- Email: [email protected]
or hyperfractionated radiotherapy: a multivariate analysis of 1076 rtog patients
Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 2, pp. 327–331, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
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CLINICAL INVESTIGATION
Lung
INTERFRACTION INTERVAL DOES NOT AFFECT SURVIVAL OF PATIENTS WITH NON-SMALL CELL LUNG CANCER TREATED WITH CHEMOTHERAPY AND/OR HYPERFRACTIONATED RADIOTHERAPY: A MULTIVARIATE ANALYSIS OF 1076 RTOG PATIENTS MARIA WERNER-WASIK, M.D.,* CHARLES SCOTT, PH.D.,† MARY L. GRAHAM, M.D.,‡ COLUM SMITH, M.D.,§ ROGER W. BYHARDT, M.D.,\ MACK ROACH III, M.D.,¶ AND E. JAMES ANDRAS, M.D.# *Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University and Kimmel Cancer Center, †Radiation Therapy Oncology Group, Philadelphia, PA; ‡Radiation Oncology Center, Washington University, St. Louis, MO; §Tom Baker Cancer Center, Calgary, Alberta, Canada; \Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; ¶Department of Radiation Oncology, UCSF, San Francisco, CA; #Radiological Associates of Sacramento Medical Group, Sacramento, CA Purpose: It was observed by Jeremic et al. that a shorter interfraction interval (IFI) was associated with an improved survival in patients (pts) with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT), with or without chemotherapy (CT). Our analysis was undertaken to verify this hypothesis. Methods and Materials: Records of patients treated on 5 Radiation Therapy Oncology Group (RTOG) studies were reviewed, and an actual IFI, defined as a mean of all daily IFIs, was calculated. RT dose was 1.2 Gy BID to 69.6 Gy. The relationship between the length of IFI and the median survival time and incidence of esophagitis was investigated. Results: In 682 pts eligible for this analysis, a full dose of RT was delivered and at least 90% of all daily IFIs were available. The actual mean IFI was as follows: 4 – 4.9 h in 51% of pts; 5–5.9 h in 17%; 6 – 6.9 h in 28% and 7– 8 h in 4%. In multivariate analysis, only lack of weight loss, use of CT, low nodal stage and good KPS, but not IFI (4 – 6 h vs. 6 – 8 h) were associated with an improved survival for all pts (p values: <0.0001; <0.0001; 0.006; 0.006, and 0.73, respectively), as well as for HFX-RT only pts. For the CT–HFX-RT pts, not enough data points are available for a meaningful analysis. Length of IFI did not influence the incidence of Grade 3 or higher esophagitis (p 5 0.82), but use of CT was associated with a 12-fold greater risk of developing severe esophagitis (p < 0.0001). Conclusion: Length of IFI (4 – 6 h vs. 6 – 8 h) did not influence survival and acute complications incidence in pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy. Previously identified factors, such as use of CT, minimal weight loss, good KPS and low nodal stage, were confirmed again to be associated with a favorable prognosis in a multivariate analysis. Use of CT was associated with a 12-fold greater risk of developing severe esophagitis than HFX-RT alone. It appears that an IFI of 4-8 hr is acceptable in clinical practice for pts with NSCLC, treated with HFX-RT. © 1999 Elsevier Science Inc. Lung cancer, Radiotherapy, Hyperfractionation, Chemotherapy, Esophagitis.
INTRODUCTION
phase I/II randomized study, which established a dose of 69.6 Gy in two daily 1.2 Gy fractions as the lowest dose of HF-RT possibly associated with improved median survival time (MST) of 13 months (mo) and no increase in normal tissue toxicity, when compared to patients historically treated with once daily RT (1, 2). A subsequent study (RTOG 88-08/ECOG 4588/SWOG 89-92) (3) directly compared HF-RT (69.6 Gy) to standard once daily RT (60.0 Gy in 2.0 Gy fractions) and to induction chemotherapy (CT), followed by standard thoracic RT. A tandem of pilot trials tested the feasibility and effectiveness of two different che-
The Radiation Therapy Oncology Group (RTOG) conducted several studies in the 1980s and early 1990s investigating the role of altered fractionation in radiation therapy (RT) in the definitive treatment of favorable patients with locally advanced or inoperable non-small cell lung cancer (LA-NSCLC). Hyperfractionated RT (HF-RT) seemed ideally suited for that purpose as means of delivering higher effective doses of radiation and, at the same time, not increasing the incidence of late effects. The initial dose escalation trial (RTOG 83-11) was a Poster Presentation at ASTRO 1997. Request reprints to: Maria Werner-Wasik, M.D., Bodine Center for Cancer Treatment, Thomas Jefferson University Hospital, 111 South 11th Street, Philadelphia, PA 19107-5097.
Accepted for publication 15 January 1999.
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Table 1. Radiation Therapy Oncology Group (RTOG) studies for patients with locally advanced/inoperable non-small cell lung cancer (NSCLC), using hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy Study number
Number of patients
Number of analyzable patients
HFX-RT dose (Gy)
Concurrent CT
83-11 88-08 (arm 3) 90-15 91-06 92-04 (arm 2)
884 163 42 79 83
475 85 21 50 51
60.4, 64.8, 69.6,* 74.4, 79.2 69.6 69.6 69.6 69.6
None None Cisplatin1vinblastine Cisplatin1oral etoposide Cisplatin1oral etoposide
* Only patients who received 69.6 Gy were considered analyzable.
