Response to Drs. Peschel and Wallner

I. J. Radiation Oncology 0 Biology ??Physics

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always feasible. Detailed evaluation of our patients’ responses to surgery was beyond the intended scope of our evaluation in this paper. IVY A. PETERSEN,M.D. Division of Radiation Oncology Mayo Clinic Rochester, MN 55905 SARAHS. DONALDSON,M.D. Department of Radiation Oncology I. Ross MCDOUGALL, M.B., CH.B., PH.D. Division of Nuclear Medicine Stanford University Hospital Stanford, CA 94305

Volume 23, Number I, 1992 restricted to a few large cancer centers who have a significant experience with this technique. Hopefully, over the next 5-10 years, the precise role of the new transperineal implant method with either Iodine-125 or Palladium-103 will become more clearly defined. RICHARDE. PESCHEL,M.D., PH.D. Department of Therapeutic Radiology Yale University School of Medicine 333 Cedar Street New Haven, CT 065 IO KENT E. WALLNER, M.D. Radiation Oncology Memorial Sloan Kettering Cancer Center 1275 York Avenue New York, NY 1002 1

I. Petersen, I. A.; Kriss, J. P.; McDougall, I. R.; Donaldson, S. S. Prog-

nostic factors in the radiotherapy of Graves’ ophthalmopathy. Int. J. Radiat. Oncol. Biol. Phys. 19: 259-264; 1990. 2. Parsons, J. T.; Fitzgerald, D. R.; Hood, C. I.; Ellingwood, K. E.; Bova, F. J.; Million, R. R. The effects of irradiation on the eye and optic nerve. Int. J. Radiat. Oncol. Biol. Phys. 9: 609-622; 1983. IODINE-125 IMPLANTS

FOR PROSTATE CANCER

To the Editor: In a recent paper, Koprowski et al. (1) raised serious and legitimate doubts about the efficacy of Iodine-125 implants for local prostate cancer. We share many of the concerns of these authors. However, we would like to highlight several problems with their study: I. It is unclear whether Koprowski et al. reviewed the detailed dosimetry for each patient to determine the adequacy of the implant. Koprowski et al. state “. those dosimetry films that were available for review appeared satisfactory .” This suggests to us that a full physics review was not performed. This would be a serious flaw in their analysis since both the Memorial Sloan Kettering Cancer Center (MSKCC: 236 Stage A2 and B patients) and Yale University (14 I Stage A2, B, and C patients) data indicate a significant difference in local control as a function of the adequacy of the implant (IMP) as shown below (2). The local control rate (48%) for Stage B patients quoted by Koprowski et a/. is consistent with inadequate treatment. Without a detailed dosimetry analysis of each implant, therefore, their data must be viewed with caution. The Koprowski et al. data represents neither a single institution nor a single investigator experience but is a summary from several different hospitals and at least five different radiation therapists. During the study period (l978-1985), IO1 patients were implanted. Therefore, on average, each radiation therapist performed only 2.5 implants per year. With such a limited experience, it is unlikely that any of the radiation oncologists would have become proficient using the implant technique. Therefore, we agree with the statement of Koprowski et al. that ‘I. . this does not appear to be a desirable way to perform this procedure.” The 5-year disease free survival (NED) for the 98 implant patients with Stage A2 and B disease (55%) reported by Koprowski et al. is vastly inferior to the 5-year NED survival for 456 Stage A2 and B patients (8 1%)treated at six other institutions (2). Therefore, not every center performing Iodine-125 implants has had the same poor experience as Koprowski et al. Finally, the implant results reported by Koprowski et al. may have little or no relevance to the newer transperineal implant techniques which use: (a) careful pre-implant ultrasound or CT scanning treatment planning, (b) ultrasound guided seed placement, and (c) newer isotopes such as Palladium- 103 which deliver a higher dose rate. The exact role of implant therapy for prostate cancer remains undefined. We agree with Koprowski et al. that implant therapy should be Table 1. Local control

rates vs adequacy of implant Local control rates

Adequate treatment Inadequate treatment

IMP (MSKCC)

