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© 1999 American Society for Clinical Oncology Phase III Comparison of Twice-Daily Split-Course Irradiation Versus Once-Daily Irradiation for Patients With Limited Stage Small-Cell Lung CarcinomaFrom the Mayo Clinic and Mayo Foundation, Rochester, and Duluth Community Clinical Oncology Program, Duluth, MN; Carle Cancer Center Community Clinical Oncology Program, Urbana, and Illinois Oncology Research Association Community Clinical Oncology Program, Peoria, IL; Oschner Community Clinical Oncology Program, New Orleans, LA; Saskatchewan Cancer Foundation (Saskatoon Cancer Centre, Saskatoon, and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada); Meritcare Hospital Community Clinical Oncology Program, Fargo, ND; and Nebraska Oncology Group (Creighton University, University of Nebraska Medical Center, and Associates), Omaha, NE. Address reprint requests to James A. Bonner, MD, University of Alabama at Birmingham, Department of Radiation Oncology, 619 South 19th St, WTI 105, Birmingham, AL 35233-6832
PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m2 x 3) and cisplatin (30 mg/m2 x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m2 x 3) and cisplatin (30 mg/m2 x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response.
RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis ( CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.
THE USE OF TWICE-DAILY irradiation with a slight reduction in the individual fraction dose (1.5 Gy) compared with conventional once-daily irradiation (1.8 to 2.0 Gy) makes substantial theoretical sense for malignancies with radiation survival curves characterized by minimal "shoulders." The shoulder region of the radiation survival curve is the portion of the curve that generally occurs at lower doses of irradiation (< 2 Gy) and represents the portion of the curve in which the rate of cytotoxicity with respect to dose of irradiation is somewhat reduced until higher doses of irradiation are reached. At higher doses of irradiation, the shoulder is overcome and more rapid (with respect to dose of irradiation) cytotoxicity occurs. Small-cell lung cancer is a malignancy in which the radiation survival curve has demonstrated these characteristics of a minimal shoulder (compared with non–small-cell lung cancer).1 Therefore, in the mid 1980s, investigators began to explore twice-daily thoracic irradiation (TDTI) with slightly reduced individual fraction doses (1.5 Gy) compared with conventional once-daily thoracic irradiation (ODTI) with fraction doses of 1.8 Gy to 2.0 Gy in an effort to deliver more rapid thoracic irradiation (TI) in patients with small-cell lung cancer. Turrisi et al2 reported a pilot trial in 1988 in which patients with limited-stage small-cell lung cancer were treated with TDTI beginning on day 1 of the first of four cycles of etoposide/cisplatin (EP). The TDTI delivered a total dose of 45 Gy (30 fractions) over the initial 3 weeks of treatment. The 2-year survival rate of 56% was a very promising result, and the Eastern Cooperative Oncology Group (ECOG) repeated the pilot trial and obtained similar promising results.3 Subsequently, the ECOG began a phase III randomized trial of ODTI (50.4 Gy in 28 fractions) compared with TDTI (45 Gy in 30 fractions), with both TI regimens beginning on day 1 of the first of 4 cycles of EP chemotherapy. The initial results of this trial showed that TDTI (compared with ODTI) resulted in an increase in esophagitis and improved local control but not survival.4 The mature results of the trial have recently shown a survival advantage for the use of TDTI.5 Late in the 1980s, Mayo Clinic investigators performed a pilot trial using TDTI consisting of 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy in 16 fractions.6,7 The two courses of 24 Gy in 16 fractions were initiated with cycles 4 and 5 of chemotherapy. This split course, twice-daily regimen was a modification of similar regimens that had been used successfully in the treatment of head and neck cancer at the Massachusetts General Hospital (MGH).8 It should be noted that the MGH head and neck regimen resulted in a slightly reduced treatment time compared with conventional treatment. However, the Mayo Clinic regimen included chemotherapy with each course of irradiation, but overall treatment time was somewhat prolonged compared with that of conventional treatment. The Mayo Clinic trial showed a median survival of 26.5 months, with a 2-year survival rate of 55%.7 These results were comparable to those reported by Turrisi et al.3 Subsequently, the North Central Cancer Treatment Group (NCCTG) initiated a phase III study to test the question of whether TDTI (48 Gy in 32 fractions, with a 2.5-week break after 16 fractions) could improve upon the results of ODTI (50.4 Gy in 28 fractions), and the promising results of the Mayo Clinic pilot trial6,7 served as the basis of the phase III trial. The NCCTG trial differed from the ECOG trial in that TI was started at cycle 4 of chemotherapy, thus allowing for the treatment of what has been termed the "postchemotherapy tumor volumes"9 and perhaps less normal lung tissue. Additionally, the TDTI was split into two courses to coincide with two cycles of chemotherapy. This first report of the NCCTG phase III trial is mature, with only 17% of patients alive and in the study, 13% alive and off study, and 70% of patients off study because of death. The 185 deaths observed to date combined with a sensitivity/conditional power analysis that tested the potential hazard rates for the patients remaining alive in both treatment groups confirmed that the initial study specifications have been met.
