Editorial
Treatment or Monitoring for Early Prostate Cancer
Anthony V. D’Amico, M.D., Ph.D.
N Engl J Med 2016; 375:1482-1483October 13, 2016DOI: 10.1056/NEJMe1610395
The “best” initial approach to early (low-risk or intermediate-risk)1 prostate cancer remains unknown. Specifically, does active monitoring with the use of prostate-specific antigen (PSA) testing as opposed to treatment lead to increased metastasis and death from prostate cancer? If yes, then which treatment, radical prostatectomy or radiation with or without short-term (3 to 6 months) androgen-suppression therapy, minimizes metastasis and death from prostate cancer?
Hamdy and colleagues now report in the Journal the results of a randomized comparison of three of these four approaches after a median follow-up of 10 years,2 and Donovan and colleagues present data on patient-reported health-related quality of life at 6 years of follow-up.3 Men were screened with PSA testing and presented at a median age of 62 years with favorable clinical characteristics: 76% had stage T1c (PSA-detected) disease, 77% and 21% had tumors with Gleason scores of 6 and 7, respectively (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and the median PSA level was 4.6 ng per milliliter. Although a median follow-up of 10 years was too short to evaluate the primary outcome of prostate-cancer mortality in this favorable cohort (death from prostate cancer occurred in 8 of the 545 men assigned to active monitoring, 5 of the 553 men assigned to surgery, and 4 of the 545 men assigned to radiotherapy), it was adequate to evaluate the secondary outcome of the incidence of metastatic disease, defined as bony, visceral, or lymph-node metastasis on imaging or a PSA level above 100 ng per milliliter.
Several important observations were made. First, men assigned to active monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P=0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring.
Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was established. The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which are not inconsequential.4
Second, within the prerandomization stratum of age, a near-significant interaction (P=0.09 for interaction) was observed given that men 65 years of age or older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment.
This finding probably reflects the fact that advancing age is associated with higher-grade disease than disease identified at an initial biopsy5 owing to sampling error, resulting in undergrading, the risk of which rises with the increasing prostate-gland volume6 that occurs with advancing age.7
Should the interaction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age or older with early prostate cancer who today are increasingly being placed on active surveillance,8 given that the reduction in death from prostate cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09) in the Prostate Cancer Intervention versus Observation Trial (PIVOT) only trended toward significance (P=0.09).9
However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.10
Finally, a trend favoring radiation and short-course androgen-deprivation therapy over surgery was observed. Specifically, the point estimate for the hazard ratio for death from prostate cancer when comparing these two treatments was 0.80 (95% CI, 0.22 to 2.99). If this trend becomes significant, then one may consider radiation and androgen-deprivation therapy as a preferred option for otherwise healthy men 65 years of age or older with early prostate cancer for whom treatment as compared with monitoring may be more effective (P=0.09 for interaction) in reducing death from prostate cancer.
For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis.
Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.2
In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy.
Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.
This editorial was published on September 14, 2016, at NEJM.org.
Source Information
From the Department of Radiation Oncology, Brigham and Women’s Hospital and Dana–Farber Cancer Institute, Boston.
martes, 8 de noviembre de 2016
Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion
Original Article
Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion
Nancy M. Heddle, M.Sc., Richard J. Cook, Ph.D., Donald M. Arnold, M.D., Yang Liu, M.Math., Rebecca Barty, M.Sc., Mark A. Crowther, M.D., P.J. Devereaux, M.D., Ph.D., Jack Hirsh, M.D., Theodore E. Warkentin, M.D., Kathryn E. Webert, M.D., David Roxby, M.App.Sc., Magdalena Sobieraj-Teague, M.D., Andrea Kurz, M.D., Daniel I. Sessler, M.D., Priscilla Figueroa, M.D., Martin Ellis, M.D., and John W. Eikelboom, M.D.
October 24, 2016DOI: 10.1056/NEJMoa1609014
Background
Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients.
Methods
In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type.
Results
From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer).
Conclusions
Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744.)
Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion
Nancy M. Heddle, M.Sc., Richard J. Cook, Ph.D., Donald M. Arnold, M.D., Yang Liu, M.Math., Rebecca Barty, M.Sc., Mark A. Crowther, M.D., P.J. Devereaux, M.D., Ph.D., Jack Hirsh, M.D., Theodore E. Warkentin, M.D., Kathryn E. Webert, M.D., David Roxby, M.App.Sc., Magdalena Sobieraj-Teague, M.D., Andrea Kurz, M.D., Daniel I. Sessler, M.D., Priscilla Figueroa, M.D., Martin Ellis, M.D., and John W. Eikelboom, M.D.
October 24, 2016DOI: 10.1056/NEJMoa1609014
Background
Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients.
Methods
In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type.
Results
From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer).
Conclusions
Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744.)
Recurrent Squamous-Cell Carcinoma of the Head and Neck
Original Article
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Robert L. Ferris, M.D., Ph.D., George Blumenschein, Jr., M.D., Jerome Fayette, M.D., Ph.D., Joel Guigay, M.D., A. Dimitrios Colevas, M.D., Lisa Licitra, M.D., Kevin Harrington, Ph.D., F.R.C.P., F.R.C.R., Stefan Kasper, M.D., Everett E. Vokes, M.D., Caroline Even, M.D., Francis Worden, M.D., Nabil F. Saba, M.D., Lara C. Iglesias Docampo, M.D., Robert Haddad, M.D., Tamara Rordorf, M.D., Naomi Kiyota, M.D., Ph.D., Makoto Tahara, M.D., Ph.D., Manish Monga, M.D., Mark Lynch, Ph.D., William J. Geese, Ph.D., Justin Kopit, Ph.D., James W. Shaw, Pharm.D., Ph.D., M.P.H., and Maura L. Gillison, M.D., Ph.D.
October 9, 2016DOI: 10.1056/NEJMoa1602252
Background
Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti–programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.
Methods
In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.
Results
The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.
Conclusions
Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636.)
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Robert L. Ferris, M.D., Ph.D., George Blumenschein, Jr., M.D., Jerome Fayette, M.D., Ph.D., Joel Guigay, M.D., A. Dimitrios Colevas, M.D., Lisa Licitra, M.D., Kevin Harrington, Ph.D., F.R.C.P., F.R.C.R., Stefan Kasper, M.D., Everett E. Vokes, M.D., Caroline Even, M.D., Francis Worden, M.D., Nabil F. Saba, M.D., Lara C. Iglesias Docampo, M.D., Robert Haddad, M.D., Tamara Rordorf, M.D., Naomi Kiyota, M.D., Ph.D., Makoto Tahara, M.D., Ph.D., Manish Monga, M.D., Mark Lynch, Ph.D., William J. Geese, Ph.D., Justin Kopit, Ph.D., James W. Shaw, Pharm.D., Ph.D., M.P.H., and Maura L. Gillison, M.D., Ph.D.
October 9, 2016DOI: 10.1056/NEJMoa1602252
Background
Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti–programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.
Methods
In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.
Results
The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.
Conclusions
Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636.)
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