Original Article
Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
Joaquim Bellmunt, M.D., Ph.D., Ronald de Wit, M.D., Ph.D., David J. Vaughn, M.D., Yves Fradet, M.D., Jae-Lyun Lee, M.D., Ph.D., Lawrence Fong, M.D., Nicholas J. Vogelzang, M.D., Miguel A. Climent, M.D., Daniel P. Petrylak, M.D., Toni K. Choueiri, M.D., Andrea Necchi, M.D., Winald Gerritsen, M.D., Ph.D., Howard Gurney, M.D., David I. Quinn, M.D., Ph.D., Stéphane Culine, M.D., Ph.D., Cora N. Sternberg, M.D., Yabing Mai, Ph.D., Christian H. Poehlein, M.D., Rodolfo F. Perini, M.D., and Dean F. Bajorin, M.D., for the KEYNOTE-045 Investigators*
February 17, 2017DOI: 10.1056/NEJMoa1613683
Urothelial cancer is highly lethal in the metastatic state.1 Platinum-based combination chemotherapy remains the standard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months,2 and cisplatin-based combinations with a median overall survival of 12 to 15 months.3 However, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide,4,5 and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care.6,7 Because the median overall survival with second-line therapy is only 6 to 7 months, effective options are needed in patients with previously treated advanced urothelial carcinoma.
Monoclonal antibodies against programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) have shown robust antitumor activity and a manageable safety profile in many advanced malignant conditions,8 including urothelial cancer.9-14 Pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against PD-1, can disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T cells. Pembrolizumab showed antitumor activity in patients with advanced urothelial carcinoma in the phase 1b KEYNOTE-012 study9 and the phase 2 KEYNOTE-052 study.12 In the international, randomized, open-label, phase 3 KEYNOTE-045 trial, we compared pembrolizumab with investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine as second-line therapy in patients with advanced urothelial carcinoma that progressed during or after the receipt of platinum-based chemotherapy.
Methods
Patients
Patients who were 18 years of age or older were eligible for enrollment if they had histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra that showed predominantly transitional-cell features on histologic testing, had progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months after the receipt of platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease, had received two or fewer lines of systemic chemotherapy for advanced disease previously, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1,15 and had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0, 1, or 2 (on a 5-point scale, with 0 indicating no symptoms and higher numbers indicating greater disability). Patients who had an ECOG performance-status score of 2 (indicating that the patient is ambulatory and capable of all self-care but is unable to carry out any work activities and is out of bed more than 50% of waking hours) and had one or more of the established poor prognostic factors for second-line therapy (i.e., hemoglobin concentration of <10 g per deciliter, presence of liver metastases, and receipt of the last dose of most recent chemotherapy <3 months before enrollment)16,17 were excluded from enrollment. Patients were ineligible if they had received anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapy previously. Full eligibility criteria are listed in the trial protocol, available with the full text of this article at NEJM.org.
Trial Design and Treatment
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab (at a dose of 200 mg) or investigator’s choice of paclitaxel (at a dose of 175 mg per square meter of body-surface area), docetaxel (at a dose of 75 mg per square meter), or vinflunine (at a dose of 320 mg per square meter), all administered intravenously every 3 weeks. Randomization was stratified according to ECOG performance-status score (0 or 1 vs. 2), presence of liver metastases (yes vs. no), hemoglobin concentration (<10 g per deciliter vs. ≥10 g per deciliter), and time since the last dose of chemotherapy (<3 months vs. ≥3 months). Treatment assignment was not blinded. Treatment was continued until RECIST-defined disease progression,15 development of an unacceptable level of toxic effects, withdrawal of consent, decision by the investigator to discontinue treatment, or the completion of 2 years of pembrolizumab therapy.
Patients with disease progression, according to the investigator’s assessment of radiographic results, and a clinically stable status could continue to receive the therapy at the discretion of the investigator. Patients in the pembrolizumab group who had a complete response could discontinue treatment if they had received pembrolizumab for at least 24 weeks and for at least two doses beyond the time of initial complete response. There was no planned crossover on disease progression. Full information about guidance regarding the treatment decisions is provided in the protocol.
Assessments
PD-L1 expression was assessed in formalin-fixed tumor samples at a central laboratory with the use of the commercially available PD-L1 IHC 22C3 pharmDx assay (Dako North America). The kits were purchased at full cost. Archival tumor samples and newly obtained core or excisional biopsy samples from nonirradiated sites were permitted. There were no restrictions on the age of the archival samples or on the number of intervening therapies received after the sample was obtained. All samples, regardless of whether they were archival or newly obtained, were analyzed by the central laboratory during the screening process, and only the patients whose samples could be evaluated for PD-L1 expression were permitted to enroll in the study. PD-L1 expression was categorized as the PD-L1 combined positive score, defined as the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells.12
Tumor imaging was scheduled for week 9, followed by every 6 weeks during the first year and every 12 weeks thereafter. Response to treatment was assessed according to RECIST15 by means of blinded, independent, central radiologic review. During follow-up for survival, patients were contacted every 12 weeks for survival assessment. The full assessment schedule is provided in the trial protocol. All the adverse events and abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
End Points
At the second interim analysis, the coprimary end points were overall survival and progression-free survival, which were assessed in the total population and in the population of patients who had a tumor PD-L1 combined positive score of 10% or more. Overall survival was defined as the time from randomization to death from any cause. Progression-free survival was defined as the time from randomization to disease progression or death from any cause.
Secondary efficacy end points, which were assessed in the total population and in the population of patients who had a tumor PD-L1 combined positive score of 10% or more, included the objective response rate, defined as the percentage of patients who had a confirmed complete or partial response, and the duration of confirmed response, defined as the time from the first documented complete or partial response to disease progression or death. Safety in the total population was also a secondary end point. The full list of end points is provided in the protocol.
Efficacy was assessed in the intention-to-treat population, which included all the patients who were assigned to a treatment group. Safety was assessed in the as-treated population, which included all the patients who received at least one dose of study treatment.
Trial Oversight
The trial was designed by academic advisors and employees of the sponsor (Merck). Data were collected by investigators and their site personnel and analyzed by statisticians who were employees of the sponsor. Results were interpreted by the academic authors, by authors who were employees of the sponsor, and by other employees of the sponsor who did not fulfill all the authorship criteria as outlined by the International Committee of Medical Journal Editors. An external data and safety monitoring committee oversaw the trial and assessed efficacy and safety at the time of prespecified interim analyses that were performed by statisticians from QuintilesIMS, with funding by the sponsor.
The trial protocol and all the amendments were approved by the appropriate ethics body at each center. The trial was conducted in accordance with the protocol and its amendments, with Good Clinical Practice guidelines, and with the provisions of the Declaration of Helsinki. All the patients provided written informed consent before enrollment.
All the authors attest that the trial was conducted in accordance with the protocol and all the amendments, attest that they had access to the data used for the writing of the manuscript, and vouch for the accuracy and completeness of the data and analyses. The first draft of the manuscript was written by the first and last authors, with input from authors who were employees of the sponsor. Assistance with manuscript preparation was provided by a medical writer employed by the sponsor. All the authors participated in reviewing and editing the manuscript and made the decision to submit the manuscript for publication.
Statistical Analysis
Overall survival, progression-free survival, and duration of response were estimated with the use of the Kaplan–Meier method. In the analysis of overall survival, patients who were alive or lost to follow-up had their data censored at the time of last contact. In the analysis of progression-free survival, patients who were alive and without disease progression or who were lost to follow-up had their data censored at the time of last tumor assessment. Between-group differences in overall survival and progression-free survival were calculated with the use of a stratified log-rank test. Hazard ratios and associated 95% confidence intervals were calculated with the use of a stratified Cox proportional-hazards model and Efron’s method of handling ties. Differences in the response rate were calculated with the stratified Miettinen and Nurminen method. The same stratification factors that were used for randomization were applied to all stratified efficacy analyses.
The overall family-wise type I error rate was strictly controlled at a one-sided alpha level of 2.5%. We calculated that enrollment of 470 patients would provide the study with 88% power to show a hazard ratio for death of 0.781 or better in the analysis of overall survival in the pembrolizumab group versus the chemotherapy group in the total population and 86% power to show a hazard ratio of 0.625 or better in the pembrolizumab group versus the chemotherapy group among patients who had a tumor PD-L1 combined positive score of 10% or more.