Eligibility Patients who were enrolled in this study were required to have histologic or cytologic confirmation of small-cell lung cancer. If a patient had only a cytologic diagnosis, investigators were required to submit an operative report, pathology report, and slides for review. Patients with mixed small-cell and non–small-cell histologic features were not eligible. Patients were required to have limited-stage disease as follows: disease confined to one hemithorax and ipsilateral supraclavicular fossa and encompassable within a tolerable TI field as determined by a radiation oncologist. Patients with minimal pleural effusions that were not thought to be easily assessable for diagnosis (mild blunting of the costophrenic angle on chest radiographs or a small effusion seen on chest computed tomography) were allowed in the study. Patients were required to have an ECOG performance score of 0, 1, or 2, leukocytes  3,500/µL, platelets 100,000 µL, hemoglobin 9.5 g/dL, and serum creatinine  1.5 times the institutional upper limit of normal. Patients were required to have measurable or nonmeasurable but assessable disease as previously defined.10
Patients were not allowed entry onto the study if they had contralateral supraclavicular disease, contralateral hilar disease, or metastatic disease. Other contraindications to study entry were previous malignant disease (except nonmelanomatous skin or in situ cervix carcinoma) unless a 3-year disease-free interval had occurred, increased bilirubin levels, AST or alkaline phosphatase levels greater than three times the institutional upper limit, major surgery performed
Because randomization occurred approximately 3 to 4 months after registration, the following characteristics were required at randomization: thoracic disease that had responded, remained stable, or progressed to a minor degree that would still allow an acceptable TI field as deemed by the radiation oncologist; ECOG performance status of 0, 1, or 2; leukocytes Before entry onto the study, the patients were required to have a complete medical history; physical examination; complete blood count; chemistry studies, including bilirubin, AST, alkaline phosphatase, creatinine, and calcium; chest radiography; electrocardiography; computed tomography of the head (with contrast agent), chest, and upper abdomen through the adrenals; pulmonary function tests; bone scan; bone marrow biopsy (unilateral); pregnancy test for fertile women; and a radiation oncology consultation. After three cycles of chemotherapy, all of these studies were repeated except for electrocardiography, bone marrow biopsy, and pregnancy test. Investigators at all participating institutions were required to obtain approval from their individual institutional review boards before beginning to enroll patients onto this trial. The trial was open from September 1990 through November 1996, and 324 patients were enrolled in the study. After central review, 13 patients were found to be ineligible; therefore, 311 assessable patients were enrolled in the study. Of these 311 patients, 262 were randomized to TDTI or ODTI.
Treatment
Postrandomization treatment. Treatment consisting of ODTI is outlined in Fig 1. Patients received 50.4 Gy in 28 fractions (1.8 Gy per day) of TI given concomitantly with two cycles of EP. The initial anteroposterior/posteroanterior (AP/PA) TI fields included the residual tumor (if any) with a 2-cm margin, bilateral supraclavicular areas, mediastinum to the level of 5 cm below the carina or lower if subcarinal disease was present after the initial chemotherapy, and the ipsilateral hilum. The total isocenter midplane dose was 39.6 Gy in 22 fractions through the AP/PA fields, and the final 10.80 Gy in 6 fractions was delivered through oblique fields with an angle of 30 to 45 degrees. The off-cord oblique fields extended from 2 cm superior to the sternal notch to the same inferior border as the AP/PA fields and included the same anatomic areas, except the supraclavicular areas (unless there was initial ipsilateral supraclavicular involvement, in which case it was included). The maximal spinal cord dose was not to exceed 45 Gy, and investigators were required to submit isodose plans for axial sections through the central axis, 2 cm inferior to the superior border of the field and 2 cm superior to the inferior border of the field. Investigators were required to use photon energies of 4 to 10 MV, because of optimal dose considerations.11 Patients received two cycles of chemotherapy during the once-daily regimen.
