NCCN Updates Its Clinical Practice Guidelines

TON - July 2013 Vol 6 No 6 — July 29, 2013

Updates to the Clinical Practice Guidelines of the National Comprehensive Cancer Network (NCCN) were presented at the NCCN’s 2013 Annual Conference, held in Hollywood, Florida, in March. While for most tumor sites, updates were few and minor, the NCCN introduced inaugural guidelines for penile cancer.

New Guidelines for Penile Cancer

Penile cancer is a rare malignancy (0.5% of all cancers) whose management has been heterogeneous. The standard of care remains complete tumor excision and eradication of negative margins, but in many patients, less-invasive management can be appropriate. For more superficial disease, less-invasive options can be considered, based on the stage and grade of the tumor. These include topical treatment with either imiquimod 5% or 5-fluorouracil cream, which can produce “excellent outcomes,” according to Philippe E. Spiess, MD, of the H. Lee Moffitt Cancer Center, Tampa, Florida.

For more extensive tumors, radical surgery is the chief recommendation. Options include wide local excision, laser, radiation therapy, glansectomy, and partial/total penectomy. Penile-preserving surgery maintains function and quality of life in a select cohort with small lesions, where negative margins can be obtained. For bulky disease with positive lymph nodes, neoadjuvant chemotherapy has proven effective. A nomogram is recommended for predicting metastatic lymph node involvement, as it outperforms the conventional clinical risk categories. The NCCN did not recommend dynamic sentinel node biopsy, owing to its low sensitivity and inadequacy in detecting occult inguinal disease.

Acute Promyelocytic Leukemia:
A Nonchemotherapy Option

“For the first time, the NCCN guidelines have taken chemotherapy out of the up-front treatment for acute promyelocytic leukemia (APL),” said Margaret R. O’Donnell, MD, City of Hope Comprehensive Cancer Center, Duarte, California.

The guidelines for APL were changed as a result of a study by Lo-Coco and colleagues presented at the 2012 American Society of Hematology Annual Meeting, which compared the gold standard for newly diagnosed non–high-risk APL—simultaneous all-trans retinoic acid (ATRA) and chemotherapy (idarubicin)—with the chemotherapy-free combination of ATRA and arsenic trioxide (ATO).1 Complete responses were observed in 97% of patients, but 2-year event-free survival was 97% in the experimental arm versus 87% in controls. For patients with low- or intermediate-risk APL, the guidelines now recommend induction with ATRA plus ATO.

New Agents in Colorectal Cancer

Two new agents recently approved for metastatic colorectal cancer are now included in the NCCN guidelines—ziv-aflibercept and regorafenib—though their overall benefit is relatively minor, Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center, New York, acknowledged.

“We had hoped ziv-aflibercept would be the next step forward, but in the registration study it provided only a 1.5-month overall survival benefit,” he noted. When added to FOLFIRI (fluorouracil/leucovorin/ irinotecan) as a second-line treatment in the VELOUR (Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin-Based Regimen) trial, ziv-aflibercept improved overall survival from 12.1 months to 13.5 months (P = .0032) and progression-free survival from 4.7 to 6.9 months (P = .0001).2 This benefit is similar to what is achieved with bevacizumab, though at a higher financial and toxicity cost, Saltz noted.

A 12-week regimen exceeds $30,000, while a course of bevacizumab costs less than $14,000. “This cost difference was a deal breaker for our physicians at Sloan-Kettering. We decided there is no need for ziv-aflibercept at this time,” he added.

In the updated guidelines, ziv-aflibercept is acceptable when added to FOLFIRI or irinotecan, but should not be used as a single agent, in combination with FOLFIRI after failure of FOLFIRI/bevacizumab, or added to a failed regimen. Bevacizumab was also added as an option after first progression, in combination with FOLFIRI, irinotecan, FOLFOX (fluorouracil/ leucovorin/oxaliplatin), or CapeOx (capecitabine/oxaliplatin).

Regorafenib was added to the guidelines as a treatment option after first, second, or third progression, depending on previous lines of therapy, based on the 1.4-month survival advantage seen in the CORRECT (Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer) trial.3

Giant Cell Tumor of the Bone

New treatment pathways for giant cell tumor of bone (GCTB) and chordoma debuted in the updated version of the guidelines for bone cancer. These are rare neoplasms; therefore, clinicians lack familiarity with them. While GCTB is considered a benign disease, it carries a 2% risk for metastasis.

