Preoperative Chemotherapy Followed by Concurrent Chemoradiation Therapy Based Hyperfractionated Accelerated Radiotherapy and Definitive Surgery in Locally Advanced Non-Small Cell LungCancer: Mature Results of a Phase II Trial
Locally advanced non-small cell lung cancer (NSCLCa) has a very poor prognosis. By the American Joint Committee on Cancer, the stages included in the definition of locally advanced NSCLCa are IIIA and IIIB. These tumors are defined as less than 2 cm distal to the carina or invasive into the chest wall, diaphram, mediastinum, pericardium or heart, great vessels, trachea, esophagus, malignant pleural effusion. These stages also include metastases to scalene, supraclavicular, contralateral hilar, mediastinal and/or subcarinal lymph nodes. Overall survival at 5 years is on the order of 5 ? 15%.
Most patients with locally advanced NSCLCa are unresectable. The best form of therapy appears to be combined modality treatment with chemoradiotherapy. Prior studies from the Cancer and Leukemia Group B (CALGB) and European Organization for Research and Treatment of Cancer (EORTC) have proven the effectiveness of cisplatin-based chemotherapy combined with radiation therapy over radiotherapy alone. Numerous other studies from the Radiation Therapy Oncology Group, the French multi-institutional group and others have also confirmed these findings. The University of Pittsburgh and Fox Chase Cancer Center have published some of their initial results of taxol/carboplatin concurrent with radiotherapy for this locally advanced disease with very promising results. It is too preliminary to gauge whether this regimen will be more efficacious than cisplatin-based regimens.
In neoadjuvant therapy, combined modality (chemoradiotherapy) appears to be better than chemotherapy or radiotherapy alone. A Brazilian trial reported in abstract only that resection, response and freedom from relapse rates were better with cisplatin-based chemoradiation than chemotherapy alone preoperatively. Neoadjuvant radiotherapy alone can achieve pathological complete response rates of 25%, but has not affected overall survival.
The current study from Germany evaluates preoperative chemoradiation therapy?s role in unresectable locally advanced NSCLCa. The parallel North American study is from the South Western Oncology Group (SWOG) protocol 8805. The results were reported in 1995. One hundred and twenty-six patients with pathological stage IIIA and IIIB were enrolled. Chemotherapy was cisplatin and vinblastine with concurrent thoracic radiation. The response and resectability rates were 59% and 71%. Pathological complete response was seen in 21% of the patients. Three year overall survival was only 26%.
Materials and Methods:
Ninety-four patients were enrolled between 1991 and 1994. Mediastinoscopies were done on all patients at the time of diagnosis and preoperatively, post chemoradiation. Nearly an equal number of stage IIIA and IIIB patients were enrolled. Eligibility criteria were detailed in Table 1 of the article. Those patients with supraclavicular lymph adenopathy or malignant pleural effusion were not eligible.
The chemotherapy was cisplatin and etoposide for 3 cycles followed by a cycle concurrent with radiation of the thorax for 45Gy in 1.5Gy fractions twice daily. Prophalactic cranial irradiation was done after 4 of the initial 28 patients had brain relapses early in their treatment. Following chemoradiation, the patient had a mediastinoscopy as mentioned above and surgical resection if one or no lymph nodes were found.
Median follow up was 43 months.
The clinical response rate of induction chemotherapy followed by chemoradiation was 64% (10% clinical complete response and 54% clinical partial response). Only 62 of the initial 94 patients went on to surgical resection. Two had such diffuse disease at the time of surgery, that only exploration was done. Ten patients had an incomplete resection with gross or microscopic residual disease left. Fifty patients had a complete resection with negative margins of resection. Of those 50 cases, 24 (26%) had a pathological complete response or no evidence of disease in the surgical specimen. Of the 29 patients that had stable disease, 10 had a complete resection with 3 of those being pathological complete responses. Seven of 9 patients with clinical complete response had complete resections, while only 3 (33% of clinical complete responders) had a pathological complete response. Sixty patients had either ipsilateral or contralateral mediastinal lymphadenopathy pathologically. Of those, 77% (46 patients) had pathological complete response in the mediastinum to chemoradiation therapy.
Toxicity is detailed on tables 4 and 5 of the article. The grade 4 hematological toxicities were 15% after chemoradiation. The most significant non-hematological toxicity was severe esophagitis seen in 37% of the patients after chemoradiation. A total of 6 treatment related deaths were reported for entire treatment group. Four were related to postoperative complications and 2 were related sepsis following induction therapy.
The overall survival rates at 3 years for stage IIIA and IIIB were 36% and 26%, respectively. The 4 year rates were 31% and 26%, respectively. LDH was a very significant prognostic factor ? those with LDH > 240 had an overall 4 year survival of 0% vs 37% for those with LDH > 240. Median survival for those with clinical complete response was not yet reached, while those with partial response to therapy had a median survival of 30 months. Clinically stable disease patients had a 17 month median survival. Those with progressive disease at the time of induction therapy had a median survival of 6.5 months. Those who were able to undergo a complete resection had an overall survival of 46% at 4 years with a median survival of 42 months, while those who could not had a 11% survival with a median of 13 months.
A total of 62 patients have relapsed. Of the 50 cases that underwent a complete resection, 18 have relapsed (13 distantly and 5 locoregionally). The 44 patients that did not receive complete resection or any resection at all had a relapse or progression rate of 55% locally. A total of 16 had brain metastases as the the initial site of relapse.
The prophalactic cranial irradiation (PCI) given was 30Gy in 15 fractions of 2Gy. The 3 year probability of relapsing in the brain was 54% for those not receiving PCI (first 28) and 13% for the 47 who had received it and were eligible for resection. Median survival was not significantly different - 20 months those that had not gotten PCI versus 26 months with PCI.
Based on the SWOG and this German phase II trial, neoadjuvant chemoradiation therapy is feasible and promising. The question is whether surgery makes any difference in this group of patients. There have been results from the recent literature on definitive chemoradiation therapy with agents taxol/carboplatin yielding survivals greater than 30% - 40%. Thjs is being addressed by the current randomized RTOG protocal 93-09 (preoperative chemoradiation and surgery versus definitive chemoradiation). Unfortunately, the chemotherapy is cisplatin-based, which is still considered the standard at most institutions. PCI for non-small cell lung cancer is still very controversial. This study was not convincing on this issue. Despite significantly improved probability for less brain relapses, survival is not improved. The patients compared in this trial were skewed. The 47 that received PCI had responses enough that they were considered for surgery, while the first 28 were consecutively the first 28 without eliminating in any of the cases. Bottom line, there was a selection bias in reporting, and it was not randomized.