Combination of Fast Neutron Irradiation and Permanent Prostate Brachytherapy in Intermediate and High Risk Localized Prostate Cancer

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I. J. Radiation Oncology

● Biology ● Physics

Volume 63, Number 2, Supplement, 2005

level of 4.95 (range 0.85 to 7.51, N⫽6) to 0.92 (range 0.3 to 1.57, N⫽5) at 4-months (p⬍0.01). Side-effect profile and PSA response were similar to a comparable patient group treated with 103Pd seeds at our institution. Conclusions: This is the first report in the literature of the use of 103Pd coils in the clinic — specifically, in their successful application to the interstitial brachytherapy treatment of localized prostate cancer. Excellent visualization, stability, and dosimetry of the implanted coils were achieved. Implantation was well-tolerated, no procedural complications were observed, and acute side effects were modest and improved within 4 months. PSA levels responded rapidly and significantly. 103Pd coils offer comparable clinical outcomes in the short-term, and may provide additional benefits in the long-term, in comparison to traditional seed implant technologies.

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Intensity Modulated Radiotherapy for High Risk Prostate Cancer Based on Sentinel Node Optimized Target Volume Definition

U. Ganswindt,1 F. Paulsen,1 S. Glocker,1 M. Birkner,2 M. Alber,2 S. Corvin,3 A. Anastasiadis,3 K. Eichhorn,4 R. Bares,4 M. Bamberg,1 W. Budach,5 C. Belka1 1 Radiation Oncology, University of Tuebingen, Tuebingen, Germany, 2Radiation Oncology, Medical Physics, University of Tuebingen, Tuebingen, Germany, 3Urology, University of Tuebingen, Tuebingen, Germany, 4Nuclear Medicine, University of Tuebingen, Tuebingen, Germany, 5Radiation Oncology, University of Duesseldorf, Tuebingen, Germany Purpose/Objective: Whereas cure rates for patients (pts.) with low/intermediate risk prostate cancer (PC) are good, the situation is much more problematic in high risk PC. In parallel with risk of distant seeding, the probability of locoregional lymph node metastasis increases. