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1’4, PP. Ih?l-I622
CoP>ngh,
0360-X)16/90 $3.00 + .w cc ,990 Pergamon PrtSS Pk
0 Editorial WILL ALTERED FRACTION SCHEMES ALTER THE FUTURE? JAY S. COOPER, M.D. Dept. of Radiation Oncology. New York University Medical Center. 566 First Ave., New York, NY 10016 neck cancer is standard treatment in some facilities (e.g The University of Florida (4)) and accelerated hyperfractionation with a mid-course split is standard in others (e.g.. The Massachusetts General Hospital (5)). In both examples, the regimens were developed by very experienced. reputable physicians. There is little doubt that their most recent data, describing the effects of these altered fractionation schemes, appear to show better results than was seen in historical controls (treated by once-per-day conventional radiotherapy). But do the results primarily reflect the treatment regimen or the increasing armamentarium and experience of the practitioners? Have ancillary advances, (e.g., the routine use of CT for the evaluation of the extent of disease and staging) influenced more recent results? Can these results be exported to other facilities that provide different levels of support and that serve patients from different socio-economic groups? I think we simply do not yet know. As yet another alternative, the MD Anderson group has suggested the possible repackaging of radiotherapy based on a concomitant boost technique (2). Their rearrangement scheme utilizes a mixture of conventional fractionation for part of treatment and accelerated hyperfractionation for the rest. Are they showing us a way to reap the benefits of twice daily schemes while maintaining the safety of tried and true conventional therapy? The article by Anger al. in this issue (I), likely represents an important advance in our knowledge. Surely, their study is not perfect. I would have preferred if they had stayed with their original design and ran a purely randomized prospective trial. Without it, I cannot conclude that their patients who received a concomitant boost at the end of treatment fared better than patients who got their boost initially or in mid-course. However, they have convinced me that the terminal boost technique is ut feust no newsy than the alternatives. Unlike many negative trials we have run in the past that have left us wondering if the outcome would have been different if the dose or schedule were changed slightly, the M.D. Anderson data demonstrate that if terminal concomitant boost techniques do
Advanced stage tumors of the head and neck have provided an important testing ground for new concepts of treatment. Within the past decade they have been used to evaluate radiotherapy alone and in combination with surgery, chemotherapy and various response modifiers. As the 1990’s begin. it seems appropriate to ask what have we learned thus far and where are we heading. The 1980’s began with great hope for the value of the hypoxic-cell radiosensitizer misonidazole. The rationale seemed right: (a) CT scanners showed us the presence of necrotic and hypoxic cores in the cervical lymph nodes of many patients: (b) high hemoglobin levels appeared to correlate with local control of large tumors (and what else could hemoglobin be but a surrogate measure of oxygen delivery?), and (c)the drug had proven efficacious against hypoxic cells in vitro. The trials, however, proved fruitless. Perhaps newer drugs, like Etanidazole (SR-2508). will eventually fulfill the promise, but at present hypoxic tumor cells cannot be overcome by chemicals added to radiation therapy in routine practice. Chemotherapy augmented radiotherapy regimens also received major attention in the 1980’s. We tested numerous philosophies, various drugs, and differing schedules, but failed to identify an optimal drug (or drugs). an optimum dose or an optimum schedule. Several clinical trials implied therapeutic gains, but others revealed no benefit. We have only begun to test the optimum place of chemotherapy augmented radiotherapy; is it best used by itself or in combination with surgery? Perhaps chemo/ radiotherapy can even eliminate the need for surgery as is suggested by the recently completed VA trial (3). Yet the 1990’s begin with the potential benefit of chemotherapy remaining unproven and unjustified as a radiationenhancing agent for routine use. Other researchers have tried to improve the efficacy of treatment in a more basic fashion by repackaging radiotherapy in innovative ways. In fact, part of the radiation oncology community already is convinced that such schemes are preferable to the older once-per-day regimens. Hyperfractionated radiotherapy for advanced head and
Accepted for publication
24 May 1990. 1621
1622
1. J. Radiation
Oncology
0 Biology 0 Physics
not work, we need not waste our time, money or resources to test initial or mid-course boost regimens. Where shall we go from here? In my mind it is imperative that the Oncology community support trials of altered fractionation. They can be done today without the need for drug development or additional spadework and they are essential to clarify the current variation in radiotherapy across the country. We need to learn which, if any, altered fractionation scheme(s) is(are) best or perhaps how to select patients for different forms of altered fractionation. We need to learn if altered fractionation can be used equally well in all kinds of facilities and if it can be tolerated by nutritionally deprived patients, the old and the infirmed. We will also need to mount an educational campaign. Altered fractionation schemes are relatively unknown outside the radiation oncology community. In fact, at the Strategy Meeting on Head and Neck Cancer held by the Cancer Therapy Evaluation Program (CTEP) of the Na-
December
1990, Volume
19, Number
6
tional Cancer Institute on April 17, 1989. they were not even discussed. We will also need to face economic issues. Hyperfractionation, by definition. results in an increased work load. Where will the machine time, the technologists and the radiation oncologists come from to absorb the increased demand? If the cost of health care is already so high that the purchase of equipment has to be government-regulated through certificates of need, and the fees of radiation oncologists controlled through RVS. can we seriously contemplate more costly altered fractionation schemes? Absolutely! When compared to the cost of adjuvant chemotherapy, or the likely cost of hypoxic-cell sensitizers, the advantage goes to altered fractionation schemes. When compared to the cost of recurrent head and neck cancer they are a bargain. The time has come for us to design and run scientifically unassailable trials of altered fractionation schemes so that every patient who has a head and neck cancer in the future can be treated by an optimal radiotherapy regimen.
