1111. J. Radiation Oncology Biol. Phys.. Vol. 4. pp. 573-5X Q Pertqmon Press Inc.. 1978. Prmted I” the U.S.A.

??Original Contribution

IMMEDIATE RESULTS OF WEEKLY FRACTIONATION IN EXTERNAL RADIOTHERAPY

MADHUSUDAN DVIVEDI, M.B.B.S., D.M.R.E. and DEEPAK G. PRADHAN, M.B.B.S. Department of Radiotherapy. Cancer Hospital, M.G.M. Medical College. lndore-452001, India

The feasibility of using large fractions at weekly intervals in external radiotherapy was studied to try to reduce work load on the only “Co teletherapy unit at the Cancer Hospital, Indore, India. Using the nominal standard dose (NSD) formula of Ellis, for six fractions at weekly intervals we decided to use 670 rad per fraction in patients with advanced disease. The responses were satisfactory and the treatment was tolerated well by patients.

A randomized clinical trial was conducted from May 1975 to June 1976 to evaluate this treatment schedule. Cancers of head and neck region, esophagus, breast, and uterine cervix were included in the trial. One hundred and sixty four patients were treated in the control group with conventional schedules and 177 in the trial group with weekly fractionation. In all the sites the immediate responses of local lesions and lymph nodes and the normal tissue reactions were comparable in the control and trial groups. The weekly fractionation was tolerated better by the patients.

Randomized trial with weekly fractionation, Once a week fractionation, Comparative study of conventional and weekly fractionation.

INTRODUCTION

The basis of fractionation in external radiotherapy is purely empirical; it is based on clinical experience. During the last few decades a conventional frac- tionation regime using five fractions per week for 5-7 weeks has been established for the major spectrum of malignant diseases. Several unorthodox fractionation regimes have been used for various reasons. Frac- tionation schedules using 2 or 3 fractions per week were used for technical convenience during radio- therapy with hyperbaric oxygen.6 Reduced numbers of fractions were tried for patient convenience and to reduce work load on the radiotherapy depart- ment. 2-5.7.14.20.21

Ellis” treated an 85 year old woman who developed a scar recurrence, 30 years after radical mastectomy, which continued to grow slowly for 5 years. She was treated by external radiotherapy at weekly intervals for 9 weeks and complete clinical regression was achieved. He used 380 rad at each fraction.

Retrospective studies of unplanned interrupted radiotherapy were conducted by ScanIon” and Holsti and Taskinen.18 They suggested that interrupted treatment might be more advantageous than con- ventional daily treatment. Various split course regi-

mens have since been tried.‘~2*8~‘5-‘7~‘9~22-26 The general observation was that they were tolerated better by patients without adversely affecting the results. After a controlled clinical trial, Holsti16 observed that pro- gression of tumor was observed in only 2 of the 198 patients treated during long intervals of 2-3 weeks between two sessions of radiotherapy. Furthermore, in 65-86% of patients regression continued during this interval.

We see around 2000 new patients per year. We have only one stationary @‘Co Teletherapy unit (Eldorado-6). In order to cope with the work load using conventional fractionation regimes, the unit had to be used round the clock: on an average the unit was in operation for 18.9 hr per day in 1974. With a view to minimizing this work load we decided to evaluate weekly fractionation in external radiotherapy for possible clinical ap- plication. Using the nominal standard dose (NSD) formula9,‘0~‘3 for our NSD of 1800 ret, in six fractions at weekly intervals, the dose per fraction was 682 rad. We decided to use 670 rad per fraction.

Initially from February to May 1975, we used this fractionation in 69 patients with advanced disease. Satisfactory response was observed in most of the patients and the treatment was tolerated well by the

Reprint requests to: M. S. Dvivedi, M.B.B.S., Cancer Hospital, M.G.M. Medical College, Indore-452001, India.

Accepted for publication 17 April 1978.

573

574 Radiation Oncology 0 Biology 0 Physics July-August 1978, Volume 4, No. 7 and No. 8

patients. A controlled clinical trial was launched in Carcinoma of the esophagus: patients were treated May 1975, randomizing patients according to site and by three field arrangement with an average field size stage of the disease, to compare the immediate of 16 x 8 cm. In the control group the dose to a large responses and radiation reactions on the weekly segment was 4500 rad over 4.5 weeks, followed by a fractionation schedule, against those with conven- boost dose of IOOOrad over a week by reduced tional radiotherapy regimes. The trial was completed portals. In the trial group five weekly fractions of in June 1976. The observations and results of this 670 rad each were delivered initially; the sixth frac- study are presented here. tion was a boost dose.

METHODS AND MATERIAL

Patients with malignant lesions of head and neck, uterine cervix, post-operative breast and esophagus were included in the trial; patients under 65 years of age, with histologically proved epithelial lesions were included. All patients were randomized according to the site and clinical stage of the disease. Randomiza- tion was done at the time of prescription of external radiotherapy after individualized planning, according to the random tables prepared by our statistician. The patients in the control group received conventional fractionation and those in the trial group received weekly fractionation. The patients in the control group were examined after delivery of each 1000 rad; those in the trial group were examined at each frac- tion for responses and reactions. Patients abandoning radiotherapy at any stage of the treatment were ex- cluded from the trial.

