NCCN Updates Guidelines for Kidney and Cervical Cancer

The National Comprehensive Cancer Network (NCCN), a non-profit alliance of 21 leading cancer centers worldwide, recently updated its clinical practice guidelines for kidney and cervical cancers.

NCCN develops and publishes clinical practice guidelines to promote the importance of continuous quality improvement. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology are developed and updated via an evidence-based process with explicit review of the scientific evidence by multidisciplinary panels of expert physicians from NCCN member institutions. In the U.S., they are widely recognized and applied as the standard of care in oncology in both community and academic practice settings.

Changes in the Kidney Cancer Guidelines

The NCCN panel added temsirolimus (Torisel) as an option for first-line therapy in patients with relapsed or medically unresectable stage IV renal cell carcinoma (RCC) with both predominant clear cell histology and non-clear cell histology. This recommendation was based on the recent FDA approval of temsirolimus for treatment of RCC and on safety and efficacy demonstrated in a large, multicenter, randomized clinical trial of 626 patients. The study showed that temsirolimus prolonged median overall survival.

In the study, subjects were randomly assigned to receive interferon-alfa (IFN) alone, temsirolimus alone (25 mg weekly) or the two in combination. The median duration of treatment in the temsirolimus arm was 17 weeks. The median duration of treatment in the IFN arm was 8 weeks. There was a statistically significant improvement in overall survival in the temsirolimus monotherapy arm compared with the IFN arm (10.9 vs. 7.3 months). The median progression- free survival in the temsirolimus arm was 5.5 months, compared with 3.1 months in the interferon-alfa arm. The overall response rate was 8.6% in the temsirolimus arm, compared with 4.8% in the IFN arm.

According to the NCCN panel, temsirolimus is a Category 1 recommendation for patients with poor prognosis and clear cell histology and Category 2A for patients with non-clear cell histology. Temsirolimus was also added as an option for subsequent therapy for patients with predominant clear cell histology.

Temsirolimus inhibits the mammalian target of rapamycin kinase— commonly known as mTOR—a protein kinase that controls cell growth, proliferation, motility, and survival. mTOR also regulates protein synthesis and transcription. Torisel was approved by the FDA for use in RCC on May 30, 2007.

The NCCN panel also added bevacizumab (Avastin) in combination with interferon alfa-2a as first-line therapy for patients with relapsed or medically unresectable stage IV RCC with predominant clear cell histology. This recommendation is based on the results of the AVOREN trial, which were presented during a plenary session at the 2007 American Society of Clinical Oncology meeting moderated by Bernard Escudier, MD, Institut de cancerologie Gustave Roussy, Villejuif, France.

The AVOREN trial was a randomized, controlled, double-blind, Phase III study. In the trial, nephrectomized patients with metastatic renal-cell carcinoma, no central nervous system metastases, and adequate organ function were randomized to receive interferon alfa-2a (9 MIU thrice weekly) plus either bevacizumab (10 mg/kg every two weeks) or placebo until disease progression. Tumor assessments were performed every 8 weeks until Week 32 and every 12 weeks thereafter. A total of 649 patients at 101 centers in 18 countries were randomized. The addition of bevacizumab to interferon alfa- 2a significantly increased progression-free survival (10.2 vs. 5.4 months) and objective tumor response rate (30.6% vs. 12.4%). In addition, a trend toward improved overall survival was observed with the addition of bevacizumab to interferon-alfa 2a.

Bevacizumab binds vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

Additional changes from the previous version of the NCCN kidney cancer guidelines include the following:

• The recommendations in the work-up section were modified. An abdominal/pelvic CT can be performed without contrast. The

chest x-ray and chest CT recommendations were changed to chest imaging. The MRI was clarified that it is an abdominal

MRI. A bullet was added to consider urine cytology and ureteroscopy if transitional cell carcinoma is suspected.

• The primary treatment recommendation is now the same for Stage I, II, and III. The recommendation is a surgical excision.

• Chest x-ray was removed from the list of follow- up recommendations. Chest CT was added with abdominal CT.

• For patients with relapse or stage IV and medically or surgically unresectable disease, the recommendations for interferon

and low-dose interleukin-2 were removed as treatment options in first-line therapy for predominant clear-cell histology.

• Second-line therapy was changed to subsequent therapy, and the category designations for sunitinib and sorafenib were clarified to State Category 1 following cytokine therapy and category 2B following tyrosine kinase inhibitor therapy.

Changes in the Cervical Cancer Guidelines

The NCCN cervical cancer guidelines have been updated to expand the indications for fertility-preserving surgery. Women with stage IB1 disease whose lesions are ≤2 cm are now candidates for radical trachelectomy. It is important to note that not all women with stage IB1 disease are eligible; only those with smaller lesions. Previously, only women with stage IA2 disease were candidates for radical trachelectomy.

Adjuvant treatment has been revised for some women with stages IA1-IIA disease who have had hysterectomy. For women with negative lymph nodes after surgery, pelvic RT is now a Category 1 recommendation for those women with high-risk factors. These high-risk factors include large primary tumor, deep stromal invasion and/or lymphovascular space invasion.

Positron-emission tomography scanning is no longer considered optional for ≥ stage IB2 disease, and is now recommended as part of the work-up.

Additional changes from the previous version of the NCCN cervical cancer guidelines include the following:

• Primary treatment options for women with stage Ib1 disease were expanded to include radical trachelectomy for fertility

preservation for lesions ≤2 cm, plus para-aortic lymph node dissection with or without para-aortic lymph node sampling.

• Brachytherapy was added to primary treatment for negative results after surgical staging and negative results after radiologic

imaging.

• Brachytherapy was added as a primary treatment option for “pelvic lymph node—positive/ para-aortic lymph node–negative by

surgical staging.”

Accessing NCCN Guidelines

The most recent versions of the kidney cancer and cervical cancer guidelines, as well as all NCCN Clinical Practice Guidelines in Oncology, are available in PDF format free of charge at www.nccn.org.