Thoracic Radiation Therapy Alone Compared with Combined Chemoradiotherapy for Locally Unresectable Non-Small Cell Lung Cancer A Randomized, Phase III Trial Roscoe F. Morton, MD; James R. Jett, MD; William L. McGinnis, MD; John D. Earle, MD; Terry M. Therneau, PhD; James E. Krook, MD; Thomas E. Elliott, MD; James A. Mailliard, MD; Robert A. Nelimark, MD; Andrew W. Maksymiuk, MD; Ronald G. Drummond, MD; John A. Laurie, MD; John W. Kugler, MD; and Richard T. Anderson, MD

• Objective: To compare the survival of patients with medically inoperable or unresectable stage III nonsmall cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy. • Design: Randomized, prospective phase III trial. • Setting: Multi-institutional cooperative oncology group. • Patients: A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution. • Interventions: Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy. • Main Results: Major clinical responses were observed in 31 of 56 (55%; 95% CI, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; CI, 51 % to 76%) treated with radiation only (P> 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P> 0.2). The median survival time was 313 days compared with 317 days, respectively ( P > 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (CI, 32% to 58%), 16% (CI, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (CI, 33% to 60%), 2 1 % (CI, 1 1 % to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002). • Conclusion: Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P > 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer.

Annals of Internal Medicine. 1991;115:681-686.

From the North Central Cancer Treatment Group (NCCTG). For current author addresses and a list of other group participants, see end of text.

L u n g cancer is the leading cause of death from cancer for men and women in the United States (1). Non-small cell lung cancer accounts for approximately 75% of all bronchogenic carcinoma. Surgical resection still offers the best chance for long-term survival in patients with early-stage disease, but only 20% to 25% of all lung cancers are potentially resectable at the time of diagnosis. It is estimated that 30% to 40% of patients with non-small cell lung cancer have locally unresectable tumors at initial presentation. The traditional treatment for patients with locally unresectable disease (stage HIA and IIIB) has been thoracic radiation (2, 3). The 5-year survival of patients treated with thoracic radiotherapy alone is less than 10%. A randomized study conducted by the Radiation Therapy Oncology Group (RTOG) compared treatment with four different radiation schedules consisting of 4000 cGy by split course (2000 cGy in 5 fractions over 1 week, a 2-week rest, and an additional 2000 cGy in 5 fractions over 1 week) or 4000, 5000, or 6000 cGy given continuously at 5 fractions per week (4). An early analysis of this study showed a 10% to 18% 2-year survival rate. Initial intrathoracic failure rates (within the field of irradiation) were 38% to 64% in the four groups, with the highest local recurrence rates occurring in those patients receiving 4000 cGy by split or continuous fractionation. Metastases outside of the radiation ports, with or without local recurrence, occurred in 35% to 50% of patients. Thus, there was a high rate of both local failures and distant metastases in patients treated with thoracic radiation only (4). An early report by Eagan and colleagues (5) suggested that a combined modality approach with chemoradiotherapy may result in better survival compared with radiation only; however, the study was not a randomized trial. On the basis of these reports, the North Central Cancer Treatment Group (NCCTG) conducted a randomized trial of thoracic radiation only compared with combined-modality therapy for patients with lo©1991 American College of Physicians

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cally unresectable or medically inoperable non-small cell lung cancer. The radiation regimen chosen for the study was the arm of the RTOG protocol that was thought to be superior at the time we began our study, that is, 6000 cGy per 6 weeks given continuously (5 fractions/wk) (4). The chemotherapy regimen chosen was methotrexate, doxorubicin, cyclophosphamide, and CCNU (MACC). This regimen was selected because the results of an NCCTG trial of stage IV non-small cell lung cancer that compared cyclophosphamide, doxorubicin, and cisplatin (CAP) and MACC showed no difference in response rates or survival but showed greater toxicity with CAP chemotherapy (6). Since this trial started, several trials comparing thoracic radiotherapy with continuation chemotherapy and radiotherapy have been reported. The results have been diverse. To date, it is not absolutely clear that adding chemotherapy to thoracic radiotherapy results in any survival advantage for patients with stage IIIA and IIIB non-small cell lung cancer. We report the final results of our phase III, randomized trial. Patients and Methods Prerandomization tests included a chest roentgenogram, complete blood count, chemistry profile, and isotope bone scan. A liver scan (isotope, ultrasonography, or computed tomography [CT]) was required if the aspartate aminotransferase or alkaline phosphatase level was elevated or if liver metastases were clinically suspected. A CT head scan was optional. All patients were required to have histological or cytologic proof of non-small cell lung cancer (adeno, squamous, large, or

