique and difficult challenges when caring for dying patients, including emotionally draining communication, overwhelming responsibility for life/death, limitations of oncology to heal, and prognostic uncertainty. These challenges are also eased by offering late chemotherapy.
Conclusion
The findings reveal a nuanced understanding of why oncologists find it difficult to refuse chemotherapy treatment for patients near death. Optimal end-of-life treatment decisions require supportive interventions and system change, both of which must take into account the challenges oncologists face.
Journal of Oncology Practice
Paradox of Prescribing Late Chemotherapy: Oncologists Explain
Minnie Bluhm, PhD, MPH; Cathleen M. Connell, PhD; Raymond G. De Vries, PhD; Nancy K. Janz, PhD; Kathleen E. Bickel, MD, MPhil; Maria J. Silveira, MD, MA, MPH
DISCLOSURESJ Oncol Pract. 2016;12(12):e1006-e1015.
Abstract
Purpose
The value of chemotherapy for patients with cancer in the last weeks of life warrants examination.
Late chemotherapy may not improve survival or quality of life but typically precludes hospice enrollment and may result in additional symptoms, increased use of other aggressive treatments, and worsening quality of life.
Few studies have explored oncologists' rationales for administering chemotherapy near death. This study examines the self-reported factors that influence oncologists' decisions about late chemotherapy.
Methods
In-depth individual interviews were conducted with 17 oncologists through a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. Transcripts were coded and analyzed using conventional content analysis, a qualitative method that allows the detection and analysis of patterns in the data.
Results
Clinical factors take priority in determining late chemotherapy decisions when clear treatment choices exist. When clinical factors are ambiguous, emotion becomes a highly salient influence. Oncologists view late chemotherapy to be patient driven and use it to palliate emotional distress and maintain patient hope even when physical benefit is unexpected. Oncologists experience unique and difficult challenges when caring for dying patients, including emotionally draining communication, overwhelming responsibility for life/death, limitations of oncology to heal, and prognostic uncertainty. These challenges are also eased by offering late chemotherapy.
Conclusion
The findings reveal a nuanced understanding of why oncologists find it difficult to refuse chemotherapy treatment for patients near death. Optimal end-of-life treatment decisions require supportive interventions and system change, both of which must take into account the challenges oncologists face.
lunes, 10 de julio de 2017
Brain Metastases: after brain metastases surgery, stereotactic radiosurgery may be ‘Standard of Care’
SRS After Brain Metastases Resection Could Be ‘Standard of Care’
Research indicates that stereotactic radiosurgery may be an alternative to whole brain radiotherapy for patients after brain metastases surgery
Date: 06 Jul 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Surgery and/or Radiotherapy of Cancer
medwireNews: Findings from two studies suggest that stereotactic radiosurgery (SRS) should be considered as a possible standard of care for patients who undergo surgery to remove brain metastases.
Paul Brown, from the Mayo Clinic in Rochester, Minnesota, USA, and co-workers report results from a phase III trial comparing postoperative SRS (single fraction of 12–15 Gy) with whole-brain radiotherapy (WBRT; 30 Gy in 10 daily fractions or 37.5 Gy in 15 fractions) for patients with a single resection cavity of less than 5.0 cm diameter.
After a median of 11.1 months, the 98 patients randomly assigned to receive SRS had longer survival free from cognitive deterioration than the 96 patients given WBRT, at a median of 3.7 versus 3.0 months and a hazard ratio (HR) of 0.47. Cognitive deterioration at 6 months was significantly less common with SRS than WBRT (52 vs 85%), the researchers add.
Although SRS was associated with a shorter time to intracranial tumour progression than WBRT (median 6.4 vs 27.5 months), overall survival did not significantly differ between the treatment arms (median 12.2 vs 11.6 months).
And SRS was associated with lower frequencies of the most common grade 3 or 4 treatment-related adverse events of hearing impairment (3 vs 9%) and cognitive disturbance (3 vs 5%).
“Taken in context with other phase 3 trials assessing SRS to the surgical bed, the implication for clinical care is that SRS in the postoperative setting is a viable treatment option to improve surgical bed control and should be considered a standard of care and a less toxic alternative than WBRT”, the researchers suggest.
