In1 J. Rodrarwn Oncology Bwl. Php Vol. Pnnted in the U.S.A All rights reserved.
24, pp.
0360-3016/92 $5.00 t .OO Copyright (c 1992 Pergamon Press Ltd.
573-574
0 Correspondence
RESPONSE
TO DR. OLESON
To the Editor: 1 would like to thank Dr. Oleson for his perceptive and thought-provoking editorial (7) concerning our recent study on thermoradiotherapy for the treatment of microscopic residual local-regional recurrent breast cancer (5). While I am in general agreement with his comments, there are four issues raised to which 1 would like to respond. First, the biological rationale for the use of hyperthermia (HT) as an adjunct to radiation therapy (XRT) in the treatment of microscopic residual cancer is essentially the same as the rationale for its use in the treatment of larger tumor masses as we summarized in our paper. It has been well established in transplanted rodent tumors that a significant number of hypoxic cells can be present even in microscopic tumors, implying that hypoxia may be a factor in patients with subclinical disease (6). In addition, tumors growing in previously irradiated tissues may have impaired blood supply which might result in an increase in the proportion of hypoxic cells (4). Residual tumor deposits within superficial scar tissue may likewise have hypoxic, nutrient deprived regions which could exhibit enhanced sensitivity to HT. Second, thermoradiosensitization has been noted even at the mean minimum temperatures obtained in this study. Therefore, the possible clinical effectiveness of our XRT-HT treatment reaimens should not come as a surprise. Thermal enhancement of radiation killing has been reported in cultured Chinese hamster lung cells at a temperature of 40°C (8) and in Chinese hamster fibroblasts at 40.5”C (I). Third, as Dr. Oleson suggests, the presence of large blood vessels with high blood flow near tumor sites in the head and neck area may create more difficulty for the use of HT in this region. Nonetheless, randomized trials which compared XRT-HT to identical courses of XRT alone have demonstrated higher complete response rates (IO) and survival rates (3) with the addition of HT for large tumors at these sites. Relatively radioresistant hypoxic tumor cells may be located primarily at a distance from the blood vessels and be more poorly perfused. Since an inverse correlation has been reported between tumor blood flow and the steady-state temperatures achieved during HT as estimated by thermal washout rate (9), effective temperatures may be anticipated in the regions of the hypoxic cells. Therefore, it is anticipated that HT may be a useful adjunct to XRT in the treatment of microscopic tumor deposits in the head and neck region in situations where full dose XRT cannot be used. Finally, I am in full agreement with the need for a randomized trial to confirm and quantify the efficacy of HT added to XRT in the treatment of microscopic residual tumors. Our group at Stanford continues to refine our array applicators and remains firmly committed to helping make our hyperthermia system available for use in multi-institutional trials. It appears that only a limited number (perhaps one or two) of HT treatments may be needed as an adjunct to XRT for the treatment of areas of microscopic residual disease and early as well as late side effects of XRT-HT are within an acceptable range (2). This favorable risk (and cost) versus potential benefit ratio should encourage the prompt institution of trials to confirm the value of HT in conjunction with XRT in the treatment of microscopic residual local-regional recurrences of breast cancer.
3.
4.
5.
6.
I. 8.
9.
10.
combined radiation therapy and hyperthermia. Int. .I. Hyperthennia (in press). Datta, N. R.; Bose, A. K.; Kapoor, H. R.; Gupta, S. Head and neck cancers: Results of thermoradiotherapy versus radiotherapy. Int. J. Hyperthermia 6:479-486; 1990. Ito, H.; Barkley, T. Jr.; Peters, L. J.; Milas, L. Modification oftumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: Prolonged growth delay but reduced curability. Int. J. Radiat. Oncol. Biol. Phys. 11:547-553;1985. Kapp, D. S.; Cox, R. S.; Barnett, T. A.; Ben-Yosef, R. Thermoradiotherapy for residual microscopic cancer: Elective or post-excisional hyperthermia and radiation therapy in the management of localregional recurrent breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 24(2):261-278;1992. Moulder, J. E.; Dutreix, J.; Rockwell, S.; Siemann, D. W. Applicability of animal tumor data to cancer therapy in humans. Int. J. Radiat. Oncol. Biol. Phys. 14:9 13-927;1988. Oleson, J. R. Adjuvant hyperthermia for recurrent breast cancer. Int. J. Radiat. Oncol. Biol. 24(2):381-382:1992. Robinson, J. E.; Wizenberg, M. J. Thermal sensitivity and the effect of elevated temperatures on the radiation sensitivity of Chinese hamster cells. Acta. Rad. (Ther.) 13:24 l-249; 1974. Samulski, T. V.; Fessenden, P.; Valdagni, R.; Kapp, D. S. Correlations of thermal washout rate, steady state temperatures, and tissue type in deep seated recurrent or metastatic tumors. Int. J. Radiat. Oncol. Biol. Phys. 13:907-9 16; 1987. Valdagni, R.; Amichetti, M.; Pani, G. Radical radiation alone versus radical radiation plus microwave hyperthermia for N, (TNM-UICC) neck nodes: A prospective randomized clinical trial, Int. J. Radiat. Oncol. Biol. Phys. 15: 13-24; 1988.