The protocol specified two interim analyses before the final analysis. After reviewing the first interim analysis, the data and safety monitoring committee recommended continuing the study as planned. The second interim analysis was based on a cutoff date of September 7, 2016, and was performed after 334 deaths had occurred in the total population and 104 deaths had occurred in the population of patients who had a tumor PD-L1 combined positive score of 10% or more. The data and safety monitoring committee reviewed the results of the second interim analysis on October 18, 2016, and recommended early termination of the trial because pembrolizumab met the superiority thresholds for overall survival in the coprimary populations (Table S1 in the Supplementary Appendix, available at NEJM.org). All the data reported herein are those from the second interim analysis. The full statistical analysis plan is available in the protocol.
Results
Patients and Treatment
A total of 748 patients were screened for enrollment at 120 sites in 29 countries. Between November 5, 2014, and November 13, 2015, a total of 542 patients were randomly assigned to pembrolizumab (270 patients) or investigator’s choice of chemotherapy (272). Of these, 266 patients in the pembrolizumab group and 255 in the chemotherapy group received treatment (Fig. S1 in the Supplementary Appendix). In the chemotherapy group, 84 patients received docetaxel, 84 received paclitaxel, and 87 received vinflunine. The demographic and disease characteristics of the patients at baseline were generally balanced between the two treatment groups (Table 1Table 1Demographic and Disease Characteristics at Baseline in the Intention-to-Treat Population., and Table S2 in the Supplementary Appendix). A total of 164 patients (30.3%), including 74 patients in the pembrolizumab group and 90 in the chemotherapy group, had a tumor PD-L1 combined positive score of 10% or more (Table S3 in the Supplementary Appendix).
The median duration of follow-up, defined as the time from randomization to September 7, 2016, was 14.1 months (range, 9.9 to 22.1). In the as-treated population, the median duration of study treatment was 3.5 months (range, <0.1 to 20.0) in the pembrolizumab group and 1.5 months (range, <0.1 to 14.2) in the chemotherapy group. A total of 49 patients (18.4%) in the pembrolizumab group and 3 (1.2%) in the chemotherapy group were still receiving study treatment at the time of data cutoff (Fig. S1 in the Supplementary Appendix). In the intention-to-treat population, 68 patients (25.2%) in the pembrolizumab group and 91 (33.5%) in the chemotherapy group received subsequent therapy, including 2 patients (0.7%) and 35 patients (12.9%), respectively, who received subsequent immunotherapy.
Overall Survival
As of September 7, 2016, a total of 334 deaths had occurred in the intention-to-treat population. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.59 to 0.91; P=0.002) (Figure 1AFigure 1Overall Survival and Progression-free Survival in the Intention-to-Treat Population.). The median overall survival was 10.3 months (95% CI, 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group. The estimated overall survival rate at 12 months was 43.9% (95% CI, 37.8 to 49.9) in the pembrolizumab group, as compared with 30.7% (95% CI, 25.0 to 36.7) in the chemotherapy group.
Pembrolizumab was also associated with significantly longer overall survival than chemotherapy in the coprimary population of patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio for death, 0.57; 95% CI, 0.37 to 0.88; P=0.005). The median overall survival was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (Fig. S2A in the Supplementary Appendix). Pembrolizumab was associated with a benefit over chemotherapy in all the subgroups examined, including among patients with liver metastases and those who had a tumor PD-L1 combined positive score of less than 1% (Figure 2Figure 2Analysis of Overall Survival in Key Subgroups.). In an analysis that considered the chemotherapy regimens separately, the benefit of pembrolizumab over chemotherapy was similar for each chemotherapy regimen (Figure 2).
Progression-free Survival
A total of 437 events of disease progression or death occurred in the intention-to-treat population, with no significant difference in the duration of progression-free survival between the pembrolizumab group and the chemotherapy group (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) (Figure 1B). The median progression-free survival was 2.1 months (95% CI, 2.0 to 2.2) in the pembrolizumab group and 3.3 months (95% CI, 2.3 to 3.5) in the chemotherapy group. The estimated progression-free survival rate at 12 months was 16.8% (95% CI, 12.3 to 22.0) in the pembrolizumab group and 6.2% (95% CI, 3.3 to 10.2) in the chemotherapy group. There was also no significant between-group difference in the duration of progression-free survival among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24) (Fig. S2B in the Supplementary Appendix).
Objective Response
In the total population, the objective response rate was significantly higher in the pembrolizumab group (21.1%; 95% CI, 16.4 to 26.5) than in the chemotherapy group (11.4%; 95% CI, 7.9 to 15.8) (P=0.001). The median time to response was 2.1 months in each group. The median duration of response was not reached in the pembrolizumab group (range, 1.6+ to 15.6+ months) and was 4.3 months (range, 1.4+ to 15.4+) in the chemotherapy group (Figure 3Figure 3Time to Response and Duration of Response in Patients with a Confirmed Objective Response.). (Plus signs indicate an ongoing response at data cutoff.)
At the time of data cutoff, 41 of 57 patients (72%) with a response in the pembrolizumab group and 11 of 31 (35%) with a response in the chemotherapy group continued to have a response. Treatment was ongoing in 36 of 57 patients with a response (63%) in the pembrolizumab group and in 2 of 31 (6%) with a response in the chemotherapy group (Figure 3). The estimated percentage of patients with a duration of response of at least 12 months was 68% in the pembrolizumab group versus 35% in the chemotherapy group. Results were similar in the population of patients who had a tumor PD-L1 combined positive score of 10% or more. Details are provided in Table S4 and Figure S3 in the Supplementary Appendix.
Adverse Events
Adverse events that were considered by the investigators to be related to treatment occurred in 60.9% of the patients treated with pembrolizumab, as compared with 90.2% of those who received chemotherapy (Table 2Table 2Adverse Events in the As-Treated Population.). Treatment-related events of grade 3, 4, or 5 severity were less frequent in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4% of patients), as was treatment-related discontinuation of therapy (5.6% vs. 11.0%). One pembrolizumab-treated patient died from treatment-related pneumonitis. Three other deaths in the pembrolizumab group were attributed by the investigators to study treatment, including one death related to urinary tract obstruction, one death related to malignant neoplasm progression, and one death of unspecified cause. In the chemotherapy group, treatment-related deaths were related to sepsis (in two patients), septic shock (in one), and unspecified cause (in one).
The most common treatment-related adverse events of any grade were pruritus (19.5% of the patients), fatigue (13.9%), and nausea (10.9%) in the pembrolizumab group and alopecia (37.6%), fatigue (27.8%), and anemia (24.7%) in the chemotherapy group (Table 2). There were no treatment-related events of grade 3, 4, or 5 severity that occurred with an incidence of 5% or more in the pembrolizumab group. In the chemotherapy group, treatment-related events of grade 3, 4, or 5 severity with an incidence of 5% or more were neutropenia (13.3%), decreased neutrophil count (12.2%), anemia (7.8%), febrile neutropenia (7.1%), and decreased white-cell count (5.1%). A summary of all the adverse events with an incidence of 5% or more, regardless of whether they were attributed to treatment by the investigator, is provided in Table S5 in the Supplementary Appendix.
The adverse events of interest with regard to pembrolizumab, regardless of whether they were attributed to study treatment by the investigator, are shown in Table 2. The only events of grade 3, 4, or 5 severity that were observed in two or more patients who were treated with pembrolizumab were pneumonitis (2.3% of the patients), colitis (1.1%), and nephritis (0.8%); there was only one grade 5 event (0.4%), which was pneumonitis.
Discussion
In this randomized, phase 3 study involving patients with advanced urothelial cancer that progressed during or after platinum-based chemotherapy, pembrolizumab resulted in significantly longer overall survival — by approximately 3 months — than the investigator’s choice of paclitaxel, docetaxel, or vinflunine (10.3 months vs. 7.4 months). Pembrolizumab had a better safety profile than did chemotherapy. The benefit of pembrolizumab over chemotherapy was seen in the total population, as well as in the coprimary population of patients who had a tumor PD-L1 combined positive score of 10% or more.
The overall survival benefit with pembrolizumab was observed across almost all the subgroups examined and was similar regardless of investigator’s choice of chemotherapy. In this trial, the benefit of pembrolizumab appeared to be independent of PD-L1 expression on tumor and infiltrating immune cells. The results of ongoing randomized, controlled trials currently being conducted in earlier lines of treatment may help elucidate the role of PD-L1 expression as a biomarker in urothelial carcinoma. A relationship between smoking status and the relative benefit of pembrolizumab was observed. The relationship between smoking and the relative benefit of immunotherapy has also been observed in patients with other advanced cancers8,18 and may reflect a high mutational load in current and former smokers.19 Genomic analysis of this relationship is warranted. The median overall survival of 7.4 months that was observed with chemotherapy is consistent with historical data for second-line, single-agent treatment.4-7
Pembrolizumab resulted in a significantly higher objective response rate than chemotherapy. Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment. Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy. As compared with responses in the chemotherapy group, responses in the pembrolizumab group were durable, with a median duration of response that was not reached over a median follow-up of 14.1 months. On the basis of the Kaplan–Meier estimates, 68% of the responses to pembrolizumab were ongoing at 12 months.
