Inr J Rudrnrmn Oncology Bml P/w Vol. 14. pp. S51456 0360-3016188 $3.00 + .I0 Printed in the U.S A. All nghts resewed. Copyright 0 1988 Pergamon Press plc

??Modalities

A 1.

2.

TIME/DOSE/FRACTIONATION TRIALS

J. Cox’ AND E. VAN DER SCHUEREN~

‘Dept. of Radiation Oncology, Columbia University, New York, NY, U.S.A.; and ‘Dept. of Radiotherapy, University Hospital, Leuven, Belgium

TIME/DOSE FRACTIONATION

COORDINATION I I I

I COOPERATIVE GROUP OF INVESTIGATOR

RTOG EORTC I I QUALITY CONTROL CASE ACCESSION

I

A

dosimetry

workshops

I common < violations

OUTCOME ANALYSIS

I

f corrective

strategy

I > failure

patterns

DISSEMINATE INFORMATION

CLINICAL PRACTICE

I. OBJECTIVES AND SPECIFIC AIMS

Objectives To explore in a systematic manner clinical studies of dose/time relationships to achieve the best therapeutic ratio (highest tumor control for lowest morbidity). To integrate clinical data and animal studies and to promote mathematical modeling of dose/time rela- tionships.

3. To employ the best available data including mathe- matical modeling for development of future trials.

4. To explore dose/time relationships that are optimal for integration with modifiers of radiation effects.

B. Specific aims 1. To explore altered fractionation, to attempt to improve

upon therapeutic ratio in the control of specific ma-

Reprint requests to: J. Cox, E. van der Schueren. Accepted for publication 4 January 1988.

s51

S52 I. J. Radiation Oncology 0 Biology 0 Physics

2.

3.

4.

A

lignant tumors (viz., to enhance local tumor control, diminish normal tissue effects, or both). To develop mathematical models based on clinical trials, augmented by studies of normal tissue effects in laboratory animals, to provide a scientific basis for fu- ture clinical trials in dose/fractionation. To design and conduct clinical trials based on the best available data and modeling. To evaluate clinical trials of radiation modifiers, es- pecially radiosensitizers and radioprotectors, hyper- thermia, and chemotherapy, and to derive the optimal dose/fraction regimens for future trials of these mod- ifiers.

II. BACKGROUND AND SIGNIFICANCE

Background Dose fractionation has been the cornerstone of clinical

radiation therapy since the determination in the early 1920’s that spermatogenesis (as a model for rapid cell re- newal systems), although not interrupted with a single large fraction of radiation which produced scrotal skin necrosis, could be permanently halted by fractionated ir- radiation.

This work formed the basis for the evaluation of frac- tionated irradiation that resulted in elimination even of deep-seated tumors while permitting recovery of normal tissues. The limitless confirmations of the influence of fraction size, numbers of fractions, and elapsed time of treatment, led to numerous attempts to express different fractionation regimens as a single number considered to be iso-effective. The most frequently used coefficients such as those expressed by Ellis. Kirk, Or-ton, and others result in calculated equivalent doses which underestimate the magnitude of increasing fraction size as a determinant of late effects. Through studies of normal tissues of laboratory animals a better understanding of the different factors de- termining the effects of fractionated irradiation has been gained, especially their impact on acute and late effects.

Assessments of clinical studies of hypofractionation, parallel to the laboratory studies and associated mathe- matical modeling confirmed the importance of fraction size as a determinant of late tissue damage. In addition, tumor control was adversely effected by the longer inter- vals between large fractions, presumably permitting a greater degree of repopulation of tumor cells than what occurs during daily applications of smaller doses.

These considerations led to the current generation of RTOG and EORTC hyperfractionation, rapid fraction- ation and accelerated fractionation studies (Table 1). This systematic investigation of fractionation factors should provide a data base for future mathematical modeling.

B. Significance Local tumor control continues to be a major factor

determining the outcome of treatment of a wide variety of malignant tumors. Since the majority of malignant tu-

1988 Volume 14. Supplement I

mors require for their control total doses which are near the limits of tolerance of the surrounding normal tissues, any approach which enhances tumor control without an increased damage to normal tissues or maintains the tu- mor control rate while diminishing effects on normal tis- sues, is worthy of becoming standard practice in radio- therapeutic management. All trials of altered fractionation are directed toward these ends. Although. fractionation as a “modality” has, by far. the longest history in radio- therapy of all potential modalities, it is still one of the most exciting areas of clinical research. In addition, clin- ical trials in this area can be conducted with wide partic- ipation on the part of all radiation oncologists since the questions involved, for the most part. are pure radiother- apeutic questions which do not necessitate interactions with other medical disciplines.

