International Journal of
Radiation Oncology biology
physics
www.redjournal.org
History
Introduction of Transperineal Image-Guided Prostate Brachytherapy Jesse N. Aronowitz, MD Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts Received Jan 14, 2014, and in revised form Apr 2, 2014. Accepted for publication Apr 4, 2014.
The modern prostate brachytherapy procedure is characterized by ultrasound guidance, template assistance, and a return to a “closed” transperineal approach. This review traces the introduction and evolution of these elements and charts the development of the procedure from the ashes of previous, failed efforts. Ó 2014 Elsevier Inc.
Introduction Prostate brachytherapy has been performed for more than a century. Urologists in Paris (1, 2) and Vienna (3) reported treating benign and malignant disease with intracavitary radium in 1909. A transperineal interstitial technique was introduced in the United States in 1915 (4). Radon seeds for permanent implantation were developed a decade later and were implanted into the prostate through suprapubic and transperineal approaches. Although the procedure was well tolerated and tumor nodules disappeared, it was abandoned because virtually all patients developed recurrence (5). Interest in prostate brachytherapy was rekindled when artificial radionuclides were introduced mid-century. It was assumed that implantation under direct visualization would result in superior source distribution, and techniques were developed that entailed surgical exposure (6-8). The initial enthusiasm for “open” retropubic implant procedures was dampened by the high incidence of local recurrence (9-11). Whereas many clinicians doubted brachytherapy’s capacity to eradicate prostate cancer (12, 13), retrospective analysis revealed that local control was stage- and dose-dependent Reprint requests to: Jesse N. Aronowitz, MD, Department of Radiation Oncology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655. Tel: (774) 442-5551; E-mail: jesse. [email protected] Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 907e915, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.04.010
(14). Before the introduction of mass screening, most patients presented with bulky or advanced disease. Without effective guidance for source distribution, fewer than one-third of implants delivered a cancericidal (140 Gy) dose to the target volume (14). During the 1970s and 1980s, however, less-invasive “closed” procedures, under fluoroscopic and/or sonographic guidance, were investigated. This review examines the development of transperineal image-guided prostate brachytherapy.
Sources This review is based on oral histories collected from clinicians, physicists, and engineers, supported and supplemented by contemporaneous literature. Interviews were as follows: Mogens Bak (June 2013), Hagen Bertermann (February 2014), John Blasko (September 2011), Komanduri Charyulu (March 2012), James Gottesman (October 2013), Peter Grimm (September 2011), Bo Hansen (April 2013), Henning Hansen (June 2013), Charles Hawtrey (August 2013), Hans Henrik Holm (April 2013), M. Christine Jacobs (December 2013), Gyo¨rgy Kova´cs Conflict of interest: none. Supplementary material www.redjournal.org.
for
this
article
can
be
found
at
908
International Journal of Radiation Oncology Biology Physics
Aronowitz
(January 2014), Stefan Loening (May 2013), Timothy Mate (September 2011), Subir Nag (April 2012), Dattatreyudu Nori (July 2012), Haakon Ragde (September 2011), Ivan Strøyer (May 2013), John Sylvester (May 2012), and Kent Wallner (May 2012).
Findings Introduction of image-guidance and the return of the closed transperineal approach Komanduri Kutumba N. Charyulu (1924-) developed a transperineal technique to implant radon seeds into patients with clinical stage C disease at the University of Miami in 1971 (15). Implantation was preceded by pelvic (55.2-57.2 Gy) and para-aortic (43.2 Gy) teletherapy. Patients were implanted in the lithotomy position. A template, consisting of parallel acrylic plates with channels drilled 1 cm apart, was hand-held against the perineum; 16-gauge needles were passed through the template and perineum by the other hand. The needles were advanced, under fluoroscopic guidance, to the contrast-filled bladder. Pubic arch interference was overcome by angling the template, or by free-hand insertion. Charyulu’s plan was to encompass the region of the prostate with a matrix of seeds, 4 cm wide, 4 cm high, and 5 cm deep (Figs. 1 and 2). He used 3 strengths of radon seeds (0.15, 1.0, and 0.8 mCi) in a Paterson-Parker distribution, to achieve a relatively homogenous distribution of 32 Gy (the relatively low prescription dose was due to radon’s high dose rate).
6A
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2A 4B 2B 4C
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2A 4B
2A 4B 2B 4C
2B 4C
2B 4C
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Fig. 1. Charyulu’s seed distribution plan for transperineal implantation of the prostate (15). The letters A, B, and C represent different strength radon seeds. Reprinted with permission.