motherapy regimens (cisplatin and oral etoposide in RTOG 91-06; cisplatin and vinblastine in RTOG 90-15) given concurrently with HF-RT to 69.6 Gy (4, 5). Finally, RTOG 92-04 study compared in a Phase II randomized fashion, induction cisplatin/vinblastine followed by concurrent CT and standard thoracic RT vs. concurrent cisplatin plus oral etoposide and HF-RT to 69.6 Gy (6). The interfraction interval (IFI) used in those RTOG studies was specified as at least 6 hours in 90-15, 91-06, and 92-04 trials, and 4 to 6 hours in 88-08 and 83-11 studies. Jeremic and Shibamoto (7) reported an analysis of 169 pts with LA-NSCLC treated by HFX-RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (with or without concurrent chemotherapy) and concluded, that pts treated with a shorter IFI (4.5–5 h) had a better median survival time (22 mo) than those treated with a longer interval of 5.5– 6 h (7 mo; p 5 0.0000). Therefore, we undertook an analysis of a potential influence of IFI on outcome among patients with lung cancer treated on the previously mentioned RTOG studies with HFX-RT, with or without the addition of chemotherapy. MATERIALS AND METHODS Records of all patients (pts) treated with HFX-RT in 5 RTOG studies (Table 1) between April 1983 and March 1994 were reviewed retrospectively. Patients were considered eligible for this analysis if their total radiation dose did not deviate from the prescribed dose of 69.6 Gy by 10% or more. In addition, patients were eligible for the analysis if treatment times were available for 90% or more of delivered treatments and if there were no treatment breaks of 7 days or longer. All patients treated on RTOG 83-11 study were centrally reviewed and were excluded, if their total dose was beyond 62.4 –76.56 Gy range. The intervals (in hours) between fractions were taken from the treatment records, as per recorded treatment times. The individual daily interfraction interval (IFI) values were available for 207 patients and not available for the remainder (n 5 475). Therefore, we used the actual interfraction interval (aIFI), defined as a mean of all daily IFIs. CT included cisplatin and either oral etoposide or vinblastine, and was delivered concurrently with thoracic irradiation. Radiation treatment volumes included the primary
tumor and mediastinum, with all lymph nodes measuring at least 2.5 cm on thoracic computerized tomography studies receiving the full prescribed dose. The detailed reports from those RTOG studies have been reported previously (1, 3– 6). The effect of aIFI on outcome was examined by separating interfraction interval into 1-h increments. Survival was estimated using the Kaplan-Meier method (8). Survival distributions were compared using the log-rank statistic (9). Multiple prognostic factors (including interval hours) were examined for their influence on survival using the Cox proportional hazards model (10). Esophagitis was scored using the RTOG Toxicity Criteria and was defined as the worst grade observed either during treatment or in followup. Differences between interval hours and esophagitis severity were examined using the linear-by-linear test (11). The influence of multiple prognostic factors on Grade 3 or higher esophagitis was examined using logistic regression. RESULTS A total of 1251 pts were enrolled on RTOG studies for NSCLC using HFX-RT (884 pts on 83-11; 163 on 88-08; 42 on 90-15; 79 on 91-06 and 83 on 92-04) (Table 1). IFI was not specified in the records of 124 patients (18 in 83-11; 56 in 88-08; 16 in 90-15; 12 in 91-06 and 32 in 92-04 studies). A total of 682 pts were found to be fully analyzable according to the criteria specified in the Methods section (475 pts on 83-11; 85 on 88-08; 21 on 90-15; 50 on 91-06 and 51 on 92-04) (Table 1). A total of 560 analyzable pts received HFX-RT and 122 pts received CT and HFX-RT. The pretreatment characteristics of analyzable patients were as follows: Stage I, 40 (6%); Stage II, 33 (5%); Stage IIIA, 340 (50%); Stage IIIB, 267 (39%), and unknown, 2 (0.02%). Weight loss of more than 5% was noted in 183 (27%). Females constituted 27% of all pts and 64% of pts were at least 60 years old. The majority of pts (87%) had Karnofsky Performance Status (KPS) of 80% or more. Squamous cell carcinoma was the most common histology (51%), followed by adenocarcinoma (26%) and large cell carcinoma (14%), with 9% of other/unknown histologies. Actual IFI (a IFI) was as follows: 4.0 – 4.9 h in 350 (51%) pts; 5.0 –5.9 h in 119 (17%) pts; 6.0 – 6.9 h in 188 (28%) pts and 7.0 – 8.0 h in 25 (4%) pts. Within each category of IFI,
HFRT in children with BST
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Table 2. Median survival time (MST) of patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy. Effect of actual interfraction interval (aIFI) (hours). IFI (h)
4.0–4.9
5–5.9 6–6.9 7–8 p Value
MST (y) All patients (n 5 682) 0.88 0.82 HFX-RT only (n 5 560) 0.88 0.91 CT–HFX-RT (n 5 122) no patients 0.48 Number of patients 350
1.16 1.64
0.02
0.91 1.10
0.58
1.36 1.77 119 188
0.58 25
the following means (standard errors) were calculated: 4.15 (0.24) for 4 –5 hours; 5.24 (0.31) for 5– 6 hours; 6.27 (0.29) for 6 –7 hours and 7.24 (0.28) for 7– 8 hours. Seven percent of all patients (n 5 48) were alive at the time of analysis. Table 2 summarizes the MST (years), depending on the aIFI. In univariate analysis, the MST were as follows: for aIFI of 4.0 – 4.9 h, 0.88 years (n 5 350); for aIFI of 5.0 –5.9 h, 0.82 year (n 5 119); for aIFI of 6.0 – 6.9, 1.16 years (n 5 188); and for aIFI of 7.0 – 8.0 h, 1.64 year (n 5 25) (p 5 0.02, when MST for 4 – 6 h is compared with MST for 6 – 8 h) (see also Fig. 1). For pts treated with HFX-RT alone, the MST were as follows: for aIFI of 4.0 – 4.9 h, 0.88 year (n 5 350); for aIFI of 5.0 –5.9 h, 0.91 year (n 5 114); for aIFI of 6.0 – 6.9, 0.91 year (n 5 89), and for aIFI of 7.0 – 8.0 h, 1.10 years (n 5 7) (p 5 0.99) (Fig. 2). For pts treated with CT-HFX-RT alone, the MST were as follows: for aIFI of 4.0 – 4.9 h, no pts were identified; for aIFI of 5.0 –5.9 h, 0.48 years (n 5 5); for aIFI of 6.0 – 6.9, 1.36 years (n 5 99), and for aIFI of 7.0 – 8.0 h, 1.77 years (n 5 18) (p 5 0.58) (Fig. 3). The effect of several pretreatment variables on the overall survival was tested using a multivariate analysis. As illustrated in Table 3, loss of #5% of body weight, good KPS ($70), low
Fig. 1. Survival of all patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy.