IMP (Yale)

76% 48%

82% 58%

I. Koprowski, C. D.; Berkenstock, K. G.; Borofsky, A. M.; Ziegler, J. C.; Lightfoot, D. A.; Brady, L. W. External beam irradiation versus 125 iodine implant in the definitive treatment of prostate carcinoma. Int. J. Radiat. Biol. Phys. 21:955-960;1991. 2. Peschel, R. E. External beam versus interstitial implant therapy for prostate cancer: A review. Endocurietherapy/Hyperthermia Oncology 6:231-237;1990. RESPONSE

TO DRS. PESCHEL AND WALLNER

To The Editor: Despite Drs. Peschel and Wallner’s valid commentary about the possible contribution of under-dosage to Hahnemann’s poor results in implant therapy, I continue to remain concerned about the widespread implementation of free-hand Iodine- 125 implants for prostate cancer. Although technical inadequacy is certainly one explanation for the aooarent discreoancv in local control rates, other hypotheses are equal& plausible explanations for these data. Many prognostic indicators are known or suspected to influence the outcome in prostatic carcinoma. Among these are: tumor stage, differentiation, the age of the patient, and the patient’s racial origin. Lymph node status is clearly a predictor of outcome, and more recently, prostate specific antigen levels have been shown to correlate with outcome in this disease. Most of the studies looking at Iodine-125 implants are uncontrolled retrospective analyses. They include highly selected patients and use widely differing measures of outcome and lengths of follow-up. It is impossible to draw reliable conclusions about the effectiveness of this technique when comparing these series with others examining outcome in external beam patients. Two recent series (1, 2)-one by Dr. Pescheladdress some of these objections by performing a retrospective cohort analysis using external beam patients from their own institution as controls. However, neither of these studies critically examines patient comparability when considering the efficacy of implants versus external beam treatment. Dr. Peschel’s own data support, in fact, the notion that there was-at least at Yale-a systematic tendency to choose more favorable patients for implant treatment. According to his publication, 90% of implant patients were grade I or 2 while only 74% of the external beam were as well differentiated. Given the number of patients involved (14 1 implant and 166 external beam), these differences are unlikely to have occurred by chance alone. It would be interesting to re-analyze these data with log rank stratification or regression techniques to see if the implant patients were still statistically equal to the external beam patients in outcome. The only conclusion possible from the Hahnemann data is that IodineI25 implants did not work nearly as well as external beam radiation for prostate cancer in comparable patient populations at that institution. As Drs. Peschel and Wallner point out, generalizing from this result is fraught with pitfalls. Nevertheless, the ball must also travel to the other half of the court. No one at anytime has convincingly demonstrated that free hand implants work as well as external beam radiation in comparable patient populations. CHRISTOPHERKOPROWSKI,M.D. Clinical Associate Professor Robert Wood Johnson Medical School University of Medicine & Dentistry of New Jersey

Kuban, D. 0.; El-Mahdi, A. M.; Schellhammer, P. F. I-125 interstitial implantation for prostate cancer: What have we learned 10 years later? Cancer 63:24 15-20; 1989.

Correspondence 2. Morton, J. D.; Peschel, R. E. Iodine-125 implants versus external beam therapy for Stages A2, B and C prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:1153-57;1988.

