Treatment of Advanced Non-Small-Cell Lung Cancer: A Review of Current Randomized Clinical Trials and an Examination of Emerging Therapies

Abstract and Introduction

Abstract

Background:

Lung cancer continues to be the leading cause of cancer-related deaths for Americans. As most patients present with nonsurgically curable disease, major efforts have been made in the treatment of advanced non-small-cell lung cancer (NSCLC) with chemotherapy. Several new agents and new combinations of chemotherapy are available.

Methods:

The author reviews randomized clinical trials investigating chemotherapy for advanced NSCLC in chemotherapy-naive patients, in patients who present with relapsed or progressive disease, and in elderly patients. Therapies that incorporate new biological agents to target specific aberrations in lung cancer are discussed.

Results:

Several clinical trials demonstrate improvement in overall survival as well as quality of life with chemotherapy treatment of advanced NSCLC. Better options are available for patients who have relapsed after first-line chemotherapy, and treatment of elderly patients with chemotherapy has demonstrated benefit in survival and quality of life. New agents that target molecular pathways are being tested in patients with early-stage disease.

Conclusions:

Despite progress with newer agents for the treatment of advanced NSCLC, only 14% of patients with the disease are alive at 5 years after initial diagnosis. New therapies are needed.

Introduction

Lung cancer continues to be the leading cause of cancer-related deaths for Americans.^[1] Despite nearly twice the estimated cases of prostate cancer in men,estimated deaths from lung cancer are nearly 3-fold higher. Similarly for women, estimated cases of breast cancer are nearly 2.5-fold higher than lung cancer, but the estimated death rate for lung cancer is nearly 2-fold higher. While age-adjusted cancer rates for lung cancer have fallen in the past decade for men, the same is not true for women. Overall, the 5-year relative survival rate for lung cancer is 14% for the years 1989-1995,which is significantly, albeit minimally, increased from 13% for the years 1974-1976 and 1980-1982.

Approximately 75% to 80% of cases are of the non-small-cell histology, and the majority of patients present with either locally advanced disease (stage III)or metastatic disease (stage IV). Importantly, patients who undergo curative surgical resection for apparent localized disease have survival rates ranging between 50% and 80%, implying the need for better systemic treatment to cure occult micrometastatic disease.Therefore, the majority of patients either present with advanced disease requiring chemotherapy or require chemotherapy at the time of relapse after surgical resection. While efforts to reduce smoking are crucial to the eventual control of the disease,newer treatments for patients who currently have the disease are critical.

For some time,the treatment of non-small-cell lung cancer (NSCLC) with cytotoxic chemotherapy remained controversial, given the unclear impact on patient survival. A review of chemotherapy for lung cancer in 1992 identified the active agents as cisplatin,mitomycin, ifosfamide, etoposide, and the vinca alkaloids vinblastine and vindesine.^[2] Response rates to single agents were approximately 20% and, while combination chemotherapy suggested improvements in response rates, the impact of chemotherapy on patient survival was unclear. This review concluded that the impact of chemotherapy on survival for patients with NSCLC was not demonstrated and "it is difficult to recommend incorporating chemotherapy into the standard care of patients with disseminated NSCLC."^[2]

Support of treating patients with advanced NSCLC came from an international collaborative meta-analysis using updated data on patients from 52 randomized clinical trials.^[3] Eleven trials examined best supportive care vs best supportive care plus chemotherapy. Two trials used long-term alkylating agents, one trial used etoposide as a single agent, and the remaining eight trials used cisplatin-based chemotherapy. All except one trial enrolled patients with locally advanced disease (stage III) as well as metastatic disease (stage IV). Use of long-term alkylator therapy was associated with an increased rate of death, although given the limited number of trials, confidence intervals were wide and statistical significance was not reached. Patients treated with cisplatin-containing regimens demonstrated a 27% reduction in the risk of death. This was equivalent to an absolute improvement in survival of 10% at 1 year with a modest improvement in median survival of 1.5 months. Further analysis did not demonstrate that any grouping based on sex, age, histology,performance status, or stage benefited any more or any less than others. The demonstration that patients who received cisplatin-based chemotherapy in addition to surgery or radiotherapy also had improved outcomes gave more support to the idea that cisplatin plays an important role in the treatment of NSCLC. It was not clear which cisplatin combination regimen was superior,but the majority of combinations consisted of cisplatin plus either a vinca alkaloid or etoposide.

This study concluded that cisplatin-based chemotherapy programs may provide a 10% absolute benefit in 1-year survival. Although the results were modest, they were nonetheless important from a public health perspective,given the large numbers of patients with nsclc who potentially would receive benefit. While cisplatin demonstrated an improvement in patient survival,its use was still greeted with a degree of unease due to its toxicity profile and difficulty in administration.The analog carboplatin was then developed, and two trials compared carboplatin to cisplatin. The first performed by the Eastern Cooperative Oncology Group(ECOG) compared three cisplatin-based regimens to single-agent carboplatin.^[4] The results demonstrated that carboplatin-treated patients had better overall survival and less toxicity compared with cisplatin-containing regimens. The second trial performed by the European Organization for Research and Treatment of Cancer(EORTC) compared cisplatin and etoposide vs carboplatin and etoposide and concluded that no significant differences in survival were apparent but that patients treated with carboplatin had significantly less leukopenia,nausea and vomiting, and diarrhea.^[5]