Chemoradiation for Locally Advanced, Unresectable NSCLC

Introduction

Lung cancer is the leading cause of cancer-related death in men and women in the United States. In 1998, an estimated 171,500 new cases were diagnosed and 160,100 patients died from the disease.[1]

Non–small-cell lung cancer (NSCLC) is diagnosed in approximately 80% of patients with primary lung cancer.[2] Although patients with malignant pleural effusion (T4) have a prognosis similar to those with metastatic disease, other patients with locally advanced, unresectable, stage III NSCLC represent a unique therapeutic challenge. Their tumors may have invaded into mediastinal organs (T4) or may have spread to mediastinal or supraclavicular lymph nodes (N2, N3).

Although such tumors may not be amenable to curative resection, the lack of overt metastatic disease allows for some optimism, and a small number of patients may be cured by definitive nonsurgical therapy. Historically, this definitive therapy was single-modality standard-fractionation thoracic radiotherapy, which resulted in a median survival of 7 to 10 months.[2]

Over the past 2 decades, several trials of combined-modality chemotherapy and radiotherapy have led to an improved outcome and a new standard of care.[3] Although the American Society of Clinical Oncology (ASCO) practice guidelines state that “chemotherapy in association with definitive thoracic radiation is appropriate for selected patients with unresectable, locally advanced non–small cell lung cancer,” no specific regimen is defined. Relevant questions include the timing of chemotherapy (sequential and/or concurrent), the specific chemotherapeutic drugs, and the dose and intensity of the radiation therapy.

This review chronicles the relevant trials that led to the change in the standard of care, as well as the more recent investigations of novel radiation schedules and new chemotherapeutic agents.

Induction Chemotherapy Followed By Conventional Radiation

Several studies of cisplatin(Drug information on cisplatin) (Platinol)–based induction chemotherapy followed by definitive radiation therapy (Table 1) have reported improvements in survival for patients with stage III, unresectable NSCLC.[4-12] In theory, induction chemotherapy may improve survival by decreasing the local tumor burden prior to definitive radiation and by eradicating sites of subclinical micrometastatic disease.

Randomized Trials

In 1990, Dillman et al published the results of a pivotal randomized study of induction chemotherapy followed by radiation vs radiation alone in stage III NSCLC.[4] This study, conducted by the Cancer and Leukemia Group B (CALGB), included 155 patients with stage IIIA/B disease. Patients had a CALGB performance status of 0 or 1 and less than a 5% loss in body weight.

Induction chemotherapy consisted of cisplatin (100 mg/m² on days 1 and 29) and vinblastine(Drug information on vinblastine) (5 mg/m² on days 1, 8, 15, 22, and 29). Conventional radiation therapy (60 Gy given in daily 200-cGy fractions, 5 days per week for 6 weeks) was started on day 50 for the patients in the induction chemotherapy group and immediately for patients assigned to radiation alone.

The response evaluation after induction chemotherapy revealed 3 complete responses and 17 partial responses (response rate, 26%). An equal percentage of patients in both arms completed all radiation therapy, and a significant survival advantage among patients who received induction chemotherapy led to the early closure of the study.[4]

The updated, 7-year follow-up results of this study, published in 1996, revealed a median survival duration of 13.7 months for patients who received induction chemotherapy vs 9.6 months for those treated with standard radiation alone (P = .012).[5] The percentages of patients surviving at 2 and 5 years were 26% and 17%, respectively, in the induction chemotherapy group, as compared with 13% and 6%, respectively in the radiation alone group.

Although toxicity, including serious infection, nausea, and severe weight loss, was greater in the induction chemotherapy arm, there were no treatment related fatalities. Also, the frequency of severe esophagitis and pneumonitis was only 1% in both treatment arms.[4]

Sause et al published the results of the confirmatory intergroup study in 1995.[6] As in the CALGB study, patient enrollment in the intergroup trial was limited to those with an excellent performance status and minimal weight loss. A total of 452 patients were eligible for enrollment and analysis.

Two of the treatment arms were identical to the CALGB trial. Patients in a third arm received hyperfractionated radiation (1.2-cGy fractions twice daily 5 days per week, for a total dose of 69.6 Gy) without induction chemotherapy. The rationale for this third arm was that increased radiation dose intensity could lead to greater local control and survival.

Updated survival analyses, published in 1997 and 1998, indicated median survival times of 11.4 months for the patients given standard radiation, 13.7 months for those treated with induction chemotherapy, and 12.2 months for those who received hyperfractionated radiation therapy.[7,8] Survival rates at 2 and 5 years were 20% and 5%, respectively, for the standard radiation group, 31% and 8%, respectively, for the induction chemotherapy group, and 24% and 6%, respectively, for the hyperfractionated radiation group. Like the CALGB, the overall survival figures of the intergroup trial favored the induction chemotherapy arm (P = .04).

Both the intergroup and CALGB studies established a role for induction chemotherapy. Furthermore, the intergroup trial found that hyperfractionated radiation could also lead to improved long-term survival.

In 1994, LeChevalier et al reported the updated results of a randomized French trial of induction chemotherapy followed by sequential radiotherapy and adjuvant chemotherapy vs radiotherapy alone.[9,10] Previously, this group had described the encouraging results, including a median survival of 15.9 months, of a phase II study of vindesine(Drug information on vindesine), CCNU (lomustine), Platinol (cisplatin), and cyclophosphamide(Drug information on cyclophosphamide) (VCPC). This combination was given for three cycles prior to and after definitive radiation therapy (65 Gy in 26 fractions given over 45 days).[11]

In a follow-up study, 353 patients were randomized to this combined- modality treatment vs the same radiation without chemotherapy.[9] Median survival was 10 months for the patients in the radiation therapy arm and 12 months for those in the combined-therapy arm. The survival rates at 2 and 5 years were 14% and 3%, respectively, in the radiation therapy group and 21% and 6%, respectively, in the combined-modality group (P = .02).[9,10,12]

Although distant metastatic progression was significantly decreased (P < .001) and survival was increased in patients treated with combined-modality therapy, local failure occurred in 92% of patients in both arms at 5 years. This accounted for the limited absolute survival benefit observed in the combined-modality group.[12] The authors of this study concluded that increased local tumor control was essential in order to “take full advantage of the effect of cisplatin-based chemotherapy on reducing metastasis.”[12]

Meta-Analyses

Although several smaller randomized trials did not show a survival advantage of induction chemotherapy in patients with NSCLC,[13-17] these studies may have lacked statistical power and/or utilized suboptimal chemotherapy. Also, three large meta-analyses recently assessed the role of induction chemotherapy.[18-20]

As part of a larger study, the Non-Small Cell Lung Cancer Cooperative Group (NSCLCCG) reviewed 22 randomized trials and updated individual data for 3,033 patient records in order to evaluate the role of chemotherapy added to definitive radiation therapy.[18] Of these trials, 11 (1,780 patients) used cisplatin-based sequential chemotherapy, whereas many of the older trials used alkylating agents or anthracycline-based therapy. The results showed a significant overall benefit for the use of chemotherapy. Trials using cisplatin-based therapy provided the greatest benefit: a 13% reduction in the risk of death and an absolute benefit of 4% (95% confidence interval [CI], 1% to 7%) at 2 years and 2% (95% CI, 1% to 4%) at 5 years.

Reporting on the results of meta-analyses based on data extracted from published studies, Marino et al and Pritchard et al found similar benefits in favor of cisplatin-based therapy.[19,20] The analysis by Pritchard et al concluded that the addition of chemotherapy to radiotherapy improved median survival from 10.3 to 12 months.[20]