0360-3016/91 $3.00 + .oO Copyright 0 1991 Pergamon Press plc
hf. .I. Rdiorion Oncology Bid. Phw., Vol. 21, pp. 1669-1670 Printed in the U.S A All rights reserved.
??Editorial
OUT ON A LIMB ON SARCOMAS ALAN H. EPSTEIN, M.D.’ AND ELI GLATSTIZIN”, M.D.* ‘Radiation Oncology Branch, National Cancer Institute Bethesda, MD 20892; and *Professor, Uniformed Services University of the Health Sciences Bethesda, MD 20814 gistic regression analysis of predictors for late effects does not account for the differences in length of follow-up), the generalizations are critically important. Technical factors do make a difference. The late effects are most severe with longer and/or wider fields, higher doses, and less sophisticated treatment planning. Unfortunately, the contribution of surgical factors is unknown. Obviously, if a full muscle group excision is performed, the functional compromise from surgery could be far more severe than any radiation effect. Outcomes such as muscle strength, range of motion, pain, contracture, etc. are thus determined conjointly by the extent of surgery and details of radiotherapy. The timing, quality, and duration of physical and rehabilitative therapy are also critical variables to be included ideally in an analysis. The next genre in the literature will undoubtedly see a more global focus. We can expect, with modern statistical technology, gradually to unravel the complex interrelationships between volume of normal and malignant tissue resected, timing of surgery with respect to administration of radiotherapy, intensity of radiotherapy, and the crucial roles of chemotherapy and especially physical therapy on late effects. The paper also suggests that functional results have improved in the more recently treated patients. The relative contributions of reduction in NSD and advancing technology (i.e., higher energies, gap wedges, and CT planning) to this change in late effects are unclear. However, it is certainly reasonable to expect further technical refinements and attendant reduction in treatment associated morbidity. If the costs of limb preservation in terms of late effects are difficult to quantitate, so are the relative benefits when compared to amputation. Studies comparing quality of life measures between radical and limb-sparing therapies have produced counterintuitive results by failing to demonstrate a quality-of-life benefit for conservative therapy (7, 11). Such studies have typically been retrospective surveys where the precise questions asked may predispose to biased answers. Also, the analysis of such data is fraught with statistical limitations. The most obvious question regarding these studies is whether they had adequate power to detect subtle yet clinically relevant differences. But the
The past decade has seen widening acceptance of multimodality organ preserving therapies for cancers of the breast, head and neck, GU and GI systems, and the extremities, as the general medical community awakens to the vast improvements in effectiveness and quality of radiation treatments . The program of limb sparing surgery with adjunctive radiation for extremity sarcomas is a paradigm of this success of conservative therapy. Historically, adult sarcomas have been considered “radioresistant” because they infrequently regress during radiotherapy, and surgery has traditionally been the definitive treatment. There is now evidence from a variety of sources that the addition of radiotherapy, either before or after conservative resection, or in select cases as definitive treatment following biopsy, offers an excellent prospect of local control (5, 8, 10). Additionally, a recent report from Memorial Sloan-Kettering Cancer Center, New York, NY has defined a role for brachytherapy as salvage treatment for previously irradiated recurrent extremity lesions (4). Clearly, patients still may succumb to distant metastases, and to date there is only a modest suggestion that currently available systemic therapy can alter the natural history of this disease (1, 3). Nevertheless, local control of extremity lesions remains an imperative and is achieved with high probability whether given preop, postop, or as intraoperative brachytherapy. The logical conclusion is that these sarcoma cells are actually sensitive, not resistant. The question is, at what kind of functional cost? It is remarkable how few published data exist in assessing post treatment results in extremity sarcomas. The report by Stinson et al. in this issue of the journal on the acute and long term effects of combined modality conservative therapy on limb function is an important first step in answering the question posed above (6). Attempt was made to correlate radiotherapy technical factors and the addition of chemotherapy to acute and late effects of treatment. This venture is a difficult one. Survival is an objective endpoint. Local control and late effects are scored by varying subjective criteria and are subject to multiple technical limitations in analysis (2) . Although the specific conclusions of this report must be viewed cautiously (lo-
Accepted for publication 9 September 199 1.
