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Guidelines NCCN Updates Treatment Guidelines... Continued from cover diately applicable to clinical practice for patients with breast cancer, announced Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Palo Alto, California, who served as chair of the breast cancer panel. Some of the leading cancer institutions that inform the NCCN guidelines have already implemented many of these recommendations. Despite the recent controversy regarding decision by the US Food and Drug Administration (FDA) to rescind the indication for bevacizumab (Avastin) in patients with metastatic breast cancer (MBC), the NCCN reaffirmed its support for using a doublet of bevacizumab and paclitaxel for this population. Carlson said the panel decided to keep the combination of bevacizumab and paclitaxel in the guidelines as a treatment option based on the fact that the data had not changed. “If the data were compelling 2 years ago, [they are] compelling enough today,” he said. The panel added a footnote acknowledging that the use of this regimen does not improve overall survival (OS) and only “modestly improves time to progression and response rates.” Carlson said panel members were less confident of the data on combining bevacizumab with other approved chemotherapy agents. The updated guidelines also reflect recent FDA approvals of eribulin (Halaven) monotherapy for women with MBC who have received at least 2 prior chemotherapy regimens, including a taxane and an anthracycline, and denosumab (Xgeva) to help prevent skeletal-related events in patients with solid tumors that have metastasized to the bone. Eribulin, a cytotoxic agent, became a “preferred” agent in MBC based on final data from the EMBRACE study, in which 762 patients were randomized to eribulin or treatment of physician’s choice (TPC). Median OS was 13.1 months in the eribulin arm versus 10.6 months in the TPC arm, representing a 19% reduction in risk with the new agent (P = .041). The rate of 1-year OS was 53.9% in the eribulin arm compared with 43.7% for the TPC arm. Significantly more patients in the eribulin arm experienced grade 3/4 neutropenia, leukopenia, and peripheral neuropathy, but study investigators described adverse events as manageable. The inclusion of denosumab was based on its approval following phase 3 trial data showing that patients randomized to denosumab experienced 23% fewer skeletal-related events (SREs) than patients given zoledronic acid (Zometa; P = .001). Denosumab also delayed the time to first onstudy SRE by 18% versus zoledronic acid
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issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time,” said Carlson.
Robert W. Carlson, MD
(P = .001). Rates of OS and diseasefree survival (DFS) were similar in the study arms. Translational Findings The panel recommended that any work-ups for metastatic lesions seek to determine the hormonal and HER2 status of the metastases “if unknown, originally negative, or not over-expressed.” This was based on a growing body of data showing discordance between hormonal status of the primary tumor and metastases. For example, a study presented at the American Society of Clinical Oncology annual meeting in 2010 identified several cases in which the hormonal status of the patient’s liver metastases did not match the hormonal status of her primary tumor. The findings resulted in treatment changes for >12% of patients. “This recommendation is likely to get stronger as these data are formally published,” Carlson said. Representing a significant change in current clinical practice, the NCCN guidelines now advise against complete axillary lymph node dissection for women with clinically node-negative T1-T2 breast tumors and fewer than 3 involved sentinel lymph nodes who undergo surgery and radiation therapy. Carlson said the recommendation is based on data from a single randomized trial, the landmark ACOSOG Z0011 study. Investigators found no difference in rates of locoregional recurrence, DFS, and OS between patients who underwent complete axillary lymph node dissection and those who had sentinel lymph node dissection. The recommendation applies only to patients who match the well-defined characteristics observed in the subset of patients who formed the study population. The panel considered whether to recommend clinicians test patients for the CYP2D6 polymorphism prior to prescribing tamoxifen but decided against it. Panel members noted significant discrepancies between major studies investigating whether this mutation is associated with tamoxifen resistance. “The current NCCN guidelines are silent on this
Prostate Cancer In updating guidelines for prostate cancer, the panel reportedly spent considerable time weighing whether the data favor active surveillance or immediate treatment for certain patient populations. James L. Mohler, MD, Roswell Park Cancer Institute, Buffalo, New York, discussed the NCCN’s recommendation to monitor more rigorously men who opt for active surveillance. “The NCCN remains concerned about overdiagnosis and overtreatment of prostate cancer, as growing evidence suggests that overtreatment commits too many men to side effects that outweigh a very small risk of prostate cancer death,” he said. He also reviewed new treatment options for advanced prostate cancer.
New Therapeutic Options: Sipuleucel-T, Cabazitaxel, Denosumab For men with advanced metastatic castration-resistant prostate cancer (CRPC), the panel voted to add sipuleucel-T (Provenge) and cabazitaxel (Jevtana) as new therapeutic options. The FDA approved both treatments in 2010, after studies showed they improved OS.
James L. Mohler, MD
Active Surveillance OK—for Some Active surveillance, also termed watchful waiting, is a viable option for patients whose risk of progression is low to very low. The “very low risk” category is reserved for men with clinically significant prostate cancer, and the 2010 guidelines incorporated strict criteria for determining which patients meet this designation. Per 2010 guidelines, active surveillance was considered suitable for men identified as “very low risk” and men considered “low risk” who have a life expectancy <10 years. The 2011 updates to the guidelines increase the level of monitoring recommended for men in the “very low risk” category whose life expectancy is <20 years. Men who elect this approach should receive the following: • Prostate-specific antigen (PSA) tests every 6 months • A digital rectal examination at least every 12 months • Repeat biopsies as often as every 12 months. Mohler outlined challenges in determining whether some men with prostate cancer should get active surveillance rather than treatment. Large clinical studies examining this question have applied different criteria for active surveillance and disease progression, making it difficult to reconcile findings between series. Concerns also remain about overtreatment rates and the clinical risks associated with biopsies. “Ultimately, this decision must be based on careful, individualized weighting of a number of factors and is an option that needs to be thoroughly discussed,” he said. Mohler added that more clinical research is required to answer this question definitively.
Sipuleucel-T, an autologous cellular immunotherapy, is classified as a category 1 recommendation, which means the evidence is strong and panel members concurred on including the drug. “It is appropriate as salvage treatment for patients with CRPC who have minimally symptomatic disease, a performance status of 0 or 1, and a life expectancy of at least 6 months,” Mohler said. The relative risk for death with sipuleucel-T was 22%, according to a study by Kantoff and colleagues published in the New England Journal of Medicine last year (P = .03). It did not improve disease progression. Serious adverse effects were minimal, but many patients had immune-modulated reactions. Cabazitaxel, a taxane, was approved in conjunction with prednisone as a second-line option for men with metastatic CRPC that recurred following therapy with a docetaxel (Taxotere)based chemotherapy regimen. In the TROPIC study, men who received cabazitaxel plus prednisone saw a 2.4month improvement in OS compared with men treated with mitoxantrone (P <.001). As was the case with the breast cancer guidelines, the NCCN added denosumab as an alternative to zoledronic acid for the prevention of SREs in patients with bone metastases. Mohler said selecting an agent for bone protection depends on whether the patient has underlying comorbidities or has received zoledronic acid previously. Denosumab did not improve OS in men with prostate cancer but did demonstrate superiority to zoledronic acid on Continued on page 40
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