NCCN 2011 Clinical Guidelines Updates

April 2011, Vol 2, No 2 - NCCN Conference


Hollywood, FL—Chairpersons of the various National Comprehensive Cancer Network (NCCN) tumor panels presented clinical practice updates at the recent 16th Annual Conference of the NCCN. Key updates, and relevant discussions, are highlighted.

Key Changes in Breast Cancer Recommendations
Robert W. Carlson, MDPivotal research in 2010 led to changes that are immediately applicable to clinical practice in breast cancer, said panel chair Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Palo Alto, CA.

Pharmacotherapy
Despite the recent controversy regarding the US Food and Drug Administration (FDA) recommendation to remove the metastatic breast cancer indication for bevacizumab (Avastin), the NCCN affirmed the combination of bevacizumab and paclitaxel in its treatment guidelines. The panel members were not as confident in the use of bevacizumab with other approved chemotherapy agents.

The NCCN decision was based on the argument that “if the data were compelling 2 years ago, they are compelling enough today,” Dr Carlson said. The panel, however, did add a footnote to the guidelines, acknowledging that the use of the drug does not improve overall survival (OS) and only “modestly improves time to progression and response rates.”

Eribulin (Halaven), a cytotoxic agent, is now a “preferred” agent for women with previously treated metastatic breast cancer, based on the 2010 EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) trial, in which 762 patients were randomized to treatment by physicians’ choice or to eribulin. One-year OS was 53.9% for the eribulin arm versus 43.7% for the treatment by physicians’ choice arm, and median OS was 13.12 months versus 10.65 months, representing a 19% risk reduction with the new agent.

The addition of denosumab (Xgeva) in this patient population to help prevent skeletal-related events was based on a study presented at the American Society of Clinical Oncology 2010 meeting (abstract 1024) showing 23% fewer skeletal-related events, versus zoledronic acid (Zometa), although OS and disease-free survival were similar to the control group.

Other Changes
The panel also recommends that the metastatic breast cancer work-up include the determination of hormonal and HER2/neu status “if unknown, originally negative, or not overexpressed.” This was based on growing evidence showing discordance between primary and recurrent disease. “This recommendation is likely to get stronger as these data are formally published,” Dr Carlson added.

Representing a significant departure from current clinical practice, the panel has given a thumbs-down to complete axillary lymph node dissection in women with clinically nodenegative T1-T2 tumors, and <3 involved sentinel lymph nodes who undergo surgery and radiation therapy. This change is based on the land mark American College of Surgeons On cology Group Z0011 study (Giuliano AE, et al. JAMA. 2011;305:569-575), which found no difference in locoregional recurrences, disease-free survival or OS between patients who underwent complete dissection and those who had a sentinel lymph node dissection only.

“The panel decided to add the recommendation to the main guidelines based on this single randomized trial,” Dr Carlson said. The recommendation is intended only for this well-defined subset of the patient population.

Finally, citing discrepancies between major studies, the panel did not recommend that patients be tested for the CYP2D6 polymorphism, which has been implicated in resistance to tamoxifen. “The current NCCN guidelines are silent on this issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time,” he said.

Prostate Cancer Update
The question of active surveillance or immediate treatment for a subset of men with prostate cancer was the focus of the updated guidelines for prostate cancer. James L. Mohler, MD, Roswell Park Cancer Institute, discussed the recommendation for more rigorous monitoring of men opting for active surveillance (or watchful waiting) and new treatment options for advanced prostate cancer.

“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,” Dr Mohler said.

Active surveillance is a viable option for many men with very low risk or even low risk of progression. In 2010, the guidelines established the “very-low-risk” category, which incorporated the strictest criteria for clinically insignificant prostate cancer. This recommendation is for active surveillance as the sole initial treatment for men meeting these criteria who have a life expectancy of >20 years. Men at low risk for prostate cancer and a life expectancy of <10 years should also be recommended for active surveillance, the guidelines state.

The 2011 guidelines made active surveillance monitoring more rigorous for men in the very-low-risk category: with a life expectancy of <20 years, prostate-specific antigen (PSA) should be measured at least every 6 months, a prostate examination must be done at least every 12 months, and repeat biopsies should be considered as often as every 12 months.

Dr Mohler noted conundrums related to active surveillance and PSA testing, including overtreatment rates, clinical risks associated with biopsies, and differing criteria for active surveillance and disease progression in large clinical series. All need to be taken into consideration in treatment decisions.

“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,” Dr Mohler said.

Pharmacotherapy
A significant change was the addition of sipuleucel-T (Provenge) as an immunotherapy option for a subset of men with recurrent metastatic prostate cancer, based on an observed OS advantage. “The guidelines have been modified to include sipuleucel-T as a category 1 recommendation. It is appropriate as salvage treatment for patients with castration-recurrent cancer who have minimally symptomatic disease, a performance status of 0 or 1, and a life expectancy of at least 6 months,” Dr Mohler noted.

The panel also voted to include cabazitaxel (Jevtana) as a new secondline option for men with castrationrecurrent metastatic disease who fail docetaxel (Taxotere), also based on observed OS advantage.

Finally, denosumab was added as an alternative to zoledronic acid (Zometa) for the prevention of skeletal- related events. The choice of agent for bone protection, however, depends on the presence of comorbidities and whether the patient has been treated with zoledronic acid previously, he emphasized.

Non–Small-Cell Lung Cancer
The use of epidermal growth factor receptor (EGFR) mutations and histologic subtype to tailor therapy are pivotal updates to the non–smallcell lung cancer (NSCLC) guidelines, said David S. Ettinger, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medi – cine, Baltimore.

