NCCN Updates Treatment Guidelines

TON - March/April 2011, VOL 4, NO 2 published on April 11, 2011
Audrey Andrews

At the 16th Annual Conference of the National Comprehensive Cancer Network (NCCN), chairpersons of the various tumor panels presented updates to the NCCN Clinical Practice Guidelines and explained the reasoning behind these changes. We review the most important updates to the guidelines for breast, prostate, and lung cancer and for various hematologic malignancies, including non-Hodgkin lymphoma and chronic myelogenous leukemia (CML). This brief overview is for informational purposes and is not intended to guide treatment decisions. You are encouraged to visit to review the complete guidelines and their respective references. Breast Cancer Pivotal research and drug approvals in the past year led to changes that are immediately applicable to clinical practice for patients with breast cancer, announced Robert W. Carlson, MD, Stanford Comp rehensive 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 de scribed 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 (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 issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time,” said Carlson.

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.

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.

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.

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 chemo therapy regimen. In the TROPIC study, men who received cabazitaxel plus prednisone saw a 2.4- month 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 multiple end points, including delaying time to first onstudy SRE.

Non–Small Cell Lung Cancer
The guideline updates provide recommendations on the need to determine the histologic subtype of non–small-cell lung cancer (NSCLC) tumors and conduct genetic tests in some patients before selecting a therapeutic regimen. David S. Ettinger, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, Baltimore, Maryland, de scribed the changes as pivotal. “We are heading toward the era of mutation driving the therapy, and it’s extremely important for our patients,” said Ettinger. In 2011, he added, “Histology matters and NOS [not otherwise specified] is unacceptable.”

When evaluating patients with recurrent or metastatic NSCLC for systemic therapy, the molecular diagnostics section of the 2011 guidelines recommends establishing the histologic subtype before testing for genetic mutations (Figure). Ettinger said all patients with adenocarcinoma should undergo molecular testing.

Testing for epithelial growth factor receptor (EGFR) is a category 1 recommendation for patients with adenocarcinoma or tumors of large cell histology and patients with NSCLC NOS. EGFR testing is not recommended in cases of squamous cell carcinoma.

In addition to updating information on EGFR and KRAS gene status, the guidelines discuss the EML4-ALK gene translocation. It is estimated that aberrations of EGFR, KRAS, and ALK drive >60,000 new cases of NSCLC in the United States each year, and each is an important predictor of response to various targeted therapies.

Crizotinib, a novel agent that targets EML4-ALK, has been submitted to the FDA for approval. It has the potential to improve prognosis for the 5% to 10% of patients positive for the EML4-ALK translocation. A recent phase 2 clinical trial of EML4-ALK–positive patients with adenocarcinoma found robust, durable responses to crizotinib, and Ettinger said updated findings from this study will be important. No standard method exists to detect the EML4-ALK translocation, but he said studies are looking at polymerase chain reaction, immunohistochem istry, and fluorescence in situ hybridization.

For patients with adenocarcinoma who progress or are resistant to first-line therapy with erlotinib (Tarceva), the guidelines have added bevacizumab (Avastin) plus a platinum doublet as a treatment option. Ettinger said combining bevacizumab with paclitaxel and carboplatin might be effective for patients with tumors of nonsquamous histology but should not be used for squamous cell carcinoma. He noted that bevacizumab is changing the landscape of treatment for stage IV NSCLC.

Non-Hodgkin Lymphoma
A new guideline on diagnosing and treating posttransplant lymphoproliferative disease (PTLD) and the reclassification of 2 therapies as category 1 recommendations in follicular lymphoma (FL) are central to the guideline updates for non-Hodgkin lymphoma (NHL). Andrew D. Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, chaired the NHL panel and discussed the revisions.