Intralesional excision with the use of a high-speed burr is advised over more extensive surgery that requires skeletal reconstruction. While recurrence is not uncommon, the use of adjuvant therapy, either thermal or chemical, ameliorates this risk. In patients with unresectable or recurrent disease, denosumab can help restore the skeletal architecture and allow a joint-conserving procedure or avoidance of surgery altogether.

For localized disease, excision is recommended; if resection carries unacceptable morbidity or the tumor is unresectable, treatment with serial embolization, denosumab, interferon, pegylated interferon, and/or radiotherapy can be used. For metastatic disease, surgery is indicated if feasible. The recommended workup includes history, physical examination, cross-sectional imaging of the primary site, chest imaging, and biopsy, with optional bone scan.

New Agents in Multiple Myeloma

“We have wonderful new agents, at least a lot more potent than prior-generation drugs,” said Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston, Massachusetts. The approval of the second-generation proteasome inhibitor carfilzomib led to its recent inclusion in the guidelines for transplant candidates, in combination with lenalidomide/dexamethasone. This triplet joins a growing list of regimens that greatly increase response rates, he said.

For relapsed/refractory disease, the updated guidelines also include carfilzomib as a preferred salvage therapy option, as well as the new immunomodulating drug pomalidomide plus low-dose dexamethasone. Other recommended regimens now also include bortezomib/vorinostat and lenalidomide/bendamustine/dexamethasone.

Updates in Non-Hodgkin Lymphoma

The growing use of lenalidomide in non-Hodgkin lymphoma is reflected in the updated guidelines. New to the guidelines for the second-line treatment of stage I-II disease is lenalidomide with or without rituximab. For chronic lymphocytic leukemia, first-line therapy now includes lenalidomide (continuous or intermittent dosing) as a treatment option, and bendamustine with or without rituximab. For relapsed/refractory disease, lenalidomide with or without rituximab is a treatment option.

New TKIs in Thyroid Cancer

With the availability of 2 new tyrosine kinase inhibitors (TKIs), “these are exciting times in thyroid cancer,” said Robert I. Haddad, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts. The TKIs now offer an option after patients become refractory to radioactive iodine.

In advanced or metastatic medullary thyroid cancer, cabozantinib and vandetanib have more than doubled progression-free survival. The guidelines now list both drugs as category 1 treatments for unresectable disease that is symptomatic or asymptomatic and structurally progressive. While not approved by the US Food and Drug Administration for thyroid cancer, other small molecule TKIs (sorafenib, sunitinib) can be considered.

New Drugs Exploit Androgen Pathway in Prostate Cancer

Two new drugs for prostate cancer take advantage of the persistence of androgen receptor expression, even in castration-resistant prostate cancer. Abiraterone acetate, an androgen synthesis inhibitor, and enzalutamide, an antiandrogen, have changed the treatment landscape, said Philip W. Kantoff, MD, of the Dana-Farber Cancer Institute/Brigham & Women’s Hospital, Boston, Massachusetts.

The guidelines include abiraterone/prednisone as a category 1 recommendation in both the pre- and postchemotherapy settings, and enzalutamide as a category 2A recommendation for docetaxel-naive men and a category 1 recommendation postchemotherapy. “These drugs have a clinically meaningful impact on survival,” Kantoff said.

Melanoma: Thin Lesions Can Forgo SLNB

A substantial change to the melanoma guidelines pertains to the indication for sentinel lymph node biopsy (SLNB), which the panel concluded is not warranted for thin lesions, ie, those ≤0.75 mm. SLNB may be considered when conventional risk factors accompany these very thin lesions. Otherwise, patients with thin lesions undergo wide excision, those with lesions 0.76 to 1.0 mm should be considered for SLNB, and those with lesions >1 mm require SLNB. The change has the potential to affect as much as 75% of patients in the average practice.

For information about the inaugural NCCN Guidelines on Survivorship, see the April issue of The Oncology Nurse-APN/PA.

References
1. Lo-Coco F, Avvisati G, Orlando SM, et al. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): results of the phase III, prospective, randomized, Intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. Blood. 2012;120:Abstract 6.
2. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506.
3. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.

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