- Email: [email protected]
The “Golden Age” of prostate brachytherapy: A cautionary tale
Brachytherapy 7 (2008) 55e59
Historical Vignette
The ‘‘Golden Age’’ of prostate brachytherapy: A cautionary tale Jesse N. Aronowitz* University of Massachusetts Medical School and the Levine Cancer Center of the UMass Memorial Medical Center, Worcester, MA
ABSTRACT
PURPOSE: To investigate the earliest attempts to use man-made isotopes for prostate brachytherapy. METHODS AND MATERIALS: Two radiogold brachytherapy programs were analyzed, using literature review and interviews of participants. RESULTS: Although 198Au has been discredited as a source for permanent prostate brachytherapy, the major flaw in the reviewed programs was the misapplication of the isotope. CONCLUSIONS: Safe and effective implant programs are grounded in the sound application of brachytherapy principles. New brachytherapy procedures should arise from the collaboration of radiation oncologists, surgeons, physicists, radiobiologists, and radiation safety specialists. Ó 2008 American Brachytherapy Society. All rights reserved.
Keywords:
Brachytherapy; History of medicine; Prostatic neoplasms; Colloidal gold
Introduction Radium was used therapeutically within a decade of its discovery, and intracavitary prostate brachytherapy was first attempted in 1909 (1, 2). Naturally occurring isotopes are not ideally suited for permanent implantation, and so the modern era of prostate brachytherapy awaited the introduction of reactor-generated radionuclides. One of the first ‘‘man-made’’ isotopes to be applied to brachytherapy was radiogold (198Au). This article reviews the history of two prominent radiogold prostate brachytherapy programs that endured for decades, and evaluates the causes of their ultimate failure.
Radiogold Permanent interstitial implantation of the prostate was first performed at New York’s Memorial Hospital before 1920, using radon sources (3). The technique was adopted in other U.S. centers, but the inability to suitably distribute the seeds within the gland hampered its efficacy, and interest waned. But the need for an alternative to prostatectomy remained; fewer than 5% of men diagnosed with prostate Received 24 August 2007; received in revised form 23 December 2007; accepted 27 December 2007. * Corresponding author. University of Massachusetts Medical School, 33 Kendall Street, Levine Cancer Center, Worcester, MA 01605. Tel.: þ1508-334-6550; fax: þ1-508-334-5624. E-mail address: [email protected] (J.N. Aronowitz)
cancer in the pre-PSA era were found to have operable disease, and so a potentially curative therapy was sought to offer to patients with locally advanced disease (4). Orthovoltage radiotherapy proved too toxic, and the dramatic responses to hormonal therapy were ephemeral (5). Prostate brachytherapy was therefore reintroduced in 1951, using a new radionuclide, 198Au (radiogold). Thousands of men were to undergo radiogold implants over the next four decades. After World War II, Congress passed the Atomic Energy Act, establishing the Atomic Energy Commission. The Oak Ridge Laboratories were transferred to civilian control, and directed to provide radioisotopes for peaceful purposes, especially medical applications. One of the first isotopes made available was 198Au, produced by bombarding gold foil with slow neutrons in a uranium pile (6). Its short half life (2.7 days) and high-energy (0.4 MeV) grays are comparable to radon (3.8 days, 0.2e2 MeV), but is safer to handle because it does not generate megavoltage photons and has no radioactive daughter products. Microparticles were suspended in pectin or gelatin, forming a colloid for use as a beta-emitter (much like 32P). It was infused intravenously (for leukemia and lymphoma) (6), instilled into pleural or peritoneal cavities (to suppress malignant effusions and ascites) (7), or injected into lymphomatous masses and solid tumors (8).
The Iowa experience The first radiogold prostate implant, in March of 1951, was unplanned (4). An 80-year-old man with hormone-
1538-4721/08/$ e see front matter Ó 2008 American Brachytherapy Society. All rights reserved. doi:10.1016/j.brachy.2007.12.004
56
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
refractory Stage C disease, was to undergo a radon implant. After the prostate had been surgically exposed, however, it was discovered that radon sources were not available. Colloidal gold was on hand (it had been used at the institution as an intraperitoneal instillation for ovarian cancer (9)), and was infiltrated into the prostate. The bulky tumor resolved, a followup biopsy was negative, and the patient remained free of evident disease for the remainder of his life (2.5 years); moreover, the treatment seemed devoid of toxicity (10). Encouraged by this case, the urologist began infiltrating colloidal gold into the prostate and seminal vesicles of other men with Stage C disease, and an enthusiastic report of his first 20 cases was published in the Journal of Urology the following year (11). The urologist, Rubin Flocks (1906e1975), was born in Brooklyn to immigrant parents. He received his medical education at Johns Hopkins, where he began his urology residency under Hugh Hampton Young. Hopkins had a ‘‘pyramid program,’’ however, and Flocks completed his training at the University of Iowa. He remained there, first as research assistant, later as faculty, and eventually as chairman of the department (’49e’74) (Hawtrey CE, written communication, February 2005). He attained national prominence, serving as president of the American Urological Association (’68e’69), the Clinical Society of Genitourinary Surgeons (’69e’70), and the American Board of Urology. The high regard of his peers was reflected in his being awarded urology’s highest honors: The Barringer Medal (’68), the Guiteras Award (’68), and the Keyes Award (’74). Flocks remained at the University of Iowa, his entire career. He died the year after retirement, of metastatic renal pelvis carcinoma, in the Rubin Flocks Prostatic Disease Center. There were compelling reasons to explore colloidal gold as the agent of prostate brachytherapy. A beta-emitter, unencapsulated gold would deposit 90% of its energy within millimeters of its deposition site, potentially sparing neighboring tissues. It was assumed that the fascia investing the prostate and seminal vesicles would limit the isotope’s migration. And there was evidence that gold microparticles would be phagocytosed by macrophages which, on circulating to draining lymph nodes, would irradiate D1 metastases (12). Initially, injection was through a combined supra- and retropubic approach (Fig. 1). But dense tumor nodules resisted infiltration and adequate distribution of the colloid throughout the gland-proved elusive; much of the material pooled in the pararectal fascia, causing severe injury (13). Some gold microparticles entered the circulation, and autoradiographs demonstrated hepatic accumulation. Although radiogold entered regional lymphatics, it did not penetrate tumor-congested nodes (13). Flocks and Culp devised several maneuvers to overcome these difficulties: Grossly, abnormal lymph nodes were resected; hyaluronidase and epinephrine were mixed into the colloid to improve distribution and reduce vascular uptake; the suspension was injected under pressure to overcome the resistance of dense
Fig. 1. A. The prostate and seminal vesicles were injected with colloidal gold after suprapubic exposure. B. It was assumed that the colloid would percolate along the fascial septa, eventually settling inside the prostate capsule (12). (Reproduction permission from the Journal of Urology.)
