In/ .I Rahnmn Oncology Bd Phys Vol. 20. pp. ,143-l Printed in the U.S.A. All rights reserved.
144 Copyright
0360-3016/91 $3.00 + .I0 0 1991 Pergamon Press plc
??Editorial PROGRESS
IN HYPERTHERMIA?
JAMES R. OLESON, M.D., PH.D. Division of Radiation Oncology, Duke University Medical Center, Durham, NC mercially available microwave applicators. The majority were delivered using equipment developed at Stanford, presumably, in part, because of advantages of the custom equipment relative to the commercial equipment. For perspective, note that one interpretation of the results of the RTOG 8 l-04 study (2) was that only lesions with largest diameters less than 3 cm could be heated “adequately” with the equipment commercially available during the conduct of that study. Of the 2 18 total evaluable patients with single lesions accrued to 81-04 over 7.5 years, only 48 (22%) had diameters less than 3 cm (average of 6.4 patients per year). If one considers only breast and chestwall sites, only 20 patients were accrued with lesions less than 3 cm in diameter (2.6 per year). Whether or not the characteristics of commercial applicators now available for superficial tumor treatment have been improved over earlier models is not well documented in the literature. I would expect that the Stanford results would be difficult to reproduce without similar custom equipment and quality control procedures. Can we infer from the Stanford results what equipment characteristics and thermal parameters would be required for effective heating of tumors with larger volumes as encountered in the majority of patients? I do not believe so, although we may have a basis for setting lower limits on performance. I do have an uneasy suspicion that dramatic improvement in heating technology and transfer of innovative technology into the community will be necessary for the potential of hyperthermia to be achieved routinely and for sufficiently large numbers of eligible patients to be available for Phase III studies or Phase II studies with temperature escalation. As other investigators develop and test new equipment, I earnestly hope that their results also will be reported in sufficient detail that we can know if we are making progress in technology and efficacy of hyperthermia. Testing the efficacy of a modality we cannot routinely deliver is very difficult.
The paper in this issue by Kapp et al. (1) is a model of careful, detailed description of a patient population, treatment regimen, and long-term results obtained in a clinical study of hyperthermia and radiation therapy for local/regional recurrences of breast carcinoma. The characterization of thermal parameters of treatment and the analysis of prognostic factors, in particular, establish an invaluable data base upon which to design future studies. The Stanford work does raise troublesome issues regarding future studies, however. The particular host and tumor-specific prognostic factors for response and duration of local control identified in the authors’ statistical analyses make biological sense, and there are no great surprises here. The lack of correlation between response/control and thermal parameters in multivariate analysis does deserve attention, and several explanations are possible. Most importantly, I would emphasize that this was not designed as a study to investigase response/control versus a controlled escalation of tumor temperatures, but, rather, is more akin to a Phase II study utilizing “maximum tolerated dose” in terms of normal tissue temperature limits. In the ideal case, all tumors would have been treated at specified temperatures consistent with normal tissue temperature limits, and no dependence of response/control upon measures of tumor temperature would be expected. Variation in tumor temperatures certainly was present, but may have been more limited than in other studies that have had poorer control and characterization of tumor and normal tissue temperatures. Of more concern is whether the reported excellent results could be reproduced by other investigators and practitioners. Various judgements were used by the Stanford investigators to select hyperthermia applicators likely to heat the tumors. Even though the average volume of tumors in their patient population was small (5.87 f 15 cm3), only 8% of treatments were delivered using com-
Reprint requests to: James R. Oleson, M.D., Ph.D., Division of Radiation Oncology, ham, NC 27710
Duke University
Accepted
Medical Center, Dur-
1143
for publication
22 February
199 1.
1144
I. J. Radiation
Oncology
0 Biology 0 Physics
May I, 1991, Volume 20, Number
5
REFERENCES 1. Kapp, D. S.; Bamett, T. A.; Cox, R. S.; Lee, E. R.; Lohrbach, A.; Fessenden, P. Hyperthermia and radiation therapy of local-regional recurrent breast cancer: prognostic factors for response and local control of diffuse or nodular tumors. Int. J. Radiat. One. Biol. Phys. 20: 1147- 1164; 199 1.
2. Perez, C. A.; Gillespie, B.; Pajak, T.; Hornback, N. B.; Emami, B.; Rubin, P. Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group. Int. J. Radiat. One. Biol. Phys. 16:551-558; 1989.