REFERENCES 1. Ang, K. K.; Peters, L. J.: Weber. R. S.; Maor, M. H.; Morrison. W. H.; Wendt. C. D.; Brown, B. W. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int. J. Radiat. Oncol. Biol. Phys. 19: 1339- 1344; 1990. 2. Knee, R.; Fields. R. S.; Peters, L. J. Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 4: 1-7: 1985. 3. Laramore, G. E.; Wolf, G. T.; Hong, W. K.; Fisher, S. G.; Spaulding, M.: Endicott, J.: Hillman. R. E.: McClathey, K.:
Fye. C. Phase III trial testing the efficacy of induction chemotherapy and definitive radiotherapy for advanced laryngeal cancer: interim report on VA CSP #268. Proc. Am. Rad. Sot. 71st Ann. Mtg. 1989:lS. 4. Parsons. J. T.; Mendenhall, W. M.: Cassisi, N. J.: Isaacs. J. H.: Million. R. R. Hyperfractionation for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:649-658; 1988. 5. Wang, C. C.; Blitzer. P. H.; Suit, H. D. Twice-a-day radiation therapy for cancer of the head and neck. Cancer 55:2 I OO2 104: 1985.
1’4, PP. Ih?l-I622
CoP>ngh,
0360-X)16/90 $3.00 + .w cc ,990 Pergamon PrtSS Pk
0 Editorial WILL ALTERED FRACTION SCHEMES ALTER THE FUTURE? JAY S. COOPER, M.D. Dept. of Radiation Oncology. New York University Medical Center. 566 First Ave., New York, NY 10016 neck cancer is standard treatment in some facilities (e.g The University of Florida (4)) and accelerated hyperfractionation with a mid-course split is standard in others (e.g.. The Massachusetts General Hospital (5)). In both examples, the regimens were developed by very experienced. reputable physicians. There is little doubt that their most recent data, describing the effects of these altered fractionation schemes, appear to show better results than was seen in historical controls (treated by once-per-day conventional radiotherapy). But do the results primarily reflect the treatment regimen or the increasing armamentarium and experience of the practitioners? Have ancillary advances, (e.g., the routine use of CT for the evaluation of the extent of disease and staging) influenced more recent results? Can these results be exported to other facilities that provide different levels of support and that serve patients from different socio-economic groups? I think we simply do not yet know. As yet another alternative, the MD Anderson group has suggested the possible repackaging of radiotherapy based on a concomitant boost technique (2). Their rearrangement scheme utilizes a mixture of conventional fractionation for part of treatment and accelerated hyperfractionation for the rest. Are they showing us a way to reap the benefits of twice daily schemes while maintaining the safety of tried and true conventional therapy? The article by Anger al. in this issue (I), likely represents an important advance in our knowledge. Surely, their study is not perfect. I would have preferred if they had stayed with their original design and ran a purely randomized prospective trial. Without it, I cannot conclude that their patients who received a concomitant boost at the end of treatment fared better than patients who got their boost initially or in mid-course. However, they have convinced me that the terminal boost technique is ut feust no newsy than the alternatives. Unlike many negative trials we have run in the past that have left us wondering if the outcome would have been different if the dose or schedule were changed slightly, the M.D. Anderson data demonstrate that if terminal concomitant boost techniques do
Advanced stage tumors of the head and neck have provided an important testing ground for new concepts of treatment. Within the past decade they have been used to evaluate radiotherapy alone and in combination with surgery, chemotherapy and various response modifiers. As the 1990’s begin. it seems appropriate to ask what have we learned thus far and where are we heading. The 1980’s began with great hope for the value of the hypoxic-cell radiosensitizer misonidazole. The rationale seemed right: (a) CT scanners showed us the presence of necrotic and hypoxic cores in the cervical lymph nodes of many patients: (b) high hemoglobin levels appeared to correlate with local control of large tumors (and what else could hemoglobin be but a surrogate measure of oxygen delivery?), and (c)the drug had proven efficacious against hypoxic cells in vitro. The trials, however, proved fruitless. Perhaps newer drugs, like Etanidazole (SR-2508). will