IMRT IN LYMPHOMA CANCER

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ASCO, NCCN Recommend EGFR Testing in Advanced Lung Cancer

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non-small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non-small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO's PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization's annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation-negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation-positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation-positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN's NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data - which primarily come from retrospective reviews with small sample sizes - are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

High-Dose Radiation Improves Lung Cancer Survival, Study Finds

Higher doses of radiation combined with chemotherapy improve survival in patients with stage III lung cancer, according to a new study by researchers at the University of Michigan Comprehensive Cancer Center.

Standard treatment for this stage of lung cancer – when the tumor is likely too large to be removed through surgery – involves a combination of radiation therapy with chemotherapy. But, this new study finds, giving chemotherapy at the same time as the radiation enhances the effect of both. Further, increasing the dose of radiation over the course of treatment also increased survival.

“When patients are diagnosed with stage III lung cancer, surgery is often not an option, and survival rates are typically quite low. Finding new ways to improve survival, even in small increments, is crucial,” says senior study author Feng-Ming Kong, M.D., Ph.D., associate professor of radiation oncology at the U-M Medical School and chief of radiation oncology at the VA Ann Arbor Healthcare System.

The study looked at 237 patients who had been treated for stage III non-small cell lung cancer at U-M and the VA Ann Arbor.

The researchers compared survival among patients treated with radiation alone, with radiation followed by chemotherapy, and with radiation and chemotherapy given at the same time. Thirty-one of the patients were also enrolled in a study in which the radiation dose was increased throughout the course of the treatment.

Patients treated with radiation alone had the worst overall survival rates, living only an average 7.4 months after diagnosis. Adding chemotherapy increased survival to 14.9 months when it was administered after completing radiation and 15.8 months when administered at the same time as radiation. After five years, 19.4 percent of the patients receiving concurrent chemotherapy were still alive, compared to only 7.5 percent of patients receiving sequential chemotherapy.

“Our study shows chemotherapy helps, and high dose radiation helps. But it’s challenging to administer these treatments at the same time because of the potential toxicity associated with the high dose radiation,” Kong says.

U-M researchers are currently looking at using PET imaging during the course of lung cancer treatment to personalize high dose radiation therapy in many individual patients. As the tumor becomes smaller during treatment, increasing the radiation dose will become more tolerable because it is targeting a smaller area. The U-M researchers believe this strategy could lead to improved treatment outcomes in many patients. Kong currently leads a clinical trial that is following patients through their treatment to look at the impact on survival of increasing radiation dose.

Lung cancer statistics: 215,000 Americans will be diagnosed with lung cancer this year and 161,800 will die from the disease, according to the American Cancer Society

Additional authors: Li Wang, M.D., Ph.D.; Candace R. Correa, M.D.; Lujun Zhao, M.D., Ph.D.; James Hayman, M.D.; Gregory P. Kalemkerian, M.D.; Susan Lyons, M.D., Ph.D.; Kemp Cease, M.D.; and Dean Brenner, M.D.

Funding was provided through the Pardee Foundation and an American Society of Clinical Oncology Career Development Award.

Reference: International Journal of Radiation Oncology*Biology*Physics, Vol. 73, No. 5, pp. 1383-1390