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Clinical perspectives of recent developments in fractionation
Clinical Perspectives of Recent Developments in Fractionation James D. Cox
he care of patients with cancer has been closely intertwined with fractionation of radiation therapy since the early realizations that ionizing radiations had biologic effects. The first uses of x-rays and radium for malignant tumors, around the turn of the century, assumed that a single application was the best way to achieve results. There was no reason to think that repeated applications would be more advantageous, especially when the eschars that were produced were observed to heal poorly or not at all] '2 The early history of the development of fractionation schedules is discussed further in the review by H.D. Thames in this issue. Pivotal observations were made by several French investigators, led by Regaud3'~: strikingly different effects were seen when single applications were compared with multiple applications of x-rays and radium to the testes of animals. A single administration produced moist desquamation of the scrotal skin without stopping spermatogenesis, whereas splitting the dose into even a few fractions greatly diminished the scrotal effects while killing the spermatogonia. The interpretation at the time was the spermatogonia resembled the rapidly proliferating cancer cells, whereas scrotal skin was a normal epithelium. Although we now know that spermatogonia have an unusually great sensitivity to fractionated irradiation because of their absence of a shoulder (repair) in their survival curve, this conclusion led in the right direction. The skin was the dose-limiting normal tissue in patients at the time, so the use of fractionated irradiation was quickly adopted by French clinicians. Within a few years, inoperable carcinomas of the larynx and tonsillar fossa were cured with the "protracted, fractionated method" that came to he associated with Coutard. 5 Parenthetically, carcinomas of
T
From the Department of Clinical Radiotherapy, The University of Texas M. D. Anderson CancerCenter, Houston, TX. Address reprint requeststo,JamesD. Cox,MD, VicePresidentfor Patient Care and Physician-in-Chief University of Texas M. D. Anderson Cancer Center, 1515 HolcombeBlvd, Houston, TX 77030. Copyright 9 1992 by W.B. Saunders Company 1053-4296/92/0201-0003505.00/0
10
the upper respiratory tract were the very first malignant tumors deep to the skin surface that were cured with external irradiation; they have served as the most important testing ground in clinical research with radiation therapy to this day. Conceptually, there are unlimited variations in fractionation. The limitations come only from the practical realities of treating patients. The early clinician-scientists tried a far wider range of fractionation schemes than is often appreciated, including multiple fractions per day, multiple split-courses with different fraction sizes within each course, and even "maintenance radiation therapy" with 1 R per day. Most solutions to the practicalities of patient care led to small numbers of fractions: this served as the basis for several attempts to establish isoeffect relationships for use in clinical practice. Strandqvist curves,6 the Nominal Standard Dose (NSD) of Ellis, 7 the Time-Dose Factors (TDFs) of Orton and Ellis and its derivative CRE (Cumulative Radiation effect), a and more recently, the alpha/beta ratios have served as useful paradigms. ~) There is a danger, reflected in the fact that there have been a series of such mathematical models, each correcting some failing of a previous model, in believing the numerical values so derived and applying them rigidly in clinical practice.
Dose-Tumor Control Relationships Certain assumptions are made about the relationships between total dose to the tumor-bearing volume and tumor control. The first is that larger tumors require higher total doses than smaller tumors. It is notable that clinical data addressing this issue only began to be available 20 years ago. Until then, the only clinical model widely used was carcinoma of the skin, which could have a greater or lesser diameter, but rarely was large in three dimensions. Shukovsky~~published a brief but important paper demonstrating a higher tumor control rate for T2 carcinomas of the supraglottic larynx with a total dose of 65 Gy than with T3 lesions: his analysis suggested quite a sensitive dependence of tumor
Seminars in Radiation Oncology, Vol 2, No 1 (Janua)y), 1992:pp 10-15
Recent Developnventsin Fr~tionation: Clinical Perspectives
control on total dose for carcinomas of the upper respiratory tract. Although there is now a considerable literature largely corroborating this relationship for epithelial malignant tumors, much less attention has been paid to other tumors, especially more radiosensitive tumors, such as Hodgkin's disease, seminoma, Wilms' tumor. Second, there is an assumption that the highest total dose tolerated by normal tissues is the most appropriate. However, this assumption is not consistent among clinicians. Certainly, it is not applied to the radiosensitive tumors noted previously. It has been tested with carcinomas of the upper aerodigestire tract, but few other tumors. It may be quite difficult to determine, clinically, whether death of patients with certain diseases, for example, carcinoma of the lung or malignant glioma, was due entirely or in part to adverse effects of the therapy instead of, or in addition to, progression of the tumor. Third, none of the models has satisfactorily accounted for the volume of tissues irradiated. For example, the Manchester approach, H using 16 large fractions 5 days per week in only 3 weeks overall time, was predicated upon irradiation of very limited tissue around the tumor, a result of early appreciation that rapid fractionation was not tolerated when large volumes were used. The contrasting approach, formalized by Fletcher, ~2 uses prolonged courses of treatment beginning with large fields to encompass suspected subclinical disease, with one or more field reductions as the total dose climbs. In too many reports that have suggested advantages with a particular fractionation regimen, there was little mention of the volume irradiated and whether a reduction in the volume was made during the course of treatment. Assumptions about repair, reoxygenation, and proliferation largely derive from laboratory rather than clinical studies. It is assumed that repair of sublethal damage, within tumors and normal tissues, is sufficiently rapid to be of little consequence with daily administration of radiation therapy alone. However, when sensitizing and cytotoxic drugs or hormones are added to irradiation, alterations of sublethal or potentially lethal damage may occur. Reoxygenation is a well-recognized advantage of fractionated radiation therapy, although it is assumed to be sufficiently incomplete to justify major clinical trials in several countries with hyperbaric oxygen and/or electron affinic drugs.
