My experience in low dose-rate radiotherapy

144 represented by the 3 data points around 10-12 days. On the other hand, if the same weight is given to each data point, the linear regression analysis shows no significant effect of overall time, but the upper 95% confidence limit on the estimated slope is 0.62 Gy/day. In other words, a significant increase in TCDs0 with increasing overall time can not be ruled out. Dubben has chosen a slightly provocative title for his letter. In our view, there are data indicating that overall treatment time affects the TCDs0. However, for the reasons given in our commentary and summarized here, the most convincing demonstration of the importance of overall treatment time is from studies in which treatment was deliberately protracted or from the preliminary experience with accelerated fractionation. We will take this opportunity to briefly comment on the two other points mentioned in the first paragraph. Concerning the apparent (fitted) inverse slope of the clinical dose-response curve, Da, we argued that the value 5 Gy assumed by Withers et al. was unrealistically low for clinical materials, and suggested D a = 18 Gy as a more realistic value. Hendry [ 3 ] has recently performed a direct analysis of all the data in the survey by Withers and colleagues and has obtained the even higher value, D a = 29 Gy. Accepting this value will further reduce the impression of a biphasic curve. On the third point, the sparse data on patients treated in less than 3 weeks, Trott has suggested that the data from the strongly accelerated trial at Mount Vernon Hospital (CHART) be included in the dog-leg plot (K. R. Trott, oral communication, July 1991) in an attempt to see if a linear back-extrapolation to these short times is realistic. In the most recent report, the head and neck patients in C H A R T had a local control rate of 62% [4]. The overall treatment

time employed is 12 days and the two dose levels that have been given are 50.4 Gy (January 1985 to April 1986) and 54.0 Gy (April 1986 to March 1990). The two dose levels give rise to TCDs0 estimates at 43.1 and 46.7 Gy, respectively. A weighted regression analysis, assuming no lag time, predicts TCDs0 = 43.9 Gy for an overall time of 12 days, which is in good agreement with the C H A R T data. Although it is not possible to decide this question from the C H A R T results alone, taken together with the other data from the literature they are consistent with an interpretation where the time lag is shorter than 12 days. In summary, we maintain that the slope of the TCDs0 vs. time relationship may be confounded by the practice of dose prescription. There is no convincing demonstration of the 4-week lag time, and all data from 1.5 to 10 weeks can be fitted with a single slope. Finally, the ambiguities pointed out in the interpretation of many historical studies should not be regarded as a discouragement but rather as an incitement to do properly sized randomized trials of accelerated fractionation. Sincerely, S~ren M. Bentzen a and Howard D. Thames b (received 3 June 1992,

accepted 4 June 1992) aDanish Cancer Society, Department of Experimental Clinical Oncology, Norrebrogade 44, DK-8000 Aarhus C., Denmark, bDepartment of Biomathematics, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA

References 1 Bentzen, S. M. and Thames, H.D. Clinical evidence for tumor clonogen regeneration: interpretations of the data. Radiother. Oncol. 22: 161-166, 1991. 2 Dubben, H.H. No clinical evidence for the influence of overall treatment time on TCDso of head and neck tumours. Radiother. Oncol., this issue. 3 Hendry, J.H. Treatment acceleration: the relative time factors and doseresponse slopes for tumours and normal tissues. Radiother. Oncol., submitted, 1992.

4 Saunders, M. I., Dische, S., Grosch, E. J., Fermont, D. C., Ashford, R. F., Maher, E. J. and Makepeace, A.R. Experience with CHART. Int. J. Radiat. Oncol. Biol. Phys. 21: 871-878, 1991. 5 Withers, H. R., Taylor, J. M. G. and Maciejewski, B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol. 27: 131-146, 1988.

R A D I O N 01057 MY E X P E R I E N C E IN LOW D O S E - R A T E R A D I O T H E R A P Y

To the Editors, My experience in low dose-rate radiotherapy can be summed up as a quest to optimize the therapeutic ratio by exploiting the differential response of healthy and malignant tissue to the delivery of a tumorocidal dose of radiotherapy in as short a time as possible. From their experience with radium, Jean Pierquin and George Richard (Fondation Curie, Paris) taught me, before 1950, that only with low dose rate could the duration of a course of radiotherapy be shortened to several days [7]. To them, the essential virtue of brachytherapy was the continuous low dose rate which enabled one to deliver a high dose in few days, instead of over several weeks as in external radiotherapy. My personal project for the past 40 years unfolded in several

stages. In the 1950s (Institut Gustave Roussy, Villejuif), I demonstrated that the new brachytherapy techniques, using new "artificial" sources of gold-198 and then (early 1960s) iridium-192 with afterloading, permitted successful treatment of large target volumes [ 1 ]. For the first time it was possible to prove that the efficacy of low dose-rate radiotherapy in large tumour volumes was comparable to that of fractionated external beam radiotherapy. In the 1960s (Institut Gustave Roussy, Villejuif) I applied this to large relatively radioresistant tumours, such as recurrent inoperable and massive cervical adenopathy from oropharyngeal cancers, and found that one could successfully deliver 60 Gy [2]. To be able to accomplish in a few days what was impossible with high dose rate external radiotherapy fractionated over several weeks proved that slow and continuous irradiation maximized the differential between healthy and malignant tissue and enabled a high dose to be delivered over a very short time.