With a median follow-up of 4.5 years, 70% of his transperineal patients had no evidence of persistent disease (his patients with early-stage disease, implanted by an open retropubic approach, did not fare as well). Serious late effects were rare. When radon seeds became unavailable, Charyulu substituted radiogold (198Au) grains, injected with a Marsden-type gun. P. Pradeep Kumar began implanting 125I seeds transperineally at the University of Nebraska in 1979 (16). A preoperative CT scan was used to calculate the seed requirement to deliver 160 Gy. The patient was placed in the “semi-lithotomy position” with contrast in the bladder. A central guide needle (without a flange) was passed anterior to the anus and rectum, under direction of a finger in the rectum. The template was slid over the needle, and flanged implant needles were then inserted in a triangular pattern (bordered on 2 sides by the pubic arch and by the rectum posteriorly). Needle parallelism and depth of insertion were monitored by fluoroscopy. An average of 50 seeds (0.3-0.5 mCi each) were implanted with a Mick applicator (Mick Radio-Nuclear Instruments, Mount Vernon, NY). Fifty-eight patients underwent the procedure between 1979 and 1985 (17). The average total implant activity was 24 mCi, and minimal peripheral dose (as calculated from postoperative orthogonal films) was 154 Gy. Kumar reported 85% 5 year local control (18). He began implanting seeds in braided absorbable sutures (obtained from the 3M Corporation, St. Paul, MN) in 1983 (19). This approach maintained spacing and allowed placement of extracapsular seeds without risk of migration. The time to perform an implant was reduced to 45 minutes (20), and the procedure was offered as an outpatient service in 1987 (18). Memorial Sloan-Kettering brachytherapists transitioned from the discredited “open” retropubic implants to transperineal implants in the mid-1980s. Patients underwent a planning CT scan with an obturator in the rectum (21). The prostate was delineated on the scan, its volume calculated, and the activity of the implant was determined by a nomogram. A treatment plan, incorporating the location of the seeds and their distance from the perineum, was generated (22). A custom acrylic template, with holes drilled according to the treatment plan, was fabricated for each case (Fig. 3) (23). Patient positioning was recapitulated intraoperatively with the rectal obturator attached to the perineal template. Needles were inserted under fluoroscopic guidance, and seeds were implanted by a Mick applicator. Transrectal ultrasonography was incorporated into the procedure by 1990 (23).
Incorporation of sonography Hans Henrik Holm (1931-) was a resident physician in Copenhagen when he began experimenting with a borrowed industrial ultrasound unit. He visited physicist Carl Hellmuth Hertz (1920-1990; he was the son of a Physics
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Fig. 2. (a) Anterior and (b) lateral radiographs of a Charyulu transperineal implant (15). The prostate was not visualized or directly targeted; instead, a region enveloping the prostate was implanted. Because the gland was not dissected from surrounding tissues (as had been done in “open” implants), Charyulu could intentionally implant extracapsular seeds. Reprinted with permission. Nobelist and grandnephew of Heinrich Hertz, after whom the unit of wave frequency was named) in Lund, Sweden. Hertz explored medical applications of sonography with cardiologist Inge Edler (“father of echocardiography” [24], 1911-2001), neurosurgeon Lars Leksell (“father of radiosurgery,” 1907-1986), and obstetrician Bertil Sunde´n (25). Holm was awarded a state grant to obtain a Somascope (Physionics, Denver, CO) in 1964 and was allowed to take the unit with him to Gentofte Hospital, where he was accepted for urology training. He attracted a cadre of young clinicians to his Gentofte “Ultrasound Laboratory” (Fig. 4), where they investigated a wide range of ultrasound applications (26), from surgical diagnostics (27, 28) to fetal echocardiography (29). His laboratory partnered with the Danish Central Welding Institute (which would later become the Danish Institute of Biomedical Engineering) to refine and adapt equipment. A product of this collaboration was a device for B-mode directed puncture (1969) (30). Equipment was designed to be mobile, so that bedside procedures could be performed. The Gentofte group developed techniques for interventional sonography in the 1970s, including percutaneous biopsy of abdominal organs (31-34), drainage of cysts and abscesses (35), pericardiocentesis, amniotic fluid sampling, and percutaneous nephrostomy (36). Holm and his collaborators authored several texts on diagnostic (37) and interventional sonography (38). The Danish Welding Institute introduced a probe with transducers for transurethral and transrectal imaging in 1974 (39). When attached to a “fixing sledge” (stepper unit) that retracted the probe at 5-mm intervals, it allowed planimetric volume determinations (40). A template mounted on the probe shaft directed prostate and seminal vesicle biopsies (41). Holm and his ultrasound laboratory were transferred with the Department of Urology to Herlev Hospital in 1976. Bru¨el and Kjær (B&K; a Danish acoustical engineering firm [Nærum, Denmark]) acquired the Danish Welding Institute’s interests in medical sonography in 1977, maintaining the productive association with Holm.
