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Real-time magnetic resonance image-guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 42, No. 3, pp. 507–515, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98 $19.00 1 .00
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Clinical Investigation REAL-TIME MAGNETIC RESONANCE IMAGE-GUIDED INTERSTITIAL BRACHYTHERAPY IN THE TREATMENT OF SELECT PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER ANTHONY V. D’AMICO, M.D., PH.D.,* ROBERT CORMACK, PH.D.,* CLARE M. TEMPANY, M.D.,† SANJAYA KUMAR, M.D.,‡ GEORGE TOPULOS, M.D.,§ HANNE M. KOOY, PH.D.\ AND C. NORMAN COLEMAN, M.D.* *Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02215; Departments of †Radiology, ‡Urology, and Anesthesiology, Brigham and Women’s Hospital, Boston, MA; and \Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
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Purpose: This study was performed to establish the dose-localization capability and acute toxicity of a real-time intraoperative magnetic resonance (MR) image-guided approach to prostate brachytherapy in select patients with clinically localized prostate cancer. Methods and Materials: Nine patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1cNxM0 prostate cancer, prostate-specific antigen (PSA) < 10 ng/ml, biopsy Gleason score not exceeding 3 1 4, and endorectal coil MR stage T2 disease were enrolled into this study. The prescribed minimum peripheral dose was 160 Gy to the clinical target volume (CTV), which was the MR-defined peripheral zone (PZ) of the prostate gland. Using a real-time 0.5 Tesla intraoperative MR imaging unit, 5-mm image planes were obtained throughout the prostate gland. The PZ of the prostate gland, anterior rectal wall, and prostatic urethra were identified on the T2 weighted axial images by an MR radiologist. An optimized treatment plan for catheter insertion was generated intraoperatively. Each catheter containing the 125Iodine sources was placed under real-time MR guidance to ensure that its position in the coronal, sagittal, and axial planes was in agreement with the planned trajectory. Real-time dose– volume histogram analyses were used intraoperatively to optimize the dosimetry. Results: For the 9 study patients, 89 –99% (median 94%) of the CTV received a minimum peripheral dose of 160 Gy and > 95% of the volume of the prostatic urethra and 42– 89% (median 70%) of the volume of the anterior rectal wall received doses that were below the reported tolerance. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and no patient required more than a limited course (< 3 weeks) of oral a-1 blockers for postimplant urethritis. Conclusions: Real-time MR-guided interstitial radiation therapy provided the ability to achieve the planned optimized dose–volume histogram profiles to the CTV and healthy juxtaposed structures intraoperatively, with minimal acute morbidity. © 1998 Elsevier Science Inc. Prostate cancer, Radiation therapy, Magnetic resonance imaging, Implant, Dose–volume histogram.
INTRODUCTION Adenocarcinoma of the prostate is currently the most commonly diagnosed cancer in men in the USA and the second leading cause of cancer mortality (1). The natural history of clinically localized, and therefore potentially curable disease, is often protracted. As a result, adverse side effects sustained from the primary treatment persist for extended periods, often over a decade. Therefore, it is important that the treatment, whose goal is to permanently eradicate the disease, also has acceptable complication rates, leaving the patient with an acceptable quality of life after therapy is complete. Brachytherapy is the therapeutic delivery of radiation to a
diseased site by the insertion, either temporarily or permanently, of seeds containing radioactive material. The dose distribution around a single source falls off approximately as l/r2, where r is the distance from the source center. The use of brachytherapy exploits the dose fall-off effect, by placing sufficient sources within the cancer-bearing volume to deliver the prescription dose to the entire cancer while a rapid decrease in dose beyond the volume-containing sources occurs. The rapid dose fall-off, therefore, provides the basis on which a high intraprostatic dose can be delivered while maintaining subtolerance doses in the healthy juxtaposed tissues. The current method of prostate brachytherapy in the USA uses a 2-dimensional (2D) transrectal ultrasound imaging
Reprint requests to: Anthony V. D’Amico, M.D., Ph.D., Joint Center for Radiation Therapy, Harvard Medical School, 330
Brookline Avenue - 5th floor, Boston, MA 02215. Accepted for publication 9 July 1998. 507
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plane for radioactive seed guidance (2). Using this approach, less than ideal placement of radioactive sources sometimes occurs (3). In the early experience with this approach, inadvertent placement of the radioactive sources led to complications that included impotence, rectal-prostatic fistula, rectal bleeding, colostomy, superficial urethral necrosis, and urinary incontinence. A real-time 3-dimensional (3D) magnetic resonance (MR) imaging-guided prostate brachytherapy implant technique that utilizes both realtime MR imaging and a real-time dose–volume histogram (DVH) analysis program has been designed and implemented. Using this technique, the selection of the appropriate seed strength, seed number, and catheter trajectory can be made intraoperatively and then checked for accuracy using real-time MR imaging within seconds. Therefore, in theory, this technique is capable of achieving optimized dose distributions in both the CTV and healthy adjacent structures that may translate into both improved cancer control and quality of life, respectively. Although prostate brachytherapy using transrectal ultrasound guidance lacks long-term follow-up (i.e., 15 years), it has become a primary treatment option in the USA. Therefore, advancements using a brachytherapy technique that may increase cancer control rates, while potentially limiting gastrointestinal, genitourinary, and sexual function morbidity, would be critical to the growing number of prostate cancer patients who are choosing prostate brachytherapy as their primary treatment. In this study, a report of the dose– volume histogram analyses and acute morbidity of the first 9 patients treated using a real-time intraoperative MRguided system is presented. METHODS AND MATERIALS Patient entry requirements Between November 1997 and February 1998, 9 patients underwent an MR-guided prostate radiation implant at the Brigham and Women’s Hospital. At this institution, the policy for patient selection includes only those men with 1997 American Joint Commission on Cancer (CASEAJCC) clinical stage T1cNXM0 prostate cancer (4), PSA , 10 ng/ml, biopsy Gleason score not more than 3 1 4, and endorectal coil MR stage T2 disease. In addition, patients who had urinary daytime frequency less than every 3 h and/or nocturia exceeding 3 h that was not medically controlled were not eligible for study entry. All patients with a prior history of a transurethral resection of the prostate (TURP) were excluded. Staging In all cases, staging evaluation included a history and physical examination, including a digital rectal exam (DRE), serum PSA, endorectal coil magnetic resonance imaging (MRI) scan of the prostate, bone scan, and a transrectal ultrasound-guided (TRUS) needle biopsy of the
