Trimodality Therapy for Non–Small-Cell Lung Cancer

ABSTRACT: Prospects for the multimodality treatment of nonâsmall-cell lung cancer have improved substantially with the demonstration of fairly dramatic results, in terms of 5-year survival, in several phase III trials that employed neoadjuvant chemoradiotherapy prior to surgical resection in patients with locally advanced, resectable disease. Moreover, the combination of chemotherapy and radiation therapy has an established role in the treatment of unresectable stage III nonâsmall-cell lung cancer. The history of the development of multimodality therapies will be reviewed and compared with postoperative adjuvant therapy. The role of trimodality therapy in patients with stage IIIB disease is discussed, along with future directions for improving the cure rates of advanced nonâsmall-cell lung cancer. [ONCOLOGY 13(Suppl 5):101-106, 1999] Introduction The role of neodajuvant chemotherapy in the treatment of resectable stage IIIA nonsmall-cell lung cancer was established in several trials. Rosell et al randomly allocated 60 patients with stage IIIA nonsmall-cell lung cancer to receive either three cycles of chemotherapy followed by surgery and postoperative mediastinal radiotherapy, or surgery followed by radiotherapy.[1] At 3 years, there were no survivors in the surgery plus radiotherapy group, but 30% of patients in the group treated with neoadjuvant chemotherapy survived. The difference in median survival (26 vs 8 months) was highly significant (P < .001). Pass et al randomized 27 patients to receive either preoperative chemotherapy, surgery, and postoperative chemotherapy or surgery and postoperative mediastinal irradiation.[2] A trend toward increased overall and median survival was observed in the group that received chemotherapy, but at the time of the report, it had not yet reached statistical significance (P = .095). Finally, Roth et al studied a group of 60 patients who were staged with mediastinoscopy and allocated to receive either six cycles of perioperative chemotherapy and surgery or surgery alone.[3] The estimated 3-year survival rate was 56% in the neoadjuvant chemotherapy group compared to 15% for those who had surgery alone. In an update of the results after a median follow-up of 82 months, the survival increase in the perioperative chemotherapy group was maintained.[4] Taken together, these trials found roughly a 30% improvement in median survival when neoadjuvant chemotherapy was combined with surgery. These findings are in striking contrast to those obtained with postoperative adjuvant chemotherapy. In general, chemotherapy given after surgery has resulted in no survival benefit at 5 years in most studies.[5-7] Some of these studies showed an increase in recurrence-free survival that did not manifest as a prolongation of overall survival. A few other studies showed a survival benefit, although it was of relatively small magnitude.[8,9] Because of persistent confusion about the benefits of postoperative chemotherapy, a large meta-analysis of all available randomized trials evaluating postoperative chemotherapy was conducted.[10] This analysis suggested that chemotherapy given after surgery provided a small benefit (approximately 5%) in long-term survival. In contrast, the three trials described above identified an average improvement of 30% in long-term survival when chemotherapy was administered before surgery. However, not all prospective trials have found a survival advantage with the addition of neoadjuvant chemotherapy. The Cancer and Leukemia Group B (CALGB) began a phase II comparison of best local-regional therapy with or without neoadjuvant chemotherapy. A total of 47 patients were randomized between the two treatment arms. No difference in the rate of complete surgical resection, failure-free survival, nor overall survival was observed.[11] The study was ultimately closed because of an inability to accrue patients. Nonetheless, it is important to realize that the standard use of neoadjuvant chemotherapy is based on studies involving fewer than 150 patients. The remainder of this article will evaluate the available data on the trimodality treatment of stage IIIA and IIIB nonsmall-cell lung cancer, as well as developing data on the neoadjuvant treatment of stage II lung cancer. Surgery With or Without Radiotherapy for Stage IIIA Disease Before revision of the International System for Staging Lung Cancer in 1997,[12] T3N0 lesions were considered stage IIIA nonsmall-cell lung cancer. This review will include only those results for patients with N2 disease. Table 1 summarizes the surgical results of representative large series of patients with N2 nodal involvement who underwent resection. Attention is drawn to the differences in survival for patients with radiographic or clinically evident nodal involvement as opposed to lesser nodal involvement identified only at surgery. Martini and colleagues from Memorial Sloan-Kettering Cancer Center (MSKCC, New York, NY) have collected the most extensive data.