intheU.S.A. ht.3.Radiation (kco@y Bid.pkys., 1976, Vol.I,pp_373-374.Pcrpmon Press.FriaIed
CURE HAS ITS TOMORROWS GIULIO J. D’ANGIO, M.D. Department of RadiationTherapy, MemorialHospital, 1275York Ave., NY 10021,U.S.A. Children with cancer are being cured in ever-increasing numbers, and the day is not too far distant, it seems, when most of the malignant conditions of childhood will be brought under control. While the energies and attention of those treating these children quite properly continue to be focused on this goal, there is a growing realization that successful treatment has its consequences. The tender tissues of the developing child are particularly vulnerable to the aggressive treatments used in the management of patients with cancer. Disturbance of normal growth and development, impairment of function of vital organs, gonadal and genetic adversities and oncogenesis are all to be anticipated in long term survivors of childhood cancer. Pediatric oncologists and others managing children with cancer are diverting some of their attention from cure itself to the consequences of cure. The papers by Verzosa et al. and by Jereb et al. in this issue are examples of studies being conducted to understand the untoward consequences of therapy. Verzosa et al. report the results of a study of patients receiving cranial irradiation for acute leukemia. They find no impairment of intellect or psychologic disturbance in the patients so treated. This is a reassuring finding because of the frequent use of ‘irradiation for the suppression of leukemic infiltration of the meninges in patients with leukemia and lymphosarcoma. However, there is evidence from the same institution that the procedure is not so benign when coupled with methotrexate given systemically. Price and Jamieson’ found leukoencephalopathy in patients receiving the combination of treatments. Others have reported similar findings in irradiated
leukemic children various receiving chemotherapies.’ Indeed, both irradiation alone’ (unlike the Verzosa report), and systemic methotrexate alone’ have been implicated by others in their reports of patients with impairment of both physical and intellectual development. Additional experience is needed before the risks are identified with greater certainty. The reports by Jereb et al. (pp. 217-225) and Harrison et al. (pp. 227-234) both have roots in the same general problem. The focus is on stratagems designed to produce better local control and over-all survival in the diseases they discuss. Stress also is placed on refinements of treatment techniques so as to achieve local control at minimum cost in radiation damage. Jereb and colleagues especially point up the pronounced increase in radiation-associated complications in patients who receive multiple-agent chemotherapy regimens which include drugs that augment radiation effects. Adriamycin has recently been identified as one of these, and acts much like actinomycin D as a radiation enhancer and reactivator.‘ Even some of the more familiar therapeutic agents have been found to increase radiation effects when given in higher doses. Thus, high-dose regimens of methotrexate’ have many of the same properties as actinomycin D, and the author has observed the same clinical reaction in association with the use of high doses of cyclophosphamide. Experience with multi-modal therapy employing combinations of these agents has shown that doses and volumes irradiated with relative impunity in the past, even in association with actinomycin D, are no longer tolerable. These considerations are especially perti373
374
Radiation Oncology 0 Biology 0 Physics
nent to pediatric oncology, but the multimodal approach pioneered in pediatrics is now being applied to adults with increasing frequency. The lessons learned from children apply equally to the adult population. The fact that the complications may be less evident in older patients should not lead to a false sense of security. The rapidly developing and growing structures of children manifest the late effects of chemotherapy, radiation therapy and their combination more quickly, but there is no reason to suspect that the same cells and tissues in adults are not subject to similar adversities, albeit with more delay. Considerations of this kind have already prompted the convening of two symposia. The first dealt with these problems in childhood;’ the second, entitled “The Delayed Consequences of Cancer Therapy: Proven and Potential”, was more general in s~ope.~ The proceedings of these symposia make the issue clear: treatment methods must be evaluated carefully with respect to both their benefits and potential hazards, now that more patients are living for longer periods of time. It is truly heartening that clinicians must now be concerned with these problems,
1.
2. 3. 4.
5.