11
Repopulation in Normal and Neoplastic Tissues The phenomenon of repopulation after irradiation has long been recognized clinically as well as in cellular radiation biology. It can be observed directly in the reappearance of mucosa or epidermis after denudation of the submucosa or dermis, sometimes before completion of irradiations. Since normal tissues, at least stratified squamous cells, seem to recover from the acute reactions to radiation therapy more rapidly than tumors, it is often assumed that the proliferative potential is greater for normal cells. This has been thought to be a result of homeostatic controls existing for normal cells, but not for tumors. 7 The long intervals between fractions with hypofractionation and split-course radiation therapy have been rationalized on this basis. However, several findings suggest that proliferation of viable tumor cells during a course of radiation therapy" may be more important clinically than previously appreciated. The decreased tumor control with hypofractionation, discussed below, is one. Another is the higher recurrence rate with an interruption of 2 weeks or more, ie, a split-course, with standard fractionationf ~'HThird is the analysis of clinical trials by Withers et al ~5which indicated that courses of radiation therapy that took longer than 4 weeks required progressively higher doses to achieve the same degree of t u m o r control. Fourth, Pajak et a116 found that interruptions of standard fractionation resulting in delays of 14 days or more for completion of irradiation for carcinomas of the upper aerodigestive tract in Radiation Therapy Oncology Group (RTOG) trials, were associated with decreased local control and survival. A subsequent study of interruptions in the RTOG hyperfractionation trial for advanced carcinomas of the upper aerodigestive tract (Protocol 83-13) confirmed these findings ofPajak et al and suggested that even lesser delays, 5 days or more beyond the elapsed time permitted by the protocol, were clinically disadvantageous. ~7 Additional support for the importance of tumor repopulation during treatment was presented by O'Sullivan et al. 1~
The ramifications of proliferation of tumor clonogens during treatment are considerable and extend beyond the field of radiation oncology. If, as suggested by Withers et al, L~there is a set time at which proliferation accelerates following the first insult, then induction chemotherapy before either radiation
12
JamesD. Cox
therapy or surgical resection could be disadvantageous.
Large-Dose Fractionation The use of large individual fractions, usually given less frequently than daily, arose out of the same considerations as omitting treatments on Saturdays and Sundays. The standard work week in many countries, combined with limitations of equipment and personnel, resulted in pressures from hospital administrations and health care workers to complete all treatments in an 8-hour work day, 5 days per week. A rationalization was provided by isoeffect formulae that seemed to permit treatments one, two, or three times per week without sacrifice in either tumor control or normal tissue effects. The formulae were derived from laboratory experiments and observations of acute effects in the skin of patients; late effects were then thought to parallel acute reactions. Tumors were considered to have limited proliferative ability in the relatively short overall time, even with intervals as long as a week between consecutive fractions. This was the era of NSD and TDF. Few clinical trials were launched to test the hypotheses put forth in the isoeffect formulae. However, when the results of retrospective studies of large-dose fractionation were combined with data from clinical trials, large-dose fractionation seemed a failure, both in regard to late effects and tumor control. .9The NSD, TDF, and CRE formulae had not predicted the magnitude of late effects, which evolved over several years rather than the few months assumed, and there was a more striking dissociation between acute and late effects than had been anticipated. Further, higher recurrence rates with hypofractionation suggested sufficient proliferation of tumor cells between fractions to overcome the cell killing from the large-sized fractions. Finally, the best that anyone expected was equivalency between large dose and more standard fractionation: no trial suggested improvements in outcome with large dose fractionation, and several suggested deleterious effects, either in tumor control, late effects, or both. How large does the individual fraction have to be to produc e a clinically significant adverse outcome? Ten gray in a single fraction, repeated twice at monthly intervals for palliative treatment of advanced pelvic malignant tumors, resulted in a very high complication rate2~ the risk was greatly reduced
when four fractions of 3.7 Gy were given twice daily on 2 consecutive days. 21 The frequency of radiation myelopathy was markedly higher with fraction sizes of 3 to 6 Gy compared with smaller fractions. ~-~4A comparison of 3.3 Gy with 2.5 Gy per fraction in the treatment of Hodgkin's disease showed a higher rate of complications with larger fractions. 25Horiot et a126 reported a greater risk of morbidity with irradiation for carcinoma of the glottis using 2.75 Gy per fraction compared with 2.2 Gy. Recently, data were presented from the Patterns of Care Study 27 in the United States which showed that fractions of 1.8 Gy to 2.0 Gy were associated with a lower morbidity rate than larger fractions in treatment of carcinoma of the cervix. So, the risk of late effects is probably a continuous function that becomes clinically demonstrable around 2 Gy.
Multiple Fractions per Day The use of two or more fractions per day, separated by several hours, has been attempted since the time of Coutard. To date, there has not been sufficient evidence of benefit to accept such treatment as standard. There are data that suggest superiority of hyperfractionation (HFX) 2~and accelerated fractionation (AFX) ~9'3~over standard, but the only direct comparison in a randomized clinical trial that has been published to date has shown benefit only in a subset of patients treated by HXF. 3~ In the context of accelerated proliferation, HFX and AFX have different rationales. HFX permits a higher total dose due to greater tolerance of normal tissues with small sized fractions, and thus could counteract the effects of tumor proliferation. AFX permits the same total dose used with standard fractionation to be achieved in a shorter period and thus could avoid much of the proliferation. There are four altered fractionation schemes of particular interest at the present time. A HFX regimen has been pursued in total dose-seeking trials of the RTOG, 32viz. 1.2 Gy twice daily separated by 5 hours or more. 33 An AFX-HFX regimen has been championed by Wang, ~9viz. 1.6 Gy twice daily with a planned interruption after 38.4 Gy; the twice daily treatments enable the overall time to be kept as short as 6 weeks. AFX via concomitant boost has undergone several iterations at the M. D. Anderson Cancer Center3~: the latest version uses 1.8 Gy to a large field over a 6-week period to achieve a total dose of 54 Gy, with a small field added during the last
13
Recent Developmentsin Fractionatio~" Clinical Perspectives
2 weeks giving an additional 1.5 Gy. This too is completed in 6 weeks. The most accelerated of the AFX regimens is that developed at the Mt. Vernon Hospital in the United Kingdom in which three fractions of 1.5 Gy, separated by 6 hours, are given each day for 12 consecutive days: a total dose of 54 Gy is achieved before the expected pseudomembranous inflammation begins. 3~ The R T O G has completed a limited comparison of the M. D. Anderson and Wang AFX regimens (Protocol 88-09) to determine their tolerance in multiple institutions. An ambitious Phase Ill fractionation trial (Protocol 90-03) with four arms has been planned for the R T O G and should be completed within 3 years. This trial includes advanced carcinomas of the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. The standard fractionation arm uses a shrinking field approach, and requires a total dose of 70 Gy (2 Gy x 35F in 46 days minimum) in 35 fractions to all known tumor. The H F X arm requires 81.6 Gy in 68 fractions with 1.2 Gy given twice daily over a period of 7 weeks (45 days minimum). The M. D. Anderson AFX by concomitant boost (1.8 Gy x 30F with 1.5 Gy x 12F = 72 Gy in 39 days minimum) and the Wang AFX (b.i.d. 1.6 Gy x 42F with planned gap = 67.2 Gy in 39 days minimum) regimens are the two remaining arms. A minimum of 6 hours is required between any two fractions in order to avoid the late effects found with average intervals of 4.5 hours and less 3~ (Table 1).