New Guidelines for Transplant Complication
“PTLD has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation,” said Zelenetz. Advances in our understanding of the pathogenesis of PTLD and improvements in detection strategies are allowing clinicians to identify patients at high risk of the disease earlier. “The single biggest risk factor for PTLD is the presence of an Epstein-Barr virus [EBV] mismatch between the recipient and the donor,” he said. “The time from organ transplant is critically important, with most of these lesions developing within the first year.”

The NCCN guidelines specify tests for PTLD and designate them as “essential” or “useful in selected cases.” Essential tests include histopathology, immuno phenotyping, and the EBVencoded RNA in situ hybridization assay. EBV viral load is deemed “useful in selected cases.”

Depending on PTLD subtype, recommended treatment options include reducing immunosuppression, which is effective in 23% to 64% of patients; single-agent rituximab (Rituxan), associated with a response rate as high as 90% in patients with early and polymorphic lesions; and gancyclovir or another antiviral prophylaxis for EBV-positive patients. Although chemoimmunotherapy is also an option, Zelenetz said, “I would reserve chemoimmunotherapy for patients in whom other, simpler maneuvers have failed.”

Stronger Evidence for Follicular Lymphoma Regimens
In the FL section of the guidelines, the combination of bendamustine (Treanda) and rituximab (B-R) was upgraded to a category 1 recommendation for first-line treatment. A pivotal trial compared B-R with standard therapy using cyclophosphamide, doxorubicin, vincristine, prednisone, and ritux imab (CHOP-R). B-R was as sociated with significant improvement in progression- free survival (PFS) and the rate of complete response versus CHOP-R; OS was similar in both trial arms.

Consolidation with 90Y ibritumomab tiuxetan (Zevalin), a radiotherapy agent, followed by rituximab maintenance therapy was also reclassified as a category 1 recommendation for treatment after first remission. Patients on this regimen had prolonged PFS but no improvement in OS.

Because “no maintenance strategy in FL has yet demonstrated a benefit in OS,” Zelenetz said observation remains an appropriate option in the NCCN algorithm for initial treatment of the disease. He emphasized the importance of individualized treatment planning for patients with FL.

Chronic Myelogenous Leukemia Two newer tyrosine kinase inhibitors (TKIs) received new indications as first-line treatment options for chronic myelogenous leukemia (CML) in the past year. Susan O’Brien, MD, the University of Texas M. D. Anderson Cancer Center, Houston, said the NCCN panel updated guidelines to include nilotinib (Tasigna) and dasatinib (Sprycel) as options for patients with newly diagnosed Philadelphia chromosome–positive CML. Studies show dasatinib and nilotinib are associated with significantly higher response rates than imatinib (Gleevec) at 12 months and fewer patients treated with these agents progressed to accelerated phase or blast crisis.

Data from the ENESTnd study, reported at the 2010 annual meeting of the American Society of Hematology, showed that >60% of patients with newly diagnosed CML had achieved major molecular response at 24 months with nilotinib compared with 37% of patients treated with imatinib. Less than 2% of nilotinib-treated patients progressed to accelerated phase or blast crisis, experienced by 4% to 6% of patients in the imatinib arm. “This is the most clinically relevant data in the short-term, because transformation heralds a very poor prognosis,” said O’Brien.

The phase 3 DASISION study compared dasatinib, an SRC inhibitor, with imatinib in patients with newly diagnosed CML in the chronic phase. At a median of 12 months’ follow-up, patients in the dasatinib arm were more likely to have experienced major molecular response and complete cytogenetic response than patients treated with imatinib.

O’Brien said trials indicate these newer agents offer nearly identical improvements in short-term end points, although their ultimate effect on PFS and OS has not been determined. Adverse effects with both agents are considered manageable. With 3 approved first-line agents, oncologists have the option of starting patients on one of the newer drugs at diagnosis or initiating treatment with imatinib and switching to nilotinib or dasatinib in the secondline. Both have proven highly effective in patients resistant to or intolerant of imatinib who do not have the T315I mutation, which renders patients resis tant to all available TKIs.

These and other guidelines are available free of charge to registered users of the NCCN Website at

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