III. SUMMARY OF PROGRESS IN CLINICAL TRIALS

il. Past (closed) clinical trials I. R TOG. Previous (closed) clinical trials of the RTOG

in fractionation are listed in Table I. It may be seen that the emphasis was on common fractionation in compar- ison with split-course regimens.lm4 In general, the findings from these studies were a suggestion of a slight increase in late morbidity in the split-course regimens that em- ployed large sizes. This was most marked in Protocol 73- 01 which confirmed a dose response in the local control of carcinoma of the lung and poorer tumor control and greater normal tissue effects with the split-course regimen.’ Protocol 77-03 was the first study evaluating normal tissue effects of hyperfractionation (1.25 Gy b.i.d.) and accel- erated fractionation (1.5 Gy b.i.d.) and provided some pilot information for the subsequent development of hy- perfractionation and accelerated fractionation studies.6 Protocols 79-04, 79-05, 79-18, and 79-25 were actually studies of the radiosensitizing drug, Misonidazole. How- ever, they all employed altered fractionation regimens mostly with large fraction sizes, and thus, constitute back- ground experience for these particular fractionation schedules. In each case, the large fraction sizes were as- sociated with some greater degree of normal tissue effect. This was most marked in Protocol 79-25.

Protocol 79- 13 was a prospective, randomized study of common fractionation to total doses of 68 to 73 Gy vs hyperfractionation, 1.2 Gy b.i.d., to a total dose of 60 Gy. In spite of the low total dose, the hyperfractionation arm has given identical results to the common fractionation regimen.5 Protocol 8 l-08 developed a pilot experience for high-dose irradiation for carcinoma of the lung’: enough patients were treated with the dose of 69.4 Gy to encourage the development of the randomized Phase I/II study, 83- 1 1. Finally, Protocol 83- 12 was a single-institution pilot study of rapid fractionation at Washington University us- ing a field within a field so that the large field received a total dose of 50 Gy in 28 fractions whereas the small field

Fractionation trials 0 J. COX AND E. VAN DER SCHUEREN s53

Table 1. Past (closed) clinical trials in fractionation (selected)

RTOG protocol Site Fractionation Date open Date closed

Number of patients

71-01 Tonsil 7 l-02 Tongue 71-03 Nasopharynx 71-04 Bladder 7 l-05 Cervix 73-01 Lung 73-02 Lung 77-03 H&N/Es0 79-04 H&N 79-05 Pelvis 79-13 H&N 79-18 Glioma 79-25 Lung 8 l-08 Lung 83-12 Lung

Common/split Common/split Hyper/accel Rapid HYPO Hyper Commonfhypo HYPO Hyper Rapid

2-1-71 8-20-80 147 2-l-71 S-20-80 143 2-l-71 8-20-80 128 2-1-71 S-20-80 148 2-1-71 S-20-80 304 6-l-73 8-17-78 482 6-l-73 2-15-79 410 3-16-77 8-22-79 83 6-6-79 2-17-83 42 10-15-79 8-4-82 46 8-20-79 7-l 3-83 210 10-19-79 l-26-83 318 l-7-80 7-13-83 117 3-27-8 1 5-25-83 125 4-l-83 2-28-85 59

received a dose of 75 Gy with the same number of fractions in a five and one-half week period.

2. EORTC (Table 2). Two pilot studies followed by randomized studies, have been carried out, one in glioma and one in head and neck cancer. These are more exten- sively discussed under the specific sites (brain and head and neck). Shortly, it can be said that both studies were based on the administration of three fractions per day thus aiming at reducing the overall treatment time. In the brain study a dose of 30 Gy was given in 1 week, followed by another dose of 30 Gy after a 2 week interval. In this set-up overall treatment time for 60 Gy was reduced from 6 to 4 weeks. No therapeutic gain could be demonstrated.