Cf-252 NEUTRON CAPTURE THERAPY AND TELETHERAPY To fhe Editor: In a recent article we called attention to the possibility of enhancing “‘Cf-neutron therapy using “‘B compounds (1). We appreciate the opportunity to advise the oncology community about still other potential uses of the man-made neutron-emitting isotope, Californium-252, for the treatment of certain radioresistant tumors encountered in radiation oncology. We, at the University of Kentucky, and researchers at other institutions have worked on various aspects of exploiting the nuclear properties of 252Cffor the benefit of cancer treatment. 252Cfhas two distinct applications in radiation oncology: (1) as an alternative interstitial or intracavitary brachytherapy source (5) and (2) as a source of thermal or epithermal neutrons in boron neutron capture therapy (BNCT) (4, II). The use of 252Cfas an interstitial and intracavitary fast neutron source has been extensively documented at the University of Kentucky and shows that *“Cf is effective for the treatment of the more advanced stages of many cancers (5, 6, 7). In particular these include a variety of presentations of cervical cancers, including bulky/barrel shaped cancers and high stage cancers (8). It is effective against bulky body surface or aero-digestive cancers (5,6,7). It shows efficacy against malignant gliomas in early clinical trials (2, 9, IO). For malignant gliomas the use of 252Cf for interstitial therapy has been tested and it was postulated that enhancement of radiation dose was possible for malignant gliomas and other tumors by means of BNCT (I, 12, 13). The use of *‘*Cf in combination with “B-labeled tumor-seeking compounds offers attractive potential benefits in interstitial therapy, and we (I) and Yanch et al. (12) have presented, respectively, experimental and theoretical evidence that in the clinical use of interstitial/intracavitary sources of *‘*Cf,a clinically useful selective enhancement of the radiation dose to tumor may be achieved. This can be accomplished when the tumor contains the stable isotope “‘B at practically achievable concentrations. Certain drugs appear to offer potential for such “B-enhanced therapy (3, 6, I I). *‘*Cf can also be used as a source of neutrons for external beam teletherapy (I 3). For BNCT, 252Cfprovides an alternative neutron source to nuclear reactors by providing a potential beam source for clinical trials. Zamenhof et al. (14) originally showed that a suitable moderated and filtered source of *“Cf could produce a usable thermal or epithermal neutron beam for boron neutron capture therapy. Since “‘Cf is a fast neutron and gamma ray emitter, such a *‘*Cf irradiator would need to contain various materials to “soften” the fast neutrons and to filter out the gammas. Prototype designs of such equipment, including the incorporation of ?J as a subcritical neutron multiplier, are currently under development at the University of Kentucky (I 3) and at the Massachusetts Institute of Technology. In the United States, prototypical reactor-based thermal and epithermal neutron beams for external beam boron-neutron capture therapy have been developed at the MIT Research Reactor and at the Brookhaven Medical Research Reactor. The clinical potential of BNCT needs to be tested using such reactor-based facilities and clinical trials of BNCT for cutaneous melanomas and glioblastomas are planned at New England Medical Center/Massachusetts Institute of Technology beginning in the Fall of 1991. If BNCT is effective, the need for the development of alternative hospital-based neutron sources other than research reactors, such as 252Cfoffers, will become important to Radiation Oncology. As well as requiring the optimization of neutron beams, BNCT will require boron compounds which localize well in tumors (3, 6). In fact, some improved boron compounds for BNCT have been developed in recent years, For example, the L-isomer of boronated phenylalanine (BPA) has been studied extensively and biodistribution, toxicity, and survival experiments, have shown it to be a potentially effective compound for BNCT of human and animal tumors (3, 4, 1I). The monomer of the compound sodium-mercaptoundecahydrododecaborate (abbreviated BSH) has been used in Japan to treat over 100 patients with grade III-IV astrocytomas by thermal neutron beam BNCT (4). BPA has been used in Japan to treat melanomas (1 I). In conclusion, we believe that neutrons for the treatment of cancer are rightly being revisited. Neutrons represent an important and powerful focus for the radiation therapy of cancer. Enhancing Cf-252 effects in tumor by using boron-loaded agents and neutron capture can potentially