Table 1. Patient Characteristics* Characteristic

Age, y Mean Range Male, n(%) Female, n(%) Performance score, n(%) 0, 1 2 Weight loss, n(%) < 10% > 10% Size of primary tumor, n(%) < 3 cm 3 to 6 cm > 6 cm Cell type, n(%) Squamous Adeno Large Mixed Stage of Disease* I 11 IIIA IIIB

Thoracic Radiation Therapy (n = 58)

Thoracic Radiation Therapy plus MACC {n = 56)

63 39 to 76 42 (72) 16 (28)

62 38 to 77 39 (70) 17 (30)

52 (90) 6(10)

50 (89) 6(11)

49 (84) 9(16)

50 (89) 6(11)

10 (17) 36 (62) 12 (21)

6(11) 35 (63) 15 (27)

29 (50) 17 (29) 11(19) 1(2)

26 (46) 15 (27) 15 (27) 0

4(7) 1(2) 31 (53) 22 (40)

1 (2) 0 39 (70) 16 (29)

* Patients were retrospectively staged according to the New International Staging System (24); MACC = methotrexate, doxorubicin, cyclophosphamide, lomustine (CCNU).

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mixed histology), confirmed by pathologic review by the NCCTG Pathology Committee. No previous chemotherapy or radiotherapy was allowed. Patients were included in whom the disease was inoperable for medical reasons, unresectable or incompletely resected, and confined to one hemithorax with or without ipsilateral supraclavicular involvement (stage III of the old American Joint Committee for Cancer Staging system) (7). All patients had to have pulmonary function that was clinically judged as sufficient to tolerate the planned thoracic radiotherapy. All patients had to have measurable or evaluable disease. Contraindications to protocol enrollment included a leukocyte count of less than 4.0 x 109/L or a platelet count of less than 130 x 109/L, a creatinine level greater than 50% above the institutional upper limit of normal, any elevation of the direct bilirubin, pleural effusion, or an Eastern Cooperative Oncology Group (ECOG) performance score of 3 or 4. Patients with a previous history of cancer, other than nonmelanomatous skin cancer or in-situ cervical cancer, were excluded unless they had a 5-year disease-free interval. We also excluded patients with significant cardiac disease, defined as a myocardial infarction within 3 months or any disorder requiring daily use of digitalis, nitroglycerin, or antiarrhythmic agents. All patients signed an informed consent that was approved by the respective institutional review board. Therapeutic Interventions Patients were stratified by ECOG performance score: 0,1 compared with 2; histology: squamous compared with adeno compared with large compared with mixed; maximum tumor diameter: less than 3 cm compared with 3 to 6 cm compared with more than 6 cm; and NCCTG institution. Patients were then randomized to receive either thoracic radiotherapy or chemotherapy with identical thoracic irradiation. Thoracic radiotherapy was initiated on day 1 in the radiotherapy-only arm and consisted of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Radiotherapy was not interrupted except if toxicity necessitated doing so. Lead blocks were used to shield the spinal cord so that the total spinal cord dose was 4600 cGy or less. Treatment was given with megavoltage energy (cobalt-60 or greater) with a minimum target skin distance of 70 cm. Parallel opposed anterior and posterior ports were implemented and included the primary tumor, hilar and mediastinal lymph nodes; both ports were treated daily. Treatment portals extended from the suprasternal notch to 5 cm below the carina and included 1 cm of the medial portion of the contralateral lung. The involved portion of the ipsilateral lung was completely encompassed with a 2-cm margin of normal lung outside the grossly evident disease. The supraclavicular fossa was included in the radiation port only if it was clinically involved. The margin of the portal extended superiorly 2 cm beyond the palpable disease. The total tumor dose was calculated at the central axis midplane point. Radiation quality control was performed on all cases by the NCCTG Radiotherapy Quality Control Committee. Combined-modality therapy consisted of two cycles of chemotherapy followed by thoracic radiotherapy identical to that previously outlined that began 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic irradiation was completed, patients were given another two cycles of chemotherapy (total of four cycles). Patients whose disease progressed after the first or second cycle of chemotherapy were treated with thoracic radiotherapy, and further chemotherapy was omitted. The chemotherapy regimen consisted of intravenous methotrexate, 40 mg/m2 body surface area; intravenous doxorubicin, 40 mg/m2; intravenous cyclophosphamide, 400 mg/m2; and oral CCNU, 30 mg/m2. All agents were given on day 1 of the cycle. Courses were repeated every 28 days except while the patient was receiving thoracic irradiation. Leukocyte and platelet counts were measured weekly for patients receiving either regimen. For leukocyte nadirs of > 1 . 0 x 109/L to < 1.5 x 109/L or platelet nadirs of > 50 x 109/L to < 75 x 109/L, the dosage of all drugs was decreased 20%. For leukocyte nadirs < 1.0 x 109/L or platelet nadirs < 50 x 109/L, the dosage of all drugs was decreased by 40%. After the radiotherapy or combined-modality therapy was completed, patients were re-staged with chest roentgenogram,