Fig. 2. Survival of patients with locally advanced/inoperable nonsmall cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) alone.
nodal stage (N0 vs. N1) and addition of CT to RT, were associated with an improved survival in all patients (p values: ,0.0001; 0.0001; 0.02; and 0.0001 for all pts and ,0.0001; 0.0002; 0.025 and not applicable, for HFX-RT pts, respectively). However, the length of aIFI (4–6 h vs. 6–8 h) did not influence the survival significantly (p 5 0.55 for all pts and 0.44 for HFX-RT pts). When IFI was analyzed as a continuous variable rather than divided into 1 h intervals, the IFI length had still no effect on survival (for all patients, p 5 0.67 or IFI analyzed as a continuous variable vs. p 5 0.73 for IFI analyzed as 1-h intervals). In the subgroup of pts treated with CT-HFX-RT not enough data points were available for a meaningful analysis. Esophagitis (Grades 1–5) occurred in the majority of patients and its incidence increased with the increasing aIFI. Among patients treated with aIFI of 4.0 – 4.9 h, 75% (26/ 350) experienced any esophagitis; 5.0 –5.9 h, 79% (94/195);
Fig. 3. Survival of patients with locally advanced/inoperable nonsmall cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) and chemotherapy.
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Table 3. Correlation of pretreatment variables and length of actual interfraction interval (aIFI) with median survival time (MST) of patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy (p values) (multivariate analysis) Variable
All patients
HFX-RT patients
CT–HFX-RT patients
Weights loss # 5% vs. . 5% ,0.0001 ,0.0001 KPS $ 70% 0.006 0.0002 Low nodal stage Analysis not (N0 vs. N1) 0.008 0.025 possible Chemotherapy ,0.0001 not applicable Length of IFI (4–6 h vs. 6–8 h) 0.73 0.44
6.0 – 6.9 h, 84% (157/188), and 7.0 – 8.0 h, 92% (23/25); p , 0.0001). However, because the “RT only” trials (RTOG 83-11 and 88-08) recommended a shorter IFI (4 – 6 h) than the “RT and chemotherapy” trials (90-15, 91-06, and 92-04) (at least 6 h), the use of chemotherapy might have affected the increasing incidence of esophagitis among patients treated with longer IFIs. Therefore, a logistic regression analysis was performed, in which out of four pretreatment variables examined (chemotherapy vs. no chemotherapy; KPS of #70 vs. 80 –100; nodal status, N0 vs. N1, and aIFI), only chemotherapy was associated with a significant (nearly 12-fold) increase in Grade 3 or higher esophagitis (Table 4). In patients treated with HFX-RT alone, Grade 3 or higher esophagitis occurred in 7% (38/560) patients, and in patients treated with chemotherapy and HFX-RT, in 41% (50/122) patients. DISCUSSION HFX-RT is a common type of altered fractionation used in radiation therapy. It entails the use of a smaller than “standard” fraction size of radiation (typically 0.9 –1.3 Gy) given more than once daily (usually 2–3 times), which allows the delivery of an increased total dose over the unchanged treatment duration. Because there seems to be a preferential sparing of late-reacting tissues with smaller Table 4. Correlation of pretreatment variables with Grade 3 or higher esophagitis in patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy
Chemotherapy vs. no chemotherapy KPS (#70 vs. 80–100) Weight loss N0 stage vs. N1 Interfraction interval NS 5 not significant.