144 Copyright
0360-3016/91 $3.00 + .I0 0 1991 Pergamon Press plc
??Editorial PROGRESS
IN HYPERTHERMIA?
JAMES R. OLESON, M.D., PH.D. Division of Radiation Oncology, Duke University Medical Center, Durham, NC mercially available microwave applicators. The majority were delivered using equipment developed at Stanford, presumably, in part, because of advantages of the custom equipment relative to the commercial equipment. For perspective, note that one interpretation of the results of the RTOG 8 l-04 study (2) was that only lesions with largest diameters less than 3 cm could be heated “adequately” with the equipment commercially available during the conduct of that study. Of the 2 18 total evaluable patients with single lesions accrued to 81-04 over 7.5 years, only 48 (22%) had diameters less than 3 cm (average of 6.4 patients per year). If one considers only breast and chestwall sites, only 20 patients were accrued with lesions less than 3 cm in diameter (2.6 per year). Whether or not the characteristics of commercial applicators now available for superficial tumor treatment have been improved over earlier models is not well documented in the literature. I would expect that the Stanford results would be difficult to reproduce without similar custom equipment and quality control procedures. Can we infer from the Stanford results what equipment characteristics and thermal parameters would be required for effective heating of tumors with larger volumes as encountered in the majority of patients? I do not believe so, although we may have a basis for setting lower limits on performance. I do have an uneasy suspicion that dramatic improvement in heating technology and transfer of innovative technology into the community will be necessary for the potential of hyperthermia to be achieved routinely and for sufficiently large numbers of eligible patients to be available for Phase III studies or Phase II studies with temperature escalation. As other investigators develop and test new equipment, I earnestly hope that their results also will be reported in sufficient detail that we can know if we are making progress in technology and efficacy of hyperthermia. Testing the efficacy of a modality we cannot routinely deliver is very difficult.
The paper in this issue by Kapp et al. (1) is a model of careful, detailed description of a patient population, treatment regimen, and long-term results obtained in a clinical study of hyperthermia and radiation therapy for local/regional recurrences of breast carcinoma. The characterization of thermal parameters of treatment and the analysis of prognostic factors, in particular, establish an invaluable data base upon which to design future studies. The Stanford work does raise troublesome issues regarding future studies, however. The particular host and tumor-specific prognostic factors for response and duration of local control identified in the authors’ statistical analyses make biological sense, and there are no great surprises here. The lack of correlation between response/control and thermal parameters in multivariate analysis does deserve attention, and several explanations are possible. Most importantly, I would emphasize that this was not designed as a study to investigase response/control versus a controlled escalation of tumor temperatures, but, rather, is more akin to a Phase II study utilizing “maximum tolerated dose” in terms of normal tissue temperature limits. In the ideal case, all tumors would have been treated at specified temperatures consistent with normal tissue temperature limits, and no dependence of response/control upon measures of tumor temperature would be expected. Variation in tumor temperatures certainly was present, but may have been more limited than in other studies that have had poorer control and characterization of tumor and normal tissue temperatures. Of more concern is whether the reported excellent results could be reproduced by other investigators and practitioners. Various judgements were used by the Stanford investigators to select hyperthermia applicators likely to heat the tumors. Even though the average volume of tumors in their patient population was small (5.87 f 15 cm3), only 8% of treatments were delivered using com-
Reprint requests to: James R. Oleson, M.D., Ph.D., Division of Radiation Oncology, ham, NC 27710
Duke University
Accepted
Medical Center, Dur-
1143
for publication
22 February
199 1.
1144
I. J. Radiation
Oncology
0 Biology 0 Physics
May I, 1991, Volume 20, Number
5
REFERENCES 1. Kapp, D. S.; Bamett, T. A.; Cox, R. S.; Lee, E. R.; Lohrbach, A.; Fessenden, P. Hyperthermia and radiation therapy of local-regional recurrent breast cancer: prognostic factors for response and local control of diffuse or nodular tumors. Int. J. Radiat. One. Biol. Phys. 20: 1147- 1164; 199 1.
2. Perez, C. A.; Gillespie, B.; Pajak, T.; Hornback, N. B.; Emami, B.; Rubin, P. Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group. Int. J. Radiat. One. Biol. Phys. 16:551-558; 1989.
