Nonsmall-cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women in the United States each year. As the recently revised international staging system indicates, patient survival is directly related to stage. Survival rates with surgical resection of early stage disease (stage I and II) have improved. However, this subgroup accounts for only a small fraction of the 140,000 new cases of NSCLC each year. Even in this favorable category, 20% to 40% of patients develop recurrence, which typically manifests as distant metastases.
Locally advanced (stage III) disease, which represents approximately 50,000 cases annually, is more common. This category of tumors is heterogeneous and, for treatment planning purposes, can be divided into several patient subgroups (Table 1): stage IIIA without mediastinal node involvement (T3 N1), IIIA N2 (minimal bulk), IIIA N2 (bulky)/IIIB (T4 or N3 without malignant pleural effusion), and stage IIIB (malignant pleural effusion). All of these subgroups are now candidates for combined modality therapy with curative intentexcept in those patients with malignant pleural effusion (whose natural history and treatment options mimic those of stage IV [metastatic] disease).
A multidisciplinary clinical research effort that integrates combinations of chemotherapy, radiotherapy, and/or surgery into the therapeutic approach against advanced NSCLC has evolved within the past 10 years. In a number of phase III clinical trials, cisplatin(Drug information on cisplatin) (Platinol)-based chemotherapyeither in combination with thoracic radiation or administered before surgeryhas improved survival more effectively than radiotherapy or surgery alone.[3-9] In addition, a number of new chemotherapeutic agents are now incorporated into combined modality regimens. These recent advances, including the rationale and design of ongoing clinical research studies investigating new treatment regimens, are reviewed on the following pages.
A variety of approaches that integrate chemotherapy, radiation, and/or surgery into combined modality treatment of NSCLC are illustrated in Table 2. Each has potential advantages and disadvantages. Both bimodality (chemotherapy plus radiotherapy, or chemotherapy plus surgery) and trimodality (chemotherapy plus radiotherapy plus surgery) options are under investigation.
In both options, NSCLC is considered to be a two-compartment model consisting of a combination of local-regional disease and distant micrometastases in which thoracic irradiation or surgical resection addresses the issue of local control, while the use of chemotherapy (or other systemic antineoplastic agents) addresses occult distant spread. Additionally, chemotherapy may play a cytoreductive role locally or a radiosensitizing role, as described above.
For the purpose of this discussion, these approaches to combined modality therapy can be divided into two avenues: (1) definitive chemoradiotherapy (nonsurgical combined modality therapy), and (2) preoperative (neoadjuvant or induction) chemotherapy with or without radiotherapy followed by surgical resection. A third avenue, postoperative adjuvant therapy, is not detailed in this review.
Definitive Chemoradiotherapy Studies
Sequential therapy, in which chemotherapy is completed prior to the administration of radiotherapy, is the most widely recognized approach to chemoradiotherapy for locally advanced NSCLC. Because sequential chemoradiation avoids overlapping toxicities, full doses and optimal schedules of both modalities may be used, but the duration of therapy is prolonged. In addition, the potential for chemotherapeutic radiosensitization is lost. By comparison, concurrent chemoradiation optimizes both the radiosensitizing and local cytoreductive potential of chemotherapy. There is no delay in use of either modality, but concurrent therapy entails the risk of overlapping toxicity. Conceptually, enhanced toxicity with concurrent therapy may preclude delivery of full doses of either modality, depending on the chemotherapeutic regimen and radiation dose schedule.
A number of phase III trials have compared sequential chemoradiation to radiotherapy alone in stage III NSCLC and their overall results have been subjected to meta-analysis.[3-7,10] In a landmark Cancer and Leukemia Group B (CALGB) study, a limited 5-week course of chemotherapy (100 mg/m² cisplatin during weeks 1 and 5 plus vinblastine(Drug information on vinblastine) (Velban), 5 mg/m²/week during weeks 15) followed by radiotherapy (60 Gy/30 fractions) was delivered in clinical stage III patients who had good performance status (01) and minimal weight loss (< 5%). Results were compared to patients who received the same radiotherapy alone. Despite the brief duration of exposure to this platinum-based chemotherapy, survival was significantly greater in the combined modality treatment arm (P = .006). Although median survival was modestly improved (13.8 vs 9.7 mo), survival at 2 years (26% vs 13%) doubled. These results were confirmed in a subsequent Intergroup trial (Radiation Therapy and Oncology Group [RTOG] 88-08), comparing identical radiotherapy and sequential chemoradiotherapy arms with those of the previous CALGB study.