In the head and neck trial, a dose of 48 Gy was given in 2 weeks, followed by a second series of 24 Gy to a total of 72 Gy after 3 or 4 week intervals. In this way, the overall treatment time was not significantly different than the normal 7 weeks for 70 Gy. The main difference was a very rapid administration of the first 48 Gy (2 weeks). The longer interval time was necessary in view of the brisk acute mucosal reactions. Again, no therapeutic difference could be demonstrated.

B. Present (current) clinical trials 1. RTOG. The present emphasis is on hyperfraction-

ation and accelerated fractionation (Table 3) except for metastatic melanoma where the question of large fraction size and increased efficacy is being addressed. These stud- ies have accrued patients more rapidly than initially ex- pected. Total dose questions are being addressed with the hyperfractionation studies, and at the present time the maximum total dose being studied with malignant gliomas is 8 1.6 Gy, with bladder it is 69.9 Gy, with lung it is 79.2 Gy and with head and neck it is 8 1.6 Gy. Perhaps the most important accelerated fractionation study is Protocol 84-07 which is accelerated fractionation via a concomitant boost. The large field receives 1.8 Gy 5 days a week to a total dose of 45 Gy. An additional 1.8 Gy is delivered on

2 days each week with a separation of at least 4 hr from the second dose, resulting in a total dose of 63 Gy in 5 weeks in 35 fractions. The total dose has been escalated in this study such that the large field receives 50.4 Gy and the concomitant boost field receives 70.2 Gy.

2. EORTC: Fraction size. A trial on oropharyngeal tu- mors studies two fractions per day of 1.15 Gy to a total dose of 80 Gy, in comparison to daily fractions of 2 Gy to a total of 70 Gy. In this study, a correction for the total dose of 15% is taken in account for the reduction of the fraction size. This trial is still in progress and will probably be closed in 1986.

C. Future clinical trials 1. RTOG. Future clinical trials that fall within the

realm of the modality committee on dose/time/delivery will continue in the direction of hyperfractionation and accelerated fractionation. It is anticipated that there will be new information from current Phase I/II trials to sug- gest the most fruitful future direction.

2. EORTC. A new accelerated fractionation study has been started in 1985 in the head and neck region. This trial aims at administering the total dose of 70 Gy in 5 weeks. The main difference with the previous study is that treatment is started with the administration of 24 Gy in 1 week which does not lead to the development of acute mucositis making it possible to start up the second block of 48 Gy in 2 weeks after an interval of only 2 weeks. In this way, the study is the exact reversal of the one which was carried out previously and it should be possible to assess the effect of a reduction of 2 to 3 weeks in average total treatment time. Initial studies have demonstrated that from the point view of early tolerance this is feasible.

A pilot study is presently in progress in the brain tu- mors. In this study, the identical fractionation schedule of the previous randomized trial is used with 3 fractions of 2 Gy per day. Here however, the treatment is not in- terrupted after 30 Gy but is continued. For the moment,

s54 I. J. Radiation Oncology 0 Biology 0 Physics 1988 Volume 14. Supplement I

Table 2. Phase II and 11 studies on fractionation by the Radiotherapy Group of the E.O.R.T.C.

E.O.R.T.C. protocol File Phase Fract. Date op. Cl.

Number pat.

Brain II Accel. 2280 I Head + neck II Accel. 2178 12/80 179 2279 I Oropharynx III Hyper 2/80 Open 336

Brain III Accel. Head + neck 111 Accel. 2/s I lo/84 523 Brain II Accel.

2285 1 Head + neck III Accel. 12/85 Open 19

a feasibility study is carried out with escalating doses which have now reached 48 Gy in 9 days.

IV. FUTURE DEVELOPMENT OF TRIALS

Regimens to he studied The effect of a fractionated radiation is determined by

the fraction size, the interval between irradiations, overall treatment time, and the total dose used. While all these factors have specific influences on the biological effects, it is usually impossible to modify any of these factors without affecting the others as they are directly interre- lated.

1. Factors of.fraction size. Clinical studies have been done using fraction size which are significantly larger or smaller than 2 Gy.