“The implication for future research is that continued refinement of the SRS technique, such as fractionated or preoperative radiosurgery, is needed to further improve outcomes such as surgical bed control”, they state.
Anita Mahajan, from The University of Texas MD Anderson Cancer Center in Houston, USA, and co-investigators also studied the use of SRS after brain metastases resection, this time in patients who had one to three tumours removed, each with a maximum cavity diameter of 4 cm.
Twelve-month freedom from local recurrence was achieved by 72% of the 64 patients who were randomly assigned to receive a single SRS fraction of 12–16 Gy within 30 days of surgery but just 43% of the 68 patients who were assigned to receive observation alone, giving a significant HR of 0.46.
Median overall survival was at least 17 months in both treatment arms and the researchers note that this is higher than reported for studies comparing SRS and WBRT in patients with up to three cavities. “The higher survival could be because our study was done at a tertiary cancer centre and could also reflect improvements in systemic treatments”, they hypothesize.
The authors of a comment accompanying the articles in The Lancet Oncology describe the trials as being “of crucial importance” in providing evidence supporting a role for SRS in patients with surgical cavities.
Simon Lo, from the University of Washington School of Medicine in Seattle, USA, and co-writers say that the study by Anita Mahajan et al “confirms that radiation to surgical cavities is a standard of care and improves local control more than does observation, and that SRS is a safe and effective alternative to WBRT as a postoperative treatment.”
Observing that SRS did not give a sufficient radiation dose for control of microscopic disease in the study by Paul Brown et al, the commentators hypothesize that “postoperative hypofractionated SRS could be an attractive option to facilitate dose escalation while minimising the risk of radiation necrosis by widening the therapeutic window.”
But they note that a head-to-head trial comparing single-fraction versus hypofractionated SRS has yet to be performed and they emphasize the need for future research to also focus on understanding patterns of local and marginal failure, identification of a purported subgroup of patients who could avoid any radiation, and the optimal timing of adjuvant SRS.
References
Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol; Advance online publication 4 July 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30441-2
Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol; Advance online publication 4 July 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30414-X
Lo SS, Chang EL, Sahgal A. Radiosurgery for resected brain metastases–a new standard of care? Lancet Oncol; Advance online publication 4 July 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30448-5
martes, 4 de julio de 2017
The Changing Face of Informed Consent
The Changing Face of Informed Consent
Christine Grady, R.N., Ph.D.
In the classic interaction in which informed consent is obtained for research, an investigator presents the potential participant with information regarding a new therapeutic, diagnostic, or prophylactic intervention and then asks the participant to read and sign a detailed written consent document. This traditional prototype is becoming outdated. Informed consent, which is ethically essential in most clinical research, respects persons’ rights to decide whether participation in the research is compatible with their interests, including their interests in protection from exploitation and harm.1,2 In the process of informed consent, participants are given an opportunity to understand relevant information about research participation and to make a voluntary choice.3 Required by ethical guidelines and regulations unless explicitly waived by institutional review boards,4-7 informed consent is thus a means of protecting the rights and welfare of participants while they contribute to the advancement of knowledge.
Over the past 50 years, the informed consent process has become increasingly regulated and standardized, while the challenges remain persistent and hard to overcome.8 Consent forms are increasingly long and complicated, obscuring important details, and are often designed to serve the interests of institutions and sponsors. Data show that participants often have a limited understanding of study information even when they have signed a consent form.8 Technological advances driving changes in research methods and information practices have influenced how we think about informed consent for research, which raises the possibility of new approaches to informed consent and innovative options for obtaining it.
Changing Research Methods
Unprecedented opportunities to answer important clinical research questions are available through the analysis of massive amounts of data (“big” data) in commercial, health care, research, and government databases, in social media and mobile devices, and in growing collections of biologic specimens and clinical and genomic data. Data are amassed quickly and easily, sometimes through passive technologies such as location-based mobile devices, through registries, or through systems of electronic health records or data and biospecimens collected for other purposes. Innovative studies are being developed that are conducted entirely through the Internet, as described below by Cummings and Rowbotham, or through the use of smartphone apps, as described below by McConnell and Ashley. Such research allows “access” to participants remotely without the constraints of time or location. Powerful technologies enable data mining and analytics, as well as the integration of data from multiple sources.