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Table 2. Best Response by Assigned Treatment Arm Tumor Response

Regimen Thoracic Radiation Thoracic Radiation Therapy Therapy plus MACC*

n_m Complete response Partial response Regression Stable Progression

10 (17) 14 (24) 13 (22) 9 (16) 12 (21)

8 (14) 11 (20) 12 (21) 20 (36) 5 (9)

* MACC = methotrexate, doxorubicin, cyclophosphamide, and lomustine (CCNU).

complete blood count, chemistry profile, and physical examination. Other tests were done as clinically indicated. Patients were subsequently followed up with a physical examination, chest roentgenogram, complete blood count, and chemistry profile every 3 months until they had evidence of progressive disease. If the disease progressed, patients who had initially been treated with thoracic radiotherapy alone received MACC chemotherapy. The maximum cumulative dose of doxorubicin allowed was 450 mg/m2. Patients previously treated with MACC were treated at the discretion of their personal physician if they developed progressive disease. Response Criteria Tumor responses were classified as complete response or partial response in patients with measurable disease, and complete response or regression in those with evaluable disease (8-10). A measurable lesion was defined as a lesion that had clearly measurable perpendicular diameters on examination or chest roentgenogram. A complete response was defined as total disappearance of all lesions. A partial response was a reduction of 50% or more in the sum of the product of the longest perpendicular diameter of the indicator lesion. An evaluable lesion was a clinically apparent lesion on examination or chest roentgenogram that was not measurable in two dimensions. A complete response was defined as total disappearance of identifiable disease. A regression was defined as a definite decrease in size (but not total disappearance) of an evaluable lesion. Statistical Analysis The goal of the study was to test whether addition of chemotherapy would significantly increase patient survival. For an 85% power to detect an improvement in median survival from 8 months on the radiation arm only to 14 months on the combined arm, the study required 92 deaths. (For a survival study, power depends only on the number of deaths, not the number of subjects.) The original accrual goal of 150 patients in 3 years was chosen to satisfy this requirement. However, because the accrual was slower than anticipated and the follow-up per patient was therefore longer before analysis, the study required fewer patients than originally planned to obtain the 92 deaths. The final number of deaths exceeded the goal and the final power for the hypothesis was 0.86. Survival and time-to-progression curves were calculated from enrollment in the study using the Kaplan-Meier method (11); differences between curves were assessed using the logrank test (12). The effect of treatment after adjusting for other factors was assessed using a Cox proportional hazards model (13). Response rates were compared using the chi2 statistic. All analyses and comparisons were based on the patient's assigned treatment arm.