Odds ratio
p Value
11.7 1.8 NS NS NS
,0.0001 0.053 0.32 0.103 0.82
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fraction sizes (12), HFX-RT may allow dose escalation of RT without increased incidence of late tissue toxicity. However, establishing the optimal interval between fractions of HFX-RT is of crucial importance, to allow enough time for repair of irradiated late-reacting tissues (13). If fractions are spaced too closely, an unexpected increase in late tissue toxicity can happen, as described by Nguyen et al. (14) in head and neck cancer patients, receiving multiple daily small fractions (0.9 Gy every 2 h) and by Cox et al. (15) in squamous cell carcinomas of the head and neck, treated with 1.2 Gy every 4 to 8 hours to the escalating RT doses between 67.2 Gy and 81.6 Gy. Similarly, the initial experience with CHART (Continuous Hyperfractionated Accelerated Radiotherapy), where 3 daily fractions of 1.5 Gy were administered every 6 h on 12 consecutive days, resulted in 4 out of 263 pts experiencing radiation myelopathy with maximal cord doses between 45– 48.3 Gy (16). Once the minimal necessary IFI is established from the point of view of safety, the question arises, whether the elongation of IFI has any adverse effect on tumor control, and, indirectly, on patients’ survival. The IFI used in those RTOG studies reflected the radiobiologic principles of maximal tumor kill by allowing reoxygenation of tumor cells, as well as repair of sensitive normal tissues, particularly the late-reacting tissues, such as spinal cord (12,17). In a previously quoted RTOG experience (15), there was no evidence for an effect of IFI length (4.5 h or less vs. more than 4.5 h) on either loco-regional tumor control or survival rates of 447 patients with squamous cell carcinomas of the head and neck. In addition, the shorter IFI of 4.5 h or less was associated with higher frequencies of Grade 4 or higher late effects. However, in the study by Jeremic and Shibamoto (7), the shorter IFI was an independent favorable prognostic factor for survival and disease-free survival in multivariate analysis, along with female gender, younger age, good performance status, and early stage. In that study, the investigators analyzed 169 patients with NSCLC treated previously in a randomized trial, which compared HF-RT alone with chemotherapy and HF-RT (18). Interfraction intervals (4.5–5 h or 5.5– 6 h) were nonrandomly assigned to each patient and these intervals were kept constant throughout the entire treatment course. The advantage in survival due to the shorter interfraction interval was seen in both chemotherapy-radiation and radiation alone groups. This advantage was also confirmed in multivariate analysis, performed in order to account for the imbalance of prognostic factors between the treatment groups. Our analysis used a mean IFI and the standard deviations for all daily IFIs were not known. However, these deviations were presumed to be small, because the required IFIs were well defined in each protocol. Two other reports in the literature (19,20) suggested a survival benefit for a shorter IFI (4.0 – 4.4 or 4.5–5.0 h vs. 4.5– 8.0 or 5.5– 6 h) in patients with malignant gliomas receiving HF-RT, with conclusions supported in both by multivariate analysis. In our analysis, the length of aIFI (4 – 6 h vs. 6 – 8 h) did
HFRT in children with BST
not influence survival of pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy with/or without CT. Only the previously identified factors, such as use of CT, minimal weight loss, good KPS and low nodal stage, were confirmed again to be associated with a favorable prognosis in a multivariate analysis. The vast majority of our analyzable patients (n 5 682) were treated with HFX-RT alone, in contrast to Jeremic et al.’s patients (n 5 169) (7), one-half of whom received a combined modality treatment. In our subgroup of pts treated with CT–HFX-RT not enough data points were available for a meaningful multivariate analysis. In summary, the analysis of our data base of 682 patients with NSCLC, treated to a uniform dose of HF-RT of 69.6 Gy, mostly without chemotherapy, does not support the concept of a shorter IFI benefiting the overall survival. All patients were analyzed based on individual actually recorded daily treatment intervals
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rather than the recommended intervals. The effect of the IFI length on local tumor control could not be assessed, because local control data were not gathered in those studies, designed to have survival rates as a primary endpoints rather than local control. It is likely that the reason for the controversy existing in the literature with regard to the importance of the IFI affecting survival of patients treated with HF-RT lies in the inherent bias of the retrospective analyses. The review of available data does not allow the identification of the IFI associated with the best tumor control, and potentially, best survival. A prospective randomized trial of various IFIs would be necessary to identify the best IFI. However, it appears that an IFI of 4 – 8 h is acceptable in clinical practice for pts with NSCLC, treated with HFX-RT, especially because there was no evidence of increased incidence of severe esophagitis associated with the particular IFI length.
REFERENCES 1. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: Possible survival benefit with .69.6 Gy in favorable patients with stage III non-small cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990;8:1543–1555. 2. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 1987;59:1874 –1881. 3. Sause W, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995;87:198 –205. 4. Byhardt RW, Scott CB, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Results of Radiation Therapy Oncology Group 90-15. Cancer 1995;75(9):2337–2344. 5. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: Radiation Therapy Oncology Group Protocol 91-06. J Clin Oncol 1996;14:1055– 1064. 6. Komaki R, Scott C, Ettinger D, et al. Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04. Int J Radiat Oncol Biol Phys 1997; 38(1):149 –155. 7. Jeremic B, Shibamoto Y. Effect of Interfraction Interval in Hyperfractionated Radiotherapy with or without Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 1996;34:303–308. 8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 9. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719 –748.
10. Cox DR. Regression models and life-tables. J R Stat Soc B 1972;4:187–202. 11. Mehta C, Patel N. StatXact 3 for Windows: User Manual. CYTEL Software: Cambridge, 1996. 12. Fowler JF. Intervals between multiple fractions per day–Differences between early and late reactions. Acta Oncol 1988; 27:181–183. 13. Thames HD, Peters LJ, Ang KK. Time-dose considerations for normal-tissue tolerance. Front Radiat Ther Oncol 1989;23: 113–117. 14. Nguyen TD, Demange L, Froissart D, et al. Rapid hyperfractionated radiotherapy. Clinical results in 178 advanced squamous cell carcinomas of the head and neck. Cancer 1985;56:16 –19. 15. Cox JD, Pajak TF, Marcial VA, et al. ASTRO plenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from Radiation Therapy Oncology Group Protocol 8313. Int J Radiat Oncol Biol Phys 1991;6:1191–1195. 16. Saunders MI, Dische S, Grosch E, et al. Experience with CHART. Int J Radiat Oncol Biol Phys 1991;21:871– 878. 17. Hermens AF, Barendsen GW. Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after X-irradiation. Eur J Cancer 1969;5:173–189. 18. Jeremic B, Shibamoto Y, Acimovic L, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for Stage III nonsmall-cell lung cancer. J Clin Oncol 1995;13:452– 458. 19. Jeremic B, Grujicic D, Antunovic V, et al. Hyperfractionated radiation therapy followed by multiagent chemotherapy in patients with malignant glioma: A Phase II study. Int J Radiat Oncol Biol Phys 1994;30:1179 –1185. 20. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma-possible advantage observed at 72.0 Gy in 1.2 Gy BID fractions: Report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys 1993;25:193–207.