Is the classic written informed consent process and document appropriate for these research paradigms? The level of risk to participants is low and is usually thought to be primarily informational,9 which differs from the risks associated with traditional interventional clinical research; the researcher–participant relationship also differs. Some argue that although informed consent allows participants to decide about acceptable risks, it may be unnecessary for research that involves the mining of large data sets or the analysis of deidentified biospecimens, because risks are low, especially as compared with the risks of research on previously untested treatments. In addition, deidentification and privacy protections further attenuate any individual informational risk.10,11 Moreover, there is concern that requiring consent for low-risk research of this type could impede or make infeasible otherwise valuable research or could result in selection bias — that is, a situation in which persons who are willing to consent differ fundamentally from those who are not willing, thus jeopardizing the science.12,13
In the commercial marketplace, people use social media and mobile devices and contribute their data to large databases in innumerable ways, and they may be unaware of the multiple entities gathering and storing their data for future use. Persons are sometimes notified in general terms about various uses of their data, yet “[r]esearchers are rarely in a user’s imagined audience.”14 Reactions to certain research studies, such as the Facebook emotion experiment or OkCupid research,15-17 as well as empirical data, such as that gathered in association with Twitter’s population-level depression monitoring,18 provide evidence that some people feel strongly about being asked and may not consent to certain research uses.19
Research with biospecimens may pose risks that are different from those posed by research with either actively or passively gathered data, yet public and private researchers often use deidentified clinical biospecimens without consent.12 Requiring consent for the use of such samples could result in smaller, more highly selective pools of participant samples, which may impede publicly beneficial research or limit its validity. The debate about the need for and form of informed consent for research with stored biospecimens was revived by recent international discussions and proposed changes to the U.S. Common Rule (changes that were not ultimately accepted) that would have required written consent for all research use of biospecimens.20,21 Even those who favor requiring consent for biospecimen research disagree about whether consent should be broad for a wide range of future possible research or specific for each use, one-time or ongoing, and opt-in or opt-out.22-27
Other emerging clinical research paradigms, including pragmatic trials and learning health care systems — that is, systems in which interventions that are within the scope of standard practice are tested and data are gathered passively in an attempt to improve outcomes — have also provoked debate about appropriate methods of informed consent.28-31 Although more similar to the prototypical clinical trial, some of these studies pose low research risks, are more similar to quality-improvement studies than to interventional clinical research, and depend on collective participation for scientific validity. Features of some of these trials arguably permit less formal consent procedures, perhaps notification with opt-out and, in some cases, even waiver.31
In survey after survey, however, people report that they prefer to be asked and given a choice about research even if there is little risk to them.27,32-39 The challenge is finding practical, nononerous ways to respect persons’ choices that have minimal negative effects on the science. Information technology may provide new opportunities to implement informed consent with minimal intrusion.
Changing Information Technologies and Practices
Digital technology has transformed how people communicate, learn, and work; information is increasingly acquired and communicated online or through mobile devices. Society is gradually becoming paperless, and information is constantly at our fingertips. Health information is stored in electronic health records. Small tablet computers and smart phones are multiplying five times faster than the global population.40 Technological and societal changes in information practices present fresh opportunities for innovative implementation of informed consent. Apps, tablets, video, interactive computers, robots, personal digital assistants, mobile phones and smartphones, and wearable technology could help to modernize, alter, and improve methods of informed consent. Technologies permit broad standardization and easy updating of information, ready use of creative graphics, the means for remote interactive discussions, and documentation of the process. Investigators can use technologies to provide information, interact with participants, answer questions, and assess understanding on an ongoing basis. Available consent tool kits featuring visual interactive approaches aim to make informed consent more participant-centered and less focused on signing legal documents.41 Other tool kits allow researchers to create apps for medical research and include customizable visual consent templates.42 Technologies allow for methods of informed consent that are modern, green, interactive, and dynamic.43-46
Along with providing opportunities, adoption of digital and electronic methods of consent requires deliberation, evidence, and recognition of challenges (Table 1Table 1Components and Challenges of Informed Consent with Traditional Paper Forms and Electronic Methods.). Investigators and oversight bodies must still determine the appropriate content for disclosure. Replacing long, complex, technical written forms with long, complex, technical or legalistic electronic information pages would not represent progress. Indeed, very few persons read click-through agreements, a common notice-and-consent feature of computer and mobile device use, before clicking “agree.”48,49 Clicking an agreement box without engaging with the information would be the equivalent of signing a consent form without reading it. This approach to consent would probably do more to protect investigators and sponsors than to inform participants. Important additional challenges in digital consent interactions include verifying that the people who are consenting have the capacity to consent and are who they say they are (authentication). If informed consent aims to provide information that participants can use to make decisions, promoting informed consent will require the creative use of electronic technologies that are simple, easy to use, and in widespread and common use. The interactions need to be brief, engaging, informative about risks and benefits in a way that users can easily appreciate, and equipped with methods for authentication, as discussed below by Cummings and Rowbotham. Such approaches to obtaining consent could also reduce worries about possible selection bias.