The TDTI regimen consisted of 48 Gy in 32 fractions (1.5 Gy twice daily with After either ODTI or TDTI, the patients received an additional cycle of EP, followed by restaging similar to the restaging after the first three cycles of chemotherapy (noted above), with the exception that pulmonary function tests were not performed. If patients were found to have a complete response (no evidence of tumor), then they received prophylactic cranial irradiation (30 Gy in 15 fractions) encompassing the entire intracranial contents.
After the first course of treatment, chemotherapy doses were modified on the basis of hematologic, renal, and neurologic toxic effects. Nadirs of the leukocytes and platelets to levels below 1,500/µL and 50,000/µL, respectively, resulted in a 30% reduction of chemotherapy doses at the next cycle. Retreatment was not initiated until leukocyte and platelet levels reached 3,500/µL and 100,000/µL, respectively. TI could be started when leukocyte and platelet values reached 2,000/µL and 50,000/µL, respectively. Cisplatin doses were decreased by 50% for creatinine values of 1.5 to 2.0 times the institutional upper limit and discontinued for values greater than 2.0 (until values decreased below 1.5). Cisplatin was discontinued permanently for grade 3 neurosensory deficits. TI was delayed for
Follow-Up and Response Measurements
At each follow-up visit, patients were evaluated for response to treatment and whether they showed signs of local or distant disease progression. For patients with measurable disease, the criteria were as follows: complete response (CR), total disappearance of tumor; partial response,
The site of first progression was documented carefully and categorized as local or distant. Local progression was defined as progression at the primary site or regional lymph nodes. Distant progression was defined as progression at a site beyond that defined as local progression. The location of local failures with respect to the TI field was assessed. Investigators were required to submit chest radiographs that represented the intrathoracic disease before any treatment and after the first three cycles of chemotherapy and before randomization. The simulator radiographs and chest radiographs illustrating the first intrathoracic progression were required to be submitted. The radiation oncology principal investigator reviewed the location of each local progression and categorized it as "in-field" or "out-of-field," based on the borders of the simulator radiographs. The out-of-field progressions were categorized as less than 2 cm or
Study Design and Statistical Analysis A second analysis of the power specifications for the time to any local progression was performed and demonstrated that there was a 95% power to detect a difference in median time to local progression from 33 months to 63 months using a two-sided log-rank procedure with a type 1 error rate of 5%. An exponential transformation was used to translate the 2-year rates of local progression into comparable median values. The local failure analysis was performed by censoring patients who died or experienced disease progression without local failure. The power calculations were calculated assuming two-sided log-rank analyses for comparisons of survival estimates and a 5% type 1 error rate with a minimum of 24 months of follow-up after the termination of accrual.13,14
The study design included the following stratification factors (Table 1): performance status of 0 or 1 versus 2; weight loss of
All survival curves were constructed by the method of Kaplan and Meier,16 and comparisons of the curves were made by the log-rank method.13 To account for competing risks that can bias the local progression end point,1719 a cumulative incidence analysis was also performed adjusting for other competing risks of failure,20 and statistical comparisons between groups were performed by the method of Gray.21
An extensive sensitivity analysis was performed for the end points of local progression, distant progression, and survival. This analysis was undertaken to assess the potential impact of varying the distribution of censored individuals across groups on the ultimate treatment efficacy comparison. For instance, local progressions were assessed under the assumption that all patients with distant progression did not have local progression as well as under the assumption that all patients with distant progression did have local progression. This assessment was performed for the local progression only end point as well as the end point of any local progression. Survival was assessed under the assumption that all patients on one arm were to die at the time of this analysis and the patients on the other arm would live for another 2 years. Subsequently, the opposite assumption was made and tested. The balance of prognostic factors between the treatment groups was assessed by
Patient Characteristics Three hundred twenty-four patients were enrolled in the study, and after review of entry criteria, 311 were found to be eligible and thus made up the assessable population of this study. The median follow-up of the living patients was 39 months (range, 2 to 89 months), and the median survival and 3-year survival rate for the overall population were 21.3 months and 28.9%, respectively. After the first three cycles of chemotherapy, 262 patients remained in the study; because five were ineligible after chemotherapy, 14 had progression, 13 died (none due to treatment and four of sepsis), four refused further treatment, two had excessive toxic effects, one had a major deviation in treatment, and 10 had miscellaneous reasons for discontinuation. The characteristics (distribution of stratification factors) of these 262 patients with respect to the treatment they received are listed in Table 1.