Intervals: Planned and Unplanned The inconvenience of the treatments, for patient and attending physician, and the intolerance of the acute reactions, again both by the patient and physician, contribute to unplanned variability in the maximum intervals between fractions and in the overall duration of treatment. Table 2 shows the interfraction
Table 1. RTOG Protocol 90-03 Fractionation Trial in Head and Neck Cancer I. Control arm: 2 Gy x 35F = 70 Gy in 7 weeks (46 days) 2. Hyperfractionation: b.i.d. 1.2 Gy x 68F = 81.6 Gy in 45 days 3. C.C. Wang's schedule: b.i.d. 1.6 Gy x 42F with a planned gap = 67.2 Gy in 6 weeks (39 days) 4. Concomitant boost: 1.8 Gy x 30Fwith 1.5 Gy x 12F as a second session on the same day (6-hour interval) during the last part of the schedule = 72 Gy in 6 weeks
Table 2. Potential Intervals Between Consecutive Fractions (Fx) Hours*
Multiple Fx per day Daily Fx 3 Fx per week 2 Fx per week Weekend Holiday weekend 1 Fx per week Split course (2 weeks)
4-It 13-35 37-59 61-83 61-83 75-107 157-179 349-419
*Assumesmaximum workdayis 7:00A.'~tto 6:00 Pxl. intervals commonly permitted during courses of radiation therapy'. Regardless of the assumptions made about the proliferation potentials for heterogeneous populations of cells within the tumor, for at least some patients undergoing curative radiation therapy, it is almost certain that significant proliferation occurs. The planned interruptions, even weekends, can be tested, and several investigators are pursuing such studies at present. The unplanned gaps can only be assessed by evaluating the results when the planned total dose has been achieved, but the overall elapsed time of treatment has differed. This question has been addressed in several retrospective studies. 13-[8,29,35 Several studies of the effect of overall elapsed time have recently been reported. The data on the importance of prolonged overall treatment times for carcinoma of the upper aerodigestive tract are convincing. The two R T O G studies noted previously, combined with the report from the Princess Margaret Hospital of Toronto, strongly suggest that tumor control and survival rates are decreased when the overall treatment time is prolonged. Data for cancer of the prostate are conflicting. Amdur et al, '~5 from the University of Florida, reported an adverse effect on outcome with prolongations of treatment whereas Lai et a136found no demonstrable effects on local control with differing times to complete treatment from R T O G studies. However, there is a suggestion that more aggressive carcinomas of the prostate may be affected differentially by overall time: Pistenma et al :~7 reported very disappointing results for patients with metastasis to regional lymph nodes when external irradiation to the nodes included interruptions of 2 weeks. By contrast, Lawton et al ~Rreported a 10-year disease-free survival rate of 45% with external irradiation for Stage DI carcinoma of the prostate using external irradiation without such interruptions.
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James D. Cox
Summary D e s p i t e limitless v a r i a t i o n s o f f r a c t i o n a t i o n , t h e r e h a v e b e e n few p r o s p e c t i v e trials b a s e d o n clinically based hypotheses. Practical constraints of patient a n d physician a c c e p t a n c e o f p a r t i c u l a r d o s e / t i m e r e g i m e n s , a n d u n d e r r e p o r t e d differences in t h e t r e a t m e n t v o l u m e s , h a v e p r o b a b l y b l u r r e d s o m e results. Mathematical models that appropriately emphasize differences in risk factors for a c u t e a n d late effects o f radiation therapy, and greater appreciation of the importance of proliferation during the course of r a d i a t i o n t h e r a p y , have led to i n t e r e s t i n g proposals, especially for studies o f h y p e r f r a c t i o n a t i o n a n d accele r a t e d f r a c t i o n a t i o n . T h e r e is n o s u b s t i t u t e for large, prospective clinical trials to test t h e s e h y p o t h e s e s , w i t h strict q u a l i t y - a s s u r a n c e guidelines.