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prostate with Gleason score histologic grading (5). A sextant biopsy was performed using a 18 gauge Tru-Cut1 needle via a transrectal approach. The clinical stage was obtained from the DRE findings using the current 1997 AJCC staging system. Radiologic and biopsy information were not used to determine clinical stage. The PSA was obtained on an ambulatory basis prior to radiological studies and biopsy. All PSA measurements were made using the Hybritech assay (6). Treatment Interstitial prostate radiation was performed using 125Iodine sources, an MR-compatible perineal template, a peripheral loading technique, and an intraoperative 0.5-Tesla MRI unit (General Electric Medical Systems, Milwaukee, WI). A standard conventional MRI system consists of a single, long cylindrically-shaped magnet with a closed bore and similarly shaped cylindrical imaging coils. This new interventional magnet consists of two shorter cylindrical magnets with imaging coils enclosed. Between these two components, there is a 56-cm gap providing full access to the patient while imaging. Therefore, placement of MRcompatible (nonferromagnetic) catheters into the perineum can occur simultaneously during patient imaging. Within the center of the 56-cm gap is a 30 cm diameter imaging volume, within which the same quality images as obtained in a conventional 0.5-Tesla magnet can be obtained. With the exception of the “open” configuration, the magnet is identical to a conventional unit. The prescribed minimum dose to the peripheral zone of the prostate was 160 Gy. Individual source strength ranged from 0.32 to 0.44 mCi, and the total activity implanted ranged from 18.8 to 47.5 mCi using 43–120 (median 80) seeds. Eligible patients who had given consent were asked to anonymously complete a prospectively validated quality of life questionnaire (7) to establish baseline sexual, urinary, and bowel functions. This survey will be readministered at 3 months and then annually for 3 years posttherapy. At our institution, the policy for the patients pre-, peri-, and postoperative management was as follows. Patients were started on a selective inhibitor of the a-1 subtype of the a-adrenergic receptors to decrease urethral resistance to urine flow by relaxing the smooth muscle surrounding the urethra for 1 week prior to treatment and for up to 3 weeks posttherapy. Dexamethasone (Decadron®) 4 mg by mouth was used 1 day preoperatively and then intravenously intraoperatively and 4 mg by mouth BID 1 day postoperatively. This medical intervention was employed to limit the edema that can occur within the prostate due to its mechanical disruption from seed and catheter placement. Concurrent with dexamethsone use, an H2-blocker was used for protection of the gastrointestinal mucosa. Prophylactic antibiotics were used for 2 days preoperatively, intraoperatively, and then 1 week 1
Travenol Laboratories, Deerfield, IL.
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postoperatively. General anesthesia was employed during the implant procedure. After the patient was placed in the lithotomy position and anesthesized, a Foley catheter was inserted and clamped. The MR-compatible template was secured to the MR table and placed against the patient’s perineum. A rectal obturator 3.0 cm in diameter was passed through the template and into the rectum. The rectal obturator was secured to the template using an MR-compatible screw. Within the central cavity of the rectal obturator was a red rubber tube that allowed for the passage of intrarectal gas. Axial, coronal, and sagittal images were acquired at 5-mm intervals using a MR pelvic coil in a 0.5-Tesla magnetic field. The images obtained consisted of axial T1W and fast spin echo (FSE) sequences through the prostate. The FSE parameters were TR 5000/TE eff 100, Echo train length 8, FOV 20 3 20 CM, slice thickness 5 mm, with a 1-mm interslice gap, and the matrix was 192 with 2 signal averages. The T1W images had similar FOV, slice thickness, gap, and matrix; however, the TR was 500 and TE was 20. FSE images were also obtained in the coronal and sagittal planes. The peripheral zone (PZ) of the prostate was selected as the clinical target volume (CTV) and was identified on each axial slice, as were the anterior rectal wall and prostatic urethra, by an expert MR radiologist (C. M. T.). Based on the CTV and juxtaposed normal tissue volumes, desired minimum peripheral dose, and previously reported healthy tissue tolerance (8), a catheter loading was calculated using a previously described dose algorithm (9). As each catheter containing the preloaded sources was inserted, its position in the coronal, sagittal, and axial plane was identified in real-time (Fig. 1a– c) and compared to its expected location based on the optimized plan. Adjustments to account for prostate motion, edema, or catheter divergence could be made before source deposition. This process was repeated in an iterative fashion for all planned catheters. The cumulative dose–volume histograms for the CTV, anterior rectal wall, and prostatic urethra based on the actual source locations were calculated after each catheter insertion, allowing for adjustments intraoperatively if necessary. Postimplant, all patients had cystosopy to assess the integrity of the bladder neck and inspect the bladder lumen for the presence of 125Iodine seeds. Postcystoscopy, the patients were taken to the recover room and had the Foley catheter removed within 1–2 h after extubation. They were continued on maintenance fluids until a successful voiding trial was completed. All patients have had follow-up postimplant for a minimum of 1 month and maximum of 3 months (median 2 months).
Fig. 1. Real-time intraoperative catheter localization. (a) Coronal plane; (b) Sagittal plane; (c) Axial plane. Note that 125Iodine sources from previous catheter insertions can be seen as black voids on the real-time MR images. The catheter appears as a black void larger than actual size.
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Table 1. Clinical characteristics of the 9 study patients treated using MR-guided prostate interstitial radiation therapy Clinical characteristic
Median
Minimum
Maximum
Age (years) 1997 AJCC clinical stage PSA (ng/ml) Biopsy Gleason score % 1 biopsies Prostate volume (cm3) Endorectal MRI stage
60 T1cNxM0 6.7 313 50% 26 T2b
54 T1cNxM0 4.2 312 17% 19 T2a
72 T1cNxM0 9.9 314 67% 67.1 T2n
AJCC 5 American Joint Commission on Cancer Staging; PSA 5 prostate–specific antigen; % 1 5 Percent positive; MRI 5 magnetic resonance imaging.