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CLINICAL INVESTIGATION
Lung
INTERFRACTION INTERVAL DOES NOT AFFECT SURVIVAL OF PATIENTS WITH NON-SMALL CELL LUNG CANCER TREATED WITH CHEMOTHERAPY AND/OR HYPERFRACTIONATED RADIOTHERAPY: A MULTIVARIATE ANALYSIS OF 1076 RTOG PATIENTS MARIA WERNER-WASIK, M.D.,* CHARLES SCOTT, PH.D.,† MARY L. GRAHAM, M.D.,‡ COLUM SMITH, M.D.,§ ROGER W. BYHARDT, M.D.,\ MACK ROACH III, M.D.,¶ AND E. JAMES ANDRAS, M.D.# *Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University and Kimmel Cancer Center, †Radiation Therapy Oncology Group, Philadelphia, PA; ‡Radiation Oncology Center, Washington University, St. Louis, MO; §Tom Baker Cancer Center, Calgary, Alberta, Canada; \Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; ¶Department of Radiation Oncology, UCSF, San Francisco, CA; #Radiological Associates of Sacramento Medical Group, Sacramento, CA Purpose: It was observed by Jeremic et al. that a shorter interfraction interval (IFI) was associated with an improved survival in patients (pts) with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT), with or without chemotherapy (CT). Our analysis was undertaken to verify this hypothesis. Methods and Materials: Records of patients treated on 5 Radiation Therapy Oncology Group (RTOG) studies were reviewed, and an actual IFI, defined as a mean of all daily IFIs, was calculated. RT dose was 1.2 Gy BID to 69.6 Gy. The relationship between the length of IFI and the median survival time and incidence of esophagitis was investigated. Results: In 682 pts eligible for this analysis, a full dose of RT was delivered and at least 90% of all daily IFIs were available. The actual mean IFI was as follows: 4 – 4.9 h in 51% of pts; 5–5.9 h in 17%; 6 – 6.9 h in 28% and 7– 8 h in 4%. In multivariate analysis, only lack of weight loss, use of CT, low nodal stage and good KPS, but not IFI (4 – 6 h vs. 6 – 8 h) were associated with an improved survival for all pts (p values: <0.0001; <0.0001; 0.006; 0.006, and 0.73, respectively), as well as for HFX-RT only pts. For the CT–HFX-RT pts, not enough data points are available for a meaningful analysis. Length of IFI did not influence the incidence of Grade 3 or higher esophagitis (p 5 0.82), but use of CT was associated with a 12-fold greater risk of developing severe esophagitis (p < 0.0001). Conclusion: Length of IFI (4 – 6 h vs. 6 – 8 h) did not influence survival and acute complications incidence in pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy. Previously identified factors, such as use of CT, minimal weight loss, good KPS and low nodal stage, were confirmed again to be associated with a favorable prognosis in a multivariate analysis. Use of CT was associated with a 12-fold greater risk of developing severe esophagitis than HFX-RT alone. It appears that an IFI of 4-8 hr is acceptable in clinical practice for pts with NSCLC, treated with HFX-RT. © 1999 Elsevier Science Inc. Lung cancer, Radiotherapy, Hyperfractionation, Chemotherapy, Esophagitis.
INTRODUCTION
phase I/II randomized study, which established a dose of 69.6 Gy in two daily 1.2 Gy fractions as the lowest dose of HF-RT possibly associated with improved median survival time (MST) of 13 months (mo) and no increase in normal tissue toxicity, when compared to patients historically treated with once daily RT (1, 2). A subsequent study (RTOG 88-08/ECOG 4588/SWOG 89-92) (3) directly compared HF-RT (69.6 Gy) to standard once daily RT (60.0 Gy in 2.0 Gy fractions) and to induction chemotherapy (CT), followed by standard thoracic RT. A tandem of pilot trials tested the feasibility and effectiveness of two different che-
The Radiation Therapy Oncology Group (RTOG) conducted several studies in the 1980s and early 1990s investigating the role of altered fractionation in radiation therapy (RT) in the definitive treatment of favorable patients with locally advanced or inoperable non-small cell lung cancer (LA-NSCLC). Hyperfractionated RT (HF-RT) seemed ideally suited for that purpose as means of delivering higher effective doses of radiation and, at the same time, not increasing the incidence of late effects. The initial dose escalation trial (RTOG 83-11) was a Poster Presentation at ASTRO 1997. Request reprints to: Maria Werner-Wasik, M.D., Bodine Center for Cancer Treatment, Thomas Jefferson University Hospital, 111 South 11th Street, Philadelphia, PA 19107-5097.
Accepted for publication 15 January 1999.
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Table 1. Radiation Therapy Oncology Group (RTOG) studies for patients with locally advanced/inoperable non-small cell lung cancer (NSCLC), using hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy Study number
Number of patients
Number of analyzable patients
HFX-RT dose (Gy)
Concurrent CT
83-11 88-08 (arm 3) 90-15 91-06 92-04 (arm 2)
884 163 42 79 83
475 85 21 50 51
60.4, 64.8, 69.6,* 74.4, 79.2 69.6 69.6 69.6 69.6
None None Cisplatin1vinblastine Cisplatin1oral etoposide Cisplatin1oral etoposide
* Only patients who received 69.6 Gy were considered analyzable.
