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The promise of low dose rate: has it been realized?
036C-3016/78/0801-0749/$.02.00/0
Int. 3. Radiation Oncology Biol. Phys., Vol. 4, pp. 749-750 @ Pergmon Press Inc., 1978. Printed in the U.S.A.
a
Editorial
THE PROMISE
OF LOW DOSE RATE: HAS IT BEEN REALIZED? ERIC J. HALL, D.Phil.
Radiological
Research Laboratory,
Low dose-rate beam teletberapy,
College of Physicians and Surgeons, Columbia University, Street, NY 10032, U.S.A. Interstitial
630 W. 168th
implants
Low dose-rate interstitial implants have been described as the treatment of choice par excellence for some types of human cancers. The first generation of radiotherapists, practicing in the 1930s and 194Os, included a number of individuals who became highly skilled in implant techniques using radium, and who have continually expressed enthusiasm for the clinical results obtained. In later years, interstitial techniques fell out of favor, partly because of the protection problems involved and partly because of the concurrent advances in the design of beam therapy equipment. Consequently, a whole second generation of radiotherapists grew up, particularly in the United States, for whom interstitial implants are largely a lost art. Only a few centers of excellence continue to use brachytherapy for a substantial number of cases. In the past few years there has clearly been a renaissance in interstitial therapy. After-loading techniques and the introduction of ‘%, both of which help to overcome protection problems, have allowed elegant implants to be performed and have led to a revival of interest. In 1970, Pierquin described the new technique of low dose-rate beam teletherapy. Patients were treated with a @‘Co teletherapy unit at a low dose-rate (1 lo-180 rad/hr), and given about 1000 rad per day in daily sessions lasting 6-8 hr. The rationale for this method was to combine the “superior” results obtained with low dose radium procedures with the convenience and safety of beam teletherapy. This time-consuming procedure rests foursquare upon the assumption that radium techniques do in fact yield superior results to conventional fractionated high dose-rate beam therapy. This superiority is a clinical impression, and unsupported, to my knowledge, by controlled studies. However, if it is accepted, it could be attributed to three causes. First, implants can deliver a high localized dose with a rapid fall off of dose outside the target volume. Second, the dose-rate is low and continuous rather than high and intermittent. Third, the dose is
delivered in a relatively short period. For example, 6000 rad from a radium implant may be delivered in 7 days, while the same dose must be spread out over 6 weeks when given by a teletherapy unit as a series of high dose-rate fractions. If the first factor is responsible for the success of radium treatments, then low dose-rate beam therapy could not be expected to yield any advantage, since the unique dose distribution characteristic of an implant cannot possibly be simulated by any beam therapy treatment plan. If on the other hand, the success of implants is due to the low dose-rate, or the fact that the treatment is compressed into a short period, then this advantage also could be exploited by low dose-rate beam therapy. Recent experimental data with cells in culture indicate that under continuous low dose-rate exposure to -y-rays, cells tend to pile up in the GJM phase of the cell cycle where they are particularly sensitive to cell killing. There is good evidence that a population of dividing cells continuously exposed for several cell cycles becomes much more sensitive to a single acute dose of radiation, which is an indication that cells have been accumulated at a sensitive phase of the cell cycle. This would be the rationale for the superiority of low dose-rate continuous irradiation. Some eight years after his first report, Pierquin has written in this current issue of the Journal (see pages 565-572) an interesting paper updating his experience with beam therapy delivered at low dose-rate. The technique has undergone a number of revisions and changes. The most important change is the introduction of a split-course regimen whereby 3500 rad is followed by a three-week rest interval before a further 3500rad is given. This overall time is not too different from conventional fractionated beam therapy techniques, but the radiation is delivered in two concentrated 5 day periods (at the beginning and end), during which about 700 rad/day is delivered in 6-9 hr sessions at dose-rates of 90-130 rad/hr. The principal reason for the split course is to minimize the 149
750
Radiation
Oncology
0 Biology
0 Physics
normal tissue effects which proved to be a problem when a single 7 day course was used. Has the promise of low dose-rate been realized? The answer seems to be no. As time progresses, the promise recedes into the future and eludes one’s grasp. Progress in implementing low dose-rate trials is slow and suffers from the same problems as most other trials, particularly that of neutrons. First, the accrual of enough suitable patients is a problem. Second, the need to proceed cautiously means that patients with a poor prognosis must be treated who inevitably do not survive long enough for a full evaluation, particularly of late effects. The promise, then, may not have been realized as yet, but it has not been adequately put to the test. It remains a promise. This may be the time and place to point out that this is an area of research where more individuals could participate. Hundreds of cobalt units stand idle for two-thirds of their useful lifetime, which is an enormous waste of capital investment. With the addition of a filter to reduce the dose-rate.
July-August
1978, Volume
4, No. 7 and No. 8
evening or night shifts could be organized in many centers to bolster the trial of low dose-rate teletherapy. No vast involvement of technical expertise and no enormous capital expenditure is required for this project, comparable with those involved in the current trials of high LET radiations. Many more centers might consider taking part in the trial of low dose-rate teletherapy. In addition, low dose-rate beam teletherapy might be particularly suitable for combination with the new generation of hypoxic cell radiosensitizers, such as Misonidazole. Unpleasant side effects limit the number of occasions upon which these drugs can be administered, but the substantial half-life of the drug in the human (about 12-17 hr) would mean that it would be present and able to sensitize hypoxic cells throughout a low dose-rate treatment session of 8 hr during which a dose approaching a 1000 rad is given. A promise is still a promise until it is realized, or until it is shown to be impossible to fulfill.