Information technologies enable new ways of presenting information and transferring some control to participants even in research in which investigators and participants never meet, yet they do not resolve questions related to the necessity or adequacy of informed consent. As described below by Kang, regulations in India require consent interactions to be videotaped in order to enhance accountability, with the hope of improving the consent process and ensuring its adequacy.
Informed consent as a process that serves to respect autonomous choices and protect people from risks is not “one size fits all” and should be tailored to context. One-on-one interactive informed consent with detailed information about the purpose of a study as well as about its risks, benefits, and alternatives is necessary for high-stakes gene-transfer research, for example; however, in my view, it is unnecessary for studies that involve deidentified aggregate clinical data. For the latter, educating the public and notifying persons whose data will be used might sufficiently show respect without impeding the science.
Broad dialogue and empirical research should inform decisions about adopting new methods of obtaining informed consent and tailoring models of consent to changing research paradigms. Research is needed to examine whether and when any progress made through low risk–high reward research outweighs other issues, including the ethical reasons behind obtaining prototypical informed consent. Researchers should also investigate public views about informed consent for the use of big data and electronic consent methods, as well as methods promoting engagement with and comprehension of digital study information, methods of authentication and capacity assessment as part of digital consent, and the extent to which there is selection bias in research in which digital consent technologies are used. The ethical goals of informed consent and the importance of considering research context should guide us as we assimilate technology into research and the informed consent process and develop creative and effective evidence-based practices.
From the Department of Bioethics, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD. Address reprint requests to Dr. Grady at the Department of Bioethics, National Institutes of Health Clinical Center, National Institutes of Health, Bldg. 10, 1C118 Bethesda, MD 20892, or at cgrady@nih.gov.
The views expressed are those of the author and do not necessarily reflect those of the Clinical Center, the National Institutes of Health, or the Department of Health and Human Services.
I thank Frank Miller, Dave Wendler, and Carl Runge for their helpful comments.
Christine Grady, R.N., Ph.D.
In the classic interaction in which informed consent is obtained for research, an investigator presents the potential participant with information regarding a new therapeutic, diagnostic, or prophylactic intervention and then asks the participant to read and sign a detailed written consent document. This traditional prototype is becoming outdated. Informed consent, which is ethically essential in most clinical research, respects persons’ rights to decide whether participation in the research is compatible with their interests, including their interests in protection from exploitation and harm.1,2 In the process of informed consent, participants are given an opportunity to understand relevant information about research participation and to make a voluntary choice.3 Required by ethical guidelines and regulations unless explicitly waived by institutional review boards,4-7 informed consent is thus a means of protecting the rights and welfare of participants while they contribute to the advancement of knowledge.
Over the past 50 years, the informed consent process has become increasingly regulated and standardized, while the challenges remain persistent and hard to overcome.8 Consent forms are increasingly long and complicated, obscuring important details, and are often designed to serve the interests of institutions and sponsors. Data show that participants often have a limited understanding of study information even when they have signed a consent form.8 Technological advances driving changes in research methods and information practices have influenced how we think about informed consent for research, which raises the possibility of new approaches to informed consent and innovative options for obtaining it.