rolled. Seven patients (5.8%) were ineligible; two had stage IV disease, three had small-cell histology, one had a pleural effusion, and one had insufficient tissue for histologic review. The characteristics of the 114 remaining patients are presented in Table 1. The mean age was 63 years, and 7 1 % of all patients were men. There was good balance in performance scores, and 90% had an ECOG performance score of 0 or 1. A few more patients had large-cell histology and a few less had squamous histology in the combined-modality treatment group. The thoracic radiotherapy only arm had four more patients with smaller (< 3 cm) primary lesions and three fewer patients with larger primary cancers ( > 6 cm) than the combined-treatment group. None of these differences was statistically significant. At final analysis, 105 patients (92%) had died. No patient was lost to follow-up. Therapeutic Results Major responses are shown in Table 2. Twelve of 56 patients (21%) who were randomly assigned to combination therapy had a major response (complete response plus partial response plus regression) after their first two cycles of MACC (3 partial responses, 9 regressions) and 31 of the 56 (55%; CI, 42% to 68%) responded by the end of their full treatment program. These patients include two who progressed after one cycle of chemotherapy and then responded to treatment with chest irradiation. By comparison, on the radiationonly arm, 37 of 58 (64%; CI, 5 1 % to 76%) achieved a major response (P > 0.2). Of the 58 patients assigned to thoracic radiation only, 23 were treated with crossover MACC chemotherapy at progression. There were only three further responses, all of which were partial responses. Stable disease was the best response to therapy that could be achieved in 25% of all patients. The median duration of response from study entry was 265 days with radiotherapy only compared with 372 days with combination treatment (P > 0.2). The median times to progression were 192 and 199 days, respectively (P > 0.2) (Figure 1). The median survival time was 313 days with radiotherapy only and 317 days after chemoradiotherapy. Figure 2 shows the survival curves

Results The study opened in March of 1983 and closed in December of 1987. A total of 121 patients were en-

Figure 1. Time to progression measured from randomization. TRT = thoracic radiation therapy; MACC = methotrexate, doxorubicin, cyclophosphamide, and lomustine (CCNU).

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greater for the chemoradiotherapy regimen. After thoracic radiotherapy only, no patient had a leukocyte nadirs below 2.5 x 109/L or thrombocytopenia below 100 x 109/L (P = 0.002). With chemotherapy and radiotherapy, 20% of patients had leukocyte nadirs 1.0 x 109/L or less and 53% had nadirs of 2.0 x 109/L or less. Thrombocytopenia below 50 x 109/L was observed in 7% of patients. No treatment-related deaths were observed with chest irradiation only; however, two deaths were related to combination therapy (one, septic neutropenia; one, pneumonitis-fibrosis). Discussion 0

1

2

3

4

5

6

Years from randomization Figure 2. Overall survival measured from randomization. MST = median survival time; TRT = thoracic radiation therapy; MACC = methotrexate, doxorubicin, cyclophosphamide, and lomustine (CCNU).

for the two treatment regimens (P > 0.2). For patients who were initially randomized to thoracic radiation only, the 1-, 2-, and 5-year survival rates were 45% (CI, 32% to 58%), 16% (CI, 6% to 25%), and 7%. With combination chemotherapy and thoracic radiotherapy, the respective survival rates were 46% (CI, 33% to 60%), 21% (CI, 11% to 32%), and 5%. Survival was also compared after adjusting for other prognostic factors (stage, tumor size, performance score, weight loss, sex, and histologic findings) with essentially the same results. The adjusted risk ratio for radiotherapy compared with combination therapy was 1.06 (P > 0.2) compared with the unadjusted value of 1.08. Sites of First Progression Of the 58 patients who were randomized to radiotherapy only, the site or sites of first progression were known in 47 (Table 3). Twenty-two (47%) had their initial progression within the field of radiation only, and 21 (45%) had progression of disease outside the field of radiation only. Four patients had local and distant failure simultaneously. In the combined-chemotherapy group, there were 46 patients with known first sites of progression of disease. Twenty-three (50%) had their initial progression only at the primary site (infield), whereas 21 (46%) had distant metastasis only as their first progression. Two patients had both local and distant initial failures. No obvious difference in the local (infield) or distant failure rates was observed between the regimens.