Dose–volume histogram analysis Dose–volume histogram (DVH) analyses were performed intraoperatively in real-time for the CTV, anterior rectal wall, and prostatic urethra, based on the final source locations. The prescription dose of 160 Gy was calculated using the recommendations of the American Association of Physicists in Medicine Radiation Therapy Committee Task Force No. 43 guidelines (10). Anterior rectal wall tolerance was defined as 100 Gy and urethral tolerance as 400 Gy, per Wallner and colleagues (8).
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(median 70%) of the anterior rectal wall volume was within this dose limit in the 9 study patients. The range of D10’s for the anterior rectal wall was 100 Gy to 210 Gy (median 135 Gy). Figure 2a–i depicts the DVH profiles and volume summaries for the CTV, anterior rectal wall, and prostatic urethra for the 9 study patients. Acute morbidity There were no sources found upon inspection of the bladder lumen at the postimplant cystoscopy and no patient reported passing a seed during the first postoperative month. No evidence of trauma from catheter penetration into the bladder neck was noted at the time of cystoscopy. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and 4 (44%) of 9 patients required oral a-1 blockers for postimplant urethritis for up to 3 weeks postoperatively. Minor perineal skin irritation was noted in 2 (22%) of 9 patients, which resolved in all cases by the first postoperative month. No patient reported gastrointestinal or sexual dysfunction during the first postoperative month. Patients returned to work within 2–5 days (median 3 days) after the procedure.
DISCUSSION RESULTS Patient characteristics The median age of the 9 study patients was 60 years (range 54 –72). All patients had clinical stage T1cNXM0 disease, as per the 1997 AJCC staging system. The median PSA was 6.7 ng/ml (range: 4.2–9.9 ng/ml) and the biopsy Gleason score ranged from 3 1 2 to 3 1 4 with a median of 3 1 3. The percent positive biopsies ranged from 1 (17%) of 6 to 4 (67%) of 6, median 3 (50%) of 6. Bilateral disease was noted in 5 (56%) of 9 patients and 4 (44%) of 9 patients had unilateral disease based on the sextant sampling. The 1997 AJCC stage as assessed by endorectal coil MR was T2a and T2b in 3 (33%) and 6 (67%) patients, respectively. The endorectal MR-determined volume using an ellipsoid approximation [(p/6)(axial)(coronal)(sagittal)] ranged from 3 19 cm – 67.1 cm3 (median 26 cm3). The clinical characteristics of the study patients are summarized in Table 1.
Dose–volume histogram analyses The percent of the CTV receiving the minimum peripheral dose using the real-time MR-guided approach in the 9 study patients was 89 –99% (median 94%). The range of D90s for the CTV was from 156 Gy (98% prescription) to 200 Gy (125% prescription) with a median of 173 Gy. Based on a previously described estimate of 400 Gy for urethral tolerance (8), less than 5% of the urethral volume exceeded this dose across all patients. The range of D10s for the prostatic urethra was from 124 Gy to 280 Gy, with a median of 210 Gy. The rectal tolerance has been suggested to be 100 Gy (8). Using the MR-guided technique, 42– 89%
Patient selection The basis on which the patient selection rules were made in this study were derived from a concept called combined modality staging (11). This concept uses the pretreatment PSA, biopsy Gleason score, and AJCC clinical stage to determine the likelihood of organ-confined disease and subsequent freedom from PSA failure after external-beam radiation therapy (RT) or radical prostatectomy (RP). Accepting an 80% organ confinement rate and a subsequent 88% estimated 5-year freedom from PSA failure after RT or RP, respectively, identifies a specific cohort of patients on the basis of their pretreatment clinical characteristics (12–14). Specifically, these are patients with a pretreatment PSA less than 10 ng/ml, biopsy Gleason score of 6 or less, clinical stage of T1c or T2a based on the former 1992 AJCC staging system, and an endorectal coil MR showing T2 disease. Clinical stage T2a patients were excluded from participation in the current study, despite a PSA , 10 ng/ml and a biopsy Gleason score of 6 or less. The reason for this exclusion is because of recent information (15) showing a statistically and clinically significant decrement in estimated 4-year PSA failure-free survivals of 28% in patients with these PSA and Gleason score parameters, but 1992 AJCC clinical stage T2a as opposed to T1c. A possible explanation for this result is that, to prevent a significant volume of the anterior rectal wall from receiving a dose in excess of the reported rectal tolerance of 100 Gy (8), the posterior aspect of the palpable nodule may be in the rapid dose fall-off region of the implant. Therefore, this part of the nodule may not receive doses adequate for tumor sterilization. Patients with biopsy Gleason scores of 3 1 4 were
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Fig. 2. (a–i) Dose–volume histograms and volume summaries for the CTV, anterior rectal wall, and prostatic urethra for the 9 study patients.
accepted for entry, assuming all other requirements for entry were satisfied. The reason for this inclusion is that data on the histopathologic correlation between biopsy and prostatectomy Gleason scores from surgical series (16) suggest that as many as 21% of patients thought to have biopsy Gleason scores of 7 are found to have prostatectomy Gleason scores of 5 or 6. This finding was for cases in which the primary biopsy Gleason grade 5 3 or 4. In cases where the
primary biopsy Gleason grade 5 3, the 21% estimate of overgrading was conservative. Finally, an endorectal coil MR was performed on all patients by an MR expert (C. M. T.) and needed to show no evidence of extraprostatic disease for study entry. From a previous report (13), patients with an endorectal coil MR showing evidence of extracapsular penetration or seminal vesicle invasion were found to have pathologic T3 disease
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Fig. 3. Series (a) Axial T2-weighted MR images used to identify the CTV and anterior rectal wall and the prostatic urethra. Series (b) Identification of the prostate peripheral zone, anterior rectal wall, and the prostatic urethra. Series (c) Total dose received based on final 125Iodine source positions. Red 5 $ 240 Gy; Yellow 5 $ 160 and , 240 Gy; Blue 5 $ 100 and , 160 Gy; No color 5 , 100 Gy.