Response
Patterns of Progression and Survival
Overall progression-free (local and/or distant) survival was not different between the two treatment groups (P = .66; Fig 4) (Table 2). Similarly, overall survival was not different for the two treatment groups (P = .44; Fig 5). The 2- and 3-year survival rates were 47% and 34% for the once-daily arm and 45% and 29% for the twice-daily arm, respectively (Table 3). The sensitivity analysis for survival revealed that a dramatic change in the current death rate of patients would be required for the survival results to show a difference between the two groups (Table 4).
Toxicity
The use of twice-daily irradiation has been investigated as a possible superior method for the delivery of irradiation compared with once-daily irradiation in many malignancies.2325 It has been suggested that twice-daily irradiation may improve local control and, possibly, survival in squamous cell carcinoma of the head and neck.25 However, even regarding head and neck cancer, for which many investigations of this question have been performed, the oncology community eagerly awaits the results of a recently completed Radiation Therapy Oncology Group (RTOG) trial comparing conventional once-daily irradiation (70 Gy in 35 fractions) with three different twice-daily irradiation regimens. This RTOG trial accrued more than 1,000 patients. The results reported herein reveal that there was not a local control or survival advantage for the TDTI regimen used in this trial for patients with limited-stage small-cell lung cancer. The NCCTG recently published the results of a study of a TDTI regimen for patients with non–small-cell lung cancer.23 This previous phase III trial showed a suggestion of improved survival for TDTI (60 Gy in 40 fractions, with a 2-week break after 30 Gy) in comparison with conventional ODTI (60 Gy in 30 fractions) (P = .10); however, the trial was underpowered due to early closure, because it was thought that chemotherapy became a part of the standard of care when the trial had reached approximately 30% of the projected accrual. The TDTI used in the NCCTG non–small-cell lung cancer trial was similar to the regimen used in the current trial for patients with small-cell lung cancer except for a reduction in total dose for the small-cell regimen (48 Gy in 32 fractions, with a 2.5-week break after 24 Gy). The rationale for the use of TDTI for patients with small-cell lung cancer seemed even stronger than the rationale for the use of TDTI for patients with non–small-cell lung cancer, because laboratory investigations have shown a reduced shoulder of the radiation survival curve for small-cell lung cancer compared with non–small cell-lung cancer.1 Therefore, the results of the present trial were somewhat unexpected in the context of the recent NCCTG report about the population of patients with non–small-cell lung cancer.23 The ECOG has also conducted a phase III comparison of TDTI and ODTI for patients with limited-stage small-cell lung cancer, and TDTI resulted in improved survival compared with ODTI.5 There were many differences between the ECOG and NCCTG regimens (ie, the ECOG used four cycles of EP and the NCCTG used six cycles of EP with higher doses of cisplatin; the ECOG started TI on cycle 1 of chemotherapy and the NCCTG started TI on cycle 4; overall median survival of all patients was better in the NCCTG trial [21.3 months from registration] than in the ECOG trial [20.0 months]). Even with these differences in the NCCTG and ECOG trials, one could hypothesize that the NCCTG TDTI regimen is inferior to the ECOG TDTI regimen for patients with small-cell lung cancer. The NCCTG has used a break in the delivery of TDTI at approximately the midpoint of the TDTI schedule in both non–small-cell lung cancer and small-cell lung cancer. The ECOG has not used a break. This break was used on the basis of the excellent results of a similar (and very effective) twice-daily regimen for head and neck malignancies used at the MGH8 (this regimen recently was compared with once-daily irradiation in an RTOG trial [final report pending]). The rationale for the break in the current trial was based partly on the fact that toxicity may be reduced by instituting a break. More importantly, the break was instituted because it allowed for the application of the second course of TDTI at the start of a second course of chemotherapy and approximately 28 days after the start of the first course of TDTI. At this 28-day point, it is possible that the cells may be entering an accelerated repopulation phase and may be most sensitive to irradiation and chemotherapy.26 Also, it has been suggested that these rapidly proliferating (accelerated) cells may be most sensitive to twice-daily irradiation.27 In the recently published NCCTG experience with TDTI in patients with non–small-cell lung cancer,23 there seemed to be an interaction of a similar twice-daily fractionation regimen (including a break) and histologic findings. The TDTI regimen with a 2-week break (in comparison with ODTI) showed the greatest positive impact on the survival of patients with the histologic findings of non–squamous cell carcinoma (P < .05). No improvement in survival was associated with TDTI (compared with ODTI) for histologic findings of squamous cell carcinoma. Therefore, a