tumor nodules; and small volumes of highly concentrated suspension were used to reduce leakage from the gland (5). Occasionally, the gland was injected from a combination of suprapubic, perineal, and transrectal approaches; persistent nodules could be reinjected transperineally (14). It soon became apparent that the procedure was only effective for the smallest tumors (13), and 80% of posttreatment biopsies were positive (15). By 1954, Flocks and colleagues were resecting tumor nodules prior to radiogold infiltration, or performing transurethral prostate resection postoperatively (16). Eventually, he simply performed perineal prostatectomy, using radiogold as adjuvant therapy (infiltrating the colloid into periprostatic fascia and vascular pedicles) (10). Flocks et al. supported this practice by claiming better local control (95%) in Stage C disease, compared to other published series (70e80%) (17). The cost of the superior control was steep; delayed healing in 80%, and
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
‘‘persistent urethro-cutaneous fistula’’ in 2% (18). Colloidal gold continued to be used at the University of Iowa Hospitals until 1977, when its manufacture ceased; encapsulated gold grains were then substituted (at the same total activity, despite the absorption of beta-irradiation by the capsule (19)). Flocks et al. performed more than 1500 gold implants over 14 years (Hawtrey CE, written communication, March 2007). Beginning in 1984, the grains were implanted transperineally, under trans-rectal sonographic guidance (20). In retrospect, the Iowa program was seriously flawed. The inability to control the distribution of colloidal gold renders it a fearsome brachytherapy source, a dosimetry, and radiation safety nightmare. Homogenous dose distribution could not be achieved, nor could it be measured. Migration of the radioisotope to nontarget organs (especially reticulo-endothelial tissue) could greatly exceed that which remained in the gland (14). Radiation exposure to personnel was so high that surgical teams were rotated to avoid accumulation of prohibitive doses (5). Injection of the suspension under high pressure caused spattering that contaminated drapes, scrubs, and shoes. The Houston experience This first report of prostate megavoltage radiotherapy came from the Naval Hospital in San Diego, which had acquired an early cobalt unit. The second author of that paper was a young urologist, Carter Eugene Carlton (1930e) (21). Carlton acquired his undergraduate education at the University of Texas, and his medical and urology training at Baylor (Carlton CE, personal communication, February 2006). Part of his military commitment was served at the San Diego facility, then one of the world’s largest military hospitals. San Diego’s large veteran population provided Carlton with clinical experience in managing prostate cancer. Few of his patients had been diagnosed with operable disease, and so radiotherapy was often used. Although the 1965 paper reported excellent results with cobalt therapy, Carlton later indicated that ‘‘attempts to deliver (curative doses) by external beam sources alone result in an intolerable incidence of complications’’ (22). Although intrigued by Flocks’ work, there were several reasons why he did not wish to adopt the Iowa technique: He did not believe that a homogenous dose could be achieved by brachytherapy, and was concerned about the reported incidence of severe toxicity (Carlton CE, personal communication, February 2006). He was also unconvinced by reports of its efficacy, as some of Flocks’ patients had undergone concurrent hormonal therapy. On his return to Baylor, Carlton instituted a program that combined open radiogold implantation with cobalt therapy. He chose to implant gold grains (rather than colloid) because of ease of handling and more accurate placement. The procedure began with lymph node dissection, followed by incision of the endopelvic fascia and mobilization of the prostate by blunt dissection, allowing implantation under direct visualization (23). In contrast
57
to the Iowa program, the radiotherapist performed the implant at Baylor. Initially, a single gold grain was implanted in the nodule; soon the technique was modified to distribute six to ten grains throughout the gland (24) (Fig. 2). As source was delivered to Baylor once weekly, grain activity at time of implantation varied widely (between 2 and 9 mCi), depending upon the day of implantation (Spears MC, personal communication, February 2006). Cobalt (later, linac) external radiotherapy was begun 2e3 weeks later; the radio-opaque grains served as a marker for directing radiation. A total of 4000e5500 rad were delivered over 6e8 weeks (the prescribed dose and target volume depend on node status), but treatment was terminated early if the toxicity was severe. A 2-week break midway through treatment was scheduled when therapy was delivered to the entire pelvis. Combined with the 2500- to 3500-rad implant prescription, the intent was to deliver 7000e8500 rad (25). Although the procedure was designed for Stage C disease, early results were so promising (58% negative biopsies) that Carlton advocated the regimen for lower stages (23). Toxicity was low; thrombophlebitis and temporary extremity/genital edema (presumably due to the node dissection) were the major perioperative complications, each occurring in 10% of patients. In sharp contrast with Flocks’ experience, the incidence of proctitis was 16%, and fewer than 1% of patients required colostomy (26). Impotence was reported to develop in only 5% of men who were potent prior to treatment. The program proved so popular that many private urologists at affiliated hospitals participated. As many as 19 prostate implants were performed in a single day (Spears MC,
Fig. 2. The prostate was implanted with six to ten gold grains after exposure by retropubic dissection. A few seeds were clustered in the tumor nodule, and the rest dispersed throughout the gland (24). (Reproduction permission from the Journal of Urology.)