[13] Their group operated on 404 patients with N2 disease, defined by either radiographic or pathologic criteria (these patients rarely had mediastinoscopy). Most of their patients also received postoperative radiotherapy. Overall, the 5-year survival rate was 30%. For patients with radiographically detectable N2 disease, the 5-year survival rate was only 9%. In contrast to MSKCC, Pearson and colleagues from Toronto performed mediastinoscopy on 141 patients and demonstrated N2 nodal disease.[14] For patients who had enlarged nodes visible on chest x-ray and underwent resection, the survival rate at 5 years was 9%. The survival rate was 24% after surgery in patients whose mediastinal nodes were found to be involved at mediastinoscopy or at resection. In another study, Mountain found 5-year survival rates of 39% for patients with N2 squamous cell carcinoma and 14% for patients with N2 adenocarcinoma who had resection.[15] Most series show long-term survival between 8% and 20% in patients who successfully undergo surgical resection.[16] Surgical Resection and Radiotherapy for N2 Disease Adding radiotherapy, either adjuvant or neoadjuvant, to surgery adds little to the results observed with surgery alone. In a large Veterans Administration study, radiotherapy given after surgery actually decreased long-term survival.[17] Kirsh et al found 5-year survival rates of 30% for squamous cell carcinoma and 13% for adenocarcinoma in patients who were resected and treated with postoperative radiotherapy.[18] Warram studied preoperative radiotherapy, treating patients with radiographically involved mediastinal nodes with radiotherapy and then randomizing them to surgery or observation.[19] Survival at 5 years was 8% for the resected group and 6% for the radiotherapy-alone group. In another study, patients who were resected and received postoperative radiotherapy had a survival rate at 5 years of 11%.[20] At the Dana Farber Cancer Institute (Boston, MA), Sherman et al found a 5-year survival rate of 18% when patients received preoperative irradiation followed by thoracotomy.[21] The survival rate of all resectable patients was 27%. Hilaris et al obtained a 5-year survival rate of 22% by combining aggressive resection with intraoperative brachytherapy and postoperative external radiotherapy.[22] Finally, a recent large meta-analysis of randomized trials evaluating postoperative radiotherapy found a 21% increase in the relative risk of dying that was greatest for patients with N0 or N1 disease.[23] There was no demonstrable benefit of postoperative radiotherapy for patients with stage IIIA nonsmall-cell lung cancer, including those with N2 disease. Chemotherapy and Radiotherapy in Unresectable Stage III Disease While the role of chemotherapy in stage IV nonsmall-cell lung cancer has only recently been established, the combination of chemotherapy and radiotherapy has an established role in the treatment of unresectable stage III disease based on the results of large randomized studies (Table 2). Fram et al studied six cycles of CAP (cyclophosphamide, doxorubicin [Adriamycin], and cisplatin [Platinol]) chemotherapy and 57 Gy radiation in patients with histologically proven N2 disease.[24] The group found a response rate of 66% and a median survival of 9 months; there were no 5-year survivors. Dillman et al for CALGB reported a significant improvement in long-term survival when patients with stage IIIA disease were treated with the combination of chemotherapy (cisplatin and vinblastine [Velban]) and radiotherapy (60 Gy) compared with radiotherapy alone.[25] Median survival improved from 9.6 to 13.7 months (P = .012) and the 5-year survival rate improved from 6% to 17% with the combination of chemotherapy and radiotherapy.[26] These data were confirmed in subsequent studies.[27-29] Thus, combined- modality therapy, whether sequential chemotherapy and radiotherapy or concurrent radiotherapy and radiosensitizing chemotherapy, is now the standard of care for patients with unresectable stage III nonsmall-cell lung cancer, yielding 3-year survival rates between 0% and 23%. Studies of Neoadjuvant Chemoradiotherapy (Cisplatin Combinations) in N2 Disease In the 1980s, several groups began to evaluate neoadjuvant use of cisplatin-based regimens combined with radiotherapy for patients with N2 nodal disease (Table 3).[30-39] Skarin et al at the Dana-Farber Cancer Institute first studied neoadjuvant chemotherapy and radiotherapy in patients with stage IIIA disease in 1981. Their mature data were reported in 1989, revealing a 5-year survival rate of 31% and high resectability rate when CAP chemotherapy was used with both preoperative and postoperative radiotherapy.