It was a small leap from biopsies to tumor implants. After developing the procedure on organs supplied by the Pathology Department, several liver tumors were implanted with 125I separated by chromic spacers. They next turned their attention to unresectable pancreatic tumors (1980) (42). The prescription was 160 Gy, and most patients also underwent adjuvant teletherapy. By 1982, Holm was implanting 125I seeds into cancerous prostates, under the direction of a rectal ultrasound probe mounted on a sledgestepper (43). Preplanning and implantation were performed with the patient in the lithotomy position. A modified Memorial Hospital nomogram specified the implant activity needed to deliver 160 Gy (on the basis of Henschke’s system of dimension averaging [44]). A 3-cm-thick acrylic template was attached to the probe shaft (Fig. 5) (45). An immobilizing needle was first passed through the template into the anterior gland. Needles preloaded with seeds and spacers were then passed through the template, which maintained needle spacing and parallelism. The deepest (central) needles were placed first. After proper needle position was confirmed by transverse sonographic images, the central needles’ seeds were deposited. The ultrasound probe was then retracted 5 mm, and the next-deepest set of needles were placed; in this fashion, concentric circles of needles were inserted. No precautions were taken to avoid the urethra, because it was assumed that seeds implanted into the urinary tract would be passed upon voiding. Postimplant dosimetry was performed on orthogonal radiographs the following day. The first report (1983) was of 4 implants but made no mention of external irradiation (43). A 1987 report indicated that 28 patients had been implanted with 17-74 seeds, followed (in 2-4 weeks) by 40 Gy of pelvic irradiation in 20 fractions (46). Follow-up biopsies were negative in 11 of 15 cases, and toxicity was reported to be infrequent. Two years later, however, the authors reported that the dose of external radiation had been increased (to 47.4 Gy in 20 fractions), but with less favorable results (47). With a median follow-up of 3 years, almost half of the 33 patients had succumbed to prostate
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I-125 2-17-89 PROSTATE PLANNING TEMPLATE TOP
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Fig. 3. Memorial transperineal treatment plan, with obturator and custom-fabricated template (23). Note the irregular spacing and angulation of the needles. One advantage was that divergent needles reduced pubic arch issues. Reprinted with permission. cancer or were alive with metastatic disease. Of 25 patients undergoing postimplant biopsy and/or transurethral resection, 12 had pathologic evidence of persistent disease. Almost half of the patients had suffered “severe” late complications, such as hemorrhagic proctitis, anal ulceration, rectovesical fistula, or “severe persisting radiation cystitis.” The combination of disappointing disease control and high morbidity led to abandonment of the program in 1987 (48).
Early adopters of ultrasound-guided prostate brachytherapy Centers in Austria (49), Germany (50), the United Kingdom (51), the Netherlands (52), and the United States adapted Holm’s technique in the mid-1980s. In 1983, Subir Nag performed 2 transperineal 125I implants at the University of Tennessee (53). A B&K rectal ultrasound probe was used to measure the prostate. The number of 0.6-mCi seeds needed
to deliver 100 Gy was determined using the Memorial nomogram (54). Needles were passed, free-hand, through the perineum; sonography was used to ensure needle spacing and parallelism. Nag did not use a template “because it limits our spacing between the needles.” After needle insertion the ultrasound probe was removed, and fluoroscopy confirmed needle depth. Stefan Loening, a urologist at the University of Iowa, visited Copenhagen after reading Holm’s 1983 article. He began performing transperineal implants under ultrasound and fluoroscopic-guidance in October of 1984 (55). His technique differed from Holm’s in that he used a Mick applicator to implant radiogold grains. Thirty-one patients were implanted in the first 18 months (56), and 179 in 6½ years (57). The procedure was modified after acquisition of an ultrasound unit with both axial and sagittal imaging (58). Initially the prescription dose was 70 Gy; over time the dose was escalated to 90, then 150 Gy. Bulky disease was treated with a combination of brachytherapy and teletherapy (59). Patients were kept in a private hospital room
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afterloader rather than seeds. Their GammaMed IIi, introduced in 1982, had a 1.1-mm-diameter 192Ir source, thin enough to be passed into needles. Bertermann, radiologist Fred Brix, and physicist Peter Kohr initiated high-dose-rate (HDR) brachytherapy treatment for prostate cancer in August 1985 (60). Their regimen consisted of 2 HDR fractions of 15 Gy interposed among 20 fractions of 2 Gy delivered by a linear accelerator (61). Their implants were preplanned; needle insertion, treatment, and needle removal were all performed in a single procedure, with the patient anesthetized in the brachytherapy suite. Despite treating an unscreened, high-risk population, their control rates were good (69% biochemical control at 8 years) (62). Fig. 4. Participants in the Gentofte “Ultrasound Laboratory” (26). From left to right: Sten Nørby Rasmussen (internist), Søren Hancke (sonography specialist), Hans Henrik Holm (urologist), Jørgen Kvist Kristensen (urologist), and Jan Fog Pedersen (radiologist). Reprinted with permission. for up to 5 days after implantation, to reduce exposure of personnel and public to radiogold’s highly penetrating grays (58). Postimplant dosimetry was performed on orthogonal films. Response was monitored by digital examination, prostate shrinkage on serial sonography, and biopsy. Roughly half of 12-month biopsies were positive, but some became negative at 24 or 36 months (59). Toxicity was modest, with a low incidence of serious rectal injuries. The procedure was abandoned at Iowa after Loening returned to his native Germany in 1992. Urologist Hagen Bertermann intended to introduce Holm’s technique at the Christian-Albrechts-University Hospital in Kiel, Germany. His radiology colleagues were willing to collaborate but preferred using a remote
Fig. 5. Holm’s original equipment: The B&K 1850 probe with an 8531 transrectal transducer and template (45). Note that channels in the template had been premarked with needle numbers. Reprinted with permission.