58
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
personal communication, February 2006)! Baylor’s utilization of radiogold persisted into the 1990s, long after radioactive iodine and palladium were introduced. Carlton alone had performed more than 1500 implants. Carlton enjoyed a stellar career. He, too, became president of the American Urological Association and the American Board of Urology and served as president of the American Association of Genitourinary Surgeons and the Clinical Society of Genitourinary Surgeons. He was awarded the Guiteras (’89) and Young (’93) Awards. But, the Baylor implant program was also flawed. The radiotherapists were not consulted for (or even aware of) brachytherapy cases until summoned to the operating theater to implant an opened patient (Butler EB, personal communication, February 2006). Dosimetry was crude; dose was estimated by assuming that the entire implant activity was deposited at the geometrical center of the prostate, and the delivered dose was defined as the isodose that subtended a diameter equivalent to that of the gland (24). Often, it was simply assumed that the delivered dose was equivalent to the prescription dose (Butler EB, personal communication, February 2006). But it is difficult to encompass the gland with so few sources, even if perfectly placed; in actual fact, postimplant radiographs indicate that the grains were erratically placed. Years later, formal dosimetric evaluation demonstrated that Baylor’s open implants typically delivered only 500e1000 rad (rather than the prescribed 3000 rad) (27); patients therefore routinely received a total dose of !6000 rad. It is not surprising that, with longer followup, results were disappointing (28, 29). Brian Butler, a young Stanfordtrained radiation oncologist with prostate brachytherapy experience acquired in the Air Force, arrived at Baylor in 1990. Although gold seeds continued to be used, Butler revised the program in several important ways (27): Patients were seen in consultation by the radiation oncologist before the procedure. Seeds were placed transperineally, by a Mick applicator, under ultrasound guidance. Five times as many seeds were implanted, but each seed had a lower, standard (2 mCi) activity. Postimplant dosimetry, based on imaging, was routinely performed. But as implant quality improved, the number of implants decreased. The decline in referrals could be attributed to several factors: The disappointing long-term results of the earlier implants, introduction of nerve-sparing prostatectomy and intensity-modulated radiotherapy, and the dwindling role of the urologist in a closed-implant procedure (Butler EB, personal communication, February 2006). Discussion Flocks postulated that a beta-emitting source would deliver more focused radiation, thereby reducing toxicity; and experimental evidence suggested that radioactive microparticles would enter draining lymph nodes. But,
Regaud had demonstrated decades earlier that betairradiation has a ‘‘caustic’’ effect on normal tissue (30), and an earlier trial of implanting beta sources (glassencased radon) into the prostate resulted in painful tissue necrosis (3, 31). Iowa’s radiologists should have been aware of these previous experiences at leading institutions. Once it became evident that the colloid was poorly distributed in tumor nodules and diseased lymph nodes, there was no longer a rationale for its use. Colloidal gold should have been supplanted with gold grains (available since the early 1950s (32)), which do not emit beta particles, could enhance tumor implantation, and would have improved radiation safety (for both patient and personnel). Megavoltage radiation, available by 1960, would have delivered a more homogenous distribution of dose to the tumor bed than could be achieved by puddles of colloid. Yet, colloidal gold continued to be used at Iowa for 25 years, until shortly after Flocks’ death (when it became unobtainable). Iowa’s radiologists should have recognized the program’s flaws and enacted appropriate modifications. It appears, however, that their participation was limited to a supportive role (‘‘measurement. dilution. disposal of contaminated equipment. and excreta’’) (11). Flocks and Culp’s text, Radiation Therapy of Early Prostatic Cancer, did not have a radiology coauthor (5). Although seed distribution rules for volume implants had been formulated almost 30 years earlier (33), they were not used in the Baylor program. Had formal postimplant dosimetry been performed, it would have confirmed that target coverage was not being achieved. Isotope delivery should have been scheduled to avoid wide variation in source strength. Is it unfair to level criticism 3 decades later? A contemporary gold seed implant program at Houston’s St. Joseph’s Hospital (located within several miles of Baylor) avoided many of Baylor’s mistakes. Beginning in 1971, radiotherapist Augusto Guttierez performed open prostate implants with gold grains, followed by megavoltage therapy (34). Although the outline of therapy was similar, the program differed from Baylor’s in several crucial details: The radiotherapist was consulted in advance; the implanted sources were of uniform activity (1.1e1.4 mCi); implants typically contained three times as many sources; dosimetry calculations were based on postimplant radiographs; and megavoltage therapy was prescribed to complement the calculated dose delivered by the implant (35). Clearly, these principles were understood in the 1970s (Gutierrez AE, personal communication, February 2006). Why didn’t the radiologists at Iowa and the radiotherapists at Baylor recognize and rectify their programs’ flaws? In the United States, brachytherapy had almost exclusively been the province of surgeons, and Flocks and Carlton were nationally prominent, institutionally dominant surgeons. The absence of direction and oversight from radiotherapists and physicists proved detrimental to the endeavor and, ultimately, to patient care.