[30] Strauss et al treated stage IIIA patients with vindesine and platinum prior to surgery and found a response rate of 76%, a resectability rate of 62%, and a median survival of 27 months.[40] The Lung Cancer Study Group (LCSG) evaluated neoadjuvant chemoradiotherapy with CAP.[32] The protocol required that patients have a radiographic response before undergoing surgery; thus the response rate was only 51% and complete resections were achieved in 33%. The median survival was 11 months. In another LCSG study, cisplatin and 5-fluorouracil (5-FU) were used; this study also required radiographic response before allowing surgery.[34] Response occurred in 56% of patients; 9% had a complete response and 52% had complete resection. The median survival was 13 months and the 3-year survival rate was approximately 20%. The results of this study did not indicate any significant improvement in overall survival with neoadjuvant chemotherapy. Taylor et al reported the first series from Rush-Presbyterian Hospital (Chicago, IL) evaluating the treatment of 64 patients with cisplatin and 5-FU prior to 40 Gy radiotherapy.[31] Complete responses were achieved in 8% and partial responses in 48%, and 61% of patients underwent resection. The median survival was 16 months; two patients died postoperatively, for a mortality rate of 5%. In a second series from Rush-Presbyterian Hospital that compared cisplatin and 5-FU to etoposide (VePesid), cisplatin, and 5-FU in 85 patients, Faber et al reported 68% complete resections, with 20% demonstrating a pathologic complete response. The median survival was 22 months and 40% were alive at 3 years.[33] Sugarbaker et al reported a later analysis of the CALGB experience.[38] Patients received cisplatin and vinblastine, followed by surgical resection with radical lymphadenectomy and thoracic irradiation. The overall survival rate was 23% at 5 years, with 46% survival in those patients who had complete resections. The preoperative treatment of 36 stage IIIA patients with cisplatin (25 mg/m²) for two cycles combined with 55 Gy irradiation of the tumor and mediastinum was reported by Yashar et al.[37] Eighty-six percent of patients were resected, with sterilization of mediastinal nodes in 47% and complete tumor response in 28%. The 3-year survival rate was 61.7% in patients who underwent surgery and 35% in all patients. Aristu et al studied mitomycin, vindesine, and cisplatin (MVP) with intraoperative and postoperative radiotherapy in patients with stage III nonsmall-cell lung cancer.[39] The results were similar to those observed previously, with a 10-month median survival and 5-year survival rate of 29%. The postoperative mortality was 10%, and the complete resection rate was 85%. In another study, Strauss et al treated patients with cisplatin, vinblastine, and 5-FU concurrently with 30 Gy of radiation prior to surgery.[36] Of 31 patients, 25 were resected, with complete responses in 16%. There were six (15%) treatment-related deaths, three each during chemotherapy and in the postoperative period. The median survival was 15.5 months, and the 5-year survival rate was 22%. Burkes et al reported Torontos experience in 39 patients with positive ipsilateral mediastinal nodes who were treated with two cycles of MVP induction therapy.[35] Responding patients underwent thoracotomy for resection and two subsequent courses of MVP. The median survival was 18.6 months, and the 3-year survival rate was 26%. The therapy was complicated by significant toxicity; there were two postoperative deaths, four septic deaths during chemotherapy, and two episodes of pulmonary toxicity after therapy, resulting in one death. Surgical Complications After Trimodality Therapy Concerns about the greater risks of surgical resection after neoadjuvant chemotherapy have been realized, to some degree. Morbidity, operative mortality, and overall treatment mortality for the trials of trimodality therapy described above are reviewed in Table 4. Operative mortality ranged from 0% to 15%, with an average of 6.18%. Postoperative mortality in modern literature for lobectomy ranges from 2% to 4%, while the pneumonectomy rate ranges from 3% to 10%. As many of these patients required pneumonectomy to obtain margin on bulky tumors, this operative mortality is not unreasonable. Many trials had significant chemotherapeutic mortality that was greater than the surgical mortality. Continued efforts are necessary to minimize the downside of this combined-modality treatment. Neoadjuvant Chemoradiotherapy and Results in Stage IIIB (N3) Disease Patients with stage IIIB nonsmall-cell lung cancer, whether by virtue of T4 lesion or N3 nodes, have generally been considered unresectable and treated with either radiotherapy alone, or, more recently, with the combination of chemotherapy and radiotherapy. Albain et al reported the mature results of the Southwest Oncology Group (SWOG) phase II study 8805, in which patients with biopsy-proven stage III disease were treated with two cycles of induction cisplatin and etoposide plus concurrent chest radiotherapy (45 Gy).