The “Seattle technique” While visiting Copenhagen to learn Holm’s technique for sonographic imaging and biopsy of the prostate (1984), Seattle urologist Haakon Ragde (1927-) observed an implant (Fig. 6). Upon returning to the United States, he proposed an ultrasound-guided prostate brachytherapy program to Northwest Hospital’s radiation oncologist, John Blasko (1943-). Blasko had reservations regarding Ragde’s proposal. Although he had never performed a retropubic prostate implant, he was aware that long-term results were disappointing; prostate-specific antigen (PSA) had recently been introduced, revealing that most implanted tumors had recurred. Although failures had been associated with poor implant geometry, it had also been suggested that radioiodine’s low dose rate was incapable of sterilizing cancer (12). Had open implants failed because of technique or radiobiology? The former could be corrected, but the latter would not. His second concern was in regard to dose and sequencing; Blasko believed that Holm’s dosing was excessive. His review of the literature suggested that an 125I implant delivering 160 Gy would control welldifferentiated (Gleason 2-6) tumors; higher-grade tumors should first receive 45 Gy of teletherapy, followed by a dose-reduced (120-Gy) implant. Blasko agreed to participate in the program but stipulated that the procedure be performed with these modifications and be initially reserved for elderly men.
Fig. 6. From Holm’s guestbook. Haakon Ragde visited Holm in 1984, 1986, and 1993. Courtesy of H. H. Holm.
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Their technique and equipment (B&K 1846 scanner, 8531 4-MHz axial transducer, 1850 probe mounted on a stepper unit) were identical to Holm’s (63,64). Implantation was preceded by a volume study, acquiring axial images separated by 0.5 cm. The images contained “grid” markings, and a planimetric volume was calculated by the scanner’s computer. Several millimeters of margin were added to the prostate volume to determine the target volume. The treatment plan consisted of placing seeds 1.0 cm apart (the holes on their original template were separated by 1.0 cm) throughout the target volume (seeds could be placed in extracapsular locations). The total implant activity was determined by nomogram (initially, Holm’s nomogram [64]; later a modification of Memorial’s [65]), and individual seed strength was calculated by dividing total implant activity by the number of planned seeds. Computer dosimetry was used to check the adequacy of the pre-plan. Eighty to 100 seeds, of 0.30-0.40 mCi individual seed strength, were implanted. The seeds (separated by chromic suture spacers) were preloaded into 18-gauge spinal needles. The procedure was performed under spinal anesthesia, with the patient in the lithotomy position. The bladder was catheterized, drained, and filled with a 150 mL of water. A towel clip retracted the scrotum. The ultrasound probe was introduced into the rectum and anchored in the stepping unit, which was fastened to the operating room table. The probe was positioned to recreate the volume study images. After stabilizing the gland with 2 empty needles, the base of the prostate was viewed on axial imaging, and the central needles (which implanted seeds at the baseline) were placed first. Seeds were discharged by stabilizing the stylet as the needle was retracted. After the central needles were emptied, the probe was retracted, and a second cohort of seeds was implanted. In this manner all needles were discharged. Pubic arch interference was overcome either by free-hand needle angling, or by drilling holes through the bone (64)! Postimplant dosimetry was performed on orthogonal films (with contrast in the bladder, urethra, and rectum) taken 2 weeks later. Blasko’s stipulation to implant only elderly patients did not hold; their first implant, in November 1985, was of a 49-year-old Alaskan fisherman. The patient indicated that he had to get back to work and would either be implanted or depart untreated. Their second implant was not until the following spring, but thereafter the program took off; 274 men were implanted in the first 4 years (65). The practice had become so busy that Peter Grimm (1952-), Timothy Mate (1949-), and later John Sylvester (1957-) were incorporated into the program. The “Seattle” technique and equipment evolved (Fig. 7). Implants were limited to patients with prostate volumes of
Radiation Oncology biology
physics
www.redjournal.org
History
Introduction of Transperineal Image-Guided Prostate Brachytherapy Jesse N. Aronowitz, MD Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts Received Jan 14, 2014, and in revised form Apr 2, 2014. Accepted for publication Apr 4, 2014.