Int. 3. Radiation Oncology Biol. Phys., Vol. 4, pp. 749-750 @ Pergmon Press Inc., 1978. Printed in the U.S.A.
a
Editorial
THE PROMISE
OF LOW DOSE RATE: HAS IT BEEN REALIZED? ERIC J. HALL, D.Phil.
Radiological
Research Laboratory,
Low dose-rate beam teletberapy,
College of Physicians and Surgeons, Columbia University, Street, NY 10032, U.S.A. Interstitial
630 W. 168th
implants
Low dose-rate interstitial implants have been described as the treatment of choice par excellence for some types of human cancers. The first generation of radiotherapists, practicing in the 1930s and 194Os, included a number of individuals who became highly skilled in implant techniques using radium, and who have continually expressed enthusiasm for the clinical results obtained. In later years, interstitial techniques fell out of favor, partly because of the protection problems involved and partly because of the concurrent advances in the design of beam therapy equipment. Consequently, a whole second generation of radiotherapists grew up, particularly in the United States, for whom interstitial implants are largely a lost art. Only a few centers of excellence continue to use brachytherapy for a substantial number of cases. In the past few years there has clearly been a renaissance in interstitial therapy. After-loading techniques and the introduction of ‘%, both of which help to overcome protection problems, have allowed elegant implants to be performed and have led to a revival of interest. In 1970, Pierquin described the new technique of low dose-rate beam teletherapy. Patients were treated with a @‘Co teletherapy unit at a low dose-rate (1 lo-180 rad/hr), and given about 1000 rad per day in daily sessions lasting 6-8 hr. The rationale for this method was to combine the “superior” results obtained with low dose radium procedures with the convenience and safety of beam teletherapy. This time-consuming procedure rests foursquare upon the assumption that radium techniques do in fact yield superior results to conventional fractionated high dose-rate beam therapy. This superiority is a clinical impression, and unsupported, to my knowledge, by controlled studies. However, if it is accepted, it could be attributed to three causes. First, implants can deliver a high localized dose with a rapid fall off of dose outside the target volume. Second, the dose-rate is low and continuous rather than high and intermittent. Third, the dose is
delivered in a relatively short period. For example, 6000 rad from a radium implant may be delivered in 7 days, while the same dose must be spread out over 6 weeks when given by a teletherapy unit as a series of high dose-rate fractions. If the first factor is responsible for the success of radium treatments, then low dose-rate beam therapy could not be expected to yield any advantage, since the unique dose distribution characteristic of an implant cannot possibly be simulated by any beam therapy treatment plan. If on the other hand, the success of implants is due to the low dose-rate, or the fact that the treatment is compressed into a short period, then this advantage also could be exploited by low dose-rate beam therapy. Recent experimental data with cells in culture indicate that under continuous low dose-rate exposure to -y-rays, cells tend to pile up in the GJM phase of the cell cycle where they are particularly sensitive to cell killing. There is good evidence that a population of dividing cells continuously exposed for several cell cycles becomes much more sensitive to a single acute dose of radiation, which is an indication that cells have been accumulated at a sensitive phase of the cell cycle. This would be the rationale for the superiority of low dose-rate continuous irradiation. Some eight years after his first report, Pierquin has written in this current issue of the Journal (see pages 565-572) an interesting paper updating his experience with beam therapy delivered at low dose-rate. The technique has undergone a number of revisions and changes. The most important change is the introduction of a split-course regimen whereby 3500 rad is followed by a three-week rest interval before a further 3500rad is given. This overall time is not too different from conventional fractionated beam therapy techniques, but the radiation is delivered in two concentrated 5 day periods (at the beginning and end), during which about 700 rad/day is delivered in 6-9 hr sessions at dose-rates of 90-130 rad/hr. The principal reason for the split course is to minimize the 149
750
Radiation
Oncology
0 Biology
0 Physics
normal tissue effects which proved to be a problem when a single 7 day course was used. Has the promise of low dose-rate been realized? The answer seems to be no. As time progresses, the promise recedes into the future and eludes one’s grasp. Progress in implementing low dose-rate trials is slow and suffers from the same problems as most other trials, particularly that of neutrons. First, the accrual of enough suitable patients is a problem. Second, the need to proceed cautiously means that patients with a poor prognosis must be treated who inevitably do not survive long enough for a full evaluation, particularly of late effects. The promise, then, may not have been realized as yet, but it has not been adequately put to the test. It remains a promise. This may be the time and place to point out that this is an area of research where more individuals could participate. Hundreds of cobalt units stand idle for two-thirds of their useful lifetime, which is an enormous waste of capital investment. With the addition of a filter to reduce the dose-rate.
July-August
1978, Volume
4, No. 7 and No. 8
evening or night shifts could be organized in many centers to bolster the trial of low dose-rate teletherapy. No vast involvement of technical expertise and no enormous capital expenditure is required for this project, comparable with those involved in the current trials of high LET radiations. Many more centers might consider taking part in the trial of low dose-rate teletherapy. In addition, low dose-rate beam teletherapy might be particularly suitable for combination with the new generation of hypoxic cell radiosensitizers, such as Misonidazole. Unpleasant side effects limit the number of occasions upon which these drugs can be administered, but the substantial half-life of the drug in the human (about 12-17 hr) would mean that it would be present and able to sensitize hypoxic cells throughout a low dose-rate treatment session of 8 hr during which a dose approaching a 1000 rad is given. A promise is still a promise until it is realized, or until it is shown to be impossible to fulfill.