motherapy regimens (cisplatin and oral etoposide in RTOG 91-06; cisplatin and vinblastine in RTOG 90-15) given concurrently with HF-RT to 69.6 Gy (4, 5). Finally, RTOG 92-04 study compared in a Phase II randomized fashion, induction cisplatin/vinblastine followed by concurrent CT and standard thoracic RT vs. concurrent cisplatin plus oral etoposide and HF-RT to 69.6 Gy (6). The interfraction interval (IFI) used in those RTOG studies was specified as at least 6 hours in 90-15, 91-06, and 92-04 trials, and 4 to 6 hours in 88-08 and 83-11 studies. Jeremic and Shibamoto (7) reported an analysis of 169 pts with LA-NSCLC treated by HFX-RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (with or without concurrent chemotherapy) and concluded, that pts treated with a shorter IFI (4.5–5 h) had a better median survival time (22 mo) than those treated with a longer interval of 5.5– 6 h (7 mo; p 5 0.0000). Therefore, we undertook an analysis of a potential influence of IFI on outcome among patients with lung cancer treated on the previously mentioned RTOG studies with HFX-RT, with or without the addition of chemotherapy. MATERIALS AND METHODS Records of all patients (pts) treated with HFX-RT in 5 RTOG studies (Table 1) between April 1983 and March 1994 were reviewed retrospectively. Patients were considered eligible for this analysis if their total radiation dose did not deviate from the prescribed dose of 69.6 Gy by 10% or more. In addition, patients were eligible for the analysis if treatment times were available for 90% or more of delivered treatments and if there were no treatment breaks of 7 days or longer. All patients treated on RTOG 83-11 study were centrally reviewed and were excluded, if their total dose was beyond 62.4 –76.56 Gy range. The intervals (in hours) between fractions were taken from the treatment records, as per recorded treatment times. The individual daily interfraction interval (IFI) values were available for 207 patients and not available for the remainder (n 5 475). Therefore, we used the actual interfraction interval (aIFI), defined as a mean of all daily IFIs. CT included cisplatin and either oral etoposide or vinblastine, and was delivered concurrently with thoracic irradiation. Radiation treatment volumes included the primary
tumor and mediastinum, with all lymph nodes measuring at least 2.5 cm on thoracic computerized tomography studies receiving the full prescribed dose. The detailed reports from those RTOG studies have been reported previously (1, 3– 6). The effect of aIFI on outcome was examined by separating interfraction interval into 1-h increments. Survival was estimated using the Kaplan-Meier method (8). Survival distributions were compared using the log-rank statistic (9). Multiple prognostic factors (including interval hours) were examined for their influence on survival using the Cox proportional hazards model (10). Esophagitis was scored using the RTOG Toxicity Criteria and was defined as the worst grade observed either during treatment or in followup. Differences between interval hours and esophagitis severity were examined using the linear-by-linear test (11). The influence of multiple prognostic factors on Grade 3 or higher esophagitis was examined using logistic regression. RESULTS A total of 1251 pts were enrolled on RTOG studies for NSCLC using HFX-RT (884 pts on 83-11; 163 on 88-08; 42 on 90-15; 79 on 91-06 and 83 on 92-04) (Table 1). IFI was not specified in the records of 124 patients (18 in 83-11; 56 in 88-08; 16 in 90-15; 12 in 91-06 and 32 in 92-04 studies). A total of 682 pts were found to be fully analyzable according to the criteria specified in the Methods section (475 pts on 83-11; 85 on 88-08; 21 on 90-15; 50 on 91-06 and 51 on 92-04) (Table 1). A total of 560 analyzable pts received HFX-RT and 122 pts received CT and HFX-RT. The pretreatment characteristics of analyzable patients were as follows: Stage I, 40 (6%); Stage II, 33 (5%); Stage IIIA, 340 (50%); Stage IIIB, 267 (39%), and unknown, 2 (0.02%). Weight loss of more than 5% was noted in 183 (27%). Females constituted 27% of all pts and 64% of pts were at least 60 years old. The majority of pts (87%) had Karnofsky Performance Status (KPS) of 80% or more. Squamous cell carcinoma was the most common histology (51%), followed by adenocarcinoma (26%) and large cell carcinoma (14%), with 9% of other/unknown histologies. Actual IFI (a IFI) was as follows: 4.0 – 4.9 h in 350 (51%) pts; 5.0 –5.9 h in 119 (17%) pts; 6.0 – 6.9 h in 188 (28%) pts and 7.0 – 8.0 h in 25 (4%) pts. Within each category of IFI,
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Table 2. Median survival time (MST) of patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy. Effect of actual interfraction interval (aIFI) (hours). IFI (h)
4.0–4.9
5–5.9 6–6.9 7–8 p Value
MST (y) All patients (n 5 682) 0.88 0.82 HFX-RT only (n 5 560) 0.88 0.91 CT–HFX-RT (n 5 122) no patients 0.48 Number of patients 350
1.16 1.64
0.02
0.91 1.10
0.58
1.36 1.77 119 188
0.58 25
the following means (standard errors) were calculated: 4.15 (0.24) for 4 –5 hours; 5.24 (0.31) for 5– 6 hours; 6.27 (0.29) for 6 –7 hours and 7.24 (0.28) for 7– 8 hours. Seven percent of all patients (n 5 48) were alive at the time of analysis. Table 2 summarizes the MST (years), depending on the aIFI. In univariate analysis, the MST were as follows: for aIFI of 4.0 – 4.9 h, 0.88 years (n 5 350); for aIFI of 5.0 –5.9 h, 0.82 year (n 5 119); for aIFI of 6.0 – 6.9, 1.16 years (n 5 188); and for aIFI of 7.0 – 8.0 h, 1.64 year (n 5 25) (p 5 0.02, when MST for 4 – 6 h is compared with MST for 6 – 8 h) (see also Fig. 1). For pts treated with HFX-RT alone, the MST were as follows: for aIFI of 4.0 – 4.9 h, 0.88 year (n 5 350); for aIFI of 5.0 –5.9 h, 0.91 year (n 5 114); for aIFI of 6.0 – 6.9, 0.91 year (n 5 89), and for aIFI of 7.0 – 8.0 h, 1.10 years (n 5 7) (p 5 0.99) (Fig. 2). For pts treated with CT-HFX-RT alone, the MST were as follows: for aIFI of 4.0 – 4.9 h, no pts were identified; for aIFI of 5.0 –5.9 h, 0.48 years (n 5 5); for aIFI of 6.0 – 6.9, 1.36 years (n 5 99), and for aIFI of 7.0 – 8.0 h, 1.77 years (n 5 18) (p 5 0.58) (Fig. 3). The effect of several pretreatment variables on the overall survival was tested using a multivariate analysis. As illustrated in Table 3, loss of #5% of body weight, good KPS ($70), low
Fig. 1. Survival of all patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy.