Reprint requests to: A. Epstein. 1669
1670
I. J. Radiation Oncology 0 Biology 0 Physics
central issue is whether a significant number of patients treated successfully by limb-sparing surgery would subsequently elect an amputation based on quality-of-life issues. If such cases exist, they must surely be anecdotal. Multimodality limb-sparing therapy is now widely accepted. The acute and late tissue effects are significant both in incidence and degree. However, Suit and Miralbell have documented that patients experience higher survival rates if they do not have local failure (9). Thus, we must continue
November 1991, Volume 21, Number 6
to treat these lesions aggressively in order to not sacrifice the strides already made; judicious refinements are needed. This endeavor will require the early and close cooperation of all oncology specialists involved in the care of a patient with sarcoma, including the specialists in rehabilitation. Ultimately, knowledge of the complex interrelationships between host, tumor, and treatment factors should lead to further improvements in local control, survival, and quality of life.
REFERENCES 1. Chang, A. E.; Kinsella, T.; Glatstein, E.; Baker, A. R.; Sindelar, W. F.; Lotze, M. T.; Danforth, D. N.; Sugarbaker, P. H.; Lack, E. Chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity. J. Clin. Oncol. 6:1491-1500; 1988. 2. Gelman, R.; Gelber, R.; Henderson, I. C.; Coleman, C. N.; Harris, J. R. Improved methodology for analyzing local and distant recurrence. J. Clin. Oncol. 8548-555; 1990. 3. Gherlinzoni, F.; Baci, G.; Picci, P.; Campanna, R.; Calderoni, P.; Lore& E. G.; Bemini, M.; Emiliani, E.; Barbieri, E.; Normand, A.; Campanacci, M. Randomized trial for the treatment of high grade soft tissue sarcomas of the extremities: Preliminary observations. J. Clin. Oncol. 4:552558; 1986. 4. Nori, D.; Shupak, K.; Shiu, M. H.; Brennan, M. F. Role of brachytherapy in recurrent extremity sarcoma in patients treated with prior surgery and radiation. Int. J. Radiat. Oncol. Biol. Phys. 20:1229-1233; 1991. 5. Shiu, M. H.; Turnbull, A. D.; Nori, D.; Hajdu, S.; Hilaris, B. Control of locally advanced extremity soft tissue sarcomas by function-saving resection and brachytherapy. Cancer. 53:1385-1392; 1984.
6. Stinson, S. F.; DeLaney, T. F.; Greenberg, J.; Yang, J. C.; Lampert, M. H.; Hicks, J. E.; Venzon, D.; White, D. E.; Rosenberg, S. A.; Glatstein, E. Acute and long term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 21(6):1493-1499; 1991. 7. Sugarbaker, P. H.; Barofsky, I.; Rosenberg, S. A.; Gianola, F. J. Quality of life assessment of patients in extremity sarcoma clinical trials. Surgery. 91: 17-23; 1982. 8. Suit, H. D.; Menkin, H. J.; Wood, W. C.; Gebhardt, M. C.; Harmon, D. C.; Rosenberg, A. ; Tepper, J. E.; Rosenthal, D. Treatment of the patient with stage MO soft tissue sarcoma. J. Clin. Oncol. 6:854-862; 1988. 9. Suit, H. D.; Miralbell, R. Potential impact of improvements in radiation therapy on quality of life and survival. Int. J. Radiat. Oncol. Biol. Phys. 16:891-895; 1989. 10. Tepper, J. E.; Suit, H. D. Radiation therapy alone for sarcoma of soft tissue. Cancer. 56:475479; 1985. 11. Weddington, W. W.; Blindt Segraves, K.; Simon, M. A. Psychological outcome of extremity sarcoma survivors undergoing amputation or limb salvage. J. Clin. Oncol. 3:1393-1399; 1985.
hf. .I. Rdiorion Oncology Bid. Phw., Vol. 21, pp. 1669-1670 Printed in the U.S A All rights reserved.