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increase the effectiveness of neutron brachytherapy. Still additional promise is based on the dose enhancement possible with external thermal or epithermal neutron beams. If BNCT is demonstrated to be an effective treatment modality, the development of hospital-based thermal and epithermal neutron sources will become a scientific imperative. A 252Cf teletherapy machine would ( 13) greatly enhance the feasibility of conducting clinical trials by the Radiation Oncology community. This could potentially treat melanomas, glioblastomas, and recurrent body surface tumors (breast, head and neck) not adequately controlled by modem cancer therapy at the present time (6). Y. MARUVAMA J. WIERZBICKI M. ASHTARI R. J. YAES J. L. BEACH University of Kentucky Chandler Medical Center Department of Radiation Medicine Lexington, KY 40536 J. YANCH Nuclear Engineering Massachusetts Institute of Technology Boston, MA 02 I39 R. ZAMENHOF Radiation Oncology Tufts Medical School/New England Medical Centre Boston, MA 20 I 18 C. B. SCHROY M.D. Anderson Hospital Houston, TX 77030 I. Beach, J. L.; Schroy, C. B.; Ashtari, M.; Harris, M. R.; Maruyama, Y Boron neutron capture enhancement of *‘*Cfbrachytherapy. Int. J. Radiat. Oncol. B&l. Phys. 18: 1421-1427; 1990. 2. Chin. H. W.: Maruvama. Y.: Young. A. B.: Beach. J. L.: Tibbs. P.: Markesbery,’ W. Cf-252 brain implantation for mslignant glio’ma: experiences of the University of Kentucky, Lexington. Nucl. Sci. Appl. 2: 585-598; 1986. 3. Coderre, J. A.; Kalef-Ezra, J. A.; Fairchild, R. G.; Micca, P. L.; Reinstein, L.; Glass, J. D. Boron neutron capture of a murine melanoma. Cancer Res. 48: 63 13-63 16; 1988. Hatanaka, H. Boron neutron capture therapy for tumors. Nishimura, Niigata, Japan, 1986. Maruyama, Y. Cf-252 neutron brachytherapy: an advance for bulky localized tumor therapy. Nucl. Sci. Appl. BI: 697-748; 1987. Maruyama, Y. (ed.). International neutron therapy workshop. Chur. Nucl. Sci. Appl. A4: l-492; 1991. Maruyama, Y.; Beach, J. L.; Feola, J. M. Cf-252 neutron brachytherapy and fast neutron beam therapy. Nucl. Sci. Appl. B2: 187826; 1986. 8. Maruyama, Y.; Kryscio, R. J.; van Nagell, J. R.; Yoneda, J.; Donaldson, E.; Hanson, M.; Beach, J. L.; Feola, J.; Martin, A.; Parker, C. Neutron brachytherapy is better than conventional radiotherapy in advanced cervical cancer. Lancet 1: I 120- 112 I ; 1985. 9. Maruyama, Y.; Chin, H. W.; Young, A. B.; Beach, J. L.; Bean, J.; Tibbs, P. Californium 252Cfneutron brachytherapy for hemispheric malignant glioma. Radio]. 145: I7 I- 174; i982. _ IO. Miller. J. P.: Yaes. R. J.: Young. A.: Patchell. R.: Tibbs. P.: Chin. H.; Brandenburg, w.; Beker, BI’Widrzbicki, j.; Maruyama, $. Cal: ifornium neutron brachytherapy for glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 17: 228; 1989. 1I. Mishima, Y. Melanoma neutron capture therapy. N.Y.: A. R. Liss; 1989. 12. Yanch, J. C.; Zamenhof, R. G.; Wierzbicki, J.; Maruyama, Y. Comparison of dose distributions with “Boron augmentation near linear sources of *‘*Cf obtained by Monte Carlo simulation and by experimental measurement. Proceedings of the 4th International Symposium on Boron Neutron Capture Therapy. Allen, B. (ed.). New York: Plenum; (in press). 13. Wierzbicki, J.; Maruyama, Y., Alexander, C. W. Cf-252 for teletherapy and thermalized Cf-252 neutrons for brachytherapy. Nucl. Sci. Appl. A4:361-366; 1991. 14. Zamenhof, R. G.; Murray, B. W.; Brownell, G. L.; Wellum, G. R.; Tolpin, E. I. Boron neutron capture therapy for the treatment of cerebra1 gliomas. I. Theoretical evaluation of the efficacy of various neutron beams. Medical Physics 2:47-60; 1975.