The modern prostate brachytherapy procedure is characterized by ultrasound guidance, template assistance, and a return to a “closed” transperineal approach. This review traces the introduction and evolution of these elements and charts the development of the procedure from the ashes of previous, failed efforts. Ó 2014 Elsevier Inc.
Introduction Prostate brachytherapy has been performed for more than a century. Urologists in Paris (1, 2) and Vienna (3) reported treating benign and malignant disease with intracavitary radium in 1909. A transperineal interstitial technique was introduced in the United States in 1915 (4). Radon seeds for permanent implantation were developed a decade later and were implanted into the prostate through suprapubic and transperineal approaches. Although the procedure was well tolerated and tumor nodules disappeared, it was abandoned because virtually all patients developed recurrence (5). Interest in prostate brachytherapy was rekindled when artificial radionuclides were introduced mid-century. It was assumed that implantation under direct visualization would result in superior source distribution, and techniques were developed that entailed surgical exposure (6-8). The initial enthusiasm for “open” retropubic implant procedures was dampened by the high incidence of local recurrence (9-11). Whereas many clinicians doubted brachytherapy’s capacity to eradicate prostate cancer (12, 13), retrospective analysis revealed that local control was stage- and dose-dependent Reprint requests to: Jesse N. Aronowitz, MD, Department of Radiation Oncology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655. Tel: (774) 442-5551; E-mail: jesse. [email protected] Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 907e915, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.04.010
(14). Before the introduction of mass screening, most patients presented with bulky or advanced disease. Without effective guidance for source distribution, fewer than one-third of implants delivered a cancericidal (140 Gy) dose to the target volume (14). During the 1970s and 1980s, however, less-invasive “closed” procedures, under fluoroscopic and/or sonographic guidance, were investigated. This review examines the development of transperineal image-guided prostate brachytherapy.
Sources This review is based on oral histories collected from clinicians, physicists, and engineers, supported and supplemented by contemporaneous literature. Interviews were as follows: Mogens Bak (June 2013), Hagen Bertermann (February 2014), John Blasko (September 2011), Komanduri Charyulu (March 2012), James Gottesman (October 2013), Peter Grimm (September 2011), Bo Hansen (April 2013), Henning Hansen (June 2013), Charles Hawtrey (August 2013), Hans Henrik Holm (April 2013), M. Christine Jacobs (December 2013), Gyo¨rgy Kova´cs Conflict of interest: none. Supplementary material www.redjournal.org.
for
this
article
can
be
found
at
908
International Journal of Radiation Oncology Biology Physics
Aronowitz
(January 2014), Stefan Loening (May 2013), Timothy Mate (September 2011), Subir Nag (April 2012), Dattatreyudu Nori (July 2012), Haakon Ragde (September 2011), Ivan Strøyer (May 2013), John Sylvester (May 2012), and Kent Wallner (May 2012).
Findings Introduction of image-guidance and the return of the closed transperineal approach Komanduri Kutumba N. Charyulu (1924-) developed a transperineal technique to implant radon seeds into patients with clinical stage C disease at the University of Miami in 1971 (15). Implantation was preceded by pelvic (55.2-57.2 Gy) and para-aortic (43.2 Gy) teletherapy. Patients were implanted in the lithotomy position. A template, consisting of parallel acrylic plates with channels drilled 1 cm apart, was hand-held against the perineum; 16-gauge needles were passed through the template and perineum by the other hand. The needles were advanced, under fluoroscopic guidance, to the contrast-filled bladder. Pubic arch interference was overcome by angling the template, or by free-hand insertion. Charyulu’s plan was to encompass the region of the prostate with a matrix of seeds, 4 cm wide, 4 cm high, and 5 cm deep (Figs. 1 and 2). He used 3 strengths of radon seeds (0.15, 1.0, and 0.8 mCi) in a Paterson-Parker distribution, to achieve a relatively homogenous distribution of 32 Gy (the relatively low prescription dose was due to radon’s high dose rate).
6A
6B
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2A 4B 2B 4C
2B 4C
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2B 4C
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2A 4B
6B
6B
6A
6A
6B
6B
Fig. 1. Charyulu’s seed distribution plan for transperineal implantation of the prostate (15). The letters A, B, and C represent different strength radon seeds. Reprinted with permission.
