May 2013, Vol 2, No 3

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NCCN Updates Its Clinical Practice Guidelines

Audrey Andrews


Updates to the Clinical Practice Guidelines of the National Comprehensive Cancer Network (NCCN) were presented at the NCCN 18th Annual Conference held in Hollywood, FL, March 13-17, 2013. For most tumor sites, the updates were few and minor, but the NCCN did introduce inaugural guidelines for survivorship.

New Guidelines for Penile Cancer

The NCCN issued new guidelines for penile cancer, a rare malignancy (0.5% of all cancers) whose management has been quite heterogeneous. The standard of care remains complete tumor excision and eradication of negative margins. For more superficial disease, based on the stage and grade of the tumor, less invasive options can be considered. 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, FL.

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 stratification tools. The NCCN did not recommend dynamic sentinel node biopsy due to its low sensitivity and inadequacy in detecting occult inguinal disease.

New Survivorship Guidelines

A growing appreciation of the unmet needs of cancer survivors has led to a new set of guidelines for survivorship. Subtopics covered in the initial version are anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders. The guidelines are meant to be a companion to the guidelines for the individual tumor sites.

“The survivorship guidelines are intended as a library of tools for a provider to use when assessing a cancer survivor,” said Crystal S. Denlinger, MD, of Fox Chase Cancer Center, Philadelphia, PA. At the meeting, several of the topics were described.

The NCCN recommends physical activity and return to daily activities as soon as possible after cancer treatment, tailored to the individual’s abilities and preferences. The general recommendation is at least 150 minutes of moderate-intensity activity a week, coupled with strength training and stretching. The document includes an assessment pathway, advice for specific populations (such as those with lymphedema), offers examples of light, moderate, and vigorous exercise, and suggests strategies to motivate patients.

Cognitive dysfunction can occur as a complication of cancer treatment. The NCCN guidelines discuss general principles of cognitive dysfunction and provide an evaluation pathway, specific assessments, and practical interventional strategies but acknowledge that this is still an area that is not well understood and not backed by strong data.

The guidelines encourage immunizations based on age and medical condition as part of standard practice. Vaccinations against influenza, pneumonia, meningitis, and hepatitis are considered safe for cancer patients, but live attenuated vaccines such as for measles, mumps, and rubella are contraindicated or should be used cautiously. Principles for zoster (shingles) vaccination in cancer or transplant survivors are included.

Sexual dysfunction is a common experience of cancer survivors, and clinicians should assess the level of sexual activity (past and present), the impact of cancer therapy, sexual concerns or symptoms, comorbidities, risk factors, and psychosocial factors. The guidelines include validated tools for assessment: a brief sexual symptom checklist for women and a sexual health inventory for men.

Acute Promyelocytic Leukemia: A Non-Chemo 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, of City of Hope Comprehensive Cancer Center, Duarte, CA.

The guidelines for APL were changed as a result of a study presented at the 2012 American Society of Hematology Annual Meeting (Lo-Coco F, et al. Blood. 2012;120. Abstract 6), 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). Complete responses were observed in 97% of each arm, but 2-year event-free survival was 97% in the experimental arm versus 87% in controls. For patients with low/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 City, 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 as a second-line treatment in the VELOUR trial, ziv-aflibercept improved overall survival from 12 to 13.5 months (P=.0032) and progression-free survival from 4.7 to 6.9 months (P=.0007) (Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506). This benefit is similar to what is achieved with bevacizumab but at a higher toxicity and financial cost, Saltz noted.

A 12-week regimen exceeds $30,000, whereas 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 it 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, or CapeOx.

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 trial (Grothey A, et al. Lancet. 2013;381:303-312).

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 can be with serial embolization, denosumab, interferon, pegylated interferon, and/or radiotherapy. 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, MA. 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 Tyrosine Kinase Inhibitors 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, MA. 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 FDA approved for thyroid cancer, other small molecule TKIs (sorafenib, sunitinib) can be considered.

New Drugs Exploit Androgen Pathway in Prostate Cancer

Two new drugs in 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 and Women’s Hospital, Boston, MA.

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

Melanoma: Thin Lesions Can Forego Sentinel Lymph Node Biopsy

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, while 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 many as three-quarters of patients in the average practice.

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