RADIOTHERAPY BY CISPLATIN
VERSUS RADIOTHERAPY IN STAGE III NON-SMALL CANCER
ENHANCED CELL LUNG
To the Editor: We read with interest Dr. Komaki’s editorial comments on the results of clinical trials of radiotherapy (RT) and cisplatin (CDDP) in non-small cell lung cancer (NSCLC) (I). In general, we agree that well-planned Phase 111trials are essential and in particular with the possibility that differences in staging may be responsible for the discrepancies in the results reported by various groups. Given that all groups have reported low toxic effects of RT plus CDDP, we believe that it is indeed important to refine the staging procedures for Stage III NSCLC so that subgroups of patients may be identified for whom the combined modality treatment is beneficial. We would like, in addition, to mention another factor which may be important in determining the outcome of trials involving RT and chemotherapy. Experimental data collected at our center (to be published) shows that the concentration of CDDP in biopsy specimens from patients with NSCLC treated with fractionated RT varies throughout the treatment and appears to be greatest during RT fractions 4-8. Other experimental data using Vincristine (VCR) in a mouSe carcinoma (2, 3) has shown (a) that the concentration of VCR in the tumor tissue varies considerably during the fractionated RT and (b) that the addition of VCR during RT is very effective in the tumor used, but only if given during the f&t 10 RT fractions: VCR given durina the latter part of the RT treatment seems to be totally ineffective. Whether this applies also to CDDP plus RT remains to be investigated. It may be, therefore, that a careful selection of patients, by detailed staging as suggested by Dr. Komaki and a consideration of the modification of the pharmacokinetics of CDDP by the fractionated RT, may
DANIEL S. KAPP, PH.D., M.D. Department of Radiation Oncology Stanford University School of Medicine Stanford, CA 94305
1. Ben-Hur, E.; Elkind, M. M.; Bronk, B. V. Thermally enhanced radioresponse of cultured Chinese hamster cells: Inhibition of repair of sublethal damage and enhancement of lethal damage. Radiat. Res. 5838-5 l;1974. 2. Ben-Yosef, R.; Kapp, D. S. Persistent and/or late complications of 573
514
1. J. Radiation Oncology 0 Biology 0 Physics
enable us to achieve some improvement in the survival of patients with this, so far, intractable disease. MAURO G. TROVE, M.D. GIUSEPPED. ZANELLI, PH.D*
EMILIOMINATEL,M.D. GIOVANNIFRANCHIN,M.D. CARLOGOBITTI,M.D. Radiotherapy Division Centro di Riferimento Oncologico (C.R.O.) 3308 1 Aviano (PN)-Italy Komaki, R. Is concomitant cisplatin and radiotherapy more efficacious treatment than radiotherapy alone in Stage III non-small cell lung cancer? Int. J. Rad. Oncol.-Biol. Phys. 24(l): 185- 186;1992. Zanelli. G. D.: Rota. L.: Trove. M.: Grinoletto. E.: Roncadin. M. The uptake of 3H-Vincristine by’a mouse &cinoma’during a course of fractionated radiotherapy. Br. J. Cancer 60:3 IO-3 14;1989. Zanelli, G. D.; Rota, L.; Innocente, R.; Trove, M. The effect of timing of Vincristine administration during a course of fractionated radiotherapy in a mouse carcinoma. Eur. J. Cancer 28:64-66; 1992.