With a median follow-up of 4.5 years, 70% of his transperineal patients had no evidence of persistent disease (his patients with early-stage disease, implanted by an open retropubic approach, did not fare as well). Serious late effects were rare. When radon seeds became unavailable, Charyulu substituted radiogold (198Au) grains, injected with a Marsden-type gun. P. Pradeep Kumar began implanting 125I seeds transperineally at the University of Nebraska in 1979 (16). A preoperative CT scan was used to calculate the seed requirement to deliver 160 Gy. The patient was placed in the “semi-lithotomy position” with contrast in the bladder. A central guide needle (without a flange) was passed anterior to the anus and rectum, under direction of a finger in the rectum. The template was slid over the needle, and flanged implant needles were then inserted in a triangular pattern (bordered on 2 sides by the pubic arch and by the rectum posteriorly). Needle parallelism and depth of insertion were monitored by fluoroscopy. An average of 50 seeds (0.3-0.5 mCi each) were implanted with a Mick applicator (Mick Radio-Nuclear Instruments, Mount Vernon, NY). Fifty-eight patients underwent the procedure between 1979 and 1985 (17). The average total implant activity was 24 mCi, and minimal peripheral dose (as calculated from postoperative orthogonal films) was 154 Gy. Kumar reported 85% 5 year local control (18). He began implanting seeds in braided absorbable sutures (obtained from the 3M Corporation, St. Paul, MN) in 1983 (19). This approach maintained spacing and allowed placement of extracapsular seeds without risk of migration. The time to perform an implant was reduced to 45 minutes (20), and the procedure was offered as an outpatient service in 1987 (18). Memorial Sloan-Kettering brachytherapists transitioned from the discredited “open” retropubic implants to transperineal implants in the mid-1980s. Patients underwent a planning CT scan with an obturator in the rectum (21). The prostate was delineated on the scan, its volume calculated, and the activity of the implant was determined by a nomogram. A treatment plan, incorporating the location of the seeds and their distance from the perineum, was generated (22). A custom acrylic template, with holes drilled according to the treatment plan, was fabricated for each case (Fig. 3) (23). Patient positioning was recapitulated intraoperatively with the rectal obturator attached to the perineal template. Needles were inserted under fluoroscopic guidance, and seeds were implanted by a Mick applicator. Transrectal ultrasonography was incorporated into the procedure by 1990 (23).
Incorporation of sonography Hans Henrik Holm (1931-) was a resident physician in Copenhagen when he began experimenting with a borrowed industrial ultrasound unit. He visited physicist Carl Hellmuth Hertz (1920-1990; he was the son of a Physics
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Fig. 2. (a) Anterior and (b) lateral radiographs of a Charyulu transperineal implant (15). The prostate was not visualized or directly targeted; instead, a region enveloping the prostate was implanted. Because the gland was not dissected from surrounding tissues (as had been done in “open” implants), Charyulu could intentionally implant extracapsular seeds. Reprinted with permission. Nobelist and grandnephew of Heinrich Hertz, after whom the unit of wave frequency was named) in Lund, Sweden. Hertz explored medical applications of sonography with cardiologist Inge Edler (“father of echocardiography” [24], 1911-2001), neurosurgeon Lars Leksell (“father of radiosurgery,” 1907-1986), and obstetrician Bertil Sunde´n (25). Holm was awarded a state grant to obtain a Somascope (Physionics, Denver, CO) in 1964 and was allowed to take the unit with him to Gentofte Hospital, where he was accepted for urology training. He attracted a cadre of young clinicians to his Gentofte “Ultrasound Laboratory” (Fig. 4), where they investigated a wide range of ultrasound applications (26), from surgical diagnostics (27, 28) to fetal echocardiography (29). His laboratory partnered with the Danish Central Welding Institute (which would later become the Danish Institute of Biomedical Engineering) to refine and adapt equipment. A product of this collaboration was a device for B-mode directed puncture (1969) (30). Equipment was designed to be mobile, so that bedside procedures could be performed. The Gentofte group developed techniques for interventional sonography in the 1970s, including percutaneous biopsy of abdominal organs (31-34), drainage of cysts and abscesses (35), pericardiocentesis, amniotic fluid sampling, and percutaneous nephrostomy (36). Holm and his collaborators authored several texts on diagnostic (37) and interventional sonography (38). The Danish Welding Institute introduced a probe with transducers for transurethral and transrectal imaging in 1974 (39). When attached to a “fixing sledge” (stepper unit) that retracted the probe at 5-mm intervals, it allowed planimetric volume determinations (40). A template mounted on the probe shaft directed prostate and seminal vesicle biopsies (41). Holm and his ultrasound laboratory were transferred with the Department of Urology to Herlev Hospital in 1976. Bru¨el and Kjær (B&K; a Danish acoustical engineering firm [Nærum, Denmark]) acquired the Danish Welding Institute’s interests in medical sonography in 1977, maintaining the productive association with Holm.