Large fraction sizes: In the studies using large fraction sizes, usually relatively long intervals have been em- ployed between irradiations. Generally it can be stated that this combination leads to a decrease in the differ- ential effects between normal tissues and tumors. This seems to be partly due to a loss of tolerance of the normal tissues, but could also be correlated with in- creased repopulation in the tumors during the intervals. With few exceptions for example, tumors with a larger potential for repair, it does not seem fruitful to pursue studies with large fraction sizes in curative radio- therapy. Small fraction sizes: Based on experimental evidence suggesting that using smaller fraction sizes would lead to a relative sparing of late tissue damage, a number

C.

of clinical studies have been initiated in this direction in recent years in these studies fraction, sizes have been reduced down to the range of I- 1.2 Gy; total doses were increased up to 15-20s. Initial data suggest that the acute reactions for these dose levels are similar or greater. Final data on late tolerance is now being ac- cumulated. A wide variety of normal tissues is being assessed. Further development of this type of studies with the possible use of fraction sizes below 1 Gy will be determined by the data on late effects on normal tissues and tumor control. Low dose rate: Low dose rate radiotherapy is an ex- treme case of fractionation. It is commonly applied in brachytherapy and deserves further study in telether- apy. Until now, only one prospective randomized study has been carried out and sufficient preliminary infor- mation has been gathered on acute and late side effects to make it worthwhile to pursue investigations in this field.

Future development of trials It should be limited to these centers having the capa-

bility of dedicating a machine to this type of treatment, but otherwise would require relatively minor financial in- vestments, compared with some of the other modalities to be investigated.

Modification of the time factor The time-factor is important both in the overall length

of treatment and in the respective intervals between in- dividual irradiation. Assuming intervals are used which are sufficient for complete cellular repair, the main factor

Table 3. Fractionation definitions*

Schedule d No/wk Ti (hr) No T (wk) D

Common HYPE Hyper Rapid Accel

1 .O-2.5 >3.0

0.7-1.3 >2.5

1.5-2.5

5-6 24 l-4 4%168t

lo-25 2-12 5 24

10-15 4-12

25-40

i NC or

5-8 NC NC

1

55-15 4

NC 4

NC or

* Assumes dose-rate of 0.5-3.0 Gy/minute. t Intervals > 168 hr constitute “split-course.” d = dose per fraction (Gy); No/wk = number of fractions per week; Ti = interval between fractions; No = total number of fractions;

T = duration of treatment course; D = total dose (Gy); Hypo = hypofractionation; hyper = hyperfractionation; NC = no change.

Fractionation trials 0 J. COX AND E. VAN DER SCHUEREN s55

influenced would be repopulation. Any situation in which the tumor proliferates faster than the critical normal tis- sues could be influenced advantageously by reducing overall treatment time. On the other hand, every factor leading to discontinuation of therapy would have a neg- ative effect. Accelerated fractionation, defined as the use of an equivalent dose significantly larger than 10 Gy per week, has been studied in several trials recently. This was sometimes done using “normal” fraction sizes or “small” fraction sizes. This last modality would then be an accel- erated hyperfractionation. This acceleration of therapy has been limited in a number of locations by the increase in acute reactions, sometimes necessitating split-course therapy.

V. RESEARCH STRATEGY FOR IMPLEMENTATION

Priorities

a.

b.

I. a. Highest priorities general: in all departments.

Further development of studies on hyperfractionation with fraction sizes between l-2 Gy with shortened treatment times (decreased elapsed time) assessment of late effects and tumor control rates. Second series of studies in accelerated radiotherapy.

1. b. Highest priority (restricted: only possible in de- partments with spec@c injrastructure.

a. Low dose rate irradiation: studies on acute and late tolerance for localizations other than for head and neck, and breast.

b. Phase II studies on tumor effects in palliative situations. 2. Studies with high priority awaiting results from

studies in progress before activation. Further escalation of studies on hyper-fractionation will depend on the infor-

mation coming out of the studies assessing fraction sizes between 1 and 2 Gy. If late tolerance is indeed increased as predicted while tumor effect remains good, exploration of fraction sizes of less than 1 Gy have to be activated.

3. The investigation of large fraction sizes and split- course irradiation leading to prolonged overall times are not high priority at the present time. In any situation where large fraction sizes have to be used due to problems of infrastructure it is of the utmost importance to carefully document normal tissue tolerance and tumor control.

Resources 1. Patients required. (a) For Phase I/II studies: 50-75

patients; (b) For Phase III studies: 150 patients per treat- ment group.