Molecular Diagnostic Testing
The 2011 NCCN guidelines have changed the evaluation process for systemic therapy for recurrent or metastatic disease to first establish the histologic subtype and then perform EGFR testing based on that subtype. Treatment recommendations for advanced NSCLC should be tailored based on these determinations. “We are heading toward the era of mutation driving the therapy, and it’s extremely important for our patients,” said Dr Ettinger.

Therefore, a major change is evident in the molecular diagnostics section. Updated information on EGFR and KRAS gene status, as well as a new addition on EML4-ALK is included. More than 60,000 new cases of NSCLC annually are estimated to be driven by these gene mutations, Dr Ettinger said.

EGFR testing is now a category 1 recommendation for adenocarcinoma, large cell, and NSCLC not-otherwisespecified (NOS), but this is not recommended for squamous-cell carcinoma. Dr Ettinger emphasized the need to acquire tissue for genetic testing in NSCLC: “Histology matters, and NOS is unacceptable.”

All patients who have adenocarcinoma should undergo studies for molecular mutations. Although there is yet no standard method for detecting EML4-ALK in NSCLC, polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybrid – ization are being evaluated.

Pharmacotherapy
Bevacizumab plus a platinum doublet (for patients who received firstline erlotinib [Tarceva] and have adenocarcinoma) was added as a treatment option. Bevacizumab plus paclitaxel/carboplatin (Taxol/Paraplatin) may be an effective option for nonsquamous-cell tumors but not squamous-cell tumors. Bevacizumab is changing the landscape of treatment of stage IV disease, Dr Ettinger said.

Crizotinib, an agent targeting EML4- ALK, may change the prognosis of the 5% to 10% of patients with this mutation. A recent clinical trial of patients with EML4-ALK+ adenocarcinoma showed robust responses to this novel agent (Kwak EL, et al. N Engl J Med. 2010;363:1693-1703). Updated results of this study will be important.

Non-Hodgkin Lymphoma
A new guideline for posttransplant lymphoproliferative disease (PTLD) and the promotion to a category 1 recommendation for 2 therapies for follicular lymphoma took center stage in non-Hodgkin lymphoma. “PTLD has emerged as a significant complication of solid organ and allogeneic bone mar row transplantation,” said Andrew D. Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center, NY.

Understanding PTLD has helped to identify high-risk patients. “The single biggest risk factor for PTLD is the presence of an Epstein-Barr virus [EBV] mismatch between the recipient and the donor,” Dr Zelenetz said. “The time from organ transplant is critically important, with most of these lesions developing within the first year.”

The NCCN guidelines for PTLD recommend certain tests as either “essential” or “useful in selected cases.” Among the essential tests are histopathology, immunophenotyping, and the EBV-ISH assay. EBV viral load may be useful in selected cases. Depending on the PTLD subtype, recommended treatment options include the reduction of immunosuppression, which is effective in 23% to 64% of patients, and single-agent rituximab (Rituxan), particularly for early and polymorphic lesions, where responses may reach 90%. “I would reserve chemoimmunotherapy for patients in whom other simpler maneuvers have failed,” Dr Zelenetz said.

Category 1 for 2 Follicular Lymphoma Therapies
Significant changes in follicular lymphoma are centered on the upgrading of 2 therapies from lower-level recommendations to category 1 (the highest ranking). This includes the combination of bendamustine (Treanda) and rituximab (B-R) for first-line treatment, and rituximab maintenance and radio – immunotherapy (90Y ibritumomab tiuxetan [Zevalin]) following firstremission treatment.

In the 2009 pivotal trial comparing B-R plus standard therapy with CHOP (cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone [Delta sone]) plus rituximab (CHOP-R), B-R significantly improved progressionfree survival (PFS) and complete response rates versus CHOP-R, al – though there was no difference in OS.

Radioimmunotherapy after chemothe rapy and rituximab maintenance are now more strongly recommended based on an improvement in PFS following first-remission therapy, al though no improvement was seen in OS.

Observation is still an appropriate approach in the NCCN algorithm for the initial treatment of follicular lymphoma. “No maintenance strategy in [follicular lymphoma] has yet demonstrated a benefit in OS,” Dr Zelenetz said; therefore, delayed treatment remains a viable option. He emphasized the importance of individualized treatment for this patient population.

New First-Line Rx for Chronic Myelogenous Leukemia
Second-generation tyrosine kinase inhibitors, now approved for first-line therapy for chronic myelogenous leukemia (CML), offer newly diagnosed patients more options and are now recommended by the NCCN, said Susan O’Brien, MD, University of Texas M. D. Anderson Cancer Center.

The addition of nilotinib (Tasigna) and dasatinib (Sprycel) as first-line options in addition to imatinib (Gleevec) is a key update to the CML guidelines. In recent studies, dasatinib and nilotinib were associated with significantly improved response rates and reductions in accelerated or blast phase at 12 months. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, major molecular responses were achieved at 24 months by >60% of newly diagnosed patients treated with nilotinib versus 37% of patients receiving imatinib, and <2% of nilotinib-treated patients progressed to accelerated phase or blast crisis versus 4% to 6% with imatinib.

“This is the most clinically relevant data in the short-term, because transformation heralds a very poor prognosis,” Dr O’Brien noted. Other studies reported at ASH reached similar conclusions.

Dr O’Brien said the data show that the 2 newer agents are “almost identical” in improving short-term end points, although their impact on PFS and OS has not been established. With 3 approved front-line agents, oncologists can either start patients on a newer drug from the start or reserve the newer agents for salvage therapy, for which they have proved very effective.