It was a small leap from biopsies to tumor implants. After developing the procedure on organs supplied by the Pathology Department, several liver tumors were implanted with 125I separated by chromic spacers. They next turned their attention to unresectable pancreatic tumors (1980) (42). The prescription was 160 Gy, and most patients also underwent adjuvant teletherapy. By 1982, Holm was implanting 125I seeds into cancerous prostates, under the direction of a rectal ultrasound probe mounted on a sledgestepper (43). Preplanning and implantation were performed with the patient in the lithotomy position. A modified Memorial Hospital nomogram specified the implant activity needed to deliver 160 Gy (on the basis of Henschke’s system of dimension averaging [44]). A 3-cm-thick acrylic template was attached to the probe shaft (Fig. 5) (45). An immobilizing needle was first passed through the template into the anterior gland. Needles preloaded with seeds and spacers were then passed through the template, which maintained needle spacing and parallelism. The deepest (central) needles were placed first. After proper needle position was confirmed by transverse sonographic images, the central needles’ seeds were deposited. The ultrasound probe was then retracted 5 mm, and the next-deepest set of needles were placed; in this fashion, concentric circles of needles were inserted. No precautions were taken to avoid the urethra, because it was assumed that seeds implanted into the urinary tract would be passed upon voiding. Postimplant dosimetry was performed on orthogonal radiographs the following day. The first report (1983) was of 4 implants but made no mention of external irradiation (43). A 1987 report indicated that 28 patients had been implanted with 17-74 seeds, followed (in 2-4 weeks) by 40 Gy of pelvic irradiation in 20 fractions (46). Follow-up biopsies were negative in 11 of 15 cases, and toxicity was reported to be infrequent. Two years later, however, the authors reported that the dose of external radiation had been increased (to 47.4 Gy in 20 fractions), but with less favorable results (47). With a median follow-up of 3 years, almost half of the 33 patients had succumbed to prostate
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I-125 2-17-89 PROSTATE PLANNING TEMPLATE TOP
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Fig. 3. Memorial transperineal treatment plan, with obturator and custom-fabricated template (23). Note the irregular spacing and angulation of the needles. One advantage was that divergent needles reduced pubic arch issues. Reprinted with permission. cancer or were alive with metastatic disease. Of 25 patients undergoing postimplant biopsy and/or transurethral resection, 12 had pathologic evidence of persistent disease. Almost half of the patients had suffered “severe” late complications, such as hemorrhagic proctitis, anal ulceration, rectovesical fistula, or “severe persisting radiation cystitis.” The combination of disappointing disease control and high morbidity led to abandonment of the program in 1987 (48).
Early adopters of ultrasound-guided prostate brachytherapy Centers in Austria (49), Germany (50), the United Kingdom (51), the Netherlands (52), and the United States adapted Holm’s technique in the mid-1980s. In 1983, Subir Nag performed 2 transperineal 125I implants at the University of Tennessee (53). A B&K rectal ultrasound probe was used to measure the prostate. The number of 0.6-mCi seeds needed
to deliver 100 Gy was determined using the Memorial nomogram (54). Needles were passed, free-hand, through the perineum; sonography was used to ensure needle spacing and parallelism. Nag did not use a template “because it limits our spacing between the needles.” After needle insertion the ultrasound probe was removed, and fluoroscopy confirmed needle depth. Stefan Loening, a urologist at the University of Iowa, visited Copenhagen after reading Holm’s 1983 article. He began performing transperineal implants under ultrasound and fluoroscopic-guidance in October of 1984 (55). His technique differed from Holm’s in that he used a Mick applicator to implant radiogold grains. Thirty-one patients were implanted in the first 18 months (56), and 179 in 6½ years (57). The procedure was modified after acquisition of an ultrasound unit with both axial and sagittal imaging (58). Initially the prescription dose was 70 Gy; over time the dose was escalated to 90, then 150 Gy. Bulky disease was treated with a combination of brachytherapy and teletherapy (59). Patients were kept in a private hospital room
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afterloader rather than seeds. Their GammaMed IIi, introduced in 1982, had a 1.1-mm-diameter 192Ir source, thin enough to be passed into needles. Bertermann, radiologist Fred Brix, and physicist Peter Kohr initiated high-dose-rate (HDR) brachytherapy treatment for prostate cancer in August 1985 (60). Their regimen consisted of 2 HDR fractions of 15 Gy interposed among 20 fractions of 2 Gy delivered by a linear accelerator (61). Their implants were preplanned; needle insertion, treatment, and needle removal were all performed in a single procedure, with the patient anesthetized in the brachytherapy suite. Despite treating an unscreened, high-risk population, their control rates were good (69% biochemical control at 8 years) (62). Fig. 4. Participants in the Gentofte “Ultrasound Laboratory” (26). From left to right: Sten Nørby Rasmussen (internist), Søren Hancke (sonography specialist), Hans Henrik Holm (urologist), Jørgen Kvist Kristensen (urologist), and Jan Fog Pedersen (radiologist). Reprinted with permission. for up to 5 days after implantation, to reduce exposure of personnel and public to radiogold’s highly penetrating grays (58). Postimplant dosimetry was performed on orthogonal films. Response was monitored by digital examination, prostate shrinkage on serial sonography, and biopsy. Roughly half of 12-month biopsies were positive, but some became negative at 24 or 36 months (59). Toxicity was modest, with a low incidence of serious rectal injuries. The procedure was abandoned at Iowa after Loening returned to his native Germany in 1992. Urologist Hagen Bertermann intended to introduce Holm’s technique at the Christian-Albrechts-University Hospital in Kiel, Germany. His radiology colleagues were willing to collaborate but preferred using a remote
Fig. 5. Holm’s original equipment: The B&K 1850 probe with an 8531 transrectal transducer and template (45). Note that channels in the template had been premarked with needle numbers. Reprinted with permission.