??Editorial
OUT ON A LIMB ON SARCOMAS ALAN H. EPSTEIN, M.D.’ AND ELI GLATSTIZIN”, M.D.* ‘Radiation Oncology Branch, National Cancer Institute Bethesda, MD 20892; and *Professor, Uniformed Services University of the Health Sciences Bethesda, MD 20814 gistic regression analysis of predictors for late effects does not account for the differences in length of follow-up), the generalizations are critically important. Technical factors do make a difference. The late effects are most severe with longer and/or wider fields, higher doses, and less sophisticated treatment planning. Unfortunately, the contribution of surgical factors is unknown. Obviously, if a full muscle group excision is performed, the functional compromise from surgery could be far more severe than any radiation effect. Outcomes such as muscle strength, range of motion, pain, contracture, etc. are thus determined conjointly by the extent of surgery and details of radiotherapy. The timing, quality, and duration of physical and rehabilitative therapy are also critical variables to be included ideally in an analysis. The next genre in the literature will undoubtedly see a more global focus. We can expect, with modern statistical technology, gradually to unravel the complex interrelationships between volume of normal and malignant tissue resected, timing of surgery with respect to administration of radiotherapy, intensity of radiotherapy, and the crucial roles of chemotherapy and especially physical therapy on late effects. The paper also suggests that functional results have improved in the more recently treated patients. The relative contributions of reduction in NSD and advancing technology (i.e., higher energies, gap wedges, and CT planning) to this change in late effects are unclear. However, it is certainly reasonable to expect further technical refinements and attendant reduction in treatment associated morbidity. If the costs of limb preservation in terms of late effects are difficult to quantitate, so are the relative benefits when compared to amputation. Studies comparing quality of life measures between radical and limb-sparing therapies have produced counterintuitive results by failing to demonstrate a quality-of-life benefit for conservative therapy (7, 11). Such studies have typically been retrospective surveys where the precise questions asked may predispose to biased answers. Also, the analysis of such data is fraught with statistical limitations. The most obvious question regarding these studies is whether they had adequate power to detect subtle yet clinically relevant differences. But the
The past decade has seen widening acceptance of multimodality organ preserving therapies for cancers of the breast, head and neck, GU and GI systems, and the extremities, as the general medical community awakens to the vast improvements in effectiveness and quality of radiation treatments . The program of limb sparing surgery with adjunctive radiation for extremity sarcomas is a paradigm of this success of conservative therapy. Historically, adult sarcomas have been considered “radioresistant” because they infrequently regress during radiotherapy, and surgery has traditionally been the definitive treatment. There is now evidence from a variety of sources that the addition of radiotherapy, either before or after conservative resection, or in select cases as definitive treatment following biopsy, offers an excellent prospect of local control (5, 8, 10). Additionally, a recent report from Memorial Sloan-Kettering Cancer Center, New York, NY has defined a role for brachytherapy as salvage treatment for previously irradiated recurrent extremity lesions (4). Clearly, patients still may succumb to distant metastases, and to date there is only a modest suggestion that currently available systemic therapy can alter the natural history of this disease (1, 3). Nevertheless, local control of extremity lesions remains an imperative and is achieved with high probability whether given preop, postop, or as intraoperative brachytherapy. The logical conclusion is that these sarcoma cells are actually sensitive, not resistant. The question is, at what kind of functional cost? It is remarkable how few published data exist in assessing post treatment results in extremity sarcomas. The report by Stinson et al. in this issue of the journal on the acute and long term effects of combined modality conservative therapy on limb function is an important first step in answering the question posed above (6). Attempt was made to correlate radiotherapy technical factors and the addition of chemotherapy to acute and late effects of treatment. This venture is a difficult one. Survival is an objective endpoint. Local control and late effects are scored by varying subjective criteria and are subject to multiple technical limitations in analysis (2) . Although the specific conclusions of this report must be viewed cautiously (lo-
Accepted for publication 9 September 199 1.