Table I shows the distribution of patients in control and trial groups for different regions.

249 patients entered the trial group and 254 the control group. 341 patients completed their respective fractionation schedules, 164 in the control group and 177 patients in the trial group. Patients were evenly distributed in both groups according to extent of the disease for all sites.

Radiotherapy All fields were treated at each fraction for all sites

in control and trial groups. Head and Neck lesions: most of the patients were

treated with wedged fields; the average field size was 10 x 8 cm. The control group received 6000 rad in 6 weeks, with treatments 5 days a week; the trial group received 6 fractions of 670 rad each at weekly inter- vals.

Table I. Distribution of patients in the control and trial groups for different regions

Region Control Trial Head and neck 96 106 Uterine cervix 50 48 Breast 13 12 Esophagus 5 II

Total: 164 177

Carcinoma of the breast: patients were treated by tangential fields with an average size of 16x 5 cm. Internal mammary nodes were treated with average field size of 15 X 5 cm. The size for the supraclavicular field was 18 x 9 cm. The dose to the axilla was topped up by a posterior axillary field of 8 x 8 cm. In the control group 4500 rad were given in 4.5 weeks; in trial group five fractions of 670rad each were delivered at weekly intervals.

Carcinoma of the uterine cervix: the control patients received 20 fractions of 230 rad each in 4 weeks, irradiating the whole pelvis. One anterior and two posterior oblique fields were used. The average field size for anterior field was 16 x 14cm and for posterior oblique fields, it was 16 x 8 cm. The patients in the trial group received 5 fractions of 670rad at weekly intervals. Both groups received intracavitary treatment by Cathetron, high intensity afterloading device, in two fractions over 5 days; 1258rad were delivered to point “A” at each fraction.

RESULTS

Head and Neck Tumors: 96 patients completed radiotherapy in the control group. Disease was staged clinical Stage II in 29 patients, Stage III in 48 and Stage IV in 19. 106 patients completed radiotherapy in the trial group. Disease was staged clinical Stage II in 35 patients, Stage III in 46 and Stage IV in 25.

In the responders the initial regression of growth and brisk mucosal reactions generally were observed at dose levels around 2000rad in the control group and just before the 3rd weekly fraction in the trial group. Radiotherapy had to be interrupted for a few days because of reactions in 24 of 96 patients in the control group and 13 of 106 patients in trial group. The general observation was that the reactions were less severe and swallowing was maintained better in patients who received treatment with weekly frac- tionation.

Complete regression of tumor occurred between dose levels of 4400-5000 rad in the control group and between the 4th and 5th weekly fraction in the trial group. In most patients, the mucosal reactions receded by 5000rad in the control group and the 5th weekly fraction in the trial group. Table 2 shows the responses in local lesions and lymph node deposits in the control and trial groups.

Immediate results of weekly fractionation in external radiotherapy 0 M. DVIVEDI and D. G. PRADHAN

Table 2. Head and neck tumors. Immediate responses in control and trial groups

Complete Number of Total number regression patients Complete

of patients of local presenting regression treated growth* with nodes of nodes?

Site Control Trial Control Trial Control Trial Control Trial

Cheek 26 30 17 16 22 26 13 11 Alveolus 10 12 6 7 8 9 3 5 Hard palate 0 1 0 1 0 1 0 0 Floor of mouth 2 1 1 1 2 1 0 0 Tongue 9 9 6 5 6 6 4 4 Oropharynx 32 32 23 26 26 29 12 21 Hypopharynx 13 13 13 12 10 11 4 4 Larynx 4 8 4 8 2 5 2 3

Total: 96 106 (72?%) (7?%) 76 88 (5:) (54?%)

*x2 = 0.337; p * 0.05. t** = 0.037; p * 0.05.

Table 3. Carcinoma uterine cervix. Bowel problems warranting rest during radiotherapy in the control and trial groups

Control Trial

After 8th After 13th After After After fraction fraction 2nd 3rd 4th

Duration (1840 rad) (2990 rad) fraction fraction fraction

One week 9 4 4 3 3 More than 0 2 1 2 2

one week

57s

Table 3 shows the responses of local lesions and of the parametrium in patients with carcinoma uterine cervix; the control and trial groups are presented.

In the responders local lesions regressed during external radiotherapy. Complete regression of local growths was achieved in 78% of the control group and 8 I .2% of the trial group.

Table 3 shows the occasions requiring interruption of radiotherapy because of bowel problems in both groups.

Radiotherapy had to be interrupted in 18 of the 50 patients in the control group. The rest period was less than 1 week in 13 patients; the duration was more than 1 week in 4. In the trial group 15 of 48 patients developed bowel problems warranting rest. For IO patients the next fraction had to be postponed a few days while it had to be postponed 1 week for 5 patients.