References 1. De1 RegatoJA: Historical changes in time-dose relationship in therapeutic radiology. Front Radiat Ther Oncol 3:1-5, 1968 2. Buschke F: Radiation therapy: The past, the present, the future.Janeway Lecture, 1969.AmJ Roentgenol 108:236-246, 1970 3. Regaud C, Nogier T: Sterilization roentgenienne totale et definitives, sans radiodermite, des testicules du Belier adulte: conditions de sa realisation. Compt Rend Soc Biol 70:202-203, 1911 4. Regaud C: Influence de la duree d'irradiation sur les effects determines dans le testicule par le radium. Compt Rend Soc Bio186:787-790, 1922 5. Coutard H: Roentgentherapy of epitheliomas of the tonsillar region, hy~popharynx and larynx, from 1920 to 1926. Am J Roentgeno128:313-331, 1932 6. Strandqvist M: Studien uber die kumulative Wirkun der rontgenstrahlen bei Fraktionierung. Acta RadioJ 55:1-300, 1944 (suppl) 7. Ellis F: Relationship of biological effect to dose-timefractionation factors in radiotherapy', in Ebert M, Howard M (eds): Current Topics in Radiation Research. Amsterdam, North Holland Publishing, 1968, pp 357-397 8. Orton CG, Ellis F: A simplification in the use of the NSD concept in practical radiotherapy. BrJ Radio146:529-537, 1973 9. FowlerJF: Review: The linear-quadratic formula and progress in fractionated radiotherapy. BrJ Radio162:679-694, 1989 10. Shukovsky LF: Dose, time, volume relationships in squamous cell carcinoma of the supraglottic larynx. Am J Roentgenol 113:27-29, 1970 11. Paterson R: Treatment of malignant disease by radium and x-ray: Being a practice of radiotherapy. Baltimore, MD, Williams & Wilkins, 1949 12. Fletcher GH: Textbook of radiotherapy, 3rd ed. Philadelphia, PA, Lea & Febiger, 1980 13. Parsons JT, Bova FJ, Million RR: A re-evaluation of splitcourse technique for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 6:1645-1652, 1980 14. OvergaardJ, Hjelm-Hansen M, Johansen LV, Andersen A.P: Comparison of conventional and split-course radiotherapy as
primary treatment in carcinoma of the larynx. Acta Oncol 27:147-152, 1988 15. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 1988 16. Pajak TF, Laramore GE, Marcial VA, et al: Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG Report. IntJ Radiat Oncol Biol Phys 20:13-20, 199I 17. CoxJD, Pajak TF, Marcial VA, et al: Interruptions adversely affect local control and survival with hyperfractionated radiation therapy of carcinomas of the respiratory/digestive tracts: New evidence for accelerated proliferation from RTOG Protocol 8313. Proceedings of American Radium Society, pp 1-2, 199l (abstr) 18. O'Sullivan B, Maki E, Keane T: The influence of treatment time on local control by external beam radiotherapy in carcinoma of the tonsil. Proceedings of American Radium Society, p 2, 1991 (abstr) 19. CoxJD: Large dose fractionation (hypofractionation). Cancer 55:2105-2111, 1985 (suppl) 20. Spanos WJ, Wasserman T, Meoz R, et al: Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: Final report of RTOG Phase I/II study. IntJ Radiat Oncol Biol Phys 13:1479-1482, 1987 2 I. Spanos WJ, Guse C, Perez CA, et al: Phase II study of muhiple daily fractions in the palliation of advanced pelvic malignancies: Preliminary report of RTOG 8502. Int J Radiat Oncol Biol Phys 17:659-661, 1989 22. Dische S, Martin WMC, Anderson P: Radiation myelopathy in patients treated for carcinoma of bronchus using a six-fraction regime of radiotherapy. BrJ Radio154:29-35, 1981 23. Hatlevoll R, Host H, Haalhus O, et al: Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: A retrospective study. Int J Radiat Oncol Biol Phys 9:41-44, 1983 24. Perez CA, Azarnia N, CoxJD, Shapiro S: Sequelae of definitive irradiation in the treatment of carcinoma of the lung, in G Motta (ed): Lung Cancer, Advanced Concepts and Present Status, Genoa, Grafica LP, 1989, pp 237-256 25. Cosset.JM, Henry-Amar M, Girinski T, et al: Late toxicity of radiotherapy in HD: Role of fraction size. Acta Oncol 27:123129, 1988 26. Horiot J-C, Fletcher GH, Ballantyne AJ, et al: Analysis of failures of early vocal cord cancers. Radiology 103:663-665, 1972 27. Lanciano R, Martz K, Montana G, et al: Pretreatment and treatment factors associated with complications in squamous cell cancer of the uterine cervix: A final report of the 1973 and 1978 patterns of care studies. Proceedings of American Radium Society, p 17, 1991 (abstr) 28. ParsonsJT, Mendenhall WM, Cassisi NJ, et al: Hyperfraetionation for head and neck cancer. IntJ Radiat Oncol Biol Phys 14:649-658, 1988 29. Wang CC: Twice-daily radiation therapy for head and neck carcinomas. Front Radiat Ther Oncol 22:93-98, 1988 30. Saunders MI, Dische S, Hong A, et al: Continuous hyperfractionated accelerated radiotherapy in locally advanced carcinoma of the head and neck region. 17:1287-1293, 1989 31. Horiot J-C, Le Fur R, N'Guyen T, et al: Hyperfractionationated compared with conventional radiotherapy in oropharyn-
RecentDevelopmentsin Fractionation:ClinicalPerspectives
32.
33.
34.
35.
