Although combined modality treatment with chemotherapy and radiotherapy has improved survival in stage III NSCLC, local tumor progression remains problematic. New strategies designed to enhance local tumor control, such as the use of radiation sensitizing drugs, 3-dimensional treatment planning techniques or altered radiation fractionation schedules may further improve survival outcome (14-17). Combining chemotherapy with some of these newer radiation therapy strategies has yielded extremely promising preliminary survival results and therefore warrant continued investigation (18). In summary, improved local control, as well as improved control of extrathoracic micrometastases should result in improved survival in patients with locally advanced NSCLC. Both modalities are necessary to achieve optimal outcome.
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2.LeChevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-Terrier M, Douillard J-Y, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small cell lung cancer: First analysis of a randomized trial in 353 patients. Journal of National Cancer Institute. 1991;83:417-423.
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5.Johnson DH. Combined-modality therapy for unresectable, stage III non-small-cell lung cancer – caveat emptor or caveat venditor. Journal of the National Cancer Institute. 1996;88(17):1 175-1177
6.LeChevalier T, Arriagada R, Tarayre M, Lacombe-Terrier M, Laplanche A, Quoix E, Ruffie P, Martin M, Douillard J-Y. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer. Journal of National Cancer Institute. 1992;84:58.
7.Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura G, Perez CA, Greco FA. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med. 1990; 113:33-38.
8.Kubota K, Furuse K, Kawahara M, Kodama N, Yamamoto M, Ogawara M, Negoro S, Masuda N, Takada M, Matsui K, et al. Role of radiotherapy in combined modality treatment of locally advanced non-small cell lung cancer. Journal of Clinical Oncology. 1994; 12(8): 1547-1552.
9.Lianes P, Chomy P, Cigolari S, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients [see comments]. Journal of Clinical Oncology. 1994; 12(2):360-7
10.Bonomi P, Kim K, Chang A, Johnson DH. Phase III trial comparing etoposide (E) cisplatin (C) versus Taxol (T) with cisplatin-G-CSF (G) versus Taxol-cisplatin in advanced non-small cell lung cancer. An Eastern Cooperative Group (ECOG) trial. Proceedings American Society Clinical Oncology. 1996; 15:382.
11.Bonomi PB, Kim K, Kugìer J, Johnson D. Comparison of survival for stage IIIB versus stage IV non-small cell lung cancer (NSCLC) patients treated with etoposide-cisplatin versus Taxol-cisplatin: an Eastern Cooperative Group (ECOG) trial. Proc Ann Meet Am Soc Clin Oncol. 1997;16:454a.
12.Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311(7010):899-909.
13.Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer - a meta-analysis. Annals of Internal Medicine. 1996; 125(9):723 ff.
14.Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, Houtte Pv, Kirkpatrick A, Koolen M, Maat B, Nijs A, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. New England Journal of Medicine. 1992;326:524-530.
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17.Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee [see comments]. Lancet. 1997;350(9072): 161-5.
18.Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. Journal of Clinical Oncology. 1996; 14(4): 1065-70.
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COMPARATIVE STUDY OF INDUCTION CHEMOTHERAPY VERSUS RADIOTHERAPY ALONE IN STAGE III NON-SMALL CELL LUNG CANCER
Dr. K.T. BHOWMIK
Consultant in Radiotherapy to Min. of Health & F.W, Professor of Radiotherapy & Head of Department, Safdarjung Hospital, New Delhi, India.
The incidence of lung cancer is much lower in India than the corresponding rates reported worldwide by other countries. Lung cancer is the leading site of cancer according to the Delhi Cancer Registry, its incidence being 6.7 and 6.8 per 100,000 persons in males in the year 1990 and 1991 respectively, while its incidence is 1.9 and 1.6 per 100,000 persons in females over the corresponding period.