HIGH-DOSE-RATE
BRACHYTHERAPY CARCINOMA
FOR CERVICAL
To the Editor: Medical procedures that require a high level of technical expertise and professional staff support should be performed in centers that have adequate patient volume, so that proficiency and high levels of quality control can be sustained. Brachytherapy for curative treatment of cervical carcinoma meets these requirements whether the brachytherapy uses low-dose-rate or high-dose-rate isotopes. The “Patterns of Care Studies” demonstrated that in the United States women treated
Volume 24, Number 3, 1992 for Stage III cervical carcinoma at institutions treating more than 50 cervical patients per year with conventional techniques have improved 4-year cancer free survival over those treated at institutions with lower patient volume (2). In the previous issue, Dr. Eifel contends that compared with low-doserate brachytherapy, high-dose-rate offers only economic advantages-reduced cost to the patient due to the outpatient treatment, and possible increased billing by the practitioner (1). Thus, patient welfare will be sacrificed, resulting in more complications and/or lower survival rates. As support for the increased complications, she sites earlier studies which showed just such results. These studies did not have the benefit of current radiobiological models to guide dose selection. Nor was computerized dose optimization performed to tailor the dose distribution to the patients disease and anatomy as can be done only with high-dose-rate brachytherapy. In an era of precision dose delivery techniques using stereotatic irradiation, 3-D conformal therapy, and high-dose-rate brachytherapy, advanced treatment methods must be evaluated in the best possible situation. By quoting Henry Kaplans’ aphorism, Dr. Eifel implies that the use of HDR brachytherapy is not worth pursuing even in the most meticulous fashion. To quote Jack Fowler, “A new method ought to be done with the best feasible accuracy, or else it’s not a fair test of the new method.” JUDITH ANNE STITT, M.D. BRUCER. THOMADSEN,PH.D. JACK F. FOWLER,PH.D., D.Sc. University of Wisconsin Comprehensive Cancer Center 600 Highland Avenue K4/B 100 Madison, WI 53593 1. Eifel, P. J. High-dose-rate brachytherapy for carcinoma of the cervix: High tech or high risk? Int. J. Rad. Oncol. Biol. Phys. 24(2):383386; 1992.
24, pp.
0360-3016/92 $5.00 t .OO Copyright (c 1992 Pergamon Press Ltd.
573-574
0 Correspondence
RESPONSE
TO DR. OLESON
To the Editor: 1 would like to thank Dr. Oleson for his perceptive and thought-provoking editorial (7) concerning our recent study on thermoradiotherapy for the treatment of microscopic residual local-regional recurrent breast cancer (5). While I am in general agreement with his comments, there are four issues raised to which 1 would like to respond. First, the biological rationale for the use of hyperthermia (HT) as an adjunct to radiation therapy (XRT) in the treatment of microscopic residual cancer is essentially the same as the rationale for its use in the treatment of larger tumor masses as we summarized in our paper. It has been well established in transplanted rodent tumors that a significant number of hypoxic cells can be present even in microscopic tumors, implying that hypoxia may be a factor in patients with subclinical disease (6). In addition, tumors growing in previously irradiated tissues may have impaired blood supply which might result in an increase in the proportion of hypoxic cells (4). Residual tumor deposits within superficial scar tissue may likewise have hypoxic, nutrient deprived regions which could exhibit enhanced sensitivity to HT. Second, thermoradiosensitization has been noted even at the mean minimum temperatures obtained in this study. Therefore, the possible clinical effectiveness of our XRT-HT treatment reaimens should not come as a surprise. Thermal enhancement of radiation killing has been reported in cultured Chinese hamster lung cells at a temperature of 40°C (8) and in Chinese hamster fibroblasts at 40.5”C (I). Third, as Dr. Oleson suggests, the presence of large blood vessels with high blood flow near tumor sites in the head and neck area may create more difficulty for the use of HT in this region. Nonetheless, randomized trials which compared XRT-HT to identical courses of XRT alone have demonstrated higher complete response rates (IO) and survival rates (3) with the addition of HT for large tumors at these sites. Relatively radioresistant hypoxic tumor cells may be located primarily at a distance from the blood vessels and be more poorly perfused. Since an inverse correlation has been reported between tumor blood flow and the steady-state temperatures achieved during HT as estimated by thermal washout rate (9), effective temperatures may be anticipated in the regions of the hypoxic cells. Therefore, it is anticipated that HT may be a useful adjunct to XRT in the treatment of microscopic tumor deposits in the head and neck region in situations where full dose XRT cannot be used. Finally, I am in full agreement with the need for a randomized trial to confirm and quantify the efficacy of HT added to XRT in the treatment of microscopic residual tumors. Our group at Stanford continues to refine our array applicators and remains firmly committed to helping make our hyperthermia system available for use in multi-institutional trials. It appears that only a limited number (perhaps one or two) of HT treatments may be needed as an adjunct to XRT for the treatment of areas of microscopic residual disease and early as well as late side effects of XRT-HT are within an acceptable range (2). This favorable risk (and cost) versus potential benefit ratio should encourage the prompt institution of trials to confirm the value of HT in conjunction with XRT in the treatment of microscopic residual local-regional recurrences of breast cancer.