Vol. 1, No. 3-4
because they are a measure of the success achieved in controlling cancer. Prophylaxis and prevention of disease remain the ultimate goals of the physician. Until these can be realized, the intermediate aim; namely, cure without complications, requires concentrated effort and hard work.3 Indiscriminate additions of drugs and concatenations of therapies do not always lead to better results; on the contrary, the increase in short and long-term complications may far outweigh the beneficial tumor effects. Complex, multimodal therapies entailing the use of multiple chemotherapeutic agents therefore need careful. scrutiny to identify and eliminate non-essential treatments from therapeutic “cocktails” so that only those found absolutely necessary for best results are retained. The clinical investigator can take pride and gain confidence and encouragement from what he has achieved in improving the cure rates of patients with cancer. Now he must realize that cure has its tomorrows, and address himself to the aftermath of therapy so that the best quality of survival can be obtained for the patients under his care.
REFERENCES Bamford, F.N., Morris-Jones, J., Pearson, D., 6. Price, R.A., Jamieson, P.A.: The central nervous system in childhood leukemia. Cancer 35: Rii, G.G., Shalct, S.M., Beardwell, C.G.: 306-318, 1975. Residual disabilities in children treated for intra-cranialspace occupying lesions. Cancer to 7. Rosen, G., Suwansirikul, S., Kwon, C., Tan, C., Wu, S.J., Beattic, E.J., Murphy, M.L.: Hi& be published. dose methotrcxatc with citrovorum factor Conference on the delayed consequences of rescue and adriamycin in childhood osteogenic cancer therapy; proven and potential. Cancer to sarcoma. Cancer 33~ 1151-1163, 1974. be published. D’Angio, G.J.: Pediatric cancer in perspective: 8. Rubinstcin, L.J., Herman, MM., Long, T.F., Wilbur, J.R.: Disseminated ncerotizing leukocure is not enough. Cancer 35: 866-870, 1975. cncephalopathy: A complication of treated Donaldson, S.S., Glick, J. M., Wilbur, J.R.: central nervous system leukemia and lymAdriamycin activating a recall phenomenon phoma. Cancer 35: 291-305, 1975. after radiation therapy. (Letter to the Editor). 9. Symposium on the late consequences of sucAnn. Interwhfed. 81: 407-408, 1974. cessful cancer treatment given children and Meadows, M.D., Evans, A.E.: Effects of adolescents. Radiology 114: 145-180, 1975. chemotherapy on the central nervous system. Cancer to be published.
CURE HAS ITS TOMORROWS GIULIO J. D’ANGIO, M.D. Department of RadiationTherapy, MemorialHospital, 1275York Ave., NY 10021,U.S.A. Children with cancer are being cured in ever-increasing numbers, and the day is not too far distant, it seems, when most of the malignant conditions of childhood will be brought under control. While the energies and attention of those treating these children quite properly continue to be focused on this goal, there is a growing realization that successful treatment has its consequences. The tender tissues of the developing child are particularly vulnerable to the aggressive treatments used in the management of patients with cancer. Disturbance of normal growth and development, impairment of function of vital organs, gonadal and genetic adversities and oncogenesis are all to be anticipated in long term survivors of childhood cancer. Pediatric oncologists and others managing children with cancer are diverting some of their attention from cure itself to the consequences of cure. The papers by Verzosa et al. and by Jereb et al. in this issue are examples of studies being conducted to understand the untoward consequences of therapy. Verzosa et al. report the results of a study of patients receiving cranial irradiation for acute leukemia. They find no impairment of intellect or psychologic disturbance in the patients so treated. This is a reassuring finding because of the frequent use of ‘irradiation for the suppression of leukemic infiltration of the meninges in patients with leukemia and lymphosarcoma. However, there is evidence from the same institution that the procedure is not so benign when coupled with methotrexate given systemically. Price and Jamieson’ found leukoencephalopathy in patients receiving the combination of treatments. Others have reported similar findings in irradiated