Durable responses in patients with advanced urothelial cancer have also been observed with the anti–PD-L1 antibodies atezolizumab,10 durvalumab,13 and avelumab14 and the anti–PD-1 antibody nivolumab.11 Atezolizumab and nivolumab are approved only in the United States for the treatment of advanced urothelial cancer that progressed during or after receipt of previous platinum-based chemotherapy. Accelerated approval of these two antibodies was based on objective-response data from single-group studies.10,11 Pembrolizumab has now been shown to result in a significant survival benefit over standard-of-care therapy in a large, randomized trial in this population.
Overall, there was no significant difference between pembrolizumab and chemotherapy with regard to progression-free survival. Beyond 6 months, the progression-free survival curves diverged in favor of pembrolizumab. Similar findings have been observed with checkpoint inhibitors in other tumor types20-24 and suggest that in contrast to its use as a surrogate end point in historical chemotherapy studies, progression-free survival may not be a reliable surrogate end point for the clinical benefit of immunotherapy. The prolonged duration of response was seen only in patients who had a response to pembrolizumab, and because less than half the patients had a response, the therapy did not exert an effect on median progression-free survival. However, the duration of response in patients who had a response was much longer than the duration of response that was seen with chemotherapy.
The safety profiles that were observed with pembrolizumab and chemotherapy were as expected, with no new or unexpected toxic effects. Immune-mediated adverse events with pembrolizumab were relatively infrequent and were mostly of grade 1 or 2 severity. Overall, the incidence of treatment-related adverse events was substantially lower with pembrolizumab than with standard chemotherapy, including fewer events of grade 3, 4, or 5 severity and fewer events that resulted in the discontinuation of treatment. The number of treatment-related deaths was the same in the pembrolizumab group and the chemotherapy group, which probably reflects the poor prognosis of patients in this population. The better safety profile of pembrolizumab than of standard chemotherapy is important, considering that patients with recurrent or refractory urothelial carcinoma are generally older and have poor performance status and multiple coexisting conditions.
The survival benefit that was observed with pembrolizumab in this previously treated population of patients with a poor prognosis supports its study in earlier stages of disease. Currently, pembrolizumab and other PD-1 and PD-L1 inhibitors are being evaluated as adjuvant therapy and as first-line therapy for advanced disease in ongoing clinical trials (e.g., ClinicalTrials.gov numbers, NCT02450331, NCT02516241, NCT02632409, NCT02807636, and NCT02853305).
In conclusion, pembrolizumab resulted in significantly longer overall survival — by approximately 3 months — than the investigator’s choice of paclitaxel, docetaxel, or vinflunine and was associated with a higher rate of objective response and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy in patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, regardless of tumor PD-L1 expression status.
viernes, 24 de febrero de 2017
lunes, 20 de febrero de 2017
Scalp Cooling to Prevent Chemo Hair Loss Shows Promise
Medscape Medical News > Oncology
Scalp Cooling to Prevent Chemo Hair Loss Shows Promise
Pam Harrison
February 14, 2017
Cooling the scalp before, during, and after chemotherapy with a proprietary scalp cooling device prevents hair loss in at least 50% of women being treated for early-stage breast cancer, although success may depend on the type of chemotherapy women receive and how skilled clinicians are in applying the cooling device.
Two separate studies of two different scalp cooling devices for the prevention of chemotherapy-induced alopecia were published online February 14 in JAMA Oncology. Both report positive results, showing that the devices do prevent some hair loss.
As the investigators explain, lowering the temperature of the scalp constricts blood vessels, reducing both blood flow and the amount of chemotherapy delivered to the hair follicles, which in turn reduces the amount of hair loss.
"At face value, these findings appear to represent a major step forward in improving the quality of life of individuals with cancer," comments Dawn L. Hershman, MD, from the Herbert Irving Comprehensive Cancer Center at NewYork–Presbyterian/Columbia University Medical Center, New York City, in an accompanying editorial.
However, she adds that the quality-of-life results need to be interpreted with caution. In addition, there are also questions about who will pay for these scalp cooling devices because this is a treatment for temporary hair loss, which "can be perceived as cosmetic."
Yet, she argues, "[o]ne of the strongest deterrents for a woman who is deciding whether to undergo chemotherapy is concern about alopecia."
In fact, an estimated 8% of women who might benefit from chemotherapy have indicated that they would refuse treatment because of their fear of hair loss, she adds.
"[I]dentifying interventions, such as scalp cooling for the prevention of chemotherapy-induced alopecia, that reduce or eliminate treatment-associated toxic effects will help ease the distress associated with chemotherapy and may, as a result, improve outcomes for patients with breast cancer," Dr Hershman concludes.
Author of a second editorial and JAMA Oncology web editor, Howard (Jack) West, MD, Swedish Cancer Institute, Seattle, Washington, agreed, telling Medscape Medical News that clinicians have not prioritized hair preservation during chemotherapy as much as they perhaps should have based on what matters to patients.
Hair loss is not a trivial consequence of chemotherapy for many patients, he emphasized.
"I think many people, especially women, may factor the potential for alopecia into their decision about receiving chemotherapy, and this could potentially lead to patients being undertreated because of their concerns about this side effect," he said.
"And given that patients are key decision makers in their treatment, I think it really helps when we can demonstrate that we are listening to their concerns and do things to minimize issues that are of greatest concern to them," he added.
SCALP Trial With Paxman Device
One of the trials used the Orbis Paxman Hair Loss Prevention System (Paxman Coolers Ltd), which is awaiting approval in the United States.
Paxman Scalp Cooling Device. Courtesy of Paxman
The Paxman device is a two-cap system consisting of an inner silicon cap in which refrigerated fluid is circulated and an outer neoprene cap that insulates the scalp. The cap is fitted snugly to the head and is held in place with a chin strap
Comment: we have been treating our patients in Cadiz (Spain) with this device for more than 5 years with comparable results.
Scalp Cooling to Prevent Chemo Hair Loss Shows Promise
Pam Harrison
February 14, 2017
Cooling the scalp before, during, and after chemotherapy with a proprietary scalp cooling device prevents hair loss in at least 50% of women being treated for early-stage breast cancer, although success may depend on the type of chemotherapy women receive and how skilled clinicians are in applying the cooling device.
Two separate studies of two different scalp cooling devices for the prevention of chemotherapy-induced alopecia were published online February 14 in JAMA Oncology. Both report positive results, showing that the devices do prevent some hair loss.
As the investigators explain, lowering the temperature of the scalp constricts blood vessels, reducing both blood flow and the amount of chemotherapy delivered to the hair follicles, which in turn reduces the amount of hair loss.
"At face value, these findings appear to represent a major step forward in improving the quality of life of individuals with cancer," comments Dawn L. Hershman, MD, from the Herbert Irving Comprehensive Cancer Center at NewYork–Presbyterian/Columbia University Medical Center, New York City, in an accompanying editorial.
However, she adds that the quality-of-life results need to be interpreted with caution. In addition, there are also questions about who will pay for these scalp cooling devices because this is a treatment for temporary hair loss, which "can be perceived as cosmetic."
Yet, she argues, "[o]ne of the strongest deterrents for a woman who is deciding whether to undergo chemotherapy is concern about alopecia."
In fact, an estimated 8% of women who might benefit from chemotherapy have indicated that they would refuse treatment because of their fear of hair loss, she adds.
"[I]dentifying interventions, such as scalp cooling for the prevention of chemotherapy-induced alopecia, that reduce or eliminate treatment-associated toxic effects will help ease the distress associated with chemotherapy and may, as a result, improve outcomes for patients with breast cancer," Dr Hershman concludes.
Author of a second editorial and JAMA Oncology web editor, Howard (Jack) West, MD, Swedish Cancer Institute, Seattle, Washington, agreed, telling Medscape Medical News that clinicians have not prioritized hair preservation during chemotherapy as much as they perhaps should have based on what matters to patients.
Hair loss is not a trivial consequence of chemotherapy for many patients, he emphasized.
"I think many people, especially women, may factor the potential for alopecia into their decision about receiving chemotherapy, and this could potentially lead to patients being undertreated because of their concerns about this side effect," he said.
"And given that patients are key decision makers in their treatment, I think it really helps when we can demonstrate that we are listening to their concerns and do things to minimize issues that are of greatest concern to them," he added.
SCALP Trial With Paxman Device
One of the trials used the Orbis Paxman Hair Loss Prevention System (Paxman Coolers Ltd), which is awaiting approval in the United States.