in 87% of the cases, despite a PSA , 10 ng/ml and a biopsy Gleason score of 6 or less. Dose–volume histogram analyses The results shown in Figure 3a–i provide evidence that the use of a real-time MR-guided image system with real-
time dosimetry resulted in the ability to deliver the planned optimized dose distributions to the CTV, prostatic urethra, and anterior rectal wall. Specifically, a minimum of 89% of the CTV received the prescription dose and at least 95% of the volume of the prostatic urethra was maintained below the reported tolerance level in all patients. Similarly, 42–
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89% (median 70%) of the volume of the anterior rectal wall was also kept below the reported tolerance level of 100 Gy. This result suggested that, despite optimal placement of 125 Iodine seeds, the 3–5-mm fat-containing space between the posterior prostatic capsule and outer muscle layer of the anterior rectal wall is not a realistic distance over which to see a fall-off in dose from 160 to 100 Gy. The experience from Ragde and colleagues (2), however, where the prescription dose of 160 Gy was delivered with a margin of 2–5 mm around the prostatic capsule and, therefore, into the outer muscle layer of the anterior rectal wall, reported minimal (1%) rectal morbidity. Therefore, the actual anterior rectal wall tolerance may be higher than the 100 Gy previously reported (8). The CTV in this study was the MR-defined peripheral zone (PZ). Ninety percent of the CTV received 89 –125% of the prescribed minimum peripheral dose across all study patients. The choice of the PZ of the prostate to represent the CTV was based on the results of prostatectomy tumormapping studies (17, 18), in which whole mounting of the prostate gland and zonal mapping of tumor were performed. The data suggested that prostate cancer in the anterior base of the prostate is rare and is almost always the result of growth of large PZ lesion into the anterior gland. In the current study, given the strict patient selection criteria, large PZ tumors with anterior extension are very unlikely. The mapping studies (17, 18) also found transition zone (TZ) primary cancers alone or in conjunction with synchronous PZ cancers in 10 –20% of the cases. Typically, however, cancers in the TZ were limited to microscopic foci unless the patient presented with bladder outlet obstructive symptoms and was diagnosed during a therapeutic TURP.
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Considering that patients with a history of a TURP were excluded in this study, at most the possibility of microscopic prostate cancer in the TZ exists. To account for the possibility of microscopic disease in the TZ, the loading technique used in this study, by design, treated most of the TZ to the prescription dose or higher. This result is illustrated for a representative case in Fig. 3a– c. Specifically, the T2-weighted axial images of the prostate on which the CTV, prostatic urethra, and anterior rectal wall were identified are shown in the Fig. 3a series. These specific regions identified by the MR radiologist (C. M. T.) are shown in the Fig. 3b series. The total doses received, based on the intraoperative loading, are shown in the corresponding Fig. 3c series. From the dose profiles in the Fig. 3c series, it can be seen that the majority of the TZ received at least the prescription dose (160 Gy) and nearly all of the TZ received at least 100 Gy. CONCLUSIONS A real-time MR-guided technique has been developed for the placement of permanent 125Iodine sources into the prostate gland. This technique utilized a real-time interactive dosimetry algorithm (9), and was able to achieve a minimum of 89% coverage (median 94%) of the CTV while simultaneously maintaining $ 95% of the prostatic urethra and most (median 70%) of the anterior rectal wall below reported tolerance levels (8). Acute morbidity using this technique was minimal. Further follow-up is needed to ascertain the impact that these DVH profiles will have on cancer control and quality of life. These endpoints are being monitored prospectively using actuarial-based statistics and a validated quality-of–life instrument.
REFERENCES 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clinicians 1998;48:6 –30. 2. Ragde H, Blasko JC, Grimm PD, Kenny GM, Sylvester JE, Hoak DC, Landin K, Cavanagh W. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442– 453. 3. Wallner K, Roy J, Zelefsky M, Fuks Z, Harrison L. Short term freedom from disease progression after I-125 prostate implantation. Int J Radiat Oncol Biol Phys 1994; 30: 405– 409. 4. Beahrs OH, Henson DE, Hutter RVP. American Joint Committee on Cancer, Manual for staging cancer. 4th ed. Philadelphia, PA: JP Lippincott, 1997. 5. Gleason DF, Veterans Administration Cooperative Urological Research Group. Histologic grading and staging of prostatic carcinoma. In: Tannenbaum M, editor. Urologic pathology. Philadelphia, PA: Lea & Febiger, 1977. p. 171–187. 6. Oesterling JE, Jacobsen SJ, Klee GG, Pettersson K, Pironen T, Abrahamsson P, Stenman U, Dowell B, Lovgren T, Lilja H. Free, complexed and total serum prostate specific antigen: The establishment of appropriate reference ranges for their concentrations and ratios. J Urol 1995; 154: 1090 –1095. 7. Talcott JA, Reiker P, Propert KJ, Clark JA, Wishnow KI, Loughlin KR, Richie JP, Kantoff PW. Patient reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997; 89: 1117–1123.
8. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32: 465– 471. 9. Cormack RA, D’Amico AV, Holupka E, Kooy HM, Powers RE, Svensson G. Real-time dosimetry based prostate implant planing system. In: Leavitt DD, Starkschal G, editors. Proceedings of the XII International Conference on the use of computers in radiation therapy. Medical Physics Publishing, 1997, vol. 1 p. 124 –126. 10. Nath R, Anderson LL, Luxton G, Weaver KA, Williamson JF, Meigooni AS. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995; 22: 209 –234. 11. D’Amico AV, Whittington R, Malkowicz SB, Schnall M, Tomaszewski JE, Schultz D, Wein A. A multivariate analysis of clinical and pathological factors which predict for prostatespecific antigen failure after radical prostatectomy for prostate cancer. Urol 1995; 154: 131–138. 12. D’Amico AV, Whittington R, Kaplan I, Beard C, Schultz D, Malkowicz SB, Tomaszewski JE, Wein A, Coleman CN. Equivalent 5 year bNED in select prostate cancer patients managed with surgery or radiation therapy despite exclusion of the seminal vesicles from the CTV. Int J Radiat Oncol Biol Phys 1997; 39: 335–340.