Fig. 2. Survival of patients with locally advanced/inoperable nonsmall cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) alone.
nodal stage (N0 vs. N1) and addition of CT to RT, were associated with an improved survival in all patients (p values: ,0.0001; 0.0001; 0.02; and 0.0001 for all pts and ,0.0001; 0.0002; 0.025 and not applicable, for HFX-RT pts, respectively). However, the length of aIFI (4–6 h vs. 6–8 h) did not influence the survival significantly (p 5 0.55 for all pts and 0.44 for HFX-RT pts). When IFI was analyzed as a continuous variable rather than divided into 1 h intervals, the IFI length had still no effect on survival (for all patients, p 5 0.67 or IFI analyzed as a continuous variable vs. p 5 0.73 for IFI analyzed as 1-h intervals). In the subgroup of pts treated with CT-HFX-RT not enough data points were available for a meaningful analysis. Esophagitis (Grades 1–5) occurred in the majority of patients and its incidence increased with the increasing aIFI. Among patients treated with aIFI of 4.0 – 4.9 h, 75% (26/ 350) experienced any esophagitis; 5.0 –5.9 h, 79% (94/195);
Fig. 3. Survival of patients with locally advanced/inoperable nonsmall cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) and chemotherapy.
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Table 3. Correlation of pretreatment variables and length of actual interfraction interval (aIFI) with median survival time (MST) of patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy (p values) (multivariate analysis) Variable
All patients
HFX-RT patients
CT–HFX-RT patients
Weights loss # 5% vs. . 5% ,0.0001 ,0.0001 KPS $ 70% 0.006 0.0002 Low nodal stage Analysis not (N0 vs. N1) 0.008 0.025 possible Chemotherapy ,0.0001 not applicable Length of IFI (4–6 h vs. 6–8 h) 0.73 0.44
6.0 – 6.9 h, 84% (157/188), and 7.0 – 8.0 h, 92% (23/25); p , 0.0001). However, because the “RT only” trials (RTOG 83-11 and 88-08) recommended a shorter IFI (4 – 6 h) than the “RT and chemotherapy” trials (90-15, 91-06, and 92-04) (at least 6 h), the use of chemotherapy might have affected the increasing incidence of esophagitis among patients treated with longer IFIs. Therefore, a logistic regression analysis was performed, in which out of four pretreatment variables examined (chemotherapy vs. no chemotherapy; KPS of #70 vs. 80 –100; nodal status, N0 vs. N1, and aIFI), only chemotherapy was associated with a significant (nearly 12-fold) increase in Grade 3 or higher esophagitis (Table 4). In patients treated with HFX-RT alone, Grade 3 or higher esophagitis occurred in 7% (38/560) patients, and in patients treated with chemotherapy and HFX-RT, in 41% (50/122) patients. DISCUSSION HFX-RT is a common type of altered fractionation used in radiation therapy. It entails the use of a smaller than “standard” fraction size of radiation (typically 0.9 –1.3 Gy) given more than once daily (usually 2–3 times), which allows the delivery of an increased total dose over the unchanged treatment duration. Because there seems to be a preferential sparing of late-reacting tissues with smaller Table 4. Correlation of pretreatment variables with Grade 3 or higher esophagitis in patients with locally advanced/inoperable non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT) with or without chemotherapy
Chemotherapy vs. no chemotherapy KPS (#70 vs. 80–100) Weight loss N0 stage vs. N1 Interfraction interval NS 5 not significant.