Paxman Scalp Cooling Device. Courtesy of Paxman
The Paxman device is a two-cap system consisting of an inner silicon cap in which refrigerated fluid is circulated and an outer neoprene cap that insulates the scalp. The cap is fitted snugly to the head and is held in place with a chin strap
Comment: we have been treating our patients in Cadiz (Spain) with this device for more than 5 years with comparable results.
PD-L1 in Cancer: ESMO Biomarker Factsheet
PD-L1 in Cancer: ESMO Biomarker Factsheet
Index
Definition of PD-1/PD-L1
Drugs Targeting the PD-1/PD-L1 Pathway
PD-L1 as a Predictive Biomarker
Quality Testing Results
Patient Selection
References
arkenau-tobias
Hendrik-Tobias Arkenau
Read more
Author: Hendrik Tobias Arkenau
Sarah Cannon Research Institute
UK
Definition of PD-1/PD-L1
PD-1 or ‘programmed-death 1’ (CD279) is a cell surface receptor that is part of the immunoglobulin superfamily. It is expressed primarily on the surface of activated T-cells 1,2. PD-L1 or ‘programmed-death ligand 1’ (CD274) is one of two PD-1 ligands. It is a transmembrane protein expressed on a variety of cell types, including antigen presenting cells, mainly Dendritic cells and macrophages 1. PD-L1 is also expressed constitutively by non-lymphoid tissue including heart, lung and others 3. Binding of PD-L1 inhibits the proliferation of activated T-cells, which is an important mechanism for negative feedback control of inflammation and autoimmunity in the peripheral effector phase of T-cell activation 1. This identifies the PD-1/PD-L1 pathway as an important immune response checkpoint.
Tumour cells can co-opt this PD-1/PD-L1 regulatory mechanism. Tumour cells may express PD-L1, with subsequent PD-1 binding and inhibition of T-cell activation allowing cancer cells to evade immune attack. PD-L1 expression can be driven by both adaptive immune resistance as well as oncogenic mechanisms 4. A range of solid and haematological malignancies have been shown to over-express PD-L1 1. Preclinical studies that found decreased tumour growth and improved survival with PD-1/PD-L1 pathway blockade provided the rationale for immune checkpoint inhibition as a novel approach in cancer treatment.
Drugs Targeting the PD-1/PD-L1 Pathway
Blockade of the PD-1/PD-L1 pathway has emerged as a promising cancer therapy preventing evasion of tumour cells from the immune system with restoration of host immunity against the tumour. Several monoclonal antibodies have been developed and licensed, and many more are in pre-clinical and clinical development that can disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T-cells, with resultant tumour recognition by cytotoxic T-cells. Remarkable clinical responses have been seen in some patients in various cancer types, including melanoma, lung, kidney, bladder cancer and others. Clinical trials are investigating immune checkpoint blockade therapies both alone, in combination with chemotherapy, small molecules, or other immune targeting agents to treat a variety of cancers. There are now several hundreds of ongoing immunotherapy combination trials 4.
Currently, two PD-1 inhibitors are approved for clinical use in both Europe and the US. Nivolumab and pembrolizumab are both human IgG4 monoclonal antibodies that block PD-1. In both Europe and the US, nivolumab is indicated for the treatment of unresectable or metastatic melanoma, alone or in combination with the anti-CTLA4 Monoclonal antibody, ipilimumab; for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior therapy; and as monotherapy for the treatment of advanced renal cell carcinoma after prior therapy 5,6. In the US, nivolumab has a wider indication and in addition, is approved for classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin 6. In the US, the Food and Drug Administration (FDA) approved the complimentary diagnostic test, PD-L1 IHC 28-8 pharmDx, for the detection of PD-L1 expression in NSCLC and melanoma tissue, to assist physicians with their treatment decisions 7.
Pembrolizumab is indicated in Europe and the US for the treatment of advanced (unresectable or metastatic) melanoma, and locally advanced (only in Europe) or metastatic NSCLC after prior therapy in patients whose tumours express PD-L18,9. In the US, the pembrolizumab licence is broader and is also indicated as first-line treatment in patients with metastatic NSCLC whose tumours express a high level of PD-L1 with no EGFR or ALK genomic tumour aberrations, and in patients with recurrent or metastatic head and neck Squamous cell carcinoma (HNSCC) after prior platinum-based chemotherapy 8. For use of pembrolizumab in metastatic NSCLC, the US licence specifies that PD-L1 status must be determined using an FDA-approved test 8. For first-line treatment of metastatic NSCLC without EGFR or ALK genomic tumour aberrations, PD-L1 must be expressed in ≥ 50% of tumour cells, and for treatment after prior therapy, it must be expressed in ≥ 1% of tumour cells 8. The FDA have approved the immunohistochemical assay, PD-L1 IHC 22C3 pharmDx, as a companion diagnostic for the detection of PD-L1 protein in NSCLC tissue 10.
IHC of PD-L1-positive Tumour
IHC of PD-L1-positive Tumour. Credit: Hendrik Tobias Arkenau
Atezolizumab is an engineered IgG1 antibody that inhibits the PD-1/PD-L1 checkpoint by interacting directly with PD-L1 and preventing its binding to PD-1, and is currently the only licensed PD-L1 inhibitor in the US. Atezolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma after prior platinum-based chemotherapy, and for metastatic NSCLC after prior therapy 11. The FDA have approved the VENTANA PD-L1 (SP142) Assay as a complimentary diagnostic, to determine the proportion of PD-L1 expressing tumour-infiltrating immune cells in urothelial carcinoma tissue, to help physicians decide which patients are most likely to respond to atezolizumab 12.
PD-L1 as a Predictive Biomarker
Defining biomarkers that predict therapeutic response to PD-1/PD-L1 blockade is an important goal 13. There is increasing evidence that PD-L1 measured by levels of Immunohistochemistry (IHC) expression is a relevant marker to predict response to treatment. The first study that provided evidence of a link between PD-L1 protein expression by tumour cells detected by IHC and response to anti-PD-1 therapy, was the first-in-human phase I nivolumab trial conducted in patients with a variety of different solid tumour types 14. Subsequently, a number of trials validated that PD-L1 expression correlates with an increased response to PD-1 and PD-L1 immune checkpoint inhibitors, but the response rate was lower than the early studies.
IHC of PD-L1-negative Tumour
IHC of PD-L1-negative Tumour. Credit: Hendrik Tobias Arkenau
Thus, while PD-L1 expression has been associated with more favourable response rates to PD-1/PD-L1 checkpoint inhibitors, PD-L1 does not appear to be a static Biomarker and does not offer binary discrimination of responsiveness.
The wording of the licences for pembrolizumab, nivolumab and atezolizumab, have different recommendations regarding PD-L1 expression that reflect the clinical trial evidence. Only pembrolizumab has an indication restricted to tumours expressing PD-L1, whereas nivolumab and atezolizumab have been approved regardless of tumour PD-L1 expression 5,6,8,9,11. Patients without PD-L1 expression can also derive benefit from these agents, with studies across multiple cancer types demonstrating a pooled response rate of 48% in patients with PD-L1-positive tumours compared with 15% in PD-L1-negative tumours 15.
Both pembrolizumab and nivolumab are licensed by the European Medicines Agency (EMA) and FDA for treatment of advanced melanoma independent of PD-L1 expression. The combination of nivolumab with ipilimumab in advanced melanoma improved progression-free survival (PFS) over nivolumab alone, in patients with low tumour PD-L1 expression measured by the PD-L1 IHC 28-8 pharmDx assay 16, and this finding is reflected in the wording of the nivolumab melanoma indication in the EU 5.
PD-L1 positivity is also associated with improved survival from nivolumab treatment in non-squamous NSCLC 17. The predictive value of PD-L1, using the PD-L1 IHC 28-8 pharmDx assay, was seen across all the efficacy end points of the CheckMate 057 study at an expression level ≥1% 7. Despite these findings, a companion diagnostic is not required for nivolumab treatment in melanoma or NSCLC 5,6. The FDA has instead approved the PD-L1 IHC 28-8 pharmDx test as a complementary test that may provide physicians more information and inform patient dialogue when deciding treatment for melanoma or NSCLC. This decision was likely influenced by limitations of the clinical data to support the assay, for example, findings from clinical trials that demonstrated similar outcomes irrespective of PD-L1 expression status 18,19,20. Furthermore, testing for PD-L1 expression in the CheckMate 057 study was retrospective and was not performed on all patient specimens but rather a subset of 78% of cases, with the potential risk of selection bias 18.