Reprint requests to: A. Epstein. 1669
1670
I. J. Radiation Oncology 0 Biology 0 Physics
central issue is whether a significant number of patients treated successfully by limb-sparing surgery would subsequently elect an amputation based on quality-of-life issues. If such cases exist, they must surely be anecdotal. Multimodality limb-sparing therapy is now widely accepted. The acute and late tissue effects are significant both in incidence and degree. However, Suit and Miralbell have documented that patients experience higher survival rates if they do not have local failure (9). Thus, we must continue
November 1991, Volume 21, Number 6
to treat these lesions aggressively in order to not sacrifice the strides already made; judicious refinements are needed. This endeavor will require the early and close cooperation of all oncology specialists involved in the care of a patient with sarcoma, including the specialists in rehabilitation. Ultimately, knowledge of the complex interrelationships between host, tumor, and treatment factors should lead to further improvements in local control, survival, and quality of life.
REFERENCES 1. Chang, A. E.; Kinsella, T.; Glatstein, E.; Baker, A. R.; Sindelar, W. F.; Lotze, M. T.; Danforth, D. N.; Sugarbaker, P. H.; Lack, E. Chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity. J. Clin. Oncol. 6:1491-1500; 1988. 2. Gelman, R.; Gelber, R.; Henderson, I. C.; Coleman, C. N.; Harris, J. R. Improved methodology for analyzing local and distant recurrence. J. Clin. Oncol. 8548-555; 1990. 3. Gherlinzoni, F.; Baci, G.; Picci, P.; Campanna, R.; Calderoni, P.; Lore& E. G.; Bemini, M.; Emiliani, E.; Barbieri, E.; Normand, A.; Campanacci, M. Randomized trial for the treatment of high grade soft tissue sarcomas of the extremities: Preliminary observations. J. Clin. Oncol. 4:552558; 1986. 4. Nori, D.; Shupak, K.; Shiu, M. H.; Brennan, M. F. Role of brachytherapy in recurrent extremity sarcoma in patients treated with prior surgery and radiation. Int. J. Radiat. Oncol. Biol. Phys. 20:1229-1233; 1991. 5. Shiu, M. H.; Turnbull, A. D.; Nori, D.; Hajdu, S.; Hilaris, B. Control of locally advanced extremity soft tissue sarcomas by function-saving resection and brachytherapy. Cancer. 53:1385-1392; 1984.
6. Stinson, S. F.; DeLaney, T. F.; Greenberg, J.; Yang, J. C.; Lampert, M. H.; Hicks, J. E.; Venzon, D.; White, D. E.; Rosenberg, S. A.; Glatstein, E. Acute and long term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 21(6):1493-1499; 1991. 7. Sugarbaker, P. H.; Barofsky, I.; Rosenberg, S. A.; Gianola, F. J. Quality of life assessment of patients in extremity sarcoma clinical trials. Surgery. 91: 17-23; 1982. 8. Suit, H. D.; Menkin, H. J.; Wood, W. C.; Gebhardt, M. C.; Harmon, D. C.; Rosenberg, A. ; Tepper, J. E.; Rosenthal, D. Treatment of the patient with stage MO soft tissue sarcoma. J. Clin. Oncol. 6:854-862; 1988. 9. Suit, H. D.; Miralbell, R. Potential impact of improvements in radiation therapy on quality of life and survival. Int. J. Radiat. Oncol. Biol. Phys. 16:891-895; 1989. 10. Tepper, J. E.; Suit, H. D. Radiation therapy alone for sarcoma of soft tissue. Cancer. 56:475479; 1985. 11. Weddington, W. W.; Blindt Segraves, K.; Simon, M. A. Psychological outcome of extremity sarcoma survivors undergoing amputation or limb salvage. J. Clin. Oncol. 3:1393-1399; 1985.