geal carcinoma: An EORTC Randomized Trial. EurJ Cancer 26:779-780, 1990 Diener-West M, Pajak TF, Bauer M, et al: Randomized dosesearching Phase ILE/II Trials of fractionation in radiation therapy for cancer.J Natl Cancer Inst 83:1065-1071, 1991 CoxJD, Pajak TF, Marcial VA, et al: Interfraction interval is a major determinant of late effects, with h~13erfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from RTOG Protocol 8313. Int J Radiat Oncol Biol Plays 20:1191-1195, 1991 Peters LJ, Ang KK, Thames HD: Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies. Acta Oncol 27:185-194, [988 Amdur RJ, Parsons JT, Fitzgerald LT, et al: The effect of
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overall treatment time on local control in patients with adenocarcinoma of the prostate treated with radiation thera W. IntJ Radiat Oncol Biol Phys 19:1377-1382, 1990 36. Lai PP, Perez CA, Shapiro SJ, et al: Carcinoma of the prostate stage B and C: Lack of influence of duration of radiotherapy on tumor control and treatment morbidity. IntJ Radiat Oncol Biol Phys 19:561-568, 1990 37. Pistenma DA, Bagshaw MA, Freiha FS: Extended-field radiation therapy for prostatic adenocarcinoma: Status report of a limited prospective trial, in Johnson DE, Samuels ML (eds): Cancer of the Genitourinary" Tract. New York, NY, Raven Press, 1979, pp 229-247 38. Lawton CA, Cox JD, Glisch C, et al: ls long-term survival possible with external beam irradiation for stage D 1 adenocarcinoma of the prostate? Cancer 1991 (in press)
he care of patients with cancer has been closely intertwined with fractionation of radiation therapy since the early realizations that ionizing radiations had biologic effects. The first uses of x-rays and radium for malignant tumors, around the turn of the century, assumed that a single application was the best way to achieve results. There was no reason to think that repeated applications would be more advantageous, especially when the eschars that were produced were observed to heal poorly or not at all] '2 The early history of the development of fractionation schedules is discussed further in the review by H.D. Thames in this issue. Pivotal observations were made by several French investigators, led by Regaud3'~: strikingly different effects were seen when single applications were compared with multiple applications of x-rays and radium to the testes of animals. A single administration produced moist desquamation of the scrotal skin without stopping spermatogenesis, whereas splitting the dose into even a few fractions greatly diminished the scrotal effects while killing the spermatogonia. The interpretation at the time was the spermatogonia resembled the rapidly proliferating cancer cells, whereas scrotal skin was a normal epithelium. Although we now know that spermatogonia have an unusually great sensitivity to fractionated irradiation because of their absence of a shoulder (repair) in their survival curve, this conclusion led in the right direction. The skin was the dose-limiting normal tissue in patients at the time, so the use of fractionated irradiation was quickly adopted by French clinicians. Within a few years, inoperable carcinomas of the larynx and tonsillar fossa were cured with the "protracted, fractionated method" that came to he associated with Coutard. 5 Parenthetically, carcinomas of
T
From the Department of Clinical Radiotherapy, The University of Texas M. D. Anderson CancerCenter, Houston, TX. Address reprint requeststo,JamesD. Cox,MD, VicePresidentfor Patient Care and Physician-in-Chief University of Texas M. D. Anderson Cancer Center, 1515 HolcombeBlvd, Houston, TX 77030. Copyright 9 1992 by W.B. Saunders Company 1053-4296/92/0201-0003505.00/0
10
the upper respiratory tract were the very first malignant tumors deep to the skin surface that were cured with external irradiation; they have served as the most important testing ground in clinical research with radiation therapy to this day. Conceptually, there are unlimited variations in fractionation. The limitations come only from the practical realities of treating patients. The early clinician-scientists tried a far wider range of fractionation schemes than is often appreciated, including multiple fractions per day, multiple split-courses with different fraction sizes within each course, and even "maintenance radiation therapy" with 1 R per day. Most solutions to the practicalities of patient care led to small numbers of fractions: this served as the basis for several attempts to establish isoeffect relationships for use in clinical practice. Strandqvist curves,6 the Nominal Standard Dose (NSD) of Ellis, 7 the Time-Dose Factors (TDFs) of Orton and Ellis and its derivative CRE (Cumulative Radiation effect), a and more recently, the alpha/beta ratios have served as useful paradigms. ~) There is a danger, reflected in the fact that there have been a series of such mathematical models, each correcting some failing of a previous model, in believing the numerical values so derived and applying them rigidly in clinical practice.
Dose-Tumor Control Relationships Certain assumptions are made about the relationships between total dose to the tumor-bearing volume and tumor control. The first is that larger tumors require higher total doses than smaller tumors. It is notable that clinical data addressing this issue only began to be available 20 years ago. Until then, the only clinical model widely used was carcinoma of the skin, which could have a greater or lesser diameter, but rarely was large in three dimensions. Shukovsky~~published a brief but important paper demonstrating a higher tumor control rate for T2 carcinomas of the supraglottic larynx with a total dose of 65 Gy than with T3 lesions: his analysis suggested quite a sensitive dependence of tumor
Seminars in Radiation Oncology, Vol 2, No 1 (Janua)y), 1992:pp 10-15
Recent Developnventsin Fr~tionation: Clinical Perspectives
control on total dose for carcinomas of the upper respiratory tract. Although there is now a considerable literature largely corroborating this relationship for epithelial malignant tumors, much less attention has been paid to other tumors, especially more radiosensitive tumors, such as Hodgkin's disease, seminoma, Wilms' tumor. Second, there is an assumption that the highest total dose tolerated by normal tissues is the most appropriate. However, this assumption is not consistent among clinicians. Certainly, it is not applied to the radiosensitive tumors noted previously. It has been tested with carcinomas of the upper aerodigestire tract, but few other tumors. It may be quite difficult to determine, clinically, whether death of patients with certain diseases, for example, carcinoma of the lung or malignant glioma, was due entirely or in part to adverse effects of the therapy instead of, or in addition to, progression of the tumor. Third, none of the models has satisfactorily accounted for the volume of tissues irradiated. For example, the Manchester approach, H using 16 large fractions 5 days per week in only 3 weeks overall time, was predicated upon irradiation of very limited tissue around the tumor, a result of early appreciation that rapid fractionation was not tolerated when large volumes were used. The contrasting approach, formalized by Fletcher, ~2 uses prolonged courses of treatment beginning with large fields to encompass suspected subclinical disease, with one or more field reductions as the total dose climbs. In too many reports that have suggested advantages with a particular fractionation regimen, there was little mention of the volume irradiated and whether a reduction in the volume was made during the course of treatment. Assumptions about repair, reoxygenation, and proliferation largely derive from laboratory rather than clinical studies. It is assumed that repair of sublethal damage, within tumors and normal tissues, is sufficiently rapid to be of little consequence with daily administration of radiation therapy alone. However, when sensitizing and cytotoxic drugs or hormones are added to irradiation, alterations of sublethal or potentially lethal damage may occur. Reoxygenation is a well-recognized advantage of fractionated radiation therapy, although it is assumed to be sufficiently incomplete to justify major clinical trials in several countries with hyperbaric oxygen and/or electron affinic drugs.