Bleeding was effectively controlled by a single fraction of 670 rad of external radiotherapy, in patients who presented with this problem.

All patients with carcinoma of the esophagus showed good subjective response except one in the control group.

Patients with carcinoma of the breast who were included in the trial all had undergone surgery; radio- therapy was given using bolus. Dry desquamation over the skin flap was observed after 2000 rad in the control group and just before the third fraction in the trial group. Patchy wet desquamation of similar in- tensity generally was observed at the completion of treatment in both the groups.

During the trial period the average working time per day of the 6oCo unit was reduced from 18.9 hr to 12.4 hr; 40% of the out of town patients in the trial group received radiotherapy on domicilliary basis travelling distances upto 500 km from the center for each treatment.

Follow up was incomplete at our center because of socio-economic factors. In the limited number of patients available for follow up no undue normal tissue reactions were observed in the patients who were treated with weekly fractionation. We did not observe any evidence of spinal cord damage in patients available for follow up who were treated with weekly fractionation for head and neck lesions and carcinoma of the esophagus. A woman of 30 was treated with weekly fractionation for carcinoma

576 Radiation Oncology 0 Biology 0 Physics July-August 1978, Volume 4, No. 7 and No. 8

breast after local excision of growth. The breast was supple with no evidence of fibrosis 2 years after radiotherapy (Fig. 1). The chest radiograph showed minimal fibrosis in the zone covered by the breast (Figs. 2 and 3).

DISCUSSION

Weekly fractionation schedule could have its own radiobiological and practical advantages. Theoretic- ally a week’s interval between fractions would pro- vide a better opportunity to the normal tissues for repair. This gap also would provide enough time for removal of cell debris by lysis and absorption, result- ing in tumor regression, revascularization and

Fig. 3. Chest radiograph two years after radiotherapy

Fig. 1. Breast cancer patient two years after radiotherapy (weekly fractionation).

Fig. 2. Chest radiograph before radiotherapy.

subsequent improved radio-responsiveness because of better oxygenation.

Ellisy,‘3 suggested that the sterilizing effect of a small number of large fractions is greater than that of a large number of small fractions; if large individual doses can be tolerated by patients perhaps resistant neoplasms could be treated better by small numbers of large fractions. He has treated many patients with large skin cancers by such methods. He also treated a patient with Stage IV carcinoma of uterine cervix with 630 rad tumor dose at weekly intervals using seven fractions. This treatment was tolerated well.

Analysis of the retrospective study of Greenberg et ul.” shows that 33 patients were treated with a one fraction per week schedule over a wide range of overall treatment time. In 17 of these patients 6 fractions were used at weekly intervals; the dose at each fraction ranged from 612 to 680 rad. The total dose was based on the tolerance of normal tissues as predicted by the NSD hypothesis of Ellis.” The acute reactions both local and systemic and a short term assessment (IO-33 months) of local tumor control in relation to surrounding normal tissue response were comparable to that with conventional fractionation. Ellis has published two years follow-up of these patients and contends that for certain types of tumors once a week radiotherapy may be more beneficial.

In our study. oral cavity and oropharynx were included in the treatment volume in the head and neck region; we observed that the mucosal reactions were less severe, the patient’s general condition was

maintained better and radiotherapy had to be inter- ally do not respond to radiotherapy by conventional rupted less frequently in patients who were treated I regimens, did regress to a considerable extent and with weekly fractionation. sometimes even became mobile.

In patients with carcinoma of the uterine cervix, although there was no significant difference in the number of patients who developed bowel problems during radiotherapy in both the groups. the severity of symptoms was much less and of a shorter duration in the patients who received radiotherapy with weekly fractionation.

None of our patients receiving weekly fractionation showed evidence of tumor progression during treat- ment.

A chi-square test was applied for statistical analysis of immediate responses. There was no significant difference in the results in the control and trial groups (Table 2).

Weekly fractionation was found to be of additional advantage in patients of carcinoma uterine cervix who presented with excessive bleeding problems. The conventional method of dealing with this problem is treatment by intracavitary radiotherapy. This is associated with the disadvantage of poor distribution of dose because of bulky local disease. Effective hemostasis could be achieved by the first fraction of 670 rad of external radiotherapy and the intracavitary treatment could be given in optimal conditions, when the local growth had regressed after completion of external radiotherapy.

In patients treated with weekly fractionation we observed that big and fixed lymph nodes which usu-

It can be concluded from the results of this study that the external radiotherapy with weekly fractiona- tion was tolerated better by the patients and produced less severe normal tissue reactions. The local controls were comparable to those attained with conventional regimen. The enlarged nodes responded better with weekly treatment. The load on the teletherapy unit was reduced considerably. During the trial period, the average working time per day of the 6oCo unit was reduced from 18.9 hr to 12.4 hr. The load on hospital beds was also reduced as 40.3% of the out station patients receiving weekly fractions as out-patients received treatment on domiciliary basis.

Immediate results of weekly fractionation in external radiotherapy 0 M. DVIVEDI and D. G. PRADHAN 571

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