possible hypothesis is that the TDTI regimen with a break (as used by the NCCTG) may be efficacious for more slowly dividing tumors than for more rapidly dividing tumors, because it has been suggested that non–squamous cell lung cancer cell lines may demonstrate decreased proliferation rates compared with either squamous cell carcinoma2830 or small-cell carcinoma.31 If this theory is correct, then the suggestion that small-cell carcinoma is the most rapidly dividing of the various histologic findings of lung cancers31 would make it the least suited carcinoma for the use of the TDTI regimen with a break. Additional work is required to determine whether this conjecture regarding fractionation, treatment breaks, and proliferation rates of the various histologic types of lung cancer is valid. Another consideration is the possibility that the TDTI irradiation may need to be given sooner in the chemotherapy regimen (cycle 1 or 2) rather than later (cycle 4 or 5) for a positive impact of TDTI versus ODTI to be realized. The optimal timing of TI in small-cell lung cancer is controversial. The Canadian National Trial showed improvement in survival for the use of TI during cycle 2 versus cycle 6 of chemotherapy32; however, the Cancer and Leukemia Group B Trial showed decreased toxicity and a suggestion of improved survival for the use of TI during cycle 4 versus cycle 1 of chemotherapy.33 Additional study will be necessary to determine whether the use of altered fractionation (TDTI v ODTI) interacts with the timing of TI in combination with chemotherapy. It is important to emphasize that the current trial was one of the few large trials for patients with limited-stage small-cell lung cancer that used TI field sizes that encompassed just the postchemotherapy tumor volumes. For patients who had a CR before TI, the irradiation volumes included only the mediastinum and ipsilateral hilum. The location of local recurrences relative to the TI field was followed closely and less than 7% of these local recurrences included a component of disease outside the treatment field, and some of these recurrences may have represented new pulmonary metastases. Therefore, these results corroborate the results of our previous retrospective work in which it was very uncommon to detect local failure outside the treatment volume in patients who had received TI encompassing the postchemotherapy tumor volumes.9 Therefore, it is reasonable to conclude that postchemotherapy tumor volumes should be encompassed within TI fields for patients who have had a response to initial chemotherapy. This finding may allow for the delivery of higher doses of TI in limited-stage small-cell lung cancer, and higher-dose TI is the subject of the current NCCTG pilot trial. The use of TI that encompasses postchemotherapy tumor volumes should allow for a marked decrease in the amount of normal lungirradiated compared with TI, including the prechemotherapy tumor volume. The current trial did not reveal an advantage in local control or survival with ODTI compared with TDTI in the treatment of patients with limited-stage small-cell lung cancer. The results presented were mature, because 70% of patients have died; however, it will be important to assess long-term survival in this group of patients. The overall survival in the present trial is similar to the best reported survival values of cooperative group trials, thus suggesting that both of the regimens used in this trial are very efficacious.
Additional participating institutions include the following: Toledo Community Hospital Community Clinical Oncology Program (CCOP), Toledo, OH (Paul L. Shaefer, MD); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA (Martin Wiesenfeld, MD); Siouxland Hematology-Oncology Associates, Sioux City, IA (John C. Michalak, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (Suresh Nair, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, MD); Quain and Ramstad Clinic, Bismarck, ND (Delano M. Pfeifle, MD); Grand Forks Clinic, Ltd, Grand Forks, ND (John A. Laurie, MD); Missouri Valley Consortium, Omaha, NE (James A. Malliard, MD); Rapid City Regional Oncology Group, Rapid City, SD (Larry P. Ebbert, MD); Iowa Oncology Research Association CCOP, Des Moines, IA (Roscoe F. Morton, MD); Billings Clinic, Billings, MT (Donald Twito, MD); CentraCare Clinic, St. Cloud, MN (Harold E. Windschitl, MD); Scottsdale CCOP, Scottsdale, AZ (Richard Wheeler, MD); Ann Arbor Regional CCOP, Ann Arbor, MI (Philip J. Stella, MD); and Arizona Minority CCOP, Phoenix, AZ (Michael Lobell, MD)
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by United States Public Health Service grants no. CA15083, CA25224, CA37404, CA35269, CA35113, CA37417, CA63849, CA35415, CA35195, CA52352, CA35103, CA35448, CA35272, CA35101, CA60276, CA63848, and CA63826 from the National Cancer Institute, Department of Health and Human Services. Presented at the American Society of Clinical Oncology Annual Meeting, Los Angeles, CA, May 16-19, 1998.
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Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 11:336-344, 1993 33. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316:912-918, 1987[Abstract] Submitted September 1, 1998; accepted May 7, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 testing.