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
Conclusion Although radiogold has been discredited as a source for prostate implants, the major flaw of the abandoned programs was misapplication. Safe and effective brachytherapy procedures are more likely to arise from the functional collaboration of radiation oncologists, surgeons, physicists, radiobiologists, and radiation safety specialists. Acknowledgment The author wishes to acknowledge the invaluable assistance of Andrew Dzaugis and Rosemary Leary, Memorial Hospital of Worcester librarians. Appendix The terms ‘‘radiologist’’ and ‘‘radiotherapist’’ (rather than the modern designation, ‘‘radiation oncologist’’) were used to reflect how these physicians were described in contemporary literature. References [1] Paschkis R, Tittinger W. Radium behandlung eines prostatasarkoms. Wein Klin Wochenschr 1910;48:1715e1716. [2] Pasteau O, Degrais P. De l’emploi du radium dans le traitement des cancers de la prostate. J Urol Med Chir 1913;4:341e366. [3] Barringer BS. Carcinoma of the prostate. In: Bagg HJ, Bailey HC, Barringer BS, et al, editors. Radium report of the Memorial Hospital. New York, NY: Paul B. Hoeber; 1924. p. 174e191. [4] Kerr HD, Flocks RH, Elkins HB, et al. The treatment of moderately advanced carcinoma of the prostate with radioactive gold. Am J Roentgenol Radium 1953;69:969e977. [5] Flocks RH, Culp DA. Radiation therapy of early prostate cancer. Springfield, IL: Charles C. Thomas; 1960. [6] Sheppard CW, Goodell JPB, Hahn PF. Colloidal gold containing the radioactive isotope Au-198 in the selective internal radiation therapy of diseases of the lymphoid system. J Lab Clin Med 1947;32:1437e1441. [7] Rose RG, Osborne MP, Stevens WB. The intracavitary administration of radioactive colloidal gold. N Engl J Med 1952;247:663e667. [8] Hahn PF, Goodell JPB, Sheppard CW, et al. Direct infiltration of radioactive isotopes as a means of delivering ionizing radiation to discrete tissues. J Lab Clin Med 1947;32:1442e1453. [9] Keetel WC, Elkins HB. Experience with radioactive colloidal gold in the treatment of ovarian cancer. Am J Obstet Gynecol 1956;71: 553e568. [10] Flocks RH, Culp DA, Elkins HB. Present status of radioactive gold therapy in management of prostatic cancer. J Urol 1959;81:178e184. [11] Flocks RH, Kerr HD, Elkins HB, et al. Treatment of carcinoma of the prostate by interstitial radiation with radio-active gold (Au198): A preliminary report. J Urol 1952;68:510e522. [12] Sherman AI, Bonbrake M, Allen WM. The application of radioactive gold in the treatment of pelvic cancer. Am J Roentgenol 1951;66: 624e638. [13] Elkins HB, Flocks RH, Culp DA. Evaluation of the use of colloidal radioactive gold in the treatment of prostatic carcinoma. Radiology 1958;70:386e389.
59
[14] Flocks RH, Elkins HB, Culp D. Treatment of cancer of prostate by interstitial injection of Au 198: Studies in problem of distribution. J Urol 1957;77:505e520. [15] Flocks RH, Kerr HD, Elkins HB, et al. The treatment of carcinoma of the prostate by interstitial radiation with radioactive gold (Au-198): A follow-up report. J Urol 1954;71:628e633. [16] Kerr HD, Flocks RH, Elkins HB, et al. Follow-up study of one hundred cases of carcinoma of the prostate treated with radioactive gold. Radiology 1955;64:637e641. [17] Flocks RH, O’Donoghue EPN, Milleman LA, et al. Management of stage C prostate cancer. Urol Clin North Am 1975;2:163e179. [18] Flocks RH. The treatment of stage C prostatic cancer with special reference to combined surgical and radiation therapy. J Urol 1973;109: 461e463. [19] Rosenberg SJ, Loening AA, Hawtrey CE, et al. Radical prostatectomy with adjuvant radioactive gold for prostatic cancer: A preliminary report. J Urol 1985;133:225e227. [20] Loening SA. Gold seed implantation in prostate brachytherapy. Semin Surg Oncol 1997;13:419e424. [21] George FW, Carlton CE, Dykhuizen RF, et al. Cobalt-60 telecurietherapy in the definitive treatment of carcinoma of the prostate: A preliminary report. J Urol 1965;93:102e109. [22] Carlton CE, Dawoud F, Hudgins P, et al. Irradiation treatment of carcinoma of the prostate: A preliminary report based on 8 years of experience. J Urol 1972;108:924e927. [23] Carlton CE, Hudgins PT, Guerriero WG, et al. Radiotherapy in the management of stage C carcinoma of the prostate. J Urol 1976; 116:206e210. [24] Hudgins PT. Irradiation of prostatic cancer combined with abdominal exploration. In: Fletcher GH, editor. Textbook of radiotherapy. Philadelphia, PA: Lea & Febiger; 1975. p. 768e772. [25] Scardino PT, Guerriero WG, Carlton CE. Surgical staging and combined therapy with radioactive gold grain implantation and external irradiation. In: Johnson DE, Boileau M, editors. Genitourinary tumors: fundamental principles and surgical techniques. New York: Grune & Stratton; 1982. p. 75e89. [26] Guerriero WG, Carlton EC, Hudgins P. Combined interstitial and external radiotherapy in the definitive management of carcinoma of the prostate. Cancer 1980;45:1922e1928. [27] Butler EB, Scardino PT, Teh BS, et al. The Baylor College of Medicine experience with gold seed implantation. Semin Surg Oncol 1997;13:406e418. [28] Scardino PT, Frankel JM, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol 1986;135:510e516. [29] Holzman M, Carlton CE, Scardino PT. The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J Urol 1991;146:1578e1582. [30] Regaud C. Some biological aspects of the radiation therapy of cancer. Am J Roentgenol Radium Ther 1924;12:97e101. [31] Failla G. The development of filtered radon implants. Am J Roentgenol Radium Ther 1926;16:507e525. [32] James AG, Henschke UK, Myers WG. The clinical use of radioactive gold (Au-198) seeds. Radiology 1953;6:1034e1039. [33] Paterson R, Parker HM. A dosage system for interstitial radium therapy. Br J Radiol 1938;11:252266. [34] Chan RC, Gutierrez AE. Carcinoma of the prostate: Its treatment by a combination of radioactive gold-grain implant and external irradiation. Cancer 1976;37:2749e2754. [35] Gutierrez AE, Merino OR. Adenocarcinoma of the prostate: Radioactive gold seed implant plus external irradiation. Int J Radiat Oncol Biol Phys 1988;15:1317e1322.