Long-term survival after thoracic irradiation only has been poor. A more recent report of the previously cited RTOG study with varying doses of radiation had a 5-year survival rate of 3% to 5% (14). In analyzing patterns of failure for two simultaneous studies conducted by RTOG and using varying doses of radiation only for localized disease, 90% of initial failures occurred within 24 months. At 2 years after radiotherapy, depending on cell type, 65% to 80% of patients had local failures (defined as relapse within the radiation port) with or without distant metastases. Distant metastases ultimately occurred in 72% to 79% of patients (14). The high rates of local failure, as well as distant metastases, have been corroborated by other investigators (15, 16), even when chemotherapy has been combined with chest radiation. These findings clearly show that there is need for both better local control and more active chemotherapy for the systemic disease. Several investigators have combined systemic chemotherapy and radiotherapy in stage III non-small cell lung cancer in nonrandomized studies and have had encouraging results (5, 15, 16). In recent years, investigators from cooperative groups have reported randomized trials comparing thoracic radiotherapy with or without chemotherapy. The Finnish group's radiotherapy consisted of 5500 cGy given by split course and was given alone or with CAP for eight cycles (17). They enrolled 119 patients on each arm of therapy with no differences observed in survival (median survival time, 311 compared with 322 days). A subset analysis of patients with stage III (65 patients per arm) suggested that the corn-

Table 3. Sites of First Progression Sites of First Known Progression

Toxicity Of the 56 patients assigned to MACC chemotherapy, 11 (20%) required dose reduction due to toxicity, primarily myelosuppression. The average dose reduction was 30%. Nonhematologic toxicity was moderate (grade 2) or less in 82% of the patients. The severe (grade 3) or greater toxicities are shown in Table 4. As expected, the combined-modality therapy was generally associated with greater toxicity except for esophagitis and pneumonitis. Myelosuppression was statistically significantly 684

Thoracic Radiation Therapy (n = 47)

Regimen Thoracic Radiation Therapy plus MACC* (n = 46) n(%)

Localt Distant* Both

22 (47) 21 (45) 4(9)

23 (50) 21 (46) 2(4)

* MACC = methotrexate, doxorubicin, cyclophosphamide, and lomustine (CCNU). t Local = progression of cancer was within the field of thoracic radiation therapy only. t Distant = progression of cancer was outside the thoracic radiation therapy portal only.