Changing Research Methods
Unprecedented opportunities to answer important clinical research questions are available through the analysis of massive amounts of data (“big” data) in commercial, health care, research, and government databases, in social media and mobile devices, and in growing collections of biologic specimens and clinical and genomic data. Data are amassed quickly and easily, sometimes through passive technologies such as location-based mobile devices, through registries, or through systems of electronic health records or data and biospecimens collected for other purposes. Innovative studies are being developed that are conducted entirely through the Internet, as described below by Cummings and Rowbotham, or through the use of smartphone apps, as described below by McConnell and Ashley. Such research allows “access” to participants remotely without the constraints of time or location. Powerful technologies enable data mining and analytics, as well as the integration of data from multiple sources.
Is the classic written informed consent process and document appropriate for these research paradigms? The level of risk to participants is low and is usually thought to be primarily informational,9 which differs from the risks associated with traditional interventional clinical research; the researcher–participant relationship also differs. Some argue that although informed consent allows participants to decide about acceptable risks, it may be unnecessary for research that involves the mining of large data sets or the analysis of deidentified biospecimens, because risks are low, especially as compared with the risks of research on previously untested treatments. In addition, deidentification and privacy protections further attenuate any individual informational risk.10,11 Moreover, there is concern that requiring consent for low-risk research of this type could impede or make infeasible otherwise valuable research or could result in selection bias — that is, a situation in which persons who are willing to consent differ fundamentally from those who are not willing, thus jeopardizing the science.12,13
In the commercial marketplace, people use social media and mobile devices and contribute their data to large databases in innumerable ways, and they may be unaware of the multiple entities gathering and storing their data for future use. Persons are sometimes notified in general terms about various uses of their data, yet “[r]esearchers are rarely in a user’s imagined audience.”14 Reactions to certain research studies, such as the Facebook emotion experiment or OkCupid research,15-17 as well as empirical data, such as that gathered in association with Twitter’s population-level depression monitoring,18 provide evidence that some people feel strongly about being asked and may not consent to certain research uses.19
Research with biospecimens may pose risks that are different from those posed by research with either actively or passively gathered data, yet public and private researchers often use deidentified clinical biospecimens without consent.12 Requiring consent for the use of such samples could result in smaller, more highly selective pools of participant samples, which may impede publicly beneficial research or limit its validity. The debate about the need for and form of informed consent for research with stored biospecimens was revived by recent international discussions and proposed changes to the U.S. Common Rule (changes that were not ultimately accepted) that would have required written consent for all research use of biospecimens.20,21 Even those who favor requiring consent for biospecimen research disagree about whether consent should be broad for a wide range of future possible research or specific for each use, one-time or ongoing, and opt-in or opt-out.22-27
Other emerging clinical research paradigms, including pragmatic trials and learning health care systems — that is, systems in which interventions that are within the scope of standard practice are tested and data are gathered passively in an attempt to improve outcomes — have also provoked debate about appropriate methods of informed consent.28-31 Although more similar to the prototypical clinical trial, some of these studies pose low research risks, are more similar to quality-improvement studies than to interventional clinical research, and depend on collective participation for scientific validity. Features of some of these trials arguably permit less formal consent procedures, perhaps notification with opt-out and, in some cases, even waiver.31
In survey after survey, however, people report that they prefer to be asked and given a choice about research even if there is little risk to them.27,32-39 The challenge is finding practical, nononerous ways to respect persons’ choices that have minimal negative effects on the science. Information technology may provide new opportunities to implement informed consent with minimal intrusion.