[41] Resection was attempted if tumors responded or were stable with treatment. Eighty-five percent of stage IIIA and 80% of stage IIIB patients were resectable. Median survivals were 13 months for stage IIIA patients and 17 months for stage IIIB patients (P = .81). Three-year survival rates were 27% (stage IIIA) and 24% (stage IIIB), with no statistical difference between disease stages. These survival times compare well to those achieved with chemoradiotherapy alone. There were no significant differences between stage IIIA and IIIB patients in any parameter in the SWOG trial; the duration of surgery, perioperative blood loss, and length of stay were similar. Further, there were no differences in the incidence of morbidity or mortality. Aristu et al studied the application of cisplatin, mitomycin, and vindesine with intraoperative and postoperative radiotherapy prior to resection in patients with stage IIIA and IIIB disease.[39] Thirty patients with stage IIIB disease were evaluable; 29% had a response and 15 patients were resected. The complete resection rate was markedly less for stage IIIB patients compared to stage IIIA patients (40% vs 85%), as was the 5-year survival rate (7% vs 29%). Overall, the operative mortality rate was 10%. The investigators concluded that the low rate of complete resections was responsible for the poor long-term survival. The use of three courses of split-dose cisplatin and etoposide was compared with 45 Gy hyperfractionated accelerated radiotherapy in stage IIIA and IIIB patients by Eberhardt et al.[42] The median survival was 20 months for stage IIIA patients and 18 months for stage IIIB patients. There was no significant difference in 4-year survival, which was 31% for stage IIIA patients and 26% for stage IIIB patients. There have been no other trials of neoadjuvant chemoradiotherapy with subsequent resection in stage IIIB patients, and no trials planned to compare neoadjuvant chemoradiation and subsequent resection with chemoradiation alone in stage IIIB patients. The current Intergroup trial designed to compare neoadjuvant chemoradiotherapy and surgery with chemoradiotherapy alone in stage IIIA patients may help to direct subsequent trials in stage IIIB patients. Preoperative Chemotherapy and Hyperfractionated Radiotherapy and Definitive Surgery in Locally Advanced NonSmall-Cell Lung Cancer Strategies for the treatment of locally advanced nonsmall-cell lung cancer have included systemic chemotherapy to treat distant disease and the use of twice-daily radiation dosing to optimize local therapy. At least two investigators have analyzed the use of neoadjuvant chemotherapy and either hyperfractionated accelerated radiotherapy or twice-daily radiation therapy before surgical resection. Eberhardt et al gave etoposide and platinum to stage IIIA and IIIB patients who then received 45 Gy hyperfractionated accelerated radiotherapy.[42] No significant difference in median survival (20 months for stage IIIA and 18 months for stage IIIB) or 4-year survival rate (31% for stage IIIA and 26% for stage IIIB) were observed between the two stages of disease. Choi studied twice-daily radiation and concurrent chemotherapy in stage IIIA nonsmall-cell lung cancer and found a 5-year survival of 37%.[43] These results compare well to other phase II trials using standard radiotherapy and chemotherapy prior to surgery, in which the average 5-year survival rate was 25%. Future Directions Although chemoradiation therapy is clearly beneficial in locally advanced unresectable nonsmall-cell lung cancer, survival improvements remain modest. Numerous questions remain about the use of multimodality regimens in potentially resectable disease. Because advanced nonsmall-cell lung cancer has resisted single- and double-modality combinations, it is very likely that increasing the cure rate of this disease will require the combination of chemotherapy, radiation, and surgery. The identification of newer chemotherapeutic agents that have been shown to be synergistic with radiation therapy is expected to enhance efficacy in trimodality regimens.[44-46] Additional studies are needed to identify the optimal combination and timing of these therapies for patients with locally advanced nonsmall-cell lung cancer. References: 1. 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