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bined regimen had a therapeutic advantage. Trovo and colleagues (18) randomized 111 patients to radiotherapy (4500 cGy/15 fractions) or combined with CAMP (cyclophosphamide, doxorubicin, methotrexate, procarbazine) every 4 weeks for 12 cycles. The median survival was 11.7 months compared with 10 months and was not statistically significant. In 1988, two cooperative groups reported results of randomized trials at the national meeting of the American Society of Clinical Oncology (19, 20). The results of our trial were negative whereas those of the other trial showed a survival advantage for combined chemoradiotherapy compared with radiotherapy only. We report herein the final results of the NCCTG trial. The addition of MACC chemotherapy to "standard thoracic radiation" did not improve survival. In contrast, the Cancer and Leukemia Group B (CALGB) reported a survival advantage with combined therapy using two cycles of vinblastin and cisplatin before irradiation (20). They deliberately selected a favorable group of patients with stage III disease and required an ECOG performance score of 0 or 1, no supraclavicular nodal involvement, and weight loss of 5% or less, with an initial goal of 240 patients. The study was closed after 180 patients were accrued. They followed strict early termination rules and reported a median survival time of 16.5 months for the combined-therapy group compared with 8.5 months for the radiation-only group (20). In a final report of this study, the median survival time had changed to 13.8 months compared with 9.7 months, but the survival advantage for combined chemoradiotherapy was P = 0.007 (21). Why are the CALGB study results positive in favor of combined therapy when the other trials are all negative (17-19)? Is it the use of cisplatin (22)? The chemotherapy regimen in two of these trials did not contain cisplatin (18, 19). However, the Finnish group used CAP and still observed no statistical difference in survival. They used two cycles of cisplatin-based chemotherapy before the radiotherapy followed by an additional six cycles of CAP. Additional evidence in patients with stage IV non-small cell lung cancer suggests that the use of cisplatin did not make the difference. A randomized trial by our group of MACC compared with CAP showed no statistical difference in response rate or survival (6). In addition, another randomized trial by different investigators compared cisplatin-based therapy with nonplatinum therapy and noted no statistical difference in survival (23). A possible explanation for the positive results of the CALGB trial may be related to selection of a favorable group of patients or to staging variables. Their trial, as well as the one we now report, was instituted before the new staging system for non-small cell lung cancer. Accordingly, there could be an inadvertent imbalance of patients with stage IIIA and IIIB disease based on the new international staging system (24). Recently, RTOG reported a dose-escalating phase MI trial with hyperfractionated thoracic radiation (1.2 Gy given twice daily). Patients with good performance scores and less than 5% weight loss who received 69.6 Gy had the best survival with a median survival time of 13 months and a 2-year survival of 29%. Survival was

Table 4. Toxicity by Treatment Arm* Toxicityt

Nausea/vomiting Grade 3 Stomatitis Grade 3 Grade 4 Esophagitis Grade 3 Radiation pneumonitis Grade 3 Grade 4 Grade 5 Cardiac Grade 3 Infection/sepsis Grade 3 Grade 4 Grade 5

Thoracic Radiation Therapy* (n = 58)

Thoracic Radiation Therapy plus MACC* (n = 56)

0

4

0 0

2 1

3

2

2 0 0

1 0 1

0

1

1 0 0

1 0 1

* MACC = methotrexate, doxorubicin, cyclophosphamide, and lomustine (CCNU). t Toxicity grades are as follows: 3 = severe; 4 = life threatening; 5 = treatment-related death; grades of toxicity are based on North Central Cancer Treatment Group toxicity criteria. t Numbers shown are the actual number of patients.

higher with the 69.6 Gy dose than with the lower doses (25). On the basis of this trial, RTOG and ECOG have opened a phase III trial in this favorable subset of stage III patients that compares hyperfractionated radiotherapy with standard (single daily dose) radiotherapy and combined chemoradiotherapy. The latter two arms are identical to the two arms tested in the previously reported trial (21). This trial will confirm or refute the CALGB results and simultaneously test the question of local control, toxicity, and survival of hyperfractionation compared with single daily fraction thoracic radiotherapy. It is unlikely that hyperfractionation will result in any change in distant metastases as the initial site of failure, but it may result in better local control. If so, it will be interesting to see if this results in survival advantage. At the other extreme of the radiation spectrum is the recent report by Johnson and colleagues (26). Their study objective was to compare survival of patients with locally advanced non-small cell lung cancer treated with vindesine alone, thoracic radiotherapy alone, or both. They randomized more than 100 patients to each of three arms. The median survival times were 10.1, 8.6, and 9.4 months, respectively (P > 0.2). They reported that radiotherapy failed to improve long-term survival. By study design, however, patients who developed progressive disease while receiving vindesine were crossed over to radiotherapy. A total of 47 patients received crossover thoracic radiotherapy. Therefore, in our opinion, they did not truly test the hypothesis of thoracic radiotherapy compared with no radiotherapy. In conclusion, MACC chemotherapy, when added to a commonly used thoracic radiation regimen, did not lead to a survival advantage. The high rate of distant metastases and local failure clearly shows that new