11
Repopulation in Normal and Neoplastic Tissues The phenomenon of repopulation after irradiation has long been recognized clinically as well as in cellular radiation biology. It can be observed directly in the reappearance of mucosa or epidermis after denudation of the submucosa or dermis, sometimes before completion of irradiations. Since normal tissues, at least stratified squamous cells, seem to recover from the acute reactions to radiation therapy more rapidly than tumors, it is often assumed that the proliferative potential is greater for normal cells. This has been thought to be a result of homeostatic controls existing for normal cells, but not for tumors. 7 The long intervals between fractions with hypofractionation and split-course radiation therapy have been rationalized on this basis. However, several findings suggest that proliferation of viable tumor cells during a course of radiation therapy" may be more important clinically than previously appreciated. The decreased tumor control with hypofractionation, discussed below, is one. Another is the higher recurrence rate with an interruption of 2 weeks or more, ie, a split-course, with standard fractionationf ~'HThird is the analysis of clinical trials by Withers et al ~5which indicated that courses of radiation therapy that took longer than 4 weeks required progressively higher doses to achieve the same degree of t u m o r control. Fourth, Pajak et a116 found that interruptions of standard fractionation resulting in delays of 14 days or more for completion of irradiation for carcinomas of the upper aerodigestive tract in Radiation Therapy Oncology Group (RTOG) trials, were associated with decreased local control and survival. A subsequent study of interruptions in the RTOG hyperfractionation trial for advanced carcinomas of the upper aerodigestive tract (Protocol 83-13) confirmed these findings ofPajak et al and suggested that even lesser delays, 5 days or more beyond the elapsed time permitted by the protocol, were clinically disadvantageous. ~7 Additional support for the importance of tumor repopulation during treatment was presented by O'Sullivan et al. 1~
The ramifications of proliferation of tumor clonogens during treatment are considerable and extend beyond the field of radiation oncology. If, as suggested by Withers et al, L~there is a set time at which proliferation accelerates following the first insult, then induction chemotherapy before either radiation
12
JamesD. Cox
therapy or surgical resection could be disadvantageous.
Large-Dose Fractionation The use of large individual fractions, usually given less frequently than daily, arose out of the same considerations as omitting treatments on Saturdays and Sundays. The standard work week in many countries, combined with limitations of equipment and personnel, resulted in pressures from hospital administrations and health care workers to complete all treatments in an 8-hour work day, 5 days per week. A rationalization was provided by isoeffect formulae that seemed to permit treatments one, two, or three times per week without sacrifice in either tumor control or normal tissue effects. The formulae were derived from laboratory experiments and observations of acute effects in the skin of patients; late effects were then thought to parallel acute reactions. Tumors were considered to have limited proliferative ability in the relatively short overall time, even with intervals as long as a week between consecutive fractions. This was the era of NSD and TDF. Few clinical trials were launched to test the hypotheses put forth in the isoeffect formulae. However, when the results of retrospective studies of large-dose fractionation were combined with data from clinical trials, large-dose fractionation seemed a failure, both in regard to late effects and tumor control. .9The NSD, TDF, and CRE formulae had not predicted the magnitude of late effects, which evolved over several years rather than the few months assumed, and there was a more striking dissociation between acute and late effects than had been anticipated. Further, higher recurrence rates with hypofractionation suggested sufficient proliferation of tumor cells between fractions to overcome the cell killing from the large-sized fractions. Finally, the best that anyone expected was equivalency between large dose and more standard fractionation: no trial suggested improvements in outcome with large dose fractionation, and several suggested deleterious effects, either in tumor control, late effects, or both. How large does the individual fraction have to be to produc e a clinically significant adverse outcome? Ten gray in a single fraction, repeated twice at monthly intervals for palliative treatment of advanced pelvic malignant tumors, resulted in a very high complication rate2~ the risk was greatly reduced
when four fractions of 3.7 Gy were given twice daily on 2 consecutive days. 21 The frequency of radiation myelopathy was markedly higher with fraction sizes of 3 to 6 Gy compared with smaller fractions. ~-~4A comparison of 3.3 Gy with 2.5 Gy per fraction in the treatment of Hodgkin's disease showed a higher rate of complications with larger fractions. 25Horiot et a126 reported a greater risk of morbidity with irradiation for carcinoma of the glottis using 2.75 Gy per fraction compared with 2.2 Gy. Recently, data were presented from the Patterns of Care Study 27 in the United States which showed that fractions of 1.8 Gy to 2.0 Gy were associated with a lower morbidity rate than larger fractions in treatment of carcinoma of the cervix. So, the risk of late effects is probably a continuous function that becomes clinically demonstrable around 2 Gy.
Multiple Fractions per Day The use of two or more fractions per day, separated by several hours, has been attempted since the time of Coutard. To date, there has not been sufficient evidence of benefit to accept such treatment as standard. There are data that suggest superiority of hyperfractionation (HFX) 2~and accelerated fractionation (AFX) ~9'3~over standard, but the only direct comparison in a randomized clinical trial that has been published to date has shown benefit only in a subset of patients treated by HXF. 3~ In the context of accelerated proliferation, HFX and AFX have different rationales. HFX permits a higher total dose due to greater tolerance of normal tissues with small sized fractions, and thus could counteract the effects of tumor proliferation. AFX permits the same total dose used with standard fractionation to be achieved in a shorter period and thus could avoid much of the proliferation. There are four altered fractionation schemes of particular interest at the present time. A HFX regimen has been pursued in total dose-seeking trials of the RTOG, 32viz. 1.2 Gy twice daily separated by 5 hours or more. 33 An AFX-HFX regimen has been championed by Wang, ~9viz. 1.6 Gy twice daily with a planned interruption after 38.4 Gy; the twice daily treatments enable the overall time to be kept as short as 6 weeks. AFX via concomitant boost has undergone several iterations at the M. D. Anderson Cancer Center3~: the latest version uses 1.8 Gy to a large field over a 6-week period to achieve a total dose of 54 Gy, with a small field added during the last
13
Recent Developmentsin Fractionatio~" Clinical Perspectives
2 weeks giving an additional 1.5 Gy. This too is completed in 6 weeks. The most accelerated of the AFX regimens is that developed at the Mt. Vernon Hospital in the United Kingdom in which three fractions of 1.5 Gy, separated by 6 hours, are given each day for 12 consecutive days: a total dose of 54 Gy is achieved before the expected pseudomembranous inflammation begins. 3~ The R T O G has completed a limited comparison of the M. D. Anderson and Wang AFX regimens (Protocol 88-09) to determine their tolerance in multiple institutions. An ambitious Phase Ill fractionation trial (Protocol 90-03) with four arms has been planned for the R T O G and should be completed within 3 years. This trial includes advanced carcinomas of the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. The standard fractionation arm uses a shrinking field approach, and requires a total dose of 70 Gy (2 Gy x 35F in 46 days minimum) in 35 fractions to all known tumor. The H F X arm requires 81.6 Gy in 68 fractions with 1.2 Gy given twice daily over a period of 7 weeks (45 days minimum). The M. D. Anderson AFX by concomitant boost (1.8 Gy x 30F with 1.5 Gy x 12F = 72 Gy in 39 days minimum) and the Wang AFX (b.i.d. 1.6 Gy x 42F with planned gap = 67.2 Gy in 39 days minimum) regimens are the two remaining arms. A minimum of 6 hours is required between any two fractions in order to avoid the late effects found with average intervals of 4.5 hours and less 3~ (Table 1).