Odds ratio
p Value
11.7 1.8 NS NS NS
,0.0001 0.053 0.32 0.103 0.82
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fraction sizes (12), HFX-RT may allow dose escalation of RT without increased incidence of late tissue toxicity. However, establishing the optimal interval between fractions of HFX-RT is of crucial importance, to allow enough time for repair of irradiated late-reacting tissues (13). If fractions are spaced too closely, an unexpected increase in late tissue toxicity can happen, as described by Nguyen et al. (14) in head and neck cancer patients, receiving multiple daily small fractions (0.9 Gy every 2 h) and by Cox et al. (15) in squamous cell carcinomas of the head and neck, treated with 1.2 Gy every 4 to 8 hours to the escalating RT doses between 67.2 Gy and 81.6 Gy. Similarly, the initial experience with CHART (Continuous Hyperfractionated Accelerated Radiotherapy), where 3 daily fractions of 1.5 Gy were administered every 6 h on 12 consecutive days, resulted in 4 out of 263 pts experiencing radiation myelopathy with maximal cord doses between 45– 48.3 Gy (16). Once the minimal necessary IFI is established from the point of view of safety, the question arises, whether the elongation of IFI has any adverse effect on tumor control, and, indirectly, on patients’ survival. The IFI used in those RTOG studies reflected the radiobiologic principles of maximal tumor kill by allowing reoxygenation of tumor cells, as well as repair of sensitive normal tissues, particularly the late-reacting tissues, such as spinal cord (12,17). In a previously quoted RTOG experience (15), there was no evidence for an effect of IFI length (4.5 h or less vs. more than 4.5 h) on either loco-regional tumor control or survival rates of 447 patients with squamous cell carcinomas of the head and neck. In addition, the shorter IFI of 4.5 h or less was associated with higher frequencies of Grade 4 or higher late effects. However, in the study by Jeremic and Shibamoto (7), the shorter IFI was an independent favorable prognostic factor for survival and disease-free survival in multivariate analysis, along with female gender, younger age, good performance status, and early stage. In that study, the investigators analyzed 169 patients with NSCLC treated previously in a randomized trial, which compared HF-RT alone with chemotherapy and HF-RT (18). Interfraction intervals (4.5–5 h or 5.5– 6 h) were nonrandomly assigned to each patient and these intervals were kept constant throughout the entire treatment course. The advantage in survival due to the shorter interfraction interval was seen in both chemotherapy-radiation and radiation alone groups. This advantage was also confirmed in multivariate analysis, performed in order to account for the imbalance of prognostic factors between the treatment groups. Our analysis used a mean IFI and the standard deviations for all daily IFIs were not known. However, these deviations were presumed to be small, because the required IFIs were well defined in each protocol. Two other reports in the literature (19,20) suggested a survival benefit for a shorter IFI (4.0 – 4.4 or 4.5–5.0 h vs. 4.5– 8.0 or 5.5– 6 h) in patients with malignant gliomas receiving HF-RT, with conclusions supported in both by multivariate analysis. In our analysis, the length of aIFI (4 – 6 h vs. 6 – 8 h) did
HFRT in children with BST
not influence survival of pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy with/or without CT. Only the previously identified factors, such as use of CT, minimal weight loss, good KPS and low nodal stage, were confirmed again to be associated with a favorable prognosis in a multivariate analysis. The vast majority of our analyzable patients (n 5 682) were treated with HFX-RT alone, in contrast to Jeremic et al.’s patients (n 5 169) (7), one-half of whom received a combined modality treatment. In our subgroup of pts treated with CT–HFX-RT not enough data points were available for a meaningful multivariate analysis. In summary, the analysis of our data base of 682 patients with NSCLC, treated to a uniform dose of HF-RT of 69.6 Gy, mostly without chemotherapy, does not support the concept of a shorter IFI benefiting the overall survival. All patients were analyzed based on individual actually recorded daily treatment intervals
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rather than the recommended intervals. The effect of the IFI length on local tumor control could not be assessed, because local control data were not gathered in those studies, designed to have survival rates as a primary endpoints rather than local control. It is likely that the reason for the controversy existing in the literature with regard to the importance of the IFI affecting survival of patients treated with HF-RT lies in the inherent bias of the retrospective analyses. The review of available data does not allow the identification of the IFI associated with the best tumor control, and potentially, best survival. A prospective randomized trial of various IFIs would be necessary to identify the best IFI. However, it appears that an IFI of 4 – 8 h is acceptable in clinical practice for pts with NSCLC, treated with HFX-RT, especially because there was no evidence of increased incidence of severe esophagitis associated with the particular IFI length.
REFERENCES 1. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: Possible survival benefit with .69.6 Gy in favorable patients with stage III non-small cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990;8:1543–1555. 2. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 1987;59:1874 –1881. 3. Sause W, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995;87:198 –205. 4. Byhardt RW, Scott CB, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Results of Radiation Therapy Oncology Group 90-15. Cancer 1995;75(9):2337–2344. 5. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: Radiation Therapy Oncology Group Protocol 91-06. J Clin Oncol 1996;14:1055– 1064. 6. Komaki R, Scott C, Ettinger D, et al. Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04. Int J Radiat Oncol Biol Phys 1997; 38(1):149 –155. 7. Jeremic B, Shibamoto Y. Effect of Interfraction Interval in Hyperfractionated Radiotherapy with or without Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 1996;34:303–308. 8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 9. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719 –748.
10. Cox DR. Regression models and life-tables. J R Stat Soc B 1972;4:187–202. 11. Mehta C, Patel N. StatXact 3 for Windows: User Manual. CYTEL Software: Cambridge, 1996. 12. Fowler JF. Intervals between multiple fractions per day–Differences between early and late reactions. Acta Oncol 1988; 27:181–183. 13. Thames HD, Peters LJ, Ang KK. Time-dose considerations for normal-tissue tolerance. Front Radiat Ther Oncol 1989;23: 113–117. 14. Nguyen TD, Demange L, Froissart D, et al. Rapid hyperfractionated radiotherapy. Clinical results in 178 advanced squamous cell carcinomas of the head and neck. Cancer 1985;56:16 –19. 15. Cox JD, Pajak TF, Marcial VA, et al. ASTRO plenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from Radiation Therapy Oncology Group Protocol 8313. Int J Radiat Oncol Biol Phys 1991;6:1191–1195. 16. Saunders MI, Dische S, Grosch E, et al. Experience with CHART. Int J Radiat Oncol Biol Phys 1991;21:871– 878. 17. Hermens AF, Barendsen GW. Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after X-irradiation. Eur J Cancer 1969;5:173–189. 18. Jeremic B, Shibamoto Y, Acimovic L, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for Stage III nonsmall-cell lung cancer. J Clin Oncol 1995;13:452– 458. 19. Jeremic B, Grujicic D, Antunovic V, et al. Hyperfractionated radiation therapy followed by multiagent chemotherapy in patients with malignant glioma: A Phase II study. Int J Radiat Oncol Biol Phys 1994;30:1179 –1185. 20. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma-possible advantage observed at 72.0 Gy in 1.2 Gy BID fractions: Report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys 1993;25:193–207.