Currently, PD-L1 IHC 22C3 pharmDx (Dako) is the only FDA-approved companion diagnostic for selecting NSCLC patients for treatment with pembrolizumab. This approval was based on results of two randomised, controlled trials that demonstrated statistically significant improvements in PFS and overall survival (OS) for patients randomised to pembrolizumab compared with chemotherapy. In a trial of 305 patients with metastatic NSCLC, whose tumours had high PD-L1 expression (expressed in ≥ 50% tumour cells), had not received prior chemotherapy and did not have EGFR or ALK genomic tumour aberrations, those who received pembrolizumab had a significant improvement in PFS for patients receiving pembrolizumab versus chemotherapy. Additionally, a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomised to pembrolizumab as compared with chemotherapy 8. In a trial of 1033 patients who were previously treated for metastatic NSCLC and expressed PD-L1 in greater than or equal to 1% tumour cells, those randomised to pembrolizumab had an improved OS compared with patients receiving docetaxel.
In a non-randomised, prospective, single-arm study of atezolizumab, PD-L1 expression in ≥ 5% tumour infiltrating immune cells, determined by the VENTANA PD-L1 (SP142) Assay, in urothelial carcinoma tissue was associated with increased objective response rate 21. In patients who were classified as positive for PD-L1 expression (≥ 5% tumour infiltrating immune cells), 26% of participants experienced a tumour response compared to 9.5% of participants who were classified as negative for PD-L1 expression (< 5% tumour infiltrating immune cells). Therefore, patients experienced a tumour response across the study; however, the greater effect in those who were classified as positive for PD-L1 expression suggests that the level of PD-L1 expression in tumour-infiltrating immune cells may help identify patients whose tumours are more likely to respond 12. Hence, the VENTANA PD-L1 (SP142) Assay has been approved by the FDA, as a complimentary diagnostic to help physicians decide which patients with urothelial cancer are most likely to respond to atezolizumab 12. Quality Testing Results The conflicting observations regarding PD-L1 as a predictive biomarker of tumour response likely reflects a number of issues, both IHC-test specific and tumour-biology-related. These include the limitations inherent in tumour sampling, with focal expression potentially missed in small biopsies, and differential PD-L1 expression apparent over time and by anatomical site in individual patients. Different IHC detection methods and antibodies, quality of samples, methods used to acquire material, and positivity thresholds may also be a factor 4. Recognising this, a Blueprint Working Group has been established with cooperation from the Pharmaceutical Industry to provide a comparison of different IHC tests and cell scoring methods for PD-L1 expression, reflecting that each drug is developed in the context of a unique biological scientific hypothesis and registration strategy. In terms of the tumour microenvironment, PD-L1 can be expressed across a wide range of cell types, creating challenges in individual cell identification 4. The impact on the tumour microenvironment that may have occurred through multiple previous cancer treatments remains undefined 4.
Index
Definition of PD-1/PD-L1
Drugs Targeting the PD-1/PD-L1 Pathway
PD-L1 as a Predictive Biomarker
Quality Testing Results
Patient Selection
References
arkenau-tobias
Hendrik-Tobias Arkenau
Read more
Author: Hendrik Tobias Arkenau
Sarah Cannon Research Institute
UK
Definition of PD-1/PD-L1
PD-1 or ‘programmed-death 1’ (CD279) is a cell surface receptor that is part of the immunoglobulin superfamily. It is expressed primarily on the surface of activated T-cells 1,2. PD-L1 or ‘programmed-death ligand 1’ (CD274) is one of two PD-1 ligands. It is a transmembrane protein expressed on a variety of cell types, including antigen presenting cells, mainly Dendritic cells and macrophages 1. PD-L1 is also expressed constitutively by non-lymphoid tissue including heart, lung and others 3. Binding of PD-L1 inhibits the proliferation of activated T-cells, which is an important mechanism for negative feedback control of inflammation and autoimmunity in the peripheral effector phase of T-cell activation 1. This identifies the PD-1/PD-L1 pathway as an important immune response checkpoint.
Tumour cells can co-opt this PD-1/PD-L1 regulatory mechanism. Tumour cells may express PD-L1, with subsequent PD-1 binding and inhibition of T-cell activation allowing cancer cells to evade immune attack. PD-L1 expression can be driven by both adaptive immune resistance as well as oncogenic mechanisms 4. A range of solid and haematological malignancies have been shown to over-express PD-L1 1. Preclinical studies that found decreased tumour growth and improved survival with PD-1/PD-L1 pathway blockade provided the rationale for immune checkpoint inhibition as a novel approach in cancer treatment.
Drugs Targeting the PD-1/PD-L1 Pathway
Blockade of the PD-1/PD-L1 pathway has emerged as a promising cancer therapy preventing evasion of tumour cells from the immune system with restoration of host immunity against the tumour. Several monoclonal antibodies have been developed and licensed, and many more are in pre-clinical and clinical development that can disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T-cells, with resultant tumour recognition by cytotoxic T-cells. Remarkable clinical responses have been seen in some patients in various cancer types, including melanoma, lung, kidney, bladder cancer and others. Clinical trials are investigating immune checkpoint blockade therapies both alone, in combination with chemotherapy, small molecules, or other immune targeting agents to treat a variety of cancers. There are now several hundreds of ongoing immunotherapy combination trials 4.
Currently, two PD-1 inhibitors are approved for clinical use in both Europe and the US. Nivolumab and pembrolizumab are both human IgG4 monoclonal antibodies that block PD-1. In both Europe and the US, nivolumab is indicated for the treatment of unresectable or metastatic melanoma, alone or in combination with the anti-CTLA4 Monoclonal antibody, ipilimumab; for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior therapy; and as monotherapy for the treatment of advanced renal cell carcinoma after prior therapy 5,6. In the US, nivolumab has a wider indication and in addition, is approved for classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin 6. In the US, the Food and Drug Administration (FDA) approved the complimentary diagnostic test, PD-L1 IHC 28-8 pharmDx, for the detection of PD-L1 expression in NSCLC and melanoma tissue, to assist physicians with their treatment decisions 7.
Pembrolizumab is indicated in Europe and the US for the treatment of advanced (unresectable or metastatic) melanoma, and locally advanced (only in Europe) or metastatic NSCLC after prior therapy in patients whose tumours express PD-L18,9. In the US, the pembrolizumab licence is broader and is also indicated as first-line treatment in patients with metastatic NSCLC whose tumours express a high level of PD-L1 with no EGFR or ALK genomic tumour aberrations, and in patients with recurrent or metastatic head and neck Squamous cell carcinoma (HNSCC) after prior platinum-based chemotherapy 8. For use of pembrolizumab in metastatic NSCLC, the US licence specifies that PD-L1 status must be determined using an FDA-approved test 8. For first-line treatment of metastatic NSCLC without EGFR or ALK genomic tumour aberrations, PD-L1 must be expressed in ≥ 50% of tumour cells, and for treatment after prior therapy, it must be expressed in ≥ 1% of tumour cells 8. The FDA have approved the immunohistochemical assay, PD-L1 IHC 22C3 pharmDx, as a companion diagnostic for the detection of PD-L1 protein in NSCLC tissue 10.
IHC of PD-L1-positive Tumour
IHC of PD-L1-positive Tumour. Credit: Hendrik Tobias Arkenau
Atezolizumab is an engineered IgG1 antibody that inhibits the PD-1/PD-L1 checkpoint by interacting directly with PD-L1 and preventing its binding to PD-1, and is currently the only licensed PD-L1 inhibitor in the US. Atezolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma after prior platinum-based chemotherapy, and for metastatic NSCLC after prior therapy 11. The FDA have approved the VENTANA PD-L1 (SP142) Assay as a complimentary diagnostic, to determine the proportion of PD-L1 expressing tumour-infiltrating immune cells in urothelial carcinoma tissue, to help physicians decide which patients are most likely to respond to atezolizumab 12.
PD-L1 as a Predictive Biomarker
Defining biomarkers that predict therapeutic response to PD-1/PD-L1 blockade is an important goal 13. There is increasing evidence that PD-L1 measured by levels of Immunohistochemistry (IHC) expression is a relevant marker to predict response to treatment. The first study that provided evidence of a link between PD-L1 protein expression by tumour cells detected by IHC and response to anti-PD-1 therapy, was the first-in-human phase I nivolumab trial conducted in patients with a variety of different solid tumour types 14. Subsequently, a number of trials validated that PD-L1 expression correlates with an increased response to PD-1 and PD-L1 immune checkpoint inhibitors, but the response rate was lower than the early studies.
IHC of PD-L1-negative Tumour
IHC of PD-L1-negative Tumour. Credit: Hendrik Tobias Arkenau
Thus, while PD-L1 expression has been associated with more favourable response rates to PD-1/PD-L1 checkpoint inhibitors, PD-L1 does not appear to be a static Biomarker and does not offer binary discrimination of responsiveness.