Intervals: Planned and Unplanned The inconvenience of the treatments, for patient and attending physician, and the intolerance of the acute reactions, again both by the patient and physician, contribute to unplanned variability in the maximum intervals between fractions and in the overall duration of treatment. Table 2 shows the interfraction
Table 1. RTOG Protocol 90-03 Fractionation Trial in Head and Neck Cancer I. Control arm: 2 Gy x 35F = 70 Gy in 7 weeks (46 days) 2. Hyperfractionation: b.i.d. 1.2 Gy x 68F = 81.6 Gy in 45 days 3. C.C. Wang's schedule: b.i.d. 1.6 Gy x 42F with a planned gap = 67.2 Gy in 6 weeks (39 days) 4. Concomitant boost: 1.8 Gy x 30Fwith 1.5 Gy x 12F as a second session on the same day (6-hour interval) during the last part of the schedule = 72 Gy in 6 weeks
Table 2. Potential Intervals Between Consecutive Fractions (Fx) Hours*
Multiple Fx per day Daily Fx 3 Fx per week 2 Fx per week Weekend Holiday weekend 1 Fx per week Split course (2 weeks)
4-It 13-35 37-59 61-83 61-83 75-107 157-179 349-419
*Assumesmaximum workdayis 7:00A.'~tto 6:00 Pxl. intervals commonly permitted during courses of radiation therapy'. Regardless of the assumptions made about the proliferation potentials for heterogeneous populations of cells within the tumor, for at least some patients undergoing curative radiation therapy, it is almost certain that significant proliferation occurs. The planned interruptions, even weekends, can be tested, and several investigators are pursuing such studies at present. The unplanned gaps can only be assessed by evaluating the results when the planned total dose has been achieved, but the overall elapsed time of treatment has differed. This question has been addressed in several retrospective studies. 13-[8,29,35 Several studies of the effect of overall elapsed time have recently been reported. The data on the importance of prolonged overall treatment times for carcinoma of the upper aerodigestive tract are convincing. The two R T O G studies noted previously, combined with the report from the Princess Margaret Hospital of Toronto, strongly suggest that tumor control and survival rates are decreased when the overall treatment time is prolonged. Data for cancer of the prostate are conflicting. Amdur et al, '~5 from the University of Florida, reported an adverse effect on outcome with prolongations of treatment whereas Lai et a136found no demonstrable effects on local control with differing times to complete treatment from R T O G studies. However, there is a suggestion that more aggressive carcinomas of the prostate may be affected differentially by overall time: Pistenma et al :~7 reported very disappointing results for patients with metastasis to regional lymph nodes when external irradiation to the nodes included interruptions of 2 weeks. By contrast, Lawton et al ~Rreported a 10-year disease-free survival rate of 45% with external irradiation for Stage DI carcinoma of the prostate using external irradiation without such interruptions.
14
James D. Cox
Summary D e s p i t e limitless v a r i a t i o n s o f f r a c t i o n a t i o n , t h e r e h a v e b e e n few p r o s p e c t i v e trials b a s e d o n clinically based hypotheses. Practical constraints of patient a n d physician a c c e p t a n c e o f p a r t i c u l a r d o s e / t i m e r e g i m e n s , a n d u n d e r r e p o r t e d differences in t h e t r e a t m e n t v o l u m e s , h a v e p r o b a b l y b l u r r e d s o m e results. Mathematical models that appropriately emphasize differences in risk factors for a c u t e a n d late effects o f radiation therapy, and greater appreciation of the importance of proliferation during the course of r a d i a t i o n t h e r a p y , have led to i n t e r e s t i n g proposals, especially for studies o f h y p e r f r a c t i o n a t i o n a n d accele r a t e d f r a c t i o n a t i o n . T h e r e is n o s u b s t i t u t e for large, prospective clinical trials to test t h e s e h y p o t h e s e s , w i t h strict q u a l i t y - a s s u r a n c e guidelines.