145

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Fig. 1 Illustration of improved therapeutic ratio of low dose rate in extemal beam radiotherapy for a large target volume (whole breast irradiation). Comparison with high dose rate and classical fractionation. Tumour response graded from 0 to 100% regression. Normal tissue sequelae are clinically inapparent from 0 to 25%, and acceptable, but with apparent sclerosis, from 25 to 50%; beyond 50%, clinical sequelae and severe with necrosis graded as 100~o. HDR: For high dose-rate radiotherapy the therapeutic ratio diminished over that of classical fractionation; normal tissue tolerance limits the dose to approximately 25 Gy. LDR: Low doserate radiotherapy improves the therapeutic ratio as compared to classical fractionation; therapeutic gain is optimal at a dose of approximately 35 Gy. CF: With classical fractionation the therapeutic ratio is acceptable with the optimal dose being approximately 55 Gy.

In the 1970s, (Institute Gustave Roussy, Villejuif) I made the important leap of transferring low dose-rate radiotherapy (1 Gy/h, 10 Gy/day) to the realm of external beam cobalt irradiation with the familiar techniques and dosimetry of standard fractionated high dose rate external beam radiotherapy. Using advanced oropharyngeai malignancies (T4), I confirmed, in the first half of 1970, my original hypothesis. It was possible to treat large target volumes, identical to those of standard fractionated external beam therapy, to a high dose over a few days if one used a low dose rate in a semi-continuous fashion. Because of the severity of the mucosal reactions, I introduced a field reduction at 45 Gy [3]. In the late 1970s (Hrpital Henri Mondor, Crrteil) I chose oropharyngeal cancer (T2b and T3) and I began a systematic comparison between standard fractionated irradiation and low dose-rate irradiation. The initial target volume was treated to a dose of 45 Gy, followed by a boost to a reduced volume from either external beam or brachytherapy to a dose of 25 Gy. In the early 1980s, longer term results confirmed my original conclusion. The therapeutic effect of low dose-rate irradiation was superior. The 3-year local control rate was 84% for 32 patients treated by low dose rate as compared to 39 % for 33 patients treated by standard fractionation. Unfortunately, the normal tissue tolerance in the group treated by low dose rate was markedly reduced. There were no catastrophes but there were certainly some disturbing late sequelae [4,5]. I thus decided to embark on a final trial this time using advanced breast cancer (Tzb and T3), treated by external beam radiotherapy with the goal of breast conservation. This tumour site appeared to be optimal to demonstrate the effects of low dose-rate irradiation in an easily evaluable and homogeneous volume. The study started in 1986 with a comparison of 45 Gy given by either low dose rate or standard fractionation. At 12 weeks post-irradiation, low dose-rate radiotherapy resulted in a spectacular tumour regression in all cases (23 patients, with 64% of

biopsies negative) which was only mediocre in patients with standard fractionation (21 patients, with 24% of biopsies negative). But, by 6 months post-treatment the cosmetic effect for those patients treated by low dose rate was only mediocre while it remained very good for those on standard fractionation. Before abandoning the study, I decided to decrease the total dose to 35 Gy for the low dose rate group. It was thus that I obtained the optimal response 35 Gy over 5 days (Fig. 1) at a low dose rate of 1 Gy per hour resulted in a very satisfactory tumour regression (0/11 < 5 0 % ; 5/11 > 5 0 % ; 6/11 100%) without sacrificing cosmesis (no mediocre result, 10/11 excellent) [6]. This trial was to be my last chance as it was undertaken in the final years of my career. It supplies the incontestable proof of the beneficial effect of low dose rate in radiotherapy. The total dose (initial target volume before boost) must be decreased by about 25 % compared to the dose required in standard fractionation at high dose rate. It appears that the optimal schedule for low dose-rate radiotherapy is as follows: 3 5 G y to the initial f i e l d + 2 0 - 2 5 G y boost = 55-60 Gy. Randomized trials for several and relatively superficial tumour sites will be necessary in order to confirm these initial promising results. Will radiobiology confirm our clinical results in the near future? The response to this question will determine how much consideration is given to my clinical experience of the past decades. Sincerely, B. Pierquin (received 4 February 1992, accepted 27 April 1992)