The wording of the licences for pembrolizumab, nivolumab and atezolizumab, have different recommendations regarding PD-L1 expression that reflect the clinical trial evidence. Only pembrolizumab has an indication restricted to tumours expressing PD-L1, whereas nivolumab and atezolizumab have been approved regardless of tumour PD-L1 expression 5,6,8,9,11. Patients without PD-L1 expression can also derive benefit from these agents, with studies across multiple cancer types demonstrating a pooled response rate of 48% in patients with PD-L1-positive tumours compared with 15% in PD-L1-negative tumours 15.
Both pembrolizumab and nivolumab are licensed by the European Medicines Agency (EMA) and FDA for treatment of advanced melanoma independent of PD-L1 expression. The combination of nivolumab with ipilimumab in advanced melanoma improved progression-free survival (PFS) over nivolumab alone, in patients with low tumour PD-L1 expression measured by the PD-L1 IHC 28-8 pharmDx assay 16, and this finding is reflected in the wording of the nivolumab melanoma indication in the EU 5.
PD-L1 positivity is also associated with improved survival from nivolumab treatment in non-squamous NSCLC 17. The predictive value of PD-L1, using the PD-L1 IHC 28-8 pharmDx assay, was seen across all the efficacy end points of the CheckMate 057 study at an expression level ≥1% 7. Despite these findings, a companion diagnostic is not required for nivolumab treatment in melanoma or NSCLC 5,6. The FDA has instead approved the PD-L1 IHC 28-8 pharmDx test as a complementary test that may provide physicians more information and inform patient dialogue when deciding treatment for melanoma or NSCLC. This decision was likely influenced by limitations of the clinical data to support the assay, for example, findings from clinical trials that demonstrated similar outcomes irrespective of PD-L1 expression status 18,19,20. Furthermore, testing for PD-L1 expression in the CheckMate 057 study was retrospective and was not performed on all patient specimens but rather a subset of 78% of cases, with the potential risk of selection bias 18.
Currently, PD-L1 IHC 22C3 pharmDx (Dako) is the only FDA-approved companion diagnostic for selecting NSCLC patients for treatment with pembrolizumab. This approval was based on results of two randomised, controlled trials that demonstrated statistically significant improvements in PFS and overall survival (OS) for patients randomised to pembrolizumab compared with chemotherapy. In a trial of 305 patients with metastatic NSCLC, whose tumours had high PD-L1 expression (expressed in ≥ 50% tumour cells), had not received prior chemotherapy and did not have EGFR or ALK genomic tumour aberrations, those who received pembrolizumab had a significant improvement in PFS for patients receiving pembrolizumab versus chemotherapy. Additionally, a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomised to pembrolizumab as compared with chemotherapy 8. In a trial of 1033 patients who were previously treated for metastatic NSCLC and expressed PD-L1 in greater than or equal to 1% tumour cells, those randomised to pembrolizumab had an improved OS compared with patients receiving docetaxel.
In a non-randomised, prospective, single-arm study of atezolizumab, PD-L1 expression in ≥ 5% tumour infiltrating immune cells, determined by the VENTANA PD-L1 (SP142) Assay, in urothelial carcinoma tissue was associated with increased objective response rate 21. In patients who were classified as positive for PD-L1 expression (≥ 5% tumour infiltrating immune cells), 26% of participants experienced a tumour response compared to 9.5% of participants who were classified as negative for PD-L1 expression (< 5% tumour infiltrating immune cells). Therefore, patients experienced a tumour response across the study; however, the greater effect in those who were classified as positive for PD-L1 expression suggests that the level of PD-L1 expression in tumour-infiltrating immune cells may help identify patients whose tumours are more likely to respond 12. Hence, the VENTANA PD-L1 (SP142) Assay has been approved by the FDA, as a complimentary diagnostic to help physicians decide which patients with urothelial cancer are most likely to respond to atezolizumab 12. Quality Testing Results The conflicting observations regarding PD-L1 as a predictive biomarker of tumour response likely reflects a number of issues, both IHC-test specific and tumour-biology-related. These include the limitations inherent in tumour sampling, with focal expression potentially missed in small biopsies, and differential PD-L1 expression apparent over time and by anatomical site in individual patients. Different IHC detection methods and antibodies, quality of samples, methods used to acquire material, and positivity thresholds may also be a factor 4. Recognising this, a Blueprint Working Group has been established with cooperation from the Pharmaceutical Industry to provide a comparison of different IHC tests and cell scoring methods for PD-L1 expression, reflecting that each drug is developed in the context of a unique biological scientific hypothesis and registration strategy. In terms of the tumour microenvironment, PD-L1 can be expressed across a wide range of cell types, creating challenges in individual cell identification 4. The impact on the tumour microenvironment that may have occurred through multiple previous cancer treatments remains undefined 4.
martes, 14 de febrero de 2017
Early Radiation Palliative Relief Demonstrated For Painful Bone Metastases
Early Radiation Palliative Relief Demonstrated For Painful Bone Metastases
A single dose of radiation may provide significant benefit to patients with painful bone metastases
Date: 13 Feb 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Palliative Care / Surgery and/or Radiotherapy of Cancer
medwireNews: Research indicates that around 40% of patients with painful bone metastases may experience pain relief and a significant improvement in their quality of life within 10 days of receiving one dose of radiation.
“[T]HUS, a single 8-Gy dose of radiotherapy for painful bone metastases should be offered to all patients, even those with poor survival”, recommend Edward Chow, from Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and co-workers in JAMA Oncology.
They report secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23 which looked at the impact of dexamethasone for the prevention of pain flare after radiotherapy in patients with one or two painful bone metastases with a worst pain score of at least 2 on a scale of 1–10.
The study used the International Bone Metastases Consensus Endpoint Definitions for a complete pain response to radiation – a pain score of 0 without an increase in analgesic intake – and partial response – a pain reduction score of 2 or more without an increase in analgesics, or an analgesic reduction of at least 25%.
In all, 40.9% of 298 patients experienced a complete (n=37) or partial response (n=85) to radiation by day 10. At day 42, the overall response rate was 38.9%, with 61 complete and 55 partial responses.
Quality of life (QoL) data were available for 72.1% of patients at day 10 and 62.7% at day 42; among these patients, 54.5% had a pain response by day 42.
Patients with a pain response were significantly more likely than those without to achieve a clinically meaningful 10-point or greater change in QoL on the EORTC Quality of Life Questionnaire Bone Metastases Module (QLQ-BM22) at day 10 than those without for pain characteristics (64.0 vs 42.6%) and psychosocial aspects (37.0 vs 20.9%).
At day 42, patients who responded to radiation had at least a 10-point difference in the average physical, emotional and global scores on the EORTC QLQ Core 15 Palliative (C15-PAL) assessment to those of nonresponders, with pain score showing the greatest difference.
These benefits included a greater reduction on the QLC C15-PAL in symptoms of pain, fatigue, appetite loss and constipation, pain characteristics, functional interference and psychosocial aspects, the researchers say, as well as significantly better responses on the QLQ-BM22 for painful sites, pain characteristics, functional interference and psychosocial aspects.
As expected, the QoL items that did not improve with pain relief, such as insomnia and dyspnoea, were not significantly better in patients who responded to radiation than those who did not.
“Thus, physicians should use other more appropriate treatment modalities to address these symptoms separately”, write Edward Chow et al.
They add: “Our evaluation time points (days 10 and 42) should be used in future studies that involve similar patient populations because they are more relevant than evaluating those with poor expected survival at 2 or even 3 months after treatment.”
Charles Thomas Jr, from the Oregon Health Sciences University in Portland, USA, writes in an accompanying editor’s note that the current study is “a step forward” from earlier reports of pain relief in this population because it used a uniform dose of radiation.
“Early pain relief may be a surrogate de facto marker of future short-term improved QOL”, he writes.
“In fact, the current trial may be immediately beneficial to patients with advanced disease and their respective caregivers and health care practitioners."
Indeed, Charles Thomas Jr emphasizes that “the NCIC CTG SC.23 observations are candidate metrics that can be incorporated into quality indicators of pain assessment by patients, caregivers, practice guidelines, health care systems, and third-party payers, all of whom are involved in value-based palliative care initiatives.”
References
McDonald R, Ding K, Brundage M, et al. Effect of radiotherapy on painful bone metastases. A secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23.JAMA Oncol; Advance online publication 9 February 2017. doi:10.1001/jamaoncol.2016.6770
Thomas Cr Jr. Single-fraction radiotherapy and early subjective improvement in pain. JAMA Oncol; Advance online publication 9 February 2017. doi:10.1001/jamaoncol.2016.6723
martes, 7 de febrero de 2017
The 21st Century Cures Act
Perspective
The 21st Century Cures Act — A View from the NIH
Kathy L. Hudson, Ph.D., and Francis S. Collins, M.D., Ph.D.