The “Seattle technique” While visiting Copenhagen to learn Holm’s technique for sonographic imaging and biopsy of the prostate (1984), Seattle urologist Haakon Ragde (1927-) observed an implant (Fig. 6). Upon returning to the United States, he proposed an ultrasound-guided prostate brachytherapy program to Northwest Hospital’s radiation oncologist, John Blasko (1943-). Blasko had reservations regarding Ragde’s proposal. Although he had never performed a retropubic prostate implant, he was aware that long-term results were disappointing; prostate-specific antigen (PSA) had recently been introduced, revealing that most implanted tumors had recurred. Although failures had been associated with poor implant geometry, it had also been suggested that radioiodine’s low dose rate was incapable of sterilizing cancer (12). Had open implants failed because of technique or radiobiology? The former could be corrected, but the latter would not. His second concern was in regard to dose and sequencing; Blasko believed that Holm’s dosing was excessive. His review of the literature suggested that an 125I implant delivering 160 Gy would control welldifferentiated (Gleason 2-6) tumors; higher-grade tumors should first receive 45 Gy of teletherapy, followed by a dose-reduced (120-Gy) implant. Blasko agreed to participate in the program but stipulated that the procedure be performed with these modifications and be initially reserved for elderly men.
Fig. 6. From Holm’s guestbook. Haakon Ragde visited Holm in 1984, 1986, and 1993. Courtesy of H. H. Holm.
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Their technique and equipment (B&K 1846 scanner, 8531 4-MHz axial transducer, 1850 probe mounted on a stepper unit) were identical to Holm’s (63,64). Implantation was preceded by a volume study, acquiring axial images separated by 0.5 cm. The images contained “grid” markings, and a planimetric volume was calculated by the scanner’s computer. Several millimeters of margin were added to the prostate volume to determine the target volume. The treatment plan consisted of placing seeds 1.0 cm apart (the holes on their original template were separated by 1.0 cm) throughout the target volume (seeds could be placed in extracapsular locations). The total implant activity was determined by nomogram (initially, Holm’s nomogram [64]; later a modification of Memorial’s [65]), and individual seed strength was calculated by dividing total implant activity by the number of planned seeds. Computer dosimetry was used to check the adequacy of the pre-plan. Eighty to 100 seeds, of 0.30-0.40 mCi individual seed strength, were implanted. The seeds (separated by chromic suture spacers) were preloaded into 18-gauge spinal needles. The procedure was performed under spinal anesthesia, with the patient in the lithotomy position. The bladder was catheterized, drained, and filled with a 150 mL of water. A towel clip retracted the scrotum. The ultrasound probe was introduced into the rectum and anchored in the stepping unit, which was fastened to the operating room table. The probe was positioned to recreate the volume study images. After stabilizing the gland with 2 empty needles, the base of the prostate was viewed on axial imaging, and the central needles (which implanted seeds at the baseline) were placed first. Seeds were discharged by stabilizing the stylet as the needle was retracted. After the central needles were emptied, the probe was retracted, and a second cohort of seeds was implanted. In this manner all needles were discharged. Pubic arch interference was overcome either by free-hand needle angling, or by drilling holes through the bone (64)! Postimplant dosimetry was performed on orthogonal films (with contrast in the bladder, urethra, and rectum) taken 2 weeks later. Blasko’s stipulation to implant only elderly patients did not hold; their first implant, in November 1985, was of a 49-year-old Alaskan fisherman. The patient indicated that he had to get back to work and would either be implanted or depart untreated. Their second implant was not until the following spring, but thereafter the program took off; 274 men were implanted in the first 4 years (65). The practice had become so busy that Peter Grimm (1952-), Timothy Mate (1949-), and later John Sylvester (1957-) were incorporated into the program. The “Seattle” technique and equipment evolved (Fig. 7). Implants were limited to patients with prostate volumes of