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13. D’Amico AV, Whittington R, Tomaszewski JE, Malkowicz SB, Schultz D, Schnall M, Wein A. A critical appraisal of the role of endorectal coil magnetic resonance imaging in the prediction of pathologic stage and postoperative prostate specific antigen failure in patients with clinically organ confined prostate cancer. J Clin Oncol 1996; 14: 1770 –1777. 14. Partin AW, Kattan MW, Subong ENP, Walsh P, Wojno KJ, Oesterling JE, Kattan MW, Scardino PT, Pearson JD. Combination of prostate specific antigen, clinical stage, and Gleason score to predict pathologic stage of localized prostate cancer: A multi-institutional update. JAMA 1997; 277: 1445– 1451. 15. D’Amico AV, Whittington R, Malkowicz SB, Blank K, Broderick GA, Schultz D, Tomaszewski JE, Wein A. Prostate
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specific antigen outcome after permanent interstitial radiation therapy in low risk prostate cancer patients with T2a versus T1c disease. Urology, 1998 (in press). 16. Cookson MS, Fleshner NE, Soloway SM, Fair WR. Correlation between Gleason score of needle biopsy and radical prostatectomy specimen: Accuracy and clinical implications. J Urol 1997; 157: 559 –562. 17. Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein JI. Pathological features of hereditary prostate cancer. J Urol 1995; 153: 987–992. 18. McNeal JE, Redwine EA, Freiha FS. Zonal distribution of adenocarcinoma of the prostate: Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988; 12: 897–902.
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Clinical Investigation REAL-TIME MAGNETIC RESONANCE IMAGE-GUIDED INTERSTITIAL BRACHYTHERAPY IN THE TREATMENT OF SELECT PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER ANTHONY V. D’AMICO, M.D., PH.D.,* ROBERT CORMACK, PH.D.,* CLARE M. TEMPANY, M.D.,† SANJAYA KUMAR, M.D.,‡ GEORGE TOPULOS, M.D.,§ HANNE M. KOOY, PH.D.\ AND C. NORMAN COLEMAN, M.D.* *Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02215; Departments of †Radiology, ‡Urology, and Anesthesiology, Brigham and Women’s Hospital, Boston, MA; and \Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
§
Purpose: This study was performed to establish the dose-localization capability and acute toxicity of a real-time intraoperative magnetic resonance (MR) image-guided approach to prostate brachytherapy in select patients with clinically localized prostate cancer. Methods and Materials: Nine patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1cNxM0 prostate cancer, prostate-specific antigen (PSA) < 10 ng/ml, biopsy Gleason score not exceeding 3 1 4, and endorectal coil MR stage T2 disease were enrolled into this study. The prescribed minimum peripheral dose was 160 Gy to the clinical target volume (CTV), which was the MR-defined peripheral zone (PZ) of the prostate gland. Using a real-time 0.5 Tesla intraoperative MR imaging unit, 5-mm image planes were obtained throughout the prostate gland. The PZ of the prostate gland, anterior rectal wall, and prostatic urethra were identified on the T2 weighted axial images by an MR radiologist. An optimized treatment plan for catheter insertion was generated intraoperatively. Each catheter containing the 125Iodine sources was placed under real-time MR guidance to ensure that its position in the coronal, sagittal, and axial planes was in agreement with the planned trajectory. Real-time dose– volume histogram analyses were used intraoperatively to optimize the dosimetry. Results: For the 9 study patients, 89 –99% (median 94%) of the CTV received a minimum peripheral dose of 160 Gy and > 95% of the volume of the prostatic urethra and 42– 89% (median 70%) of the volume of the anterior rectal wall received doses that were below the reported tolerance. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and no patient required more than a limited course (< 3 weeks) of oral a-1 blockers for postimplant urethritis. Conclusions: Real-time MR-guided interstitial radiation therapy provided the ability to achieve the planned optimized dose–volume histogram profiles to the CTV and healthy juxtaposed structures intraoperatively, with minimal acute morbidity. © 1998 Elsevier Science Inc. Prostate cancer, Radiation therapy, Magnetic resonance imaging, Implant, Dose–volume histogram.
INTRODUCTION Adenocarcinoma of the prostate is currently the most commonly diagnosed cancer in men in the USA and the second leading cause of cancer mortality (1). The natural history of clinically localized, and therefore potentially curable disease, is often protracted. As a result, adverse side effects sustained from the primary treatment persist for extended periods, often over a decade. Therefore, it is important that the treatment, whose goal is to permanently eradicate the disease, also has acceptable complication rates, leaving the patient with an acceptable quality of life after therapy is complete. Brachytherapy is the therapeutic delivery of radiation to a
diseased site by the insertion, either temporarily or permanently, of seeds containing radioactive material. The dose distribution around a single source falls off approximately as l/r2, where r is the distance from the source center. The use of brachytherapy exploits the dose fall-off effect, by placing sufficient sources within the cancer-bearing volume to deliver the prescription dose to the entire cancer while a rapid decrease in dose beyond the volume-containing sources occurs. The rapid dose fall-off, therefore, provides the basis on which a high intraprostatic dose can be delivered while maintaining subtolerance doses in the healthy juxtaposed tissues. The current method of prostate brachytherapy in the USA uses a 2-dimensional (2D) transrectal ultrasound imaging
Reprint requests to: Anthony V. D’Amico, M.D., Ph.D., Joint Center for Radiation Therapy, Harvard Medical School, 330
Brookline Avenue - 5th floor, Boston, MA 02215. Accepted for publication 9 July 1998. 507
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plane for radioactive seed guidance (2). Using this approach, less than ideal placement of radioactive sources sometimes occurs (3). In the early experience with this approach, inadvertent placement of the radioactive sources led to complications that included impotence, rectal-prostatic fistula, rectal bleeding, colostomy, superficial urethral necrosis, and urinary incontinence. A real-time 3-dimensional (3D) magnetic resonance (MR) imaging-guided prostate brachytherapy implant technique that utilizes both realtime MR imaging and a real-time dose–volume histogram (DVH) analysis program has been designed and implemented. Using this technique, the selection of the appropriate seed strength, seed number, and catheter trajectory can be made intraoperatively and then checked for accuracy using real-time MR imaging within seconds. Therefore, in theory, this technique is capable of achieving optimized dose distributions in both the CTV and healthy adjacent structures that may translate into both improved cancer control and quality of life, respectively. Although prostate brachytherapy using transrectal ultrasound guidance lacks long-term follow-up (i.e., 15 years), it has become a primary treatment option in the