A third treatment arm evaluated the role of hyperfractionated radiotherapy. Median and 2-year survival in the chemoradiotherapy arm (13.8 mo/31%) were significantly superior to both standard radiotherapy (11.4 mo/20%) and hyperfractionated radiation (12.3 mo/24%) (log rank, P = .03). However, at 5-year follow-up, survival was less than 10% in all three arms, which substantiates the need for better chemoradiotherapy strategies.
A French study in stage III disease by Le Chevalier compared a control arm of radiotherapy alone (65 Gy) to three monthly cycles of PCVC (cisplatin, lomustine(Drug information on lomustine) [CeeNU], vindesine(Drug information on vindesine) [Eldesine], and cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar]) followed by the same radiotherapy. At 3 years, 12% of patients treated with sequential chemoradiotherapy were alive vs 4% of those treated with radiotherapy alone (P = .02).[5,6] In this study, the rate of distant metastasis was significantly lower in the combined modality group (P < .001). With rigorous restaging that included bronchoscopy, local control was less than 20% on either treatment arm, which demonstrates one of the limitations of sequential chemoradiotherapy.
Several phase III trials have compared concurrent cisplatin-based chemoradiotherapy to radiotherapy alone.[12-15] The hypothesis that improved local control from chemoradiosensitization could improve survival is supported by a study from the European Organization for Research and Treatment of Cancer (EORTC), reported by Schaake-Koning et al.
Three treatment arms were evaluated: split-course radiotherapy alone, split-course radiotherapy administered concurrently with either weekly cisplatin (30 mg/m²/week), or daily cisplatin (6 mg/m²) on the days of radiotherapy. Both cisplatin-containing arms showed superior results to radiation alone, with a statistically significant survival advantage using daily cisplatin over radiotherapy alone (P = .009).
Of particular interest, improved survival with cisplatin was entirely due to increased control, with a significant difference in 2-year freedom from local recurrence in those treated in the radiotherapy-alone arm (19%) vs the chemotherapy treatment arm (30%). There was no difference in time to development of distant metastasis. These results suggest that low-dose cisplatin functioned primarily as a radiosensitizerleading to improved local control but proving ineffective against occult systemic disease. Conversely, fully cytotoxic doses of cisplatin-based chemotherapy, sequenced prior to radiation in the Le Chevalier study, were effective in eradicating distant micrometastases without an impact on local control.[5,6]
Concurrent vs Sequential Chemoradiotherapy
Most recently, the results of a Japanese study by Furuse et al directly compared concurrent vs sequential chemoradiotherapy in stage III NSCLC. In this randomized study, median and long-term survival were clearly superior in the concurrent arm (Table 3). Patients on the sequential arm received two cycles of mitomycin(Drug information on mitomycin) (Mutamycin)/vindesine/cisplatin (MVP) chemotherapy (56 Gy/2 Gy daily) prior to thoracic radiotherapy; patients on the second arm received split-course thoracic radiotherapy (56 Gy) concurrent with MVP. Median survival for the concurrent chemoradiotherapy arm was 16.5 months, significantly better than the 13.3 months observed in the sequential arm (P = .05). At 3 years, survival was 27% with concurrent therapy compared to 12.5% with sequential therapy. Furthermore, toxicity profiles were acceptable in both of these combined modality approaches, although esophagitis and myelosuppression were more frequent in the concurrent arm. If these data are confirmed by a recently completed RTOG trial, concurrent chemoradiotherapy will become the standard of care for nonsurgical therapy of stage III disease. Most ongoing clinical trials have already incorporated concurrent chemoradiotherapy into the study design.