3.
4.
5.
6.
I. 8.
9.
10.
combined radiation therapy and hyperthermia. Int. .I. Hyperthennia (in press). Datta, N. R.; Bose, A. K.; Kapoor, H. R.; Gupta, S. Head and neck cancers: Results of thermoradiotherapy versus radiotherapy. Int. J. Hyperthermia 6:479-486; 1990. Ito, H.; Barkley, T. Jr.; Peters, L. J.; Milas, L. Modification oftumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: Prolonged growth delay but reduced curability. Int. J. Radiat. Oncol. Biol. Phys. 11:547-553;1985. Kapp, D. S.; Cox, R. S.; Barnett, T. A.; Ben-Yosef, R. Thermoradiotherapy for residual microscopic cancer: Elective or post-excisional hyperthermia and radiation therapy in the management of localregional recurrent breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 24(2):261-278;1992. Moulder, J. E.; Dutreix, J.; Rockwell, S.; Siemann, D. W. Applicability of animal tumor data to cancer therapy in humans. Int. J. Radiat. Oncol. Biol. Phys. 14:9 13-927;1988. Oleson, J. R. Adjuvant hyperthermia for recurrent breast cancer. Int. J. Radiat. Oncol. Biol. 24(2):381-382:1992. Robinson, J. E.; Wizenberg, M. J. Thermal sensitivity and the effect of elevated temperatures on the radiation sensitivity of Chinese hamster cells. Acta. Rad. (Ther.) 13:24 l-249; 1974. Samulski, T. V.; Fessenden, P.; Valdagni, R.; Kapp, D. S. Correlations of thermal washout rate, steady state temperatures, and tissue type in deep seated recurrent or metastatic tumors. Int. J. Radiat. Oncol. Biol. Phys. 13:907-9 16; 1987. Valdagni, R.; Amichetti, M.; Pani, G. Radical radiation alone versus radical radiation plus microwave hyperthermia for N, (TNM-UICC) neck nodes: A prospective randomized clinical trial, Int. J. Radiat. Oncol. Biol. Phys. 15: 13-24; 1988.