Conventional modalities for the treatment of Non-Small Cell Lung Cancer (NSCLC) are surgery, radiotherapy and chemotherapy. Surgery is the treatment of choice for Stage I, II and selected Stage III patients. However only about 20-25% of patients with Stage III NSCLC have resectable diseases. Patients with unresectable Stage III NSCLC have been traditionally managed with Radiotherapy alone, which although effective in palliation, has little impact on long term survival. NSCLC is not a very chemosensitive tumor, the most active agents being Mitomycin C, Ifosfamide, Cisplatin, Vinblastine and Vindesine. Newer agents like Paclitaxel, Docetaxel and Gemcitabine are under investigation, but have been available in India for only the last couple of years. Amongst combination chemotherapy the combination of Mitomycin C, Ifosfamide and Cisplatin has a overall response rate of 51%. Induction chemotherapy and consolidation with loco-regional radiotherapy addresses the problem of distant micro / macro metastasis and loco-regional control. Thus the rationale for induction chemotherapy is to decrease the tumor bulk and to make an immediate attack on metastatic disease. In an effort to improve upon the results of treatment in locally advanced NSCLC, a randomized trial of Induction Chemotherapy and Radiotherapy versus Radiotherapy alone was carried out at Safdarjang Hospital, New Delhi from January 1, 1992 to December 31, 1996. The study group treatment protocol consisted of induction chemotherapy comprising of Mitomycin C 6mg/m2, Ifosfamide 2gm/m2, with Mesna and Cisplatin 50mg/m2 after prior hydration (MIC). After completing 3 cycles of chemotherapy administered on a single day with 21 day intervals, patients received Radiotherapy with Cobalt –60, using 80cm SAD, to the primary disease and mediastinum to a tumor dose of 55-60Gy in 5.5- 6 weeks. The control group received Radiotherapy alone by Cobalt-60, at 80cm SAD, to the primary lesion and mediastinum to a tumor dose of 55-65Gy in 5.5-6.5 weeks. From January 1, 1995 patients who failed to respond to either induction chemotherapy and radiotherapy or radiotherapy alone were randomized to receive either Gemcitabine 1000mg/m2 on D1,D8,D15 repeated every 4 weeks for 3 cycles or oral Etoposide 50mg/m2 for 21 days and repeated every 4 weeks for 3 cycles.
506 patients with histologically proven Stage III NSCLC were randomized to receive either the study protocol of induction chemotherapy and radiotherapy or radiotherapy alone in the control group. Of the 253 patients enrolled into the study group, 228 patients were evaluable for response. After completion of 3 cycles of induction chemotherapy (MIC)5.7%(13/228) patients had complete response and 45.2%(103/228) patients had partial response, thus showing an overall response rate of 50.9%. On completion of the study protocol i.e. radiotherapy after 3 cycles of MIC, the overall response rate improved to 62.3%, with complete response in 16.2%(37/228) and partial response in 46.1%(105/228). In the control group i.e. patients who received radiotherapy alone, of the 253 patients 232 were evaluable. The overall response rate was 42.2%, with complete response in 6%(14/232) and partial response in 36.2%(84/232). The mean duration of response in the study group was 13.1 months (range 7-36 months) and 8.2 months (range 4-36 months) in the control group. The difference in overall response rates is statistically significant(p=0.005).
Patients in the study group tolerated chemotherapy well. Toxicities were moderate and manageable. There were no therapy related deaths, nor did any dose modification / reduction be required during the study. Common toxicities encountered were nausea and vomiting, which was controlled by appropriate anti-emetic therapy. Myelosuppression was frequently observed but moderate, and no life-threatening infections or hemorrhages observed.
With a follow-up of 3 years, analysis of overall survival rates observed were 20.1% in the study group and 11.2% in the control group.
80 patients who failed to respond to the study/control group treatment protocol were randomised to receive either 3 cycles of Gemcitabine or 3 cycles of oral Etoposide. Response rate to Gemcitabine was 22.5% with 7.5%(3/40) complete response and 15%(6/40) partial response, while oral Etoposide showed a response rate of 7.5%(3/40) all being partial responses with no complete response. Gemcitabine was well tolerated with only slight nausea and vomiting, while oral etoposide was also fairly well tolerated, with myelosuppression being the major toxicity observed. Both these regimen are out-patient treatment protocols, but often due to poor general condition patients were required to be hospitalised for general supportive care.
This study demonstrates the efficacy of induction chemotherapy with Mitomycin Ifosfamide and Cisplatin and Radiotherapy as a therapeutic strategy for Stage III non-resectable NSCLC, with manageable toxicities. Gemcitabine appears to be a good agent for salvage therapy and has been well tolerated.
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THORACIC CONFORMAL RADIATION THERAPY: COMBINED MODALITY TREATMENT IN CONJUNCTION WITH SEQUENTIAL AND CONCOMITANT CARBOPLATIN/PACLITAXEL IN STAGE III NON-SMALL CELL LUNG CANCER (NSCLC)
M. A. SOCINSKI, J. CLARK, J. HALLE, S. LIMENTANI, R. FRASER, W. MITCHELL, M. SCHELL, J. ROSENMAN
Multidisciplinary Thoracic Oncology Program, University of North Carolina, Chapel Hill, NC, USA
Combined modality treatment of Stage III NSCLC improves survival however the optimal treatment strategy remains undefined. Randomized trials employing a sequential strategy with induction chemotherapy followed by thoracic radiation therapy (TRT) have improved survival over TRT alone (1-3). Two of these trials (2,3) have suggested that systemic chemotherapy can reduce the rate of systemic metastases. Likewise, two trial employing low-dose concurrent chemoradiotherapy have shown improved survival over TRT alone (4,5). In both of these trials, the survival benefit was achieved by enhanced local control. Both systemic metastases and local progression remain substantial problems in Stage III NSCLC and strategies directed at improving both systemic and local control will likely contribute to improving survival.