N Engl J Med 2017; 376:111-113January 12, 2017DOI: 10.1056/NEJMp1615745
The Cures Act, formally known as H.R. 34 or the 21st Century Cures Act,1 passed overwhelmingly in the U.S. House of Representatives and Senate in the waning days of the 114th Congress and was signed into law by President Barack Obama on December 13, 2016. Weighing in at nearly 1000 pages, this bipartisan bill is the product of years of hard work by Republican and Democratic lawmakers, in collaboration with a broad array of diverse stakeholders. As with any landmark piece of legislation, the complex negotiations leading up to its passage were challenging and intense. But the final provisions are well worth heralding, including increased support for state efforts to combat opioid abuse, new steps aimed at improving mental health services, and important changes affecting the Food and Drug Administration and the National Institutes of Health (NIH).
Here, we focus on aspects of the Cures Act that are directly relevant to the NIH’s mission — measures that will provide the agency with critical tools and resources to advance biomedical research across the spectrum from basic, curiosity-driven studies to advanced clinical trials of promising new therapies. Affecting everyone from researchers to research participants to patients suffering from numerous conditions, these measures will cut bureaucratic red tape that slows the progress of science, enhance data sharing and privacy protections for research volunteers, improve support for the next generation of biomedical researchers, exhort the NIH to extend its efforts to ensure inclusion of diverse populations, and provide the NIH with a bolus of additional funding over 10 years for key biomedical research initiatives.
Some key measures reduce red tape. Policies generated with the best intentions sometimes have serious adverse consequences for research. Two needlessly obstructive policies have been undone by the Cures Act — one dealing with paperwork and the other with scientific meetings.
The first, the ironically titled Paperwork Reduction Act,2 was enacted when the Internet was nascent and paper still ruled. Its purpose was to limit government’s ability to ask Americans to fill out endless forms, especially when those forms were required to receive government services or benefits. Minimizing needless paperwork and bureaucracy is an admirable goal. However, as applied to biomedical research, the law requires multiple levels of government review and public comment on any set of questions that NIH researchers propose to ask of 10 or more persons in a scientific study supported by contracts, the Intramural Research Program, and many cooperative agreements. This process rarely results in substantive changes, but it delays the start of research for 9 months, on average — dissuading investigators, especially trainees, from undertaking important studies. Through the Cures Act, lawmakers have now liberated science from this red tape by eliminating Paperwork Reduction Act requirements for NIH research — a step that will help speed the initiation of research and the generation of new knowledge.
The Cures Act’s second major red-tape–cutting measure provides much-needed relief from restrictions on support for scientific meetings. Because of a few well-publicized extravagant meetings attended by members of other federal agencies, restrictions were placed on federal employees’ travel to meetings. Those restrictions applied to government scientists’ travel to scientific meetings, severely hampering their ability to present their research and exchange ideas with other scientists.3 Scientists could not be confident that their travel applications would be approved, and requests for meeting attendance were sometimes denied. These travel restrictions generated senseless paperwork and, owing to the resulting delays in processing requests from multiple agencies, actually increased costs to the government. The Cures Act has removed these restrictions.
Other measures in the bill relate to data sharing and privacy protection. Sharing data is essential for progress in biomedical research. Rapid data sharing was key to the success of the Human Genome Project, and that same commitment has been spreading across biomedicine in the past two decades, as advances in technology and “big data” have enabled an entirely new level of data sharing and inquiry.4 Despite the clear value of sharing data, the NIH has been constrained from requiring in a straightforward way that NIH-funded investigators share their data. The Cures Act solves this problem by allowing the NIH director to require that data from NIH-supported research be shared, giving all scientists the opportunity to use these data as quickly as possible to advance biomedical research.
This new era of rapid and facile exchange of data also requires redoubled efforts to protect the privacy and confidentiality of information about research participants. People who volunteer for research need to be confident that scientists will do everything in their power to protect their private information. The Cures Act contains what we believe are the most significant advances in research privacy protections in two decades. Certificates of confidentiality, previously available to researchers upon request, will now be provided to all NIH-funded scientists conducting research that involves the collection of identifiable, sensitive information. The certificates will provide stronger protections against the disclosure of the names of participants or any other identifiable data gathered during research. In addition, the Cures Act will allow the NIH to withhold biomedical information about individuals that could be used to reidentify them through requests for records filed under the Freedom of Information Act.5
Cures Act provisions also support early-stage researchers. Today, the average age of a researcher receiving his or her first independent research grant from the NIH is 42. The NIH has been working hard to create additional opportunities for younger researchers, including dedicated awards for new and early-stage investigators. Though such efforts have proven valuable for encouraging individual researchers, they have not resulted in a lowering of the average age of independent investigators within the full NIH research portfolio. Provisions in the Cures Act will establish an office at the NIH to promote policies aimed at improving coordination and analysis of opportunities for new and early-stage investigators, as well as at attracting, retaining, and developing emerging scientists in priority research areas. Such efforts will include strategies for developing early-stage researchers who are women or members of other groups that are traditionally underrepresented in biomedical research careers. To provide further support to early-stage researchers, the Cures Act authorizes the establishment of additional programs to assist in the repayment of student loans and raises the cap on the repayment assistance available to researchers.
It is essential that biomedical research reflect, and provide a benefit to, the entire U.S. population. The Cures Act encourages diversity by setting out a path for the NIH to continue and expand its efforts to allow Americans of all stripes to participate in and benefit from NIH-funded biomedical research. These efforts will be aided by the NIH’s collection and posting of more detailed information about the participants in NIH-funded research, specifically the inclusion of key demographic groups defined by characteristics including sex, age, and minority status. The NIH is also encouraged by the legislation to carry out focused efforts to improve research related to sexual and gender minority populations, as well as work aimed at understanding and reducing health disparities between different populations.
The Cures Act provides multiyear funding for three highly innovative scientific initiatives launched by the Obama administration: the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the Precision Medicine Initiative (PMI), and the Beau Biden Cancer Moonshot. It also includes a promising new research initiative focused on regenerative medicine (see tableFunding for NIH Innovative Research Initiatives under the Cures Act.).
Each of these initiatives has its own set of audacious goals, but their basic aims are as follows. BRAIN is a sweeping effort to build technology and knowledge across an array of disciplines to elucidate how circuits in the brain function in real time and what goes wrong in disease. PMI is a transformative research infrastructure that will enable and simplify research across all diseases. Its centerpiece, dubbed All of Us, is a longitudinal cohort study involving 1 million or more Americans. The Beau Biden Cancer Moonshot is an ambitious plan to double the rate of progress in the fight against cancer, making more therapies available to more patients, while also improving our ability to detect and prevent cancer. The Cures Act regenerative medicine program is focused on clinical research using adult stem cells, including autologous stem cells. It features an innovative funding mechanism that requires a match from the grant or contract awardee.
Congress has made it clear that these focused investments are not intended as a substitute or offset for supporting NIH research through the regular appropriations process. Although the decision about the overall fiscal year 2017 funding level for the federal government to support all NIH research across disciplines and disease areas has been postponed until April 2017, the Cures Act funding is available now and will be used right away to support groundbreaking research. We remain optimistic that strong support for the NIH budget will be reflected in the ultimate decisions about the fiscal year 2017 budget and beyond.
In the meantime, Congress has provided an enormous gift to science in the form of the Cures Act, a gift that reflects a deep confidence in the promise of biomedical research to make discoveries and develop cures in the 21st century. All those who made this gift possible — the President and Vice President, lawmakers, stakeholders, and most of all, patients — deserve our heartfelt thanks.
The 21st Century Cures Act — A View from the NIH
Kathy L. Hudson, Ph.D., and Francis S. Collins, M.D., Ph.D.
N Engl J Med 2017; 376:111-113January 12, 2017DOI: 10.1056/NEJMp1615745
The Cures Act, formally known as H.R. 34 or the 21st Century Cures Act,1 passed overwhelmingly in the U.S. House of Representatives and Senate in the waning days of the 114th Congress and was signed into law by President Barack Obama on December 13, 2016. Weighing in at nearly 1000 pages, this bipartisan bill is the product of years of hard work by Republican and Democratic lawmakers, in collaboration with a broad array of diverse stakeholders. As with any landmark piece of legislation, the complex negotiations leading up to its passage were challenging and intense. But the final provisions are well worth heralding, including increased support for state efforts to combat opioid abuse, new steps aimed at improving mental health services, and important changes affecting the Food and Drug Administration and the National Institutes of Health (NIH).