References 1. De1 RegatoJA: Historical changes in time-dose relationship in therapeutic radiology. Front Radiat Ther Oncol 3:1-5, 1968 2. Buschke F: Radiation therapy: The past, the present, the future.Janeway Lecture, 1969.AmJ Roentgenol 108:236-246, 1970 3. Regaud C, Nogier T: Sterilization roentgenienne totale et definitives, sans radiodermite, des testicules du Belier adulte: conditions de sa realisation. Compt Rend Soc Biol 70:202-203, 1911 4. Regaud C: Influence de la duree d'irradiation sur les effects determines dans le testicule par le radium. Compt Rend Soc Bio186:787-790, 1922 5. Coutard H: Roentgentherapy of epitheliomas of the tonsillar region, hy~popharynx and larynx, from 1920 to 1926. Am J Roentgeno128:313-331, 1932 6. Strandqvist M: Studien uber die kumulative Wirkun der rontgenstrahlen bei Fraktionierung. Acta RadioJ 55:1-300, 1944 (suppl) 7. Ellis F: Relationship of biological effect to dose-timefractionation factors in radiotherapy', in Ebert M, Howard M (eds): Current Topics in Radiation Research. Amsterdam, North Holland Publishing, 1968, pp 357-397 8. Orton CG, Ellis F: A simplification in the use of the NSD concept in practical radiotherapy. BrJ Radio146:529-537, 1973 9. FowlerJF: Review: The linear-quadratic formula and progress in fractionated radiotherapy. BrJ Radio162:679-694, 1989 10. Shukovsky LF: Dose, time, volume relationships in squamous cell carcinoma of the supraglottic larynx. Am J Roentgenol 113:27-29, 1970 11. Paterson R: Treatment of malignant disease by radium and x-ray: Being a practice of radiotherapy. Baltimore, MD, Williams & Wilkins, 1949 12. Fletcher GH: Textbook of radiotherapy, 3rd ed. Philadelphia, PA, Lea & Febiger, 1980 13. Parsons JT, Bova FJ, Million RR: A re-evaluation of splitcourse technique for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 6:1645-1652, 1980 14. OvergaardJ, Hjelm-Hansen M, Johansen LV, Andersen A.P: Comparison of conventional and split-course radiotherapy as
primary treatment in carcinoma of the larynx. Acta Oncol 27:147-152, 1988 15. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 1988 16. Pajak TF, Laramore GE, Marcial VA, et al: Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG Report. IntJ Radiat Oncol Biol Phys 20:13-20, 199I 17. CoxJD, Pajak TF, Marcial VA, et al: Interruptions adversely affect local control and survival with hyperfractionated radiation therapy of carcinomas of the respiratory/digestive tracts: New evidence for accelerated proliferation from RTOG Protocol 8313. Proceedings of American Radium Society, pp 1-2, 199l (abstr) 18. O'Sullivan B, Maki E, Keane T: The influence of treatment time on local control by external beam radiotherapy in carcinoma of the tonsil. Proceedings of American Radium Society, p 2, 1991 (abstr) 19. CoxJD: Large dose fractionation (hypofractionation). Cancer 55:2105-2111, 1985 (suppl) 20. Spanos WJ, Wasserman T, Meoz R, et al: Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: Final report of RTOG Phase I/II study. IntJ Radiat Oncol Biol Phys 13:1479-1482, 1987 2 I. Spanos WJ, Guse C, Perez CA, et al: Phase II study of muhiple daily fractions in the palliation of advanced pelvic malignancies: Preliminary report of RTOG 8502. Int J Radiat Oncol Biol Phys 17:659-661, 1989 22. Dische S, Martin WMC, Anderson P: Radiation myelopathy in patients treated for carcinoma of bronchus using a six-fraction regime of radiotherapy. BrJ Radio154:29-35, 1981 23. Hatlevoll R, Host H, Haalhus O, et al: Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: A retrospective study. Int J Radiat Oncol Biol Phys 9:41-44, 1983 24. Perez CA, Azarnia N, CoxJD, Shapiro S: Sequelae of definitive irradiation in the treatment of carcinoma of the lung, in G Motta (ed): Lung Cancer, Advanced Concepts and Present Status, Genoa, Grafica LP, 1989, pp 237-256 25. Cosset.JM, Henry-Amar M, Girinski T, et al: Late toxicity of radiotherapy in HD: Role of fraction size. Acta Oncol 27:123129, 1988 26. Horiot J-C, Fletcher GH, Ballantyne AJ, et al: Analysis of failures of early vocal cord cancers. Radiology 103:663-665, 1972 27. Lanciano R, Martz K, Montana G, et al: Pretreatment and treatment factors associated with complications in squamous cell cancer of the uterine cervix: A final report of the 1973 and 1978 patterns of care studies. Proceedings of American Radium Society, p 17, 1991 (abstr) 28. ParsonsJT, Mendenhall WM, Cassisi NJ, et al: Hyperfraetionation for head and neck cancer. IntJ Radiat Oncol Biol Phys 14:649-658, 1988 29. Wang CC: Twice-daily radiation therapy for head and neck carcinomas. Front Radiat Ther Oncol 22:93-98, 1988 30. Saunders MI, Dische S, Hong A, et al: Continuous hyperfractionated accelerated radiotherapy in locally advanced carcinoma of the head and neck region. 17:1287-1293, 1989 31. Horiot J-C, Le Fur R, N'Guyen T, et al: Hyperfractionationated compared with conventional radiotherapy in oropharyn-
RecentDevelopmentsin Fractionation:ClinicalPerspectives
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geal carcinoma: An EORTC Randomized Trial. EurJ Cancer 26:779-780, 1990 Diener-West M, Pajak TF, Bauer M, et al: Randomized dosesearching Phase ILE/II Trials of fractionation in radiation therapy for cancer.J Natl Cancer Inst 83:1065-1071, 1991 CoxJD, Pajak TF, Marcial VA, et al: Interfraction interval is a major determinant of late effects, with h~13erfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from RTOG Protocol 8313. Int J Radiat Oncol Biol Plays 20:1191-1195, 1991 Peters LJ, Ang KK, Thames HD: Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies. Acta Oncol 27:185-194, [988 Amdur RJ, Parsons JT, Fitzgerald LT, et al: The effect of
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overall treatment time on local control in patients with adenocarcinoma of the prostate treated with radiation thera W. IntJ Radiat Oncol Biol Phys 19:1377-1382, 1990 36. Lai PP, Perez CA, Shapiro SJ, et al: Carcinoma of the prostate stage B and C: Lack of influence of duration of radiotherapy on tumor control and treatment morbidity. IntJ Radiat Oncol Biol Phys 19:561-568, 1990 37. Pistenma DA, Bagshaw MA, Freiha FS: Extended-field radiation therapy for prostatic adenocarcinoma: Status report of a limited prospective trial, in Johnson DE, Samuels ML (eds): Cancer of the Genitourinary" Tract. New York, NY, Raven Press, 1979, pp 229-247 38. Lawton CA, Cox JD, Glisch C, et al: ls long-term survival possible with external beam irradiation for stage D 1 adenocarcinoma of the prostate? Cancer 1991 (in press)