Historical Vignette
The ‘‘Golden Age’’ of prostate brachytherapy: A cautionary tale Jesse N. Aronowitz* University of Massachusetts Medical School and the Levine Cancer Center of the UMass Memorial Medical Center, Worcester, MA
ABSTRACT
PURPOSE: To investigate the earliest attempts to use man-made isotopes for prostate brachytherapy. METHODS AND MATERIALS: Two radiogold brachytherapy programs were analyzed, using literature review and interviews of participants. RESULTS: Although 198Au has been discredited as a source for permanent prostate brachytherapy, the major flaw in the reviewed programs was the misapplication of the isotope. CONCLUSIONS: Safe and effective implant programs are grounded in the sound application of brachytherapy principles. New brachytherapy procedures should arise from the collaboration of radiation oncologists, surgeons, physicists, radiobiologists, and radiation safety specialists. Ó 2008 American Brachytherapy Society. All rights reserved.
Keywords:
Brachytherapy; History of medicine; Prostatic neoplasms; Colloidal gold
Introduction Radium was used therapeutically within a decade of its discovery, and intracavitary prostate brachytherapy was first attempted in 1909 (1, 2). Naturally occurring isotopes are not ideally suited for permanent implantation, and so the modern era of prostate brachytherapy awaited the introduction of reactor-generated radionuclides. One of the first ‘‘man-made’’ isotopes to be applied to brachytherapy was radiogold (198Au). This article reviews the history of two prominent radiogold prostate brachytherapy programs that endured for decades, and evaluates the causes of their ultimate failure.
Radiogold Permanent interstitial implantation of the prostate was first performed at New York’s Memorial Hospital before 1920, using radon sources (3). The technique was adopted in other U.S. centers, but the inability to suitably distribute the seeds within the gland hampered its efficacy, and interest waned. But the need for an alternative to prostatectomy remained; fewer than 5% of men diagnosed with prostate Received 24 August 2007; received in revised form 23 December 2007; accepted 27 December 2007. * Corresponding author. University of Massachusetts Medical School, 33 Kendall Street, Levine Cancer Center, Worcester, MA 01605. Tel.: þ1508-334-6550; fax: þ1-508-334-5624. E-mail address: [email protected] (J.N. Aronowitz)
cancer in the pre-PSA era were found to have operable disease, and so a potentially curative therapy was sought to offer to patients with locally advanced disease (4). Orthovoltage radiotherapy proved too toxic, and the dramatic responses to hormonal therapy were ephemeral (5). Prostate brachytherapy was therefore reintroduced in 1951, using a new radionuclide, 198Au (radiogold). Thousands of men were to undergo radiogold implants over the next four decades. After World War II, Congress passed the Atomic Energy Act, establishing the Atomic Energy Commission. The Oak Ridge Laboratories were transferred to civilian control, and directed to provide radioisotopes for peaceful purposes, especially medical applications. One of the first isotopes made available was 198Au, produced by bombarding gold foil with slow neutrons in a uranium pile (6). Its short half life (2.7 days) and high-energy (0.4 MeV) grays are comparable to radon (3.8 days, 0.2e2 MeV), but is safer to handle because it does not generate megavoltage photons and has no radioactive daughter products. Microparticles were suspended in pectin or gelatin, forming a colloid for use as a beta-emitter (much like 32P). It was infused intravenously (for leukemia and lymphoma) (6), instilled into pleural or peritoneal cavities (to suppress malignant effusions and ascites) (7), or injected into lymphomatous masses and solid tumors (8).
The Iowa experience The first radiogold prostate implant, in March of 1951, was unplanned (4). An 80-year-old man with hormone-
1538-4721/08/$ e see front matter Ó 2008 American Brachytherapy Society. All rights reserved. doi:10.1016/j.brachy.2007.12.004
56
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
refractory Stage C disease, was to undergo a radon implant. After the prostate had been surgically exposed, however, it was discovered that radon sources were not available. Colloidal gold was on hand (it had been used at the institution as an intraperitoneal instillation for ovarian cancer (9)), and was infiltrated into the prostate. The bulky tumor resolved, a followup biopsy was negative, and the patient remained free of evident disease for the remainder of his life (2.5 years); moreover, the treatment seemed devoid of toxicity (10). Encouraged by this case, the urologist began infiltrating colloidal gold into the prostate and seminal vesicles of other men with Stage C disease, and an enthusiastic report of his first 20 cases was published in the Journal of Urology the following year (11). The urologist, Rubin Flocks (1906e1975), was born in Brooklyn to immigrant parents. He received his medical education at Johns Hopkins, where he began his urology residency under Hugh Hampton Young. Hopkins had a ‘‘pyramid program,’’ however, and Flocks completed his training at the University of Iowa. He remained there, first as research assistant, later as faculty, and eventually as chairman of the department (’49e’74) (Hawtrey CE, written communication, February 2005). He attained national prominence, serving as president of the American Urological Association (’68e’69), the Clinical Society of Genitourinary Surgeons (’69e’70), and the American Board of Urology. The high regard of his peers was reflected in his being awarded urology’s highest honors: The Barringer Medal (’68), the Guiteras Award (’68), and the Keyes Award (’74). Flocks remained at the University of Iowa, his entire career. He died the year after retirement, of metastatic renal pelvis carcinoma, in the Rubin Flocks Prostatic Disease Center. There were compelling reasons to explore colloidal gold as the agent of prostate brachytherapy. A beta-emitter, unencapsulated gold would deposit 90% of its energy within millimeters of its deposition site, potentially sparing neighboring tissues. It was assumed that the fascia investing the prostate and seminal vesicles would limit the isotope’s migration. And there was evidence that gold microparticles would be phagocytosed by macrophages which, on circulating to draining lymph nodes, would irradiate D1 metastases (12). Initially, injection was through a combined supra- and retropubic approach (Fig. 1). But dense tumor nodules resisted infiltration and adequate distribution of the colloid throughout the gland-proved elusive; much of the material pooled in the pararectal fascia, causing severe injury (13). Some gold microparticles entered the circulation, and autoradiographs demonstrated hepatic accumulation. Although radiogold entered regional lymphatics, it did not penetrate tumor-congested nodes (13). Flocks and Culp devised several maneuvers to overcome these difficulties: Grossly, abnormal lymph nodes were resected; hyaluronidase and epinephrine were mixed into the colloid to improve distribution and reduce vascular uptake; the suspension was injected under pressure to overcome the resistance of dense
Fig. 1. A. The prostate and seminal vesicles were injected with colloidal gold after suprapubic exposure. B. It was assumed that the colloid would percolate along the fascial septa, eventually settling inside the prostate capsule (12). (Reproduction permission from the Journal of Urology.)
