September 10, 2008
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Treating adenocarcinoma of the lung

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A 48-year-old white man presented to the emergency department with progressive right-sided chest pain for the past two days. The pain was nonradiating but was worse with deep inspiration. He was a heavy smoker (two packs a day) for the past 30 years, but denied use of alcohol or illicit drugs.

Wajeeha Razaq, MD
Wajeeha Razaq

He had productive cough for few months that he labeled “smoker’s cough” without hemoptysis. Also, he lost 10 lb in the last two months. On physical examination, he had tenderness at the right second and third ribs and had bronchial breathing at right upper chest on auscultation. A CAT scan of the chest was done in the emergency department that showed no pulmonary embolism, but extensive emphysema and a 5 cm right hilar mass involving the second and third ribs anteriorly and vertebral bodies posteriorly with multiple ipsilateral and contralateral mediastinal lymph nodes was noted. He was admitted to the hospital for pain control and for further work up. His pain was controlled with fentanyl patch and immediate release morphine sulphate as needed. Staging work up showed multiple lytic lesions in the bones. A brain MRI was normal as well as the CAT scan of abdomen and pelvis. A CAT scan guided core biopsy of the right hilar mass showed moderate to poorly differentiated mucin producing adenocarcinoma of the lung.

Adenocarcinoma of lung with an abundance of glandular structures
Adenocarcinoma of lung with an abundance of glandular structures.

Source: W Razaq

How will you manage this patient?

A) Single agent cisplatin.
B) Combination chemotherapy with carboplatin/taxane/bevacizumab.
C) Single agent erlotinib.
D) Best supportive care.

Wajeeha Razaq, MD, is an Assistant Professor of Medicine at the University of Nebraska, Omaha.

CASE DISCUSSION

Lung cancer is a leading cause of mortality in both men and women. It recently surpassed heart disease as the leading cause of smoking-related deaths. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis.

Systemic chemotherapy for non–small-cell lung cancer was initiated in the 1970s with adraimycin- and cyclophosphamide-containing regimens. In general, the response was short lived and no overall survival benefit was noticed. With the development of cisplatin and its better efficacy in NSCLC, the chemotherapy improved the overall survival and response rate in metastatic lung cancer. Many large randomized trials have demonstrated that incorporating platinum-based chemotherapy provides better survival and quality of life when compared with best supportive care. The largest study was the European Big Lung Trial published in 2004 which showed better survival in the treatment arm (8 months vs. 5.7 months) as compared with best supportive care. Two meta-analyses published in 1995 and in 2004 also favored the palliative chemotherapy arm.

Combination vs. single-agent chemotherapy has shown to have a better response rate, overall and mean survival. CALGB conducted a trial of 561 patients with unresectable/metastatic NSCLC and then randomly assigned patients to single-agent paclitaxel vs. paclitaxel/carboplatin. The combination arm showed a response rate of 36% vs.17% and PFS of 4.6 months vs. 2.5 months, but the OS was not statistically significant (J Clin Oncol. 2005;23:190-196). Later a meta-analysis of 65 trials also showed superiority of combination over single-agent chemotherapy. Despite a number of randomized clinical trials no combination regimen has emerged as the best initial choice. ECOG conducted a four arm randomized trial, comparing gemcitabine/cisplatin, docetaxel/cisplatin, paclitaxel/carboplatin and cisplatin/paclitaxol (N Engl J Med. 2002;346:92-98). Overall response rate and median survival were similar in all the arms.

Bevacizumab (Avastin, Genentech), a potent humanized VEGF inhibitor showed promising activity when combined with chemotherapy in phase-1 and -2 trials. Poor prognosis was noted in patients expressing high levels of VEGF and that served the basis of investigating a VEGF inhibitor in lung cancer. ECOG conducted a phase-3 randomized trial that led to the FDA approval of bevacizumab with chemotherapy. Eight-hundred seventy-eight patients with stage IIIB or IV and nonsquamous morphology were randomized to paclitaxel/carboplatin vs. paclitaxel/carboplatin and 15 mg/kg bevacizumab. Patients in the bevacizumab arm had significant improvement in objective response, OS and PFS (N Engl J Med. 2006;355:2542-2550).

Mutations in epidermal growth factor receptor (EGFR) can lead to its persistent activation that could result in uncontrolled cell production. These mutations have been recognized in cancers like lung and colon cancer and are the target of a rapidly developing class of anticancer therapy. Gefitinib (Iressa, AstraZeneca) was initially approved for second- or third-line therapy on the basis of a phase-2 study where two different doses (250 mg vs. 500 mg) were investigated. The study showed the same results when response rate and OS were compared but more toxicity was noted in 500-mg arm. (J Clin Oncol. 2003;21:2237-2246). Similarly erlotinib (Tarceva, OSI), another EGFR inhibitor was evaluated in a phase-3 study when it was compared with placebo in patients who failed first- or second-line chemotherapy regimens. An increased objective response, OS and better quality of life were seen in erlotinib arm. The parameters associated with better clinical response observed during the trials to the EGFR inhibitors are as following:

a) Asian.
b) woman.
c) adenocarcinoma.
d) nonsmoker.

Recently EGFR inhibitors were used in first-line setting for metastatic NSCLC. A phase-2 study presented at ASCO 2006 showed an overall response of 90% to erlotinib in 21 patients with mutations identified in the TK domain of EGFR gene. In another phase-2 study presented in 2007 ASCO, 58% objective response was observed when 31 chemotherapy-naive patients were treated with gefitinib. Initial data with upfront EGFR inhibitors in patients with metastatic NSCLC is promising, but longer follow-up and large randomized trials are needed to validate these results.

We treated our patient with carboplatin/paclitaxel and bevacizumab. He had a partial response after three cycles and is currently receiving the same chemotherapy.