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therapies with more effective agents are needed. One promising approach that is being pursued is the use of a hyperfractionated schedule of thoracic irradiation with concomitant chemotherapy. Trials using this approach are currently in progress. Presented in part at the annual meeting of the American Society of Clinical Oncology, New Orleans, Louisiana, on 25 May 1988. Acknowledgments: The authors thank Ms. Linda Winans for secretarial assistance and Ms. Linda Knowlton for assistance as data monitor and in the preparation of the manuscript. Grant Support: In part by Public Health Services Grants CA-25224, CA-35101, CA-35103, CA-35113, CA-35269, CA-35272, and CA-37417 from the National Cancer Institute. Requests for Reprints: James R. Jett, MD, Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905.

7. 8. 9.

10.

11. 12.

Current Author Addresses: Dr. Morton: Iowa Oncology Research Association CCOP, 1044 Seventh Street, Des Moines, IA 50314. Drs. Jett, Earle, and Therneau: Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905. Dr. McGinnis: Suite 210, Methodist Medical Plaza, 1212 Pleasant, Des Moines, IA 50309. Drs. Krook and Elliott: The Duluth Clinic CCOP, 400 East Third Street, Duluth MN 55805. Dr. Mailliard: Nebraska Oncology Group—Creighton University, University of Nebraska Medical Center and Associates, Omaha, NE 68131. Dr. Nelimark: Sioux Community Cancer Consortium CCOP, Central Plains Clinic Ltd., Suite 2000, 1000 East 21 Street, Sioux Falls, SD 57105. Dr. Maksymiuk: Saskatoon Cancer Clinic, University of Saskatchewan Campus, 200 Campus Drive, Saskatoon, Saskatchewan, S7N 4H4. Dr. Drummond: Rapid City Regional Oncology CCOP, Cancer Treatment Center, Radiology Associates, 2880 Fifth Street, Rapid City, SD 57701. Dr. Laurie: Grand Forks Clinic Ltd., 1000 South Columbia Road, Grand Forks, ND 58201. Dr. Kugler: Illinois Oncology Research Association CCOP, Suite 780, 900 Main Street, Peoria, IL 61603. Dr. Anderson: Department of Pathology, Methodist Medical Center of Illinois, 221 Northeast Glen Oak Avenue, Peoria, IL 61636.

13.

Additional participating institutions include Quain and Ramstad Clinic, Bismarck, ND 58502 (D. M. Pfeifle, MD); St. Luke's Hospital CCOP, Fargo, ND 58123 (R. Levitt, MD); Billings Clinic, Billings, MT 59103 (D. I. Twito, MD); Cedar Rapids Oncology Project, Cedar Rapids, IA 52403 (M. Wiesenfeld, MD); and Alton Ochsner Medical Foundation CCOP, New Orleans, LA 70121 (C. G. Kardinal, MD).

20.

14.

15.

16.

17.

18.

19.

21.

22. References 1. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA. 1990;40:9-26. 2. Carr DT, Childs DS Jr, Lee RE. Radiotherapy plus 5-FU compared to radiotherapy alone for inoperable and unresectable bronchogenic carcinoma. Cancer. 1972;29:375-80. 3. Sealy R, Lagakos S, Barkley T, Ryall R, Tucker RD, Lee RE, et al. Radiotherapy of regional epidermoid carcinoma of the lung: a study in fractionation. Cancer. 1982;49:1338-45. 4. Perez CA, Stanley K, Rubin P, Kramer S, Brady LW, Marks JE. Patterns of tumor recurrence after definitive irradiation for inoperable non-oat cell carcinoma of the lung. Int J Radiat Oncol Biol Phys. 1980;6:987-94. 5. Eagan RT, Lee RE, Frytak S, Scott M, Ingle JN, Creagan ET, et al. Thoracic radiation therapy and adriamycin/cisplatin-containing chemotherapy for locally advanced non-small-cell lung cancer. Cancer Clin Trials. 1981;2:381-8. 6. Krook JE, Fleming TR, Eagan RT, Cullinan S, Pfeifle D, Elliott TE, et al. Comparison of combination chemotherapy programs in ad-

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