tumor nodules; and small volumes of highly concentrated suspension were used to reduce leakage from the gland (5). Occasionally, the gland was injected from a combination of suprapubic, perineal, and transrectal approaches; persistent nodules could be reinjected transperineally (14). It soon became apparent that the procedure was only effective for the smallest tumors (13), and 80% of posttreatment biopsies were positive (15). By 1954, Flocks and colleagues were resecting tumor nodules prior to radiogold infiltration, or performing transurethral prostate resection postoperatively (16). Eventually, he simply performed perineal prostatectomy, using radiogold as adjuvant therapy (infiltrating the colloid into periprostatic fascia and vascular pedicles) (10). Flocks et al. supported this practice by claiming better local control (95%) in Stage C disease, compared to other published series (70e80%) (17). The cost of the superior control was steep; delayed healing in 80%, and
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
‘‘persistent urethro-cutaneous fistula’’ in 2% (18). Colloidal gold continued to be used at the University of Iowa Hospitals until 1977, when its manufacture ceased; encapsulated gold grains were then substituted (at the same total activity, despite the absorption of beta-irradiation by the capsule (19)). Flocks et al. performed more than 1500 gold implants over 14 years (Hawtrey CE, written communication, March 2007). Beginning in 1984, the grains were implanted transperineally, under trans-rectal sonographic guidance (20). In retrospect, the Iowa program was seriously flawed. The inability to control the distribution of colloidal gold renders it a fearsome brachytherapy source, a dosimetry, and radiation safety nightmare. Homogenous dose distribution could not be achieved, nor could it be measured. Migration of the radioisotope to nontarget organs (especially reticulo-endothelial tissue) could greatly exceed that which remained in the gland (14). Radiation exposure to personnel was so high that surgical teams were rotated to avoid accumulation of prohibitive doses (5). Injection of the suspension under high pressure caused spattering that contaminated drapes, scrubs, and shoes. The Houston experience This first report of prostate megavoltage radiotherapy came from the Naval Hospital in San Diego, which had acquired an early cobalt unit. The second author of that paper was a young urologist, Carter Eugene Carlton (1930e) (21). Carlton acquired his undergraduate education at the University of Texas, and his medical and urology training at Baylor (Carlton CE, personal communication, February 2006). Part of his military commitment was served at the San Diego facility, then one of the world’s largest military hospitals. San Diego’s large veteran population provided Carlton with clinical experience in managing prostate cancer. Few of his patients had been diagnosed with operable disease, and so radiotherapy was often used. Although the 1965 paper reported excellent results with cobalt therapy, Carlton later indicated that ‘‘attempts to deliver (curative doses) by external beam sources alone result in an intolerable incidence of complications’’ (22). Although intrigued by Flocks’ work, there were several reasons why he did not wish to adopt the Iowa technique: He did not believe that a homogenous dose could be achieved by brachytherapy, and was concerned about the reported incidence of severe toxicity (Carlton CE, personal communication, February 2006). He was also unconvinced by reports of its efficacy, as some of Flocks’ patients had undergone concurrent hormonal therapy. On his return to Baylor, Carlton instituted a program that combined open radiogold implantation with cobalt therapy. He chose to implant gold grains (rather than colloid) because of ease of handling and more accurate placement. The procedure began with lymph node dissection, followed by incision of the endopelvic fascia and mobilization of the prostate by blunt dissection, allowing implantation under direct visualization (23). In contrast
57
to the Iowa program, the radiotherapist performed the implant at Baylor. Initially, a single gold grain was implanted in the nodule; soon the technique was modified to distribute six to ten grains throughout the gland (24) (Fig. 2). As source was delivered to Baylor once weekly, grain activity at time of implantation varied widely (between 2 and 9 mCi), depending upon the day of implantation (Spears MC, personal communication, February 2006). Cobalt (later, linac) external radiotherapy was begun 2e3 weeks later; the radio-opaque grains served as a marker for directing radiation. A total of 4000e5500 rad were delivered over 6e8 weeks (the prescribed dose and target volume depend on node status), but treatment was terminated early if the toxicity was severe. A 2-week break midway through treatment was scheduled when therapy was delivered to the entire pelvis. Combined with the 2500- to 3500-rad implant prescription, the intent was to deliver 7000e8500 rad (25). Although the procedure was designed for Stage C disease, early results were so promising (58% negative biopsies) that Carlton advocated the regimen for lower stages (23). Toxicity was low; thrombophlebitis and temporary extremity/genital edema (presumably due to the node dissection) were the major perioperative complications, each occurring in 10% of patients. In sharp contrast with Flocks’ experience, the incidence of proctitis was 16%, and fewer than 1% of patients required colostomy (26). Impotence was reported to develop in only 5% of men who were potent prior to treatment. The program proved so popular that many private urologists at affiliated hospitals participated. As many as 19 prostate implants were performed in a single day (Spears MC,
Fig. 2. The prostate was implanted with six to ten gold grains after exposure by retropubic dissection. A few seeds were clustered in the tumor nodule, and the rest dispersed throughout the gland (24). (Reproduction permission from the Journal of Urology.)