RADIOTHERAPY BY CISPLATIN
VERSUS RADIOTHERAPY IN STAGE III NON-SMALL CANCER
ENHANCED CELL LUNG
To the Editor: We read with interest Dr. Komaki’s editorial comments on the results of clinical trials of radiotherapy (RT) and cisplatin (CDDP) in non-small cell lung cancer (NSCLC) (I). In general, we agree that well-planned Phase 111trials are essential and in particular with the possibility that differences in staging may be responsible for the discrepancies in the results reported by various groups. Given that all groups have reported low toxic effects of RT plus CDDP, we believe that it is indeed important to refine the staging procedures for Stage III NSCLC so that subgroups of patients may be identified for whom the combined modality treatment is beneficial. We would like, in addition, to mention another factor which may be important in determining the outcome of trials involving RT and chemotherapy. Experimental data collected at our center (to be published) shows that the concentration of CDDP in biopsy specimens from patients with NSCLC treated with fractionated RT varies throughout the treatment and appears to be greatest during RT fractions 4-8. Other experimental data using Vincristine (VCR) in a mouSe carcinoma (2, 3) has shown (a) that the concentration of VCR in the tumor tissue varies considerably during the fractionated RT and (b) that the addition of VCR during RT is very effective in the tumor used, but only if given during the f&t 10 RT fractions: VCR given durina the latter part of the RT treatment seems to be totally ineffective. Whether this applies also to CDDP plus RT remains to be investigated. It may be, therefore, that a careful selection of patients, by detailed staging as suggested by Dr. Komaki and a consideration of the modification of the pharmacokinetics of CDDP by the fractionated RT, may
DANIEL S. KAPP, PH.D., M.D. Department of Radiation Oncology Stanford University School of Medicine Stanford, CA 94305
1. Ben-Hur, E.; Elkind, M. M.; Bronk, B. V. Thermally enhanced radioresponse of cultured Chinese hamster cells: Inhibition of repair of sublethal damage and enhancement of lethal damage. Radiat. Res. 5838-5 l;1974. 2. Ben-Yosef, R.; Kapp, D. S. Persistent and/or late complications of 573
514
1. J. Radiation Oncology 0 Biology 0 Physics
enable us to achieve some improvement in the survival of patients with this, so far, intractable disease. MAURO G. TROVE, M.D. GIUSEPPED. ZANELLI, PH.D*
EMILIOMINATEL,M.D. GIOVANNIFRANCHIN,M.D. CARLOGOBITTI,M.D. Radiotherapy Division Centro di Riferimento Oncologico (C.R.O.) 3308 1 Aviano (PN)-Italy Komaki, R. Is concomitant cisplatin and radiotherapy more efficacious treatment than radiotherapy alone in Stage III non-small cell lung cancer? Int. J. Rad. Oncol.-Biol. Phys. 24(l): 185- 186;1992. Zanelli. G. D.: Rota. L.: Trove. M.: Grinoletto. E.: Roncadin. M. The uptake of 3H-Vincristine by’a mouse &cinoma’during a course of fractionated radiotherapy. Br. J. Cancer 60:3 IO-3 14;1989. Zanelli, G. D.; Rota, L.; Innocente, R.; Trove, M. The effect of timing of Vincristine administration during a course of fractionated radiotherapy in a mouse carcinoma. Eur. J. Cancer 28:64-66; 1992.
HIGH-DOSE-RATE
BRACHYTHERAPY CARCINOMA
FOR CERVICAL
To the Editor: Medical procedures that require a high level of technical expertise and professional staff support should be performed in centers that have adequate patient volume, so that proficiency and high levels of quality control can be sustained. Brachytherapy for curative treatment of cervical carcinoma meets these requirements whether the brachytherapy uses low-dose-rate or high-dose-rate isotopes. The “Patterns of Care Studies” demonstrated that in the United States women treated
Volume 24, Number 3, 1992 for Stage III cervical carcinoma at institutions treating more than 50 cervical patients per year with conventional techniques have improved 4-year cancer free survival over those treated at institutions with lower patient volume (2). In the previous issue, Dr. Eifel contends that compared with low-doserate brachytherapy, high-dose-rate offers only economic advantages-reduced cost to the patient due to the outpatient treatment, and possible increased billing by the practitioner (1). Thus, patient welfare will be sacrificed, resulting in more complications and/or lower survival rates. As support for the increased complications, she sites earlier studies which showed just such results. These studies did not have the benefit of current radiobiological models to guide dose selection. Nor was computerized dose optimization performed to tailor the dose distribution to the patients disease and anatomy as can be done only with high-dose-rate brachytherapy. In an era of precision dose delivery techniques using stereotatic irradiation, 3-D conformal therapy, and high-dose-rate brachytherapy, advanced treatment methods must be evaluated in the best possible situation. By quoting Henry Kaplans’ aphorism, Dr. Eifel implies that the use of HDR brachytherapy is not worth pursuing even in the most meticulous fashion. To quote Jack Fowler, “A new method ought to be done with the best feasible accuracy, or else it’s not a fair test of the new method.” JUDITH ANNE STITT, M.D. BRUCER. THOMADSEN,PH.D. JACK F. FOWLER,PH.D., D.Sc. University of Wisconsin Comprehensive Cancer Center 600 Highland Avenue K4/B 100 Madison, WI 53593 1. Eifel, P. J. High-dose-rate brachytherapy for carcinoma of the cervix: High tech or high risk? Int. J. Rad. Oncol. Biol. Phys. 24(2):383386; 1992.