Here, we focus on aspects of the Cures Act that are directly relevant to the NIH’s mission — measures that will provide the agency with critical tools and resources to advance biomedical research across the spectrum from basic, curiosity-driven studies to advanced clinical trials of promising new therapies. Affecting everyone from researchers to research participants to patients suffering from numerous conditions, these measures will cut bureaucratic red tape that slows the progress of science, enhance data sharing and privacy protections for research volunteers, improve support for the next generation of biomedical researchers, exhort the NIH to extend its efforts to ensure inclusion of diverse populations, and provide the NIH with a bolus of additional funding over 10 years for key biomedical research initiatives.
Some key measures reduce red tape. Policies generated with the best intentions sometimes have serious adverse consequences for research. Two needlessly obstructive policies have been undone by the Cures Act — one dealing with paperwork and the other with scientific meetings.
The first, the ironically titled Paperwork Reduction Act,2 was enacted when the Internet was nascent and paper still ruled. Its purpose was to limit government’s ability to ask Americans to fill out endless forms, especially when those forms were required to receive government services or benefits. Minimizing needless paperwork and bureaucracy is an admirable goal. However, as applied to biomedical research, the law requires multiple levels of government review and public comment on any set of questions that NIH researchers propose to ask of 10 or more persons in a scientific study supported by contracts, the Intramural Research Program, and many cooperative agreements. This process rarely results in substantive changes, but it delays the start of research for 9 months, on average — dissuading investigators, especially trainees, from undertaking important studies. Through the Cures Act, lawmakers have now liberated science from this red tape by eliminating Paperwork Reduction Act requirements for NIH research — a step that will help speed the initiation of research and the generation of new knowledge.
The Cures Act’s second major red-tape–cutting measure provides much-needed relief from restrictions on support for scientific meetings. Because of a few well-publicized extravagant meetings attended by members of other federal agencies, restrictions were placed on federal employees’ travel to meetings. Those restrictions applied to government scientists’ travel to scientific meetings, severely hampering their ability to present their research and exchange ideas with other scientists.3 Scientists could not be confident that their travel applications would be approved, and requests for meeting attendance were sometimes denied. These travel restrictions generated senseless paperwork and, owing to the resulting delays in processing requests from multiple agencies, actually increased costs to the government. The Cures Act has removed these restrictions.
Other measures in the bill relate to data sharing and privacy protection. Sharing data is essential for progress in biomedical research. Rapid data sharing was key to the success of the Human Genome Project, and that same commitment has been spreading across biomedicine in the past two decades, as advances in technology and “big data” have enabled an entirely new level of data sharing and inquiry.4 Despite the clear value of sharing data, the NIH has been constrained from requiring in a straightforward way that NIH-funded investigators share their data. The Cures Act solves this problem by allowing the NIH director to require that data from NIH-supported research be shared, giving all scientists the opportunity to use these data as quickly as possible to advance biomedical research.
This new era of rapid and facile exchange of data also requires redoubled efforts to protect the privacy and confidentiality of information about research participants. People who volunteer for research need to be confident that scientists will do everything in their power to protect their private information. The Cures Act contains what we believe are the most significant advances in research privacy protections in two decades. Certificates of confidentiality, previously available to researchers upon request, will now be provided to all NIH-funded scientists conducting research that involves the collection of identifiable, sensitive information. The certificates will provide stronger protections against the disclosure of the names of participants or any other identifiable data gathered during research. In addition, the Cures Act will allow the NIH to withhold biomedical information about individuals that could be used to reidentify them through requests for records filed under the Freedom of Information Act.5
Cures Act provisions also support early-stage researchers. Today, the average age of a researcher receiving his or her first independent research grant from the NIH is 42. The NIH has been working hard to create additional opportunities for younger researchers, including dedicated awards for new and early-stage investigators. Though such efforts have proven valuable for encouraging individual researchers, they have not resulted in a lowering of the average age of independent investigators within the full NIH research portfolio. Provisions in the Cures Act will establish an office at the NIH to promote policies aimed at improving coordination and analysis of opportunities for new and early-stage investigators, as well as at attracting, retaining, and developing emerging scientists in priority research areas. Such efforts will include strategies for developing early-stage researchers who are women or members of other groups that are traditionally underrepresented in biomedical research careers. To provide further support to early-stage researchers, the Cures Act authorizes the establishment of additional programs to assist in the repayment of student loans and raises the cap on the repayment assistance available to researchers.
It is essential that biomedical research reflect, and provide a benefit to, the entire U.S. population. The Cures Act encourages diversity by setting out a path for the NIH to continue and expand its efforts to allow Americans of all stripes to participate in and benefit from NIH-funded biomedical research. These efforts will be aided by the NIH’s collection and posting of more detailed information about the participants in NIH-funded research, specifically the inclusion of key demographic groups defined by characteristics including sex, age, and minority status. The NIH is also encouraged by the legislation to carry out focused efforts to improve research related to sexual and gender minority populations, as well as work aimed at understanding and reducing health disparities between different populations.
The Cures Act provides multiyear funding for three highly innovative scientific initiatives launched by the Obama administration: the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the Precision Medicine Initiative (PMI), and the Beau Biden Cancer Moonshot. It also includes a promising new research initiative focused on regenerative medicine (see tableFunding for NIH Innovative Research Initiatives under the Cures Act.).
Each of these initiatives has its own set of audacious goals, but their basic aims are as follows. BRAIN is a sweeping effort to build technology and knowledge across an array of disciplines to elucidate how circuits in the brain function in real time and what goes wrong in disease. PMI is a transformative research infrastructure that will enable and simplify research across all diseases. Its centerpiece, dubbed All of Us, is a longitudinal cohort study involving 1 million or more Americans. The Beau Biden Cancer Moonshot is an ambitious plan to double the rate of progress in the fight against cancer, making more therapies available to more patients, while also improving our ability to detect and prevent cancer. The Cures Act regenerative medicine program is focused on clinical research using adult stem cells, including autologous stem cells. It features an innovative funding mechanism that requires a match from the grant or contract awardee.
Congress has made it clear that these focused investments are not intended as a substitute or offset for supporting NIH research through the regular appropriations process. Although the decision about the overall fiscal year 2017 funding level for the federal government to support all NIH research across disciplines and disease areas has been postponed until April 2017, the Cures Act funding is available now and will be used right away to support groundbreaking research. We remain optimistic that strong support for the NIH budget will be reflected in the ultimate decisions about the fiscal year 2017 budget and beyond.
In the meantime, Congress has provided an enormous gift to science in the form of the Cures Act, a gift that reflects a deep confidence in the promise of biomedical research to make discoveries and develop cures in the 21st century. All those who made this gift possible — the President and Vice President, lawmakers, stakeholders, and most of all, patients — deserve our heartfelt thanks.
Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer
Original Article
Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer
William U. Shipley, M.D., Wendy Seiferheld, M.S., Himanshu R. Lukka, M.D., Pierre P. Major, M.D., Niall M. Heney, M.D., David J. Grignon, M.D., Oliver Sartor, M.D., Maltibehn P. Patel, M.D., Jean-Paul Bahary, M.D., Anthony L. Zietman, M.D., Thomas M. Pisansky, M.D., Kenneth L. Zeitzer, M.D., Colleen A.F. Lawton, M.D., Felix Y. Feng, M.D., Richard D. Lovett, M.D., Alexander G. Balogh, M.D., Luis Souhami, M.D., Seth A. Rosenthal, M.D., Kevin J. Kerlin, M.D., James J. Dignam, Ph.D., Stephanie L. Pugh, Ph.D., and Howard M. Sandler, M.D., for the NRG Oncology RTOG*
N Engl J Med 2017; 376:417-428February 2, 2017DOI: 10.1056/NEJMoa1607529
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Background
Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown.
Methods
In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival.
Results
The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). Conclusions
The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874.)
Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer
William U. Shipley, M.D., Wendy Seiferheld, M.S., Himanshu R. Lukka, M.D., Pierre P. Major, M.D., Niall M. Heney, M.D., David J. Grignon, M.D., Oliver Sartor, M.D., Maltibehn P. Patel, M.D., Jean-Paul Bahary, M.D., Anthony L. Zietman, M.D., Thomas M. Pisansky, M.D., Kenneth L. Zeitzer, M.D., Colleen A.F. Lawton, M.D., Felix Y. Feng, M.D., Richard D. Lovett, M.D., Alexander G. Balogh, M.D., Luis Souhami, M.D., Seth A. Rosenthal, M.D., Kevin J. Kerlin, M.D., James J. Dignam, Ph.D., Stephanie L. Pugh, Ph.D., and Howard M. Sandler, M.D., for the NRG Oncology RTOG*
N Engl J Med 2017; 376:417-428February 2, 2017DOI: 10.1056/NEJMoa1607529
Share:
Background
Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown.
Methods
In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival.
Results
The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). Conclusions
The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874.)
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