58
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
personal communication, February 2006)! Baylor’s utilization of radiogold persisted into the 1990s, long after radioactive iodine and palladium were introduced. Carlton alone had performed more than 1500 implants. Carlton enjoyed a stellar career. He, too, became president of the American Urological Association and the American Board of Urology and served as president of the American Association of Genitourinary Surgeons and the Clinical Society of Genitourinary Surgeons. He was awarded the Guiteras (’89) and Young (’93) Awards. But, the Baylor implant program was also flawed. The radiotherapists were not consulted for (or even aware of) brachytherapy cases until summoned to the operating theater to implant an opened patient (Butler EB, personal communication, February 2006). Dosimetry was crude; dose was estimated by assuming that the entire implant activity was deposited at the geometrical center of the prostate, and the delivered dose was defined as the isodose that subtended a diameter equivalent to that of the gland (24). Often, it was simply assumed that the delivered dose was equivalent to the prescription dose (Butler EB, personal communication, February 2006). But it is difficult to encompass the gland with so few sources, even if perfectly placed; in actual fact, postimplant radiographs indicate that the grains were erratically placed. Years later, formal dosimetric evaluation demonstrated that Baylor’s open implants typically delivered only 500e1000 rad (rather than the prescribed 3000 rad) (27); patients therefore routinely received a total dose of !6000 rad. It is not surprising that, with longer followup, results were disappointing (28, 29). Brian Butler, a young Stanfordtrained radiation oncologist with prostate brachytherapy experience acquired in the Air Force, arrived at Baylor in 1990. Although gold seeds continued to be used, Butler revised the program in several important ways (27): Patients were seen in consultation by the radiation oncologist before the procedure. Seeds were placed transperineally, by a Mick applicator, under ultrasound guidance. Five times as many seeds were implanted, but each seed had a lower, standard (2 mCi) activity. Postimplant dosimetry, based on imaging, was routinely performed. But as implant quality improved, the number of implants decreased. The decline in referrals could be attributed to several factors: The disappointing long-term results of the earlier implants, introduction of nerve-sparing prostatectomy and intensity-modulated radiotherapy, and the dwindling role of the urologist in a closed-implant procedure (Butler EB, personal communication, February 2006). Discussion Flocks postulated that a beta-emitting source would deliver more focused radiation, thereby reducing toxicity; and experimental evidence suggested that radioactive microparticles would enter draining lymph nodes. But,
Regaud had demonstrated decades earlier that betairradiation has a ‘‘caustic’’ effect on normal tissue (30), and an earlier trial of implanting beta sources (glassencased radon) into the prostate resulted in painful tissue necrosis (3, 31). Iowa’s radiologists should have been aware of these previous experiences at leading institutions. Once it became evident that the colloid was poorly distributed in tumor nodules and diseased lymph nodes, there was no longer a rationale for its use. Colloidal gold should have been supplanted with gold grains (available since the early 1950s (32)), which do not emit beta particles, could enhance tumor implantation, and would have improved radiation safety (for both patient and personnel). Megavoltage radiation, available by 1960, would have delivered a more homogenous distribution of dose to the tumor bed than could be achieved by puddles of colloid. Yet, colloidal gold continued to be used at Iowa for 25 years, until shortly after Flocks’ death (when it became unobtainable). Iowa’s radiologists should have recognized the program’s flaws and enacted appropriate modifications. It appears, however, that their participation was limited to a supportive role (‘‘measurement. dilution. disposal of contaminated equipment. and excreta’’) (11). Flocks and Culp’s text, Radiation Therapy of Early Prostatic Cancer, did not have a radiology coauthor (5). Although seed distribution rules for volume implants had been formulated almost 30 years earlier (33), they were not used in the Baylor program. Had formal postimplant dosimetry been performed, it would have confirmed that target coverage was not being achieved. Isotope delivery should have been scheduled to avoid wide variation in source strength. Is it unfair to level criticism 3 decades later? A contemporary gold seed implant program at Houston’s St. Joseph’s Hospital (located within several miles of Baylor) avoided many of Baylor’s mistakes. Beginning in 1971, radiotherapist Augusto Guttierez performed open prostate implants with gold grains, followed by megavoltage therapy (34). Although the outline of therapy was similar, the program differed from Baylor’s in several crucial details: The radiotherapist was consulted in advance; the implanted sources were of uniform activity (1.1e1.4 mCi); implants typically contained three times as many sources; dosimetry calculations were based on postimplant radiographs; and megavoltage therapy was prescribed to complement the calculated dose delivered by the implant (35). Clearly, these principles were understood in the 1970s (Gutierrez AE, personal communication, February 2006). Why didn’t the radiologists at Iowa and the radiotherapists at Baylor recognize and rectify their programs’ flaws? In the United States, brachytherapy had almost exclusively been the province of surgeons, and Flocks and Carlton were nationally prominent, institutionally dominant surgeons. The absence of direction and oversight from radiotherapists and physicists proved detrimental to the endeavor and, ultimately, to patient care.