Although the optimal chemotherapeutic regimen in NSCLC remains undefined, recent trials in advanced NSCLC have suggested that the combination of a platinum and paclitaxel is superior to non-paclitaxel containing regimens (6,7). Employing paclitaxel containing regimens in Stage III disease will likely lead to improved response rates and survival as chemotherapy is generally more active in earlier stages of disease. The use of concurrent low-dose weekly carboplatin/paclitaxel with standard TRT has been previously reported (8,9). In these Phase II trials, response rates, overall survival and toxicity profiles have been favorable.
TRT remains a crucial component of the treatment strategy. A recent trial has shown inferior survival when TRT is not included in the treatment regimen mainly due to lack of local control (10). Maximizing local control with TRT may be attempted with increased radiation dose, concurrent use of chemotherapy (or other radiosensitizing agents), improved tumor targeting in the chest, or altered fractionation schedules. Three-dimensional treatment planning may enhance local control by improved tumor targeting thereby more accurately delivering the radiation dose to the tumor mass. It may also improve the therapeutic index of TRT by limiting excessive dose to normal structures thereby reducing toxicity.
We are conducting a Phase I/II trial in which the dose of TRT is escalated utilizing conformal or three-dimensional treatment planning techniques. The treatment protocol utilizes two cycles of induction chemotherapy (carboplatin AUC=6, paclitaxel 225 mg/m2 over 3 hours) followed by concurrent chemoradiotherapy (carboplatin AUC=2, paclitaxel 45 mg/m2 over 3 hours weekly X 6) beginning on day 43. The initial dose of thoracic conformal radiation therapy (TCRT) was 60 Gy with escalation to 66 Gy, 70 Gy and 74 Gy in subsequent cohorts. Before the initiation of TCRT, all patients undergo three-dimensional treatment planning. A planning CT scan of the chest is performed with the patient in the treatment position. Lung, heart (left ventricle), skin, spinal cord, primary tumor and clinically positive lymph nodes are contoured into the treatment planning. Treatment fields are designed to deliver the first 50 Gy to the prechemotherapy primary tumor volume and mediastinum with a 1.0-2.0 cm margin. Between 45 and 50 Gy, the patients undergo another diagnostic CT scan of the chest to allow a second three-dimensional treatment plan. The boost volume includes the original tumor volume; however, no more than 25% of the lung volume receives more than 50 Gy as determined by dose-volume histograms. All radiographically positive lymph nodes present after 50 Gy are included in the mediastinal volume with a 1 cm margin. The spinal cord is excluded from the radiation fields after 45 Gy and the dose to the left ventricle is limited to 40 Gy. Dose-limiting toxicity (DLT) is defined as any grade 3-4 non-hematological toxicity, platelets less than 20,000, and grade 4 neutropenia lasting over 7 days (CALGB Expanded Toxicity Criteria used). For esophageal toxicity grading, we adopted our own toxicity grading scale where grade 3 esophagitis required hospitalization.
Twenty-seven patients with Stage III NSCLC have been entered thus far. Their characteristics include the following: 17 males, 10 females; median age 63 (range 38-68); ECOG PS 0/1/2, 20/6/1; no. with wt. loss exceeding 5%, 6; histology, squamous 8, adenocarcinoma 16, other 3; Stage IIIA/IIIB, 10/17. All patients were required to have an FEV1 of 800 cc.
Twenty-five of 27 patients are assessable for response to the two cycles of induction carboplatin/paclitaxel (C/P). There have been 14 partial responses for a response rate of 56%. Nine patients (36%) have had stable disease. Only two patients (8%) have progressed during initial induction C/P. Toxicity has been tolerable with no dose delays or dose reductions necessary.
Twenty-one of 27 patients have initiated TCRT with concurrent low-dose C/P on day 43. Reasons for failure to begin TCRT have included disease progression(2), early death (2), patient refusal (1), and co-morbid illness (1). Table I depicts the concurrent low-dose C/P and TCRT portion of the protocol.
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