Drpartement de Cancrrologie HOpital Henri Mender 94 Creteil, France

146 References 1 Pierquin, B., Chassagne, D., Pieter, E., Raynal, M. and Balllet, F. L'endocurieth~rapie par iridium 192 des carcinomes 6pidermoides de la l~vre infrrieure. J. Radiol. Electrol. 53: 207-212, 1972. 2 Pierquin, B., Raventos, E. and Chassagne, D. L'endocuriethrrapie des ad6nopathies cervicales malignes par iridium 192 (rtude de 124 cas). J. Radiol. Electrol. 51: 237-240, 1970. 3 Pierquin, B., Baillet, F., Raynal, M. and Turgard, I. L'effet diffrrentiel de rirradiation continue (ou semi-continue)/t faible drbit des carcinomes 6pidermoides. J. Radiol. Electrol. 51: 533-536, 1970. 4 Pierquin, B., Calitchi, E., Mazeron, J.J., Le Bourgeois, J.P. and Leung, S. A comparison between low dose-rate radiotherapy and conventionally

fractionated irradiation in moderately extensive cancers of the oropharynx. Int. J. Radiat. Oncol. Biol. Phys. 13: 431-439, 1985. 5 Pierquin, B., Calitchi, E., Mazeron, J. J., Le Bourgeois, J. P. and Leung, S. Update on low dose rate irradiation for cancers of the oropharynx. Int. J. Radiat. Oncol. Biol. Phys. 13: 259-261, 1987. 6 Pierquin, B., Calitchi, E., Marinello, G., Piedbois, P., Julien, M. and Le Bourgeois, J.P. Comparison entre irradiation fractionnre classique et irradiation/t faible d~bit darts le traitement local des cancers du sein 6volurs. Bull. Cancer (Radiothrr.) 78: 125-132, 1991. 7 Pierquin, J. and Richard, G. Radiothrrapie du cancer du col ut~rin. Nouvelle Pratique Chirurgicaleillstrre. Fasc. 1, pp 63-79. Doin 6dit. Paris, 1941.

RADION 01058 QUALITY CONTROL AT THE PATIENT LEVEL: ACTION OR RETROSPECTIVE INTROSPECTION

To the Editors, We appreciate the comments made by Lebesque et al. [ 1] on our paper (Mitine et al. [2]). The authors criticize the method used in our analysis of systematic and random errors and disagree with our conclusions on the value of the quality control procedures during the first session. The paper concerned [2] is part of a series of papers (3 to 6) in which a large number of distributions of deviations has been published, and where the random and systematic errors have been clearly identified and calculated as suggested by Lebesque et al. The authors [1] state that repeated set-up measurements are necessary to decide if an error is systematic or random: although they are theoretically right, this conclusion is of no practical use to assess the significance of a control procedure at the start of treatment. Following this suggestion a radiotherapist has only two solutions: either he makes repetitive measurements and he waits for a large number of sessions to know if there is a systematic error, and it is too late to correct it, or he corrects every day for any kind of deviation, increasing tremendously the treatment time and adding new systematic errors in many cases. This discussion is linked to the long standing argument on whether one should look for the data which are the most informative from the statistical point of view, or for a procedure which yields, as early as possible, and with the minimum investment of time and equipment, the most reliable data in order to be able to make and appropriate decision which can improve treatments in as many patients as possible. In medicine, absolute certainty is often only obtained at autopsy, however, while this information is useful for science and for future patients it is of relatively limited value for the patient himself. The useful decisions should have been taken, early in the treatment, based on often incomplete data by using the probability theory. Similar considerations apply to in vivo quality control. In the present paper, we have of course calculated the standard deviation (SD) from the mean value, for each beam for the dose delivered, and for the field localization. For the latter, the size of the "large systematic deviation" (5 mm) has been chosen precisely equal to 2 times SD as stated in the conclusions, in order to increase the probability of differentiating a possible systematic error from the random error as it can be expected that, if the mean is correct, 95 %

of all random deviations should fall within this limit. The distributions and SDs of the deviations from the mean values have been omitted to shorten the paper and because they seemed to us not to be very relevant in the present paper. We have deliberately decided to calculate the deviations from the first film and not from the mean value. The idea was to show the relevance of this information in relation to what he could expect to find out, should he perform systematic measurements during every session. We agree that this is not the best calculation from the statistical point of view, but we think that it is the only relevant value for the radiotherapists who, at the start of the therapy, will only have this information at his disposal to make a decision on the subsequent treatment series. Furthermore, the mean values of the distributions in Fig. 2 are very near 0, and the mean values and SD values for the first films are very similar to those for the global distributions. We agree completely with the considerations on the respective sizes of the random and systematic errors (last paragraph of the letter [1]). But can we remind the reader that we have chosen the "large systematic deviation" equal to 2 SD on purpose, to be larger than most (95%) of the random errors? It is obvious that before any judgment on the signification of a deviation, the SD for the group of patients under consideration should have been determined beforehand and the correct value of what should be defined as a "large systematic error" should have been determined. It can be found in our discussion (on-line measurements) that we recommend to perform a second measurement to verify the impact of the corrective action. In the following section (the section after off-line measurements), we have considered the possible cause of a deviation observed in the first session: random or systematic, and the necessity of repeated verification. Of course the conclusions are only valid for the head and neck patients treated with a verification system, as stated. We hope that we can convince the radiotherapists how useful it is to check every field during the first session and that they can understand the value as well as the limitations of this measurements. It is true that two measurements give more information than one, and that complete information will only be available after daily measurements. The most valuable statistical data become available from the retrospective analysis of all data giving the mean value, the SD, and the incidence of large deviations. This can be very useful to prepare general guidelines for a department. However, in clinical practice, for individual patients, it is mandatory to make early assessments, nec-