eventually fulfill the promise, but at present hypoxic tumor cells cannot be overcome by chemicals added to radiation therapy in routine practice. Chemotherapy augmented radiotherapy regimens also received major attention in the 1980’s. We tested numerous philosophies, various drugs, and differing schedules, but failed to identify an optimal drug (or drugs). an optimum dose or an optimum schedule. Several clinical trials implied therapeutic gains, but others revealed no benefit. We have only begun to test the optimum place of chemotherapy augmented radiotherapy; is it best used by itself or in combination with surgery? Perhaps chemo/ radiotherapy can even eliminate the need for surgery as is suggested by the recently completed VA trial (3). Yet the 1990’s begin with the potential benefit of chemotherapy remaining unproven and unjustified as a radiationenhancing agent for routine use. Other researchers have tried to improve the efficacy of treatment in a more basic fashion by repackaging radiotherapy in innovative ways. In fact, part of the radiation oncology community already is convinced that such schemes are preferable to the older once-per-day regimens. Hyperfractionated radiotherapy for advanced head and
Accepted for publication
24 May 1990. 1621
1622
1. J. Radiation
Oncology
0 Biology 0 Physics
not work, we need not waste our time, money or resources to test initial or mid-course boost regimens. Where shall we go from here? In my mind it is imperative that the Oncology community support trials of altered fractionation. They can be done today without the need for drug development or additional spadework and they are essential to clarify the current variation in radiotherapy across the country. We need to learn which, if any, altered fractionation scheme(s) is(are) best or perhaps how to select patients for different forms of altered fractionation. We need to learn if altered fractionation can be used equally well in all kinds of facilities and if it can be tolerated by nutritionally deprived patients, the old and the infirmed. We will also need to mount an educational campaign. Altered fractionation schemes are relatively unknown outside the radiation oncology community. In fact, at the Strategy Meeting on Head and Neck Cancer held by the Cancer Therapy Evaluation Program (CTEP) of the Na-
December
1990, Volume
19, Number
6
tional Cancer Institute on April 17, 1989. they were not even discussed. We will also need to face economic issues. Hyperfractionation, by definition. results in an increased work load. Where will the machine time, the technologists and the radiation oncologists come from to absorb the increased demand? If the cost of health care is already so high that the purchase of equipment has to be government-regulated through certificates of need, and the fees of radiation oncologists controlled through RVS. can we seriously contemplate more costly altered fractionation schemes? Absolutely! When compared to the cost of adjuvant chemotherapy, or the likely cost of hypoxic-cell sensitizers, the advantage goes to altered fractionation schemes. When compared to the cost of recurrent head and neck cancer they are a bargain. The time has come for us to design and run scientifically unassailable trials of altered fractionation schemes so that every patient who has a head and neck cancer in the future can be treated by an optimal radiotherapy regimen.
REFERENCES 1. Ang, K. K.; Peters, L. J.: Weber. R. S.; Maor, M. H.; Morrison. W. H.; Wendt. C. D.; Brown, B. W. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int. J. Radiat. Oncol. Biol. Phys. 19: 1339- 1344; 1990. 2. Knee, R.; Fields. R. S.; Peters, L. J. Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 4: 1-7: 1985. 3. Laramore, G. E.; Wolf, G. T.; Hong, W. K.; Fisher, S. G.; Spaulding, M.: Endicott, J.: Hillman. R. E.: McClathey, K.:
Fye. C. Phase III trial testing the efficacy of induction chemotherapy and definitive radiotherapy for advanced laryngeal cancer: interim report on VA CSP #268. Proc. Am. Rad. Sot. 71st Ann. Mtg. 1989:lS. 4. Parsons. J. T.; Mendenhall, W. M.: Cassisi, N. J.: Isaacs. J. H.: Million. R. R. Hyperfractionation for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:649-658; 1988. 5. Wang, C. C.; Blitzer. P. H.; Suit, H. D. Twice-a-day radiation therapy for cancer of the head and neck. Cancer 55:2 I OO2 104: 1985.