2. Sites. Brain, head and neck, lung, bladder, and cer- vix. (3: completion: see page 3 bis).

3. Completion. 1975-1980 pilot studies on hyperfrac- tionation; 1978- 198 1 pilot studies on accelerated irradia- tion; 198 1- 1986 first generation phase III; studies on hy- perfractionation (l-2 Gy) and on accelerated radiother- apy; 1986- 1990 second generation of hyperfractionation (l-2 Gy) and accelerated irradiation; 1987-199 1 pilot studies on low dose rate irradiation outside head and neck and on fraction sizes below 1 Gy.

Third world cooperation Disadvantage. The research development is moving

towards increased number of treatments while only lim- ited equipment is available.

Advantage. Depends only on equipment already avail- able (assumes good quality control for quantitative as- sessment of normal tissue reactions and tumor effect). Third World countries could contribute special patient resources, especially cervix, bladder, and head and neck.

VI. REFERENCES

1. Marcial, V., Amato, D., Brady, L., Johnson, R., Goodman, R., Martz, K., Hanley, J.: Split-course radiotherapy of car- cinoma of the urinary bladder stages C and D. A RTOG study. Am. J. Clin. Oncol. (CCT) 8: 185-199, 1985.

2. Martial, V., Hanley, J., Chang, C., Davis, L., Moscol, J.: Split-course radiation therapy of carcinoma of the naso- pharynx-Results of a national collaborative clinical trial of the RTOG. Int. J. Radiat. Oncol. Biol. Phys. 6: 409-4 14, 1980.

3. Martial, V., Hanley, J., Hendrickson, F., Ortiz, H.: Split- course radiation therapy of carcinoma of the base of the tongue: Results of a prospective national collaborative clin- ical trial conducted by the RTOG. Int. J. Radiat. Oncol. Biol. Phys. 9: 437-443, 1983.

4. Martial, V., Hanley, J., Marks, R., Rotman, M., Figueroa- Valles, N.: Split-course versus continuous pelvis irradiation in carcinoma of the uterine cervix: A prospective random- ized clinical trial of RTOG. Int. J. Radiat. Oncol. Biol. Phys. 9: 43 l-436, 1983.

5. Martial, V., Pajak, T., Chang, C.: Hyperfractionated photon

radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx and si- nuses, using radiotherapy as the only planned modality: A RTOG Report. Int. J. Radiat. Oncol. Biol. Phys. 11: 142, 1985.

6. Marks, R., Witherspoon, B., Davis, L., Rominger, J., Mar- cial, V.: Hyperfractionation-Where we stand-A prelim- inary RTOG report. Proc ASTRO Abs 96. Int. J. Radiat. Oncol. Biol. Phys. 4: 139-140, 1978.

7. Perez, C., Stanley, K., Grundy, G., Hanson, W., Rubin, P., Kramer, S., Brady, L., Marks, J., Perez-Tamayo, R., Brown, S., Concannon, J., Rotman, M.: Impact of irradiation tech- nique and tumor extent in tumor control and survival pa- tients with unresectable non-oat cell carcinoma of the lung. Cancer 50: 1091-1099, 1982.

8. Seydel, H., Diener-West, M., Urtasun, R., Podolsky, W., Cox, J., Zinninger, M.: Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: Preliminary report of a RTOG pilot study. Int. J. Radiat. Oncol. Biol. Phys. 11: 1841-1847, 1985.

S56 I. J. Radiation Oncology 0 Biology 0 Physics 1988 Volume 14, Supplement 1

VII. APPENDIX

Quality assurance Quality Assurance is critical to the conduct and results

of clinical trials in radiation therapy. Appropriateness of the initial treatment plan and adequacy of the initial treatment volume can be monitored by quality assurance centers to which copies of the simulation films and treat- ment plans must be sent within 24 to 48 hr of the start of treatment. (Considering the potential difficulties in transmitting such information across international bor- ders, either electronic transfer via phone lines or estab-

lishment of quality assurance center in each country would be necessary.) Although initial treatment planning can be carefully specified in the protocol, daily reproducibility is the weakest link. Several studies show that port films and verification films taken during treatment differ by 0.5 to 2 cm from the planning (simulator) films. Future protocols must specify the need to obtain regular portal or verifi- cation films to assure consistent delivery of the planned treatment.