J.N. Aronowitz / Brachytherapy 7 (2008) 55e59
Conclusion Although radiogold has been discredited as a source for prostate implants, the major flaw of the abandoned programs was misapplication. Safe and effective brachytherapy procedures are more likely to arise from the functional collaboration of radiation oncologists, surgeons, physicists, radiobiologists, and radiation safety specialists. Acknowledgment The author wishes to acknowledge the invaluable assistance of Andrew Dzaugis and Rosemary Leary, Memorial Hospital of Worcester librarians. Appendix The terms ‘‘radiologist’’ and ‘‘radiotherapist’’ (rather than the modern designation, ‘‘radiation oncologist’’) were used to reflect how these physicians were described in contemporary literature. References [1] Paschkis R, Tittinger W. Radium behandlung eines prostatasarkoms. Wein Klin Wochenschr 1910;48:1715e1716. [2] Pasteau O, Degrais P. De l’emploi du radium dans le traitement des cancers de la prostate. J Urol Med Chir 1913;4:341e366. [3] Barringer BS. Carcinoma of the prostate. In: Bagg HJ, Bailey HC, Barringer BS, et al, editors. Radium report of the Memorial Hospital. New York, NY: Paul B. Hoeber; 1924. p. 174e191. [4] Kerr HD, Flocks RH, Elkins HB, et al. The treatment of moderately advanced carcinoma of the prostate with radioactive gold. Am J Roentgenol Radium 1953;69:969e977. [5] Flocks RH, Culp DA. Radiation therapy of early prostate cancer. Springfield, IL: Charles C. Thomas; 1960. [6] Sheppard CW, Goodell JPB, Hahn PF. Colloidal gold containing the radioactive isotope Au-198 in the selective internal radiation therapy of diseases of the lymphoid system. J Lab Clin Med 1947;32:1437e1441. [7] Rose RG, Osborne MP, Stevens WB. The intracavitary administration of radioactive colloidal gold. N Engl J Med 1952;247:663e667. [8] Hahn PF, Goodell JPB, Sheppard CW, et al. Direct infiltration of radioactive isotopes as a means of delivering ionizing radiation to discrete tissues. J Lab Clin Med 1947;32:1442e1453. [9] Keetel WC, Elkins HB. Experience with radioactive colloidal gold in the treatment of ovarian cancer. Am J Obstet Gynecol 1956;71: 553e568. [10] Flocks RH, Culp DA, Elkins HB. Present status of radioactive gold therapy in management of prostatic cancer. J Urol 1959;81:178e184. [11] Flocks RH, Kerr HD, Elkins HB, et al. Treatment of carcinoma of the prostate by interstitial radiation with radio-active gold (Au198): A preliminary report. J Urol 1952;68:510e522. [12] Sherman AI, Bonbrake M, Allen WM. The application of radioactive gold in the treatment of pelvic cancer. Am J Roentgenol 1951;66: 624e638. [13] Elkins HB, Flocks RH, Culp DA. Evaluation of the use of colloidal radioactive gold in the treatment of prostatic carcinoma. Radiology 1958;70:386e389.
59
[14] Flocks RH, Elkins HB, Culp D. Treatment of cancer of prostate by interstitial injection of Au 198: Studies in problem of distribution. J Urol 1957;77:505e520. [15] Flocks RH, Kerr HD, Elkins HB, et al. The treatment of carcinoma of the prostate by interstitial radiation with radioactive gold (Au-198): A follow-up report. J Urol 1954;71:628e633. [16] Kerr HD, Flocks RH, Elkins HB, et al. Follow-up study of one hundred cases of carcinoma of the prostate treated with radioactive gold. Radiology 1955;64:637e641. [17] Flocks RH, O’Donoghue EPN, Milleman LA, et al. Management of stage C prostate cancer. Urol Clin North Am 1975;2:163e179. [18] Flocks RH. The treatment of stage C prostatic cancer with special reference to combined surgical and radiation therapy. J Urol 1973;109: 461e463. [19] Rosenberg SJ, Loening AA, Hawtrey CE, et al. Radical prostatectomy with adjuvant radioactive gold for prostatic cancer: A preliminary report. J Urol 1985;133:225e227. [20] Loening SA. Gold seed implantation in prostate brachytherapy. Semin Surg Oncol 1997;13:419e424. [21] George FW, Carlton CE, Dykhuizen RF, et al. Cobalt-60 telecurietherapy in the definitive treatment of carcinoma of the prostate: A preliminary report. J Urol 1965;93:102e109. [22] Carlton CE, Dawoud F, Hudgins P, et al. Irradiation treatment of carcinoma of the prostate: A preliminary report based on 8 years of experience. J Urol 1972;108:924e927. [23] Carlton CE, Hudgins PT, Guerriero WG, et al. Radiotherapy in the management of stage C carcinoma of the prostate. J Urol 1976; 116:206e210. [24] Hudgins PT. Irradiation of prostatic cancer combined with abdominal exploration. In: Fletcher GH, editor. Textbook of radiotherapy. Philadelphia, PA: Lea & Febiger; 1975. p. 768e772. [25] Scardino PT, Guerriero WG, Carlton CE. Surgical staging and combined therapy with radioactive gold grain implantation and external irradiation. In: Johnson DE, Boileau M, editors. Genitourinary tumors: fundamental principles and surgical techniques. New York: Grune & Stratton; 1982. p. 75e89. [26] Guerriero WG, Carlton EC, Hudgins P. Combined interstitial and external radiotherapy in the definitive management of carcinoma of the prostate. Cancer 1980;45:1922e1928. [27] Butler EB, Scardino PT, Teh BS, et al. The Baylor College of Medicine experience with gold seed implantation. Semin Surg Oncol 1997;13:406e418. [28] Scardino PT, Frankel JM, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol 1986;135:510e516. [29] Holzman M, Carlton CE, Scardino PT. The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J Urol 1991;146:1578e1582. [30] Regaud C. Some biological aspects of the radiation therapy of cancer. Am J Roentgenol Radium Ther 1924;12:97e101. [31] Failla G. The development of filtered radon implants. Am J Roentgenol Radium Ther 1926;16:507e525. [32] James AG, Henschke UK, Myers WG. The clinical use of radioactive gold (Au-198) seeds. Radiology 1953;6:1034e1039. [33] Paterson R, Parker HM. A dosage system for interstitial radium therapy. Br J Radiol 1938;11:252266. [34] Chan RC, Gutierrez AE. Carcinoma of the prostate: Its treatment by a combination of radioactive gold-grain implant and external irradiation. Cancer 1976;37:2749e2754. [35] Gutierrez AE, Merino OR. Adenocarcinoma of the prostate: Radioactive gold seed implant plus external irradiation. Int J Radiat Oncol Biol Phys 1988;15:1317e1322.