Innovative Procedures for Lung Cancer: Part 2

Although 29% of all cancer deaths are due to lung cancer, < 5% of NCI’s $4.8 billion budget is for lung cancer research and the CDC and Department of Defense had no money earmarked for lung cancer in 2008. Despite the up hill battle, there are advances being made in the treatment of lung cancer.

In the last blog, I talked about some interesting procedures using brachytherapy. This time I want to talk about some of the targeted therapies that are showing promise in the treatment of lung cancer.

Prior to 2006 a patient with unresectable stage III dry, meaning the absence of pericardial or pleural effusion, was treated with chemotherapy and radiation. If the disease progressed or recurred, the first line treatment was a platinum based doublet, a non-platinum containing doublet, or single-agent therapy for the elderly or those with low performance status. The patients with Stage IIIB wet and stage IV disease went directly to the doublet or single agent therapies. The overall survival was <12 months with a 1-year survival of 33% and a 2-year survival of 11%. There also was only incremental or no improvement in survival with the combination chemotherapies. Given the poor outcomes, research started to focus on other possible treatments.

Endothelial growth factor receptor (EGFR) and vascular endothelial growth factor receptors (VEGFR) are two key pathways in the development and progression of non-sqaumous cell lung cancer (NSCLC). Overexpression or dysregulation of signaling receptors can result in cell cycle progression and proliferation, angiogenesis, and increased metastatic potential. One of the targeted agents being used is erlotinib. The BR.21 study (http://content.nejm.org.ezproxy.galter.northwestern.edu/cgi/content/abstract/353/2/123) used erlotinib in the treatment of NSCLC. Patients were stratified by center, response to prior therapy, prior regimen and prior platinum. A total of 731 patients were randomized to either erlotinib and best supportive care or placebo and best supportive care. The erlotinib arm showed an overall survival of 31% vs. 22% for the placebo arm. The most common toxicity with single agent erlotinib is rash. Rash of any grade occurred in 75% of patients treated with erlotinib while only 17% of those treated with placebo. The severity of the rash may indicate survival also. Those patients with at least a grade 2-3 rash had a median survival of 19.6 months compared to 8.5 months for grade 1 rash and 1.5 months for no rash.

There are 3 genes in the ras family; H-ras, K-ras and N-ras. Mutations in one of these genes can provide information regarding possible treatment options. Oncogene activation stems from a point mutation at 12, 13, or 61. K-ras mutations occur in about 25% of lung adenocarcinomas usually codon 12.What science has also shown us is that K-ras mutated tumors are erlotinib resistant. So, using this therapy with patients that have K-ras mutations would be futile. K-ras mutations and EGFR mutations are mutually exclusive.

Tumors require new blood vessel growth. Targeted angiogenic inhibitors may act to prevent the formation of new tumor vasculature and may cause regression of existing tumor vascular structures. Actively proliferating tumor cells express more VEGF than nonproliferationg cells. VEGF expression is upregulated in many caner types, including NSCLC. Elevated serum VEGF levels have been associated with poorer outcomes in limited or early stage disease. Because of its antiangiogenic properties bavacizumab has been added to the arsenal of drugs in the treatment of NSCLC in a Phase III trial. Patients were randomized into paclitaxel and carboplatin (PC) every 3 weeks for 6 cycles or PC for 6 cycles + bevacizumab every 3 weeks to disease progression. The overall survival was significantly prolonged by the addition of bavacizumab.

Another phase III trial is studying pemetrexed. Patients are randomized into the cisplatin + pemetrexed on day 1 vs. cisplatin day 1 and gemcitabine day 1 & 8. Each cycle is repeated every 3 weeks up to 6 cycles. The overall survival in patients in the pemetrexed arm was significantly greater. On September 26, 2008, the US Food and Drug Administration approved pemetrexed injection for use in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic NSCLC. There is also a phase II trial of pemetrexed and carboplatin + bevacizumab with maintenance pemetrexed as first-line therapy for advanced NSCLC. The pemetrexed, carboplatin and bevacizumab are given every 21 days for 6 cycles. If there is a complete response, partial response or stable disease, the patient is treated with pemetrexed and bevacizumab every 21 days until disease progression or toxicity. The overall response rate is 55% with a median overall survival of 13.5 months.

With the advent of these different treatments and the knowledge we have gained about what tumors respond to what type of treatment the need for personalized medicine for lung cancer is great. In order to provide the most appropriate treatment, a patient’s tumor should be sampled and molecular biomarker studies should be performed to determine the patient prognosis and behavior of the tumor. Predicting which specific chemotherapy, radiotherapy, biologic, and targeted regimens will give the best tumor response and patient survival for that individual is key. Lung cancer kills 30,000 more American women annually than breast cancer. Incorporation of targeted therapy has made this a chronic disease in some individuals. Remarkable progress has been made in the treatment and understanding of lung cancer in the last several years.