leukemic children various receiving chemotherapies.’ Indeed, both irradiation alone’ (unlike the Verzosa report), and systemic methotrexate alone’ have been implicated by others in their reports of patients with impairment of both physical and intellectual development. Additional experience is needed before the risks are identified with greater certainty. The reports by Jereb et al. (pp. 217-225) and Harrison et al. (pp. 227-234) both have roots in the same general problem. The focus is on stratagems designed to produce better local control and over-all survival in the diseases they discuss. Stress also is placed on refinements of treatment techniques so as to achieve local control at minimum cost in radiation damage. Jereb and colleagues especially point up the pronounced increase in radiation-associated complications in patients who receive multiple-agent chemotherapy regimens which include drugs that augment radiation effects. Adriamycin has recently been identified as one of these, and acts much like actinomycin D as a radiation enhancer and reactivator.‘ Even some of the more familiar therapeutic agents have been found to increase radiation effects when given in higher doses. Thus, high-dose regimens of methotrexate’ have many of the same properties as actinomycin D, and the author has observed the same clinical reaction in association with the use of high doses of cyclophosphamide. Experience with multi-modal therapy employing combinations of these agents has shown that doses and volumes irradiated with relative impunity in the past, even in association with actinomycin D, are no longer tolerable. These considerations are especially perti373
374
Radiation Oncology 0 Biology 0 Physics
nent to pediatric oncology, but the multimodal approach pioneered in pediatrics is now being applied to adults with increasing frequency. The lessons learned from children apply equally to the adult population. The fact that the complications may be less evident in older patients should not lead to a false sense of security. The rapidly developing and growing structures of children manifest the late effects of chemotherapy, radiation therapy and their combination more quickly, but there is no reason to suspect that the same cells and tissues in adults are not subject to similar adversities, albeit with more delay. Considerations of this kind have already prompted the convening of two symposia. The first dealt with these problems in childhood;’ the second, entitled “The Delayed Consequences of Cancer Therapy: Proven and Potential”, was more general in s~ope.~ The proceedings of these symposia make the issue clear: treatment methods must be evaluated carefully with respect to both their benefits and potential hazards, now that more patients are living for longer periods of time. It is truly heartening that clinicians must now be concerned with these problems,
1.
2. 3. 4.
5.
Vol. 1, No. 3-4
because they are a measure of the success achieved in controlling cancer. Prophylaxis and prevention of disease remain the ultimate goals of the physician. Until these can be realized, the intermediate aim; namely, cure without complications, requires concentrated effort and hard work.3 Indiscriminate additions of drugs and concatenations of therapies do not always lead to better results; on the contrary, the increase in short and long-term complications may far outweigh the beneficial tumor effects. Complex, multimodal therapies entailing the use of multiple chemotherapeutic agents therefore need careful. scrutiny to identify and eliminate non-essential treatments from therapeutic “cocktails” so that only those found absolutely necessary for best results are retained. The clinical investigator can take pride and gain confidence and encouragement from what he has achieved in improving the cure rates of patients with cancer. Now he must realize that cure has its tomorrows, and address himself to the aftermath of therapy so that the best quality of survival can be obtained for the patients under his care.
REFERENCES Bamford, F.N., Morris-Jones, J., Pearson, D., 6. Price, R.A., Jamieson, P.A.: The central nervous system in childhood leukemia. Cancer 35: Rii, G.G., Shalct, S.M., Beardwell, C.G.: 306-318, 1975. Residual disabilities in children treated for intra-cranialspace occupying lesions. Cancer to 7. Rosen, G., Suwansirikul, S., Kwon, C., Tan, C., Wu, S.J., Beattic, E.J., Murphy, M.L.: Hi& be published. dose methotrcxatc with citrovorum factor Conference on the delayed consequences of rescue and adriamycin in childhood osteogenic cancer therapy; proven and potential. Cancer to sarcoma. Cancer 33~ 1151-1163, 1974. be published. D’Angio, G.J.: Pediatric cancer in perspective: 8. Rubinstcin, L.J., Herman, MM., Long, T.F., Wilbur, J.R.: Disseminated ncerotizing leukocure is not enough. Cancer 35: 866-870, 1975. cncephalopathy: A complication of treated Donaldson, S.S., Glick, J. M., Wilbur, J.R.: central nervous system leukemia and lymAdriamycin activating a recall phenomenon phoma. Cancer 35: 291-305, 1975. after radiation therapy. (Letter to the Editor). 9. Symposium on the late consequences of sucAnn. Interwhfed. 81: 407-408, 1974. cessful cancer treatment given children and Meadows, M.D., Evans, A.E.: Effects of adolescents. Radiology 114: 145-180, 1975. chemotherapy on the central nervous system. Cancer to be published.