USA. Therefore, advancements using a brachytherapy technique that may increase cancer control rates, while potentially limiting gastrointestinal, genitourinary, and sexual function morbidity, would be critical to the growing number of prostate cancer patients who are choosing prostate brachytherapy as their primary treatment. In this study, a report of the dose– volume histogram analyses and acute morbidity of the first 9 patients treated using a real-time intraoperative MRguided system is presented. METHODS AND MATERIALS Patient entry requirements Between November 1997 and February 1998, 9 patients underwent an MR-guided prostate radiation implant at the Brigham and Women’s Hospital. At this institution, the policy for patient selection includes only those men with 1997 American Joint Commission on Cancer (CASEAJCC) clinical stage T1cNXM0 prostate cancer (4), PSA , 10 ng/ml, biopsy Gleason score not more than 3 1 4, and endorectal coil MR stage T2 disease. In addition, patients who had urinary daytime frequency less than every 3 h and/or nocturia exceeding 3 h that was not medically controlled were not eligible for study entry. All patients with a prior history of a transurethral resection of the prostate (TURP) were excluded. Staging In all cases, staging evaluation included a history and physical examination, including a digital rectal exam (DRE), serum PSA, endorectal coil magnetic resonance imaging (MRI) scan of the prostate, bone scan, and a transrectal ultrasound-guided (TRUS) needle biopsy of the
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prostate with Gleason score histologic grading (5). A sextant biopsy was performed using a 18 gauge Tru-Cut1 needle via a transrectal approach. The clinical stage was obtained from the DRE findings using the current 1997 AJCC staging system. Radiologic and biopsy information were not used to determine clinical stage. The PSA was obtained on an ambulatory basis prior to radiological studies and biopsy. All PSA measurements were made using the Hybritech assay (6). Treatment Interstitial prostate radiation was performed using 125Iodine sources, an MR-compatible perineal template, a peripheral loading technique, and an intraoperative 0.5-Tesla MRI unit (General Electric Medical Systems, Milwaukee, WI). A standard conventional MRI system consists of a single, long cylindrically-shaped magnet with a closed bore and similarly shaped cylindrical imaging coils. This new interventional magnet consists of two shorter cylindrical magnets with imaging coils enclosed. Between these two components, there is a 56-cm gap providing full access to the patient while imaging. Therefore, placement of MRcompatible (nonferromagnetic) catheters into the perineum can occur simultaneously during patient imaging. Within the center of the 56-cm gap is a 30 cm diameter imaging volume, within which the same quality images as obtained in a conventional 0.5-Tesla magnet can be obtained. With the exception of the “open” configuration, the magnet is identical to a conventional unit. The prescribed minimum dose to the peripheral zone of the prostate was 160 Gy. Individual source strength ranged from 0.32 to 0.44 mCi, and the total activity implanted ranged from 18.8 to 47.5 mCi using 43–120 (median 80) seeds. Eligible patients who had given consent were asked to anonymously complete a prospectively validated quality of life questionnaire (7) to establish baseline sexual, urinary, and bowel functions. This survey will be readministered at 3 months and then annually for 3 years posttherapy. At our institution, the policy for the patients pre-, peri-, and postoperative management was as follows. Patients were started on a selective inhibitor of the a-1 subtype of the a-adrenergic receptors to decrease urethral resistance to urine flow by relaxing the smooth muscle surrounding the urethra for 1 week prior to treatment and for up to 3 weeks posttherapy. Dexamethasone (Decadron®) 4 mg by mouth was used 1 day preoperatively and then intravenously intraoperatively and 4 mg by mouth BID 1 day postoperatively. This medical intervention was employed to limit the edema that can occur within the prostate due to its mechanical disruption from seed and catheter placement. Concurrent with dexamethsone use, an H2-blocker was used for protection of the gastrointestinal mucosa. Prophylactic antibiotics were used for 2 days preoperatively, intraoperatively, and then 1 week 1
Travenol Laboratories, Deerfield, IL.
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postoperatively. General anesthesia was employed during the implant procedure. After the patient was placed in the lithotomy position and anesthesized, a Foley catheter was inserted and clamped. The MR-compatible template was secured to the MR table and placed against the patient’s perineum. A rectal obturator 3.0 cm in diameter was passed through the template and into the rectum. The rectal obturator was secured to the template using an MR-compatible screw. Within the central cavity of the rectal obturator was a red rubber tube that allowed for the passage of intrarectal gas. Axial, coronal, and sagittal images were acquired at 5-mm intervals using a MR pelvic coil in a 0.5-Tesla magnetic field. The images obtained consisted of axial T1W and fast spin echo (FSE) sequences through the prostate. The FSE parameters were TR 5000/TE eff 100, Echo train length 8, FOV 20 3 20 CM, slice thickness 5 mm, with a 1-mm interslice gap, and the matrix was 192 with 2 signal averages. The T1W images had similar FOV, slice thickness, gap, and matrix; however, the TR was 500 and TE was 20. FSE images were also obtained in the coronal and sagittal planes. The peripheral zone (PZ) of the prostate was selected as the clinical target volume (CTV) and was identified on each axial slice, as were the anterior rectal wall and prostatic urethra, by an expert MR radiologist (C. M. T.). Based on the CTV and juxtaposed normal tissue volumes, desired minimum peripheral dose, and previously reported healthy tissue tolerance (8), a catheter loading was calculated using a previously described dose algorithm (9). As each catheter containing the preloaded sources was inserted, its position in the coronal, sagittal, and axial plane was identified in real-time (Fig. 1a– c) and compared to its expected location based on the optimized plan. Adjustments to account for prostate motion, edema, or catheter divergence could be made before source deposition. This process was repeated in an iterative fashion for all planned catheters. The cumulative dose–volume histograms for the CTV, anterior rectal wall, and prostatic urethra based on the actual source locations were calculated after each catheter insertion, allowing for adjustments intraoperatively if necessary. Postimplant, all patients had cystosopy to assess the integrity of the bladder neck and inspect the bladder lumen for the presence of 125Iodine seeds. Postcystoscopy, the patients were taken to the recover room and had the Foley catheter removed within 1–2 h after extubation. They were continued on maintenance fluids until a successful voiding trial was completed. All patients have had follow-up postimplant for a minimum of 1 month and maximum of 3 months (median 2 months).
Fig. 1. Real-time intraoperative catheter localization. (a) Coronal plane; (b) Sagittal plane; (c) Axial plane. Note that 125Iodine sources from previous catheter insertions can be seen as black voids on the real-time MR images. The catheter appears as a black void larger than actual size.
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Table 1. Clinical characteristics of the 9 study patients treated using MR-guided prostate interstitial radiation therapy Clinical characteristic
Median
Minimum
Maximum
Age (years) 1997 AJCC clinical stage PSA (ng/ml) Biopsy Gleason score % 1 biopsies Prostate volume (cm3) Endorectal MRI stage
60 T1cNxM0 6.7 313 50% 26 T2b
54 T1cNxM0 4.2 312 17% 19 T2a
72 T1cNxM0 9.9 314 67% 67.1 T2n
AJCC 5 American Joint Commission on Cancer Staging; PSA 5 prostate–specific antigen; % 1 5 Percent positive; MRI 5 magnetic resonance imaging.
Dose–volume histogram analysis Dose–volume histogram (DVH) analyses were performed intraoperatively in real-time for the CTV, anterior rectal wall, and prostatic urethra, based on the final source locations. The prescription dose of 160 Gy was calculated using the recommendations of the American Association of Physicists in Medicine Radiation Therapy Committee Task Force No. 43 guidelines (10). Anterior rectal wall tolerance was defined as 100 Gy and urethral tolerance as 400 Gy, per Wallner and colleagues (8).
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(median 70%) of the anterior rectal wall volume was within this dose limit in the 9 study patients. The range of D10’s for the anterior rectal wall was 100 Gy to 210 Gy (median 135 Gy). Figure 2a–i depicts the DVH profiles and volume summaries for the CTV, anterior rectal wall, and prostatic urethra for the 9 study patients. Acute morbidity There were no sources found upon inspection of the bladder lumen at the postimplant cystoscopy and no patient reported passing a seed during the first postoperative month. No evidence of trauma from catheter penetration into the bladder neck was noted at the time of cystoscopy. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and 4 (44%) of 9 patients required oral a-1 blockers for postimplant urethritis for up to 3 weeks postoperatively. Minor perineal skin irritation was noted in 2 (22%) of 9 patients, which resolved in all cases by the first postoperative month. No patient reported gastrointestinal or sexual dysfunction during the first postoperative month. Patients returned to work within 2–5 days (median 3 days) after the procedure.
DISCUSSION RESULTS Patient characteristics The median age of the 9 study patients was 60 years (range 54 –72). All patients had clinical stage T1cNXM0 disease, as per the 1997 AJCC staging system. The median PSA was 6.7 ng/ml (range: 4.2–9.9 ng/ml) and the biopsy Gleason score ranged from 3 1 2 to 3 1 4 with a median of 3 1 3. The percent positive biopsies ranged from 1 (17%) of 6 to 4 (67%) of 6, median 3 (50%) of 6. Bilateral disease was noted in 5 (56%) of 9 patients and 4 (44%) of 9 patients had unilateral disease based on the sextant sampling. The 1997 AJCC stage as assessed by endorectal coil MR was T2a and T2b in 3 (33%) and 6 (67%) patients, respectively. The endorectal MR-determined volume using an ellipsoid approximation [(p/6)(axial)(coronal)(sagittal)] ranged from 3 19 cm – 67.1 cm3 (median 26 cm3). The clinical characteristics of the study patients are summarized in Table 1.
Dose–volume histogram analyses The percent of the CTV receiving the minimum peripheral dose using the real-time MR-guided approach in the 9 study patients was 89 –99% (median 94%). The range of D90s for the CTV was from 156 Gy (98% prescription) to 200 Gy (125% prescription) with a median of 173 Gy. Based on a previously described estimate of 400 Gy for urethral tolerance (8), less than 5% of the urethral volume exceeded this dose across all patients. The range of D10s for the prostatic urethra was from 124 Gy to 280 Gy, with a median of 210 Gy. The rectal tolerance has been suggested to be 100 Gy (8). Using the MR-guided technique, 42– 89%
Patient selection The basis on which the patient selection rules were made in this study were derived from a concept called combined modality staging (11). This concept uses the pretreatment PSA, biopsy Gleason score, and AJCC clinical stage to determine the likelihood of organ-confined disease and subsequent freedom from PSA failure after external-beam radiation therapy (RT) or radical prostatectomy (RP). Accepting an 80% organ confinement rate and a subsequent 88% estimated 5-year freedom from PSA failure after RT or RP, respectively, identifies a specific cohort of patients on the basis of their pretreatment clinical characteristics (12–14). Specifically, these are patients with a pretreatment PSA less than 10 ng/ml, biopsy Gleason score of 6 or less, clinical stage of T1c or T2a based on the former 1992 AJCC staging system, and an endorectal coil MR showing T2 disease. Clinical stage T2a patients were excluded from participation in the current study, despite a PSA , 10 ng/ml and a biopsy Gleason score of 6 or less. The reason for this exclusion is because of recent information (15) showing a statistically and clinically significant decrement in estimated 4-year PSA failure-free survivals of 28% in patients with these PSA and Gleason score parameters, but 1992 AJCC clinical stage T2a as opposed to T1c. A possible explanation for this result is that, to prevent a significant volume of the anterior rectal wall from receiving a dose in excess of the reported rectal tolerance of 100 Gy (8), the posterior aspect of the palpable nodule may be in the rapid dose fall-off region of the implant. Therefore, this part of the nodule may not receive doses adequate for tumor sterilization. Patients with biopsy Gleason scores of 3 1 4 were
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Fig. 2. (a–i) Dose–volume histograms and volume summaries for the CTV, anterior rectal wall, and prostatic urethra for the 9 study patients.
accepted for entry, assuming all other requirements for entry were satisfied. The reason for this inclusion is that data on the histopathologic correlation between biopsy and prostatectomy Gleason scores from surgical series (16) suggest that as many as 21% of patients thought to have biopsy Gleason scores of 7 are found to have prostatectomy Gleason scores of 5 or 6. This finding was for cases in which the primary biopsy Gleason grade 5 3 or 4. In cases where the
primary biopsy Gleason grade 5 3, the 21% estimate of overgrading was conservative. Finally, an endorectal coil MR was performed on all patients by an MR expert (C. M. T.) and needed to show no evidence of extraprostatic disease for study entry. From a previous report (13), patients with an endorectal coil MR showing evidence of extracapsular penetration or seminal vesicle invasion were found to have pathologic T3 disease
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Fig. 3. Series (a) Axial T2-weighted MR images used to identify the CTV and anterior rectal wall and the prostatic urethra. Series (b) Identification of the prostate peripheral zone, anterior rectal wall, and the prostatic urethra. Series (c) Total dose received based on final 125Iodine source positions. Red 5 $ 240 Gy; Yellow 5 $ 160 and , 240 Gy; Blue 5 $ 100 and , 160 Gy; No color 5 , 100 Gy.
in 87% of the cases, despite a PSA , 10 ng/ml and a biopsy Gleason score of 6 or less. Dose–volume histogram analyses The results shown in Figure 3a–i provide evidence that the use of a real-time MR-guided image system with real-
time dosimetry resulted in the ability to deliver the planned optimized dose distributions to the CTV, prostatic urethra, and anterior rectal wall. Specifically, a minimum of 89% of the CTV received the prescription dose and at least 95% of the volume of the prostatic urethra was maintained below the reported tolerance level in all patients. Similarly, 42–
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89% (median 70%) of the volume of the anterior rectal wall was also kept below the reported tolerance level of 100 Gy. This result suggested that, despite optimal placement of 125 Iodine seeds, the 3–5-mm fat-containing space between the posterior prostatic capsule and outer muscle layer of the anterior rectal wall is not a realistic distance over which to see a fall-off in dose from 160 to 100 Gy. The experience from Ragde and colleagues (2), however, where the prescription dose of 160 Gy was delivered with a margin of 2–5 mm around the prostatic capsule and, therefore, into the outer muscle layer of the anterior rectal wall, reported minimal (1%) rectal morbidity. Therefore, the actual anterior rectal wall tolerance may be higher than the 100 Gy previously reported (8). The CTV in this study was the MR-defined peripheral zone (PZ). Ninety percent of the CTV received 89 –125% of the prescribed minimum peripheral dose across all study patients. The choice of the PZ of the prostate to represent the CTV was based on the results of prostatectomy tumormapping studies (17, 18), in which whole mounting of the prostate gland and zonal mapping of tumor were performed. The data suggested that prostate cancer in the anterior base of the prostate is rare and is almost always the result of growth of large PZ lesion into the anterior gland. In the current study, given the strict patient selection criteria, large PZ tumors with anterior extension are very unlikely. The mapping studies (17, 18) also found transition zone (TZ) primary cancers alone or in conjunction with synchronous PZ cancers in 10 –20% of the cases. Typically, however, cancers in the TZ were limited to microscopic foci unless the patient presented with bladder outlet obstructive symptoms and was diagnosed during a therapeutic TURP.
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Considering that patients with a history of a TURP were excluded in this study, at most the possibility of microscopic prostate cancer in the TZ exists. To account for the possibility of microscopic disease in the TZ, the loading technique used in this study, by design, treated most of the TZ to the prescription dose or higher. This result is illustrated for a representative case in Fig. 3a– c. Specifically, the T2-weighted axial images of the prostate on which the CTV, prostatic urethra, and anterior rectal wall were identified are shown in the Fig. 3a series. These specific regions identified by the MR radiologist (C. M. T.) are shown in the Fig. 3b series. The total doses received, based on the intraoperative loading, are shown in the corresponding Fig. 3c series. From the dose profiles in the Fig. 3c series, it can be seen that the majority of the TZ received at least the prescription dose (160 Gy) and nearly all of the TZ received at least 100 Gy. CONCLUSIONS A real-time MR-guided technique has been developed for the placement of permanent 125Iodine sources into the prostate gland. This technique utilized a real-time interactive dosimetry algorithm (9), and was able to achieve a minimum of 89% coverage (median 94%) of the CTV while simultaneously maintaining $ 95% of the prostatic urethra and most (median 70%) of the anterior rectal wall below reported tolerance levels (8). Acute morbidity using this technique was minimal. Further follow-up is needed to ascertain the impact that these DVH profiles will have on cancer control and quality of life. These endpoints are being monitored prospectively using actuarial-based statistics and a validated quality-of–life instrument.
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8. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32: 465– 471. 9. Cormack RA, D’Amico AV, Holupka E, Kooy HM, Powers RE, Svensson G. Real-time dosimetry based prostate implant planing system. In: Leavitt DD, Starkschal G, editors. Proceedings of the XII International Conference on the use of computers in radiation therapy. Medical Physics Publishing, 1997, vol. 1 p. 124 –126. 10. Nath R, Anderson LL, Luxton G, Weaver KA, Williamson JF, Meigooni AS. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995; 22: 209 –234. 11. D’Amico AV, Whittington R, Malkowicz SB, Schnall M, Tomaszewski JE, Schultz D, Wein A. A multivariate analysis of clinical and pathological factors which predict for prostatespecific antigen failure after radical prostatectomy for prostate cancer. Urol 1995; 154: 131–138. 12. D’Amico AV, Whittington R, Kaplan I, Beard C, Schultz D, Malkowicz SB, Tomaszewski JE, Wein A, Coleman CN. Equivalent 5 year bNED in select prostate cancer patients managed with surgery or radiation therapy despite exclusion of the seminal vesicles from the CTV. Int J Radiat Oncol Biol Phys 1997; 39: 335–340.
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13. D’Amico AV, Whittington R, Tomaszewski JE, Malkowicz SB, Schultz D, Schnall M, Wein A. A critical appraisal of the role of endorectal coil magnetic resonance imaging in the prediction of pathologic stage and postoperative prostate specific antigen failure in patients with clinically organ confined prostate cancer. J Clin Oncol 1996; 14: 1770 –1777. 14. Partin AW, Kattan MW, Subong ENP, Walsh P, Wojno KJ, Oesterling JE, Kattan MW, Scardino PT, Pearson JD. Combination of prostate specific antigen, clinical stage, and Gleason score to predict pathologic stage of localized prostate cancer: A multi-institutional update. JAMA 1997; 277: 1445– 1451. 15. D’Amico AV, Whittington R, Malkowicz SB, Blank K, Broderick GA, Schultz D, Tomaszewski JE, Wein A. Prostate
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