Changing Information Technologies and Practices
Digital technology has transformed how people communicate, learn, and work; information is increasingly acquired and communicated online or through mobile devices. Society is gradually becoming paperless, and information is constantly at our fingertips. Health information is stored in electronic health records. Small tablet computers and smart phones are multiplying five times faster than the global population.40 Technological and societal changes in information practices present fresh opportunities for innovative implementation of informed consent. Apps, tablets, video, interactive computers, robots, personal digital assistants, mobile phones and smartphones, and wearable technology could help to modernize, alter, and improve methods of informed consent. Technologies permit broad standardization and easy updating of information, ready use of creative graphics, the means for remote interactive discussions, and documentation of the process. Investigators can use technologies to provide information, interact with participants, answer questions, and assess understanding on an ongoing basis. Available consent tool kits featuring visual interactive approaches aim to make informed consent more participant-centered and less focused on signing legal documents.41 Other tool kits allow researchers to create apps for medical research and include customizable visual consent templates.42 Technologies allow for methods of informed consent that are modern, green, interactive, and dynamic.43-46
Along with providing opportunities, adoption of digital and electronic methods of consent requires deliberation, evidence, and recognition of challenges (Table 1Table 1Components and Challenges of Informed Consent with Traditional Paper Forms and Electronic Methods.). Investigators and oversight bodies must still determine the appropriate content for disclosure. Replacing long, complex, technical written forms with long, complex, technical or legalistic electronic information pages would not represent progress. Indeed, very few persons read click-through agreements, a common notice-and-consent feature of computer and mobile device use, before clicking “agree.”48,49 Clicking an agreement box without engaging with the information would be the equivalent of signing a consent form without reading it. This approach to consent would probably do more to protect investigators and sponsors than to inform participants. Important additional challenges in digital consent interactions include verifying that the people who are consenting have the capacity to consent and are who they say they are (authentication). If informed consent aims to provide information that participants can use to make decisions, promoting informed consent will require the creative use of electronic technologies that are simple, easy to use, and in widespread and common use. The interactions need to be brief, engaging, informative about risks and benefits in a way that users can easily appreciate, and equipped with methods for authentication, as discussed below by Cummings and Rowbotham. Such approaches to obtaining consent could also reduce worries about possible selection bias.
Information technologies enable new ways of presenting information and transferring some control to participants even in research in which investigators and participants never meet, yet they do not resolve questions related to the necessity or adequacy of informed consent. As described below by Kang, regulations in India require consent interactions to be videotaped in order to enhance accountability, with the hope of improving the consent process and ensuring its adequacy.
Informed consent as a process that serves to respect autonomous choices and protect people from risks is not “one size fits all” and should be tailored to context. One-on-one interactive informed consent with detailed information about the purpose of a study as well as about its risks, benefits, and alternatives is necessary for high-stakes gene-transfer research, for example; however, in my view, it is unnecessary for studies that involve deidentified aggregate clinical data. For the latter, educating the public and notifying persons whose data will be used might sufficiently show respect without impeding the science.
Broad dialogue and empirical research should inform decisions about adopting new methods of obtaining informed consent and tailoring models of consent to changing research paradigms. Research is needed to examine whether and when any progress made through low risk–high reward research outweighs other issues, including the ethical reasons behind obtaining prototypical informed consent. Researchers should also investigate public views about informed consent for the use of big data and electronic consent methods, as well as methods promoting engagement with and comprehension of digital study information, methods of authentication and capacity assessment as part of digital consent, and the extent to which there is selection bias in research in which digital consent technologies are used. The ethical goals of informed consent and the importance of considering research context should guide us as we assimilate technology into research and the informed consent process and develop creative and effective evidence-based practices.
From the Department of Bioethics, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD. Address reprint requests to Dr. Grady at the Department of Bioethics, National Institutes of Health Clinical Center, National Institutes of Health, Bldg. 10, 1C118 Bethesda, MD 20892, or at cgrady@nih.gov.
The views expressed are those of the author and do not necessarily reflect those of the Clinical Center, the National Institutes of Health, or the Department of Health and Human Services.
I thank Frank Miller, Dave Wendler, and Carl Runge for their helpful comments.
Sentinel-Node Metastasis in Melanoma: Completion Dissection or Observation
Original Article
Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma
Mark B. Faries, M.D., John F. Thompson, M.D., Alistair J. Cochran, M.D., Robert H. Andtbacka, M.D., Nicola Mozzillo, M.D., Jonathan S. Zager, M.D., Tiina Jahkola, M.D., Ph.D., Tawnya L. Bowles, M.D., Alessandro Testori, M.D., Peter D. Beitsch, M.D., Harald J. Hoekstra, M.D., Ph.D., Marc Moncrieff, M.D., Christian Ingvar, M.D., Ph.D., Michel W.J.M. Wouters, M.D., Ph.D., Michael S. Sabel, M.D., Edward A. Levine, M.D., Doreen Agnese, M.D., Michael Henderson, M.D., Reinhard Dummer, M.D., Carlo R. Rossi, M.D., Rogerio I. Neves, M.D., Steven D. Trocha, M.D., Frances Wright, M.D., David R. Byrd, M.D., Maurice Matter, M.D., Eddy Hsueh, M.D., Alastair MacKenzie-Ross, M.D., Douglas B. Johnson, M.D., Patrick Terheyden, M.D., Adam C. Berger, M.D., Tara L. Huston, M.D., Jeffrey D. Wayne, M.D., B. Mark Smithers, M.B., B.S., Heather B. Neuman, M.D., Schlomo Schneebaum, M.D., Jeffrey E. Gershenwald, M.D., Charlotte E. Ariyan, M.D., Ph.D., Darius C. Desai, M.D., Lisa Jacobs, M.D., Kelly M. McMasters, M.D., Ph.D., Anja Gesierich, M.D., Peter Hersey, M.D., Ph.D., Steven D. Bines, M.D., John M. Kane, M.D., Richard J. Barth, M.D., Gregory McKinnon, M.D., Jeffrey M. Farma, M.D., Erwin Schultz, M.D., Sergi Vidal-Sicart, M.D., Ph.D., Richard A. Hoefer, D.O., James M. Lewis, M.D., Randall Scheri, M.D., Mark C. Kelley, M.D., Omgo E. Nieweg, M.D., Ph.D., R. Dirk Noyes, M.D., Dave S.B. Hoon, Ph.D., He-Jing Wang, M.D., David A. Elashoff, Ph.D., and Robert M. Elashoff, Ph.D.
N Engl J Med 2017; 376:2211-2222June 8, 2017DOI: 10.1056/NEJMoa1613210
Background
Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.
Methods
In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis.
Results
Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.
Conclusions
Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895.
Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma
Mark B. Faries, M.D., John F. Thompson, M.D., Alistair J. Cochran, M.D., Robert H. Andtbacka, M.D., Nicola Mozzillo, M.D., Jonathan S. Zager, M.D., Tiina Jahkola, M.D., Ph.D., Tawnya L. Bowles, M.D., Alessandro Testori, M.D., Peter D. Beitsch, M.D., Harald J. Hoekstra, M.D., Ph.D., Marc Moncrieff, M.D., Christian Ingvar, M.D., Ph.D., Michel W.J.M. Wouters, M.D., Ph.D., Michael S. Sabel, M.D., Edward A. Levine, M.D., Doreen Agnese, M.D., Michael Henderson, M.D., Reinhard Dummer, M.D., Carlo R. Rossi, M.D., Rogerio I. Neves, M.D., Steven D. Trocha, M.D., Frances Wright, M.D., David R. Byrd, M.D., Maurice Matter, M.D., Eddy Hsueh, M.D., Alastair MacKenzie-Ross, M.D., Douglas B. Johnson, M.D., Patrick Terheyden, M.D., Adam C. Berger, M.D., Tara L. Huston, M.D., Jeffrey D. Wayne, M.D., B. Mark Smithers, M.B., B.S., Heather B. Neuman, M.D., Schlomo Schneebaum, M.D., Jeffrey E. Gershenwald, M.D., Charlotte E. Ariyan, M.D., Ph.D., Darius C. Desai, M.D., Lisa Jacobs, M.D., Kelly M. McMasters, M.D., Ph.D., Anja Gesierich, M.D., Peter Hersey, M.D., Ph.D., Steven D. Bines, M.D., John M. Kane, M.D., Richard J. Barth, M.D., Gregory McKinnon, M.D., Jeffrey M. Farma, M.D., Erwin Schultz, M.D., Sergi Vidal-Sicart, M.D., Ph.D., Richard A. Hoefer, D.O., James M. Lewis, M.D., Randall Scheri, M.D., Mark C. Kelley, M.D., Omgo E. Nieweg, M.D., Ph.D., R. Dirk Noyes, M.D., Dave S.B. Hoon, Ph.D., He-Jing Wang, M.D., David A. Elashoff, Ph.D., and Robert M. Elashoff, Ph.D.
N Engl J Med 2017; 376:2211-2222June 8, 2017DOI: 10.1056/NEJMoa1613210
Background
Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.
Methods
In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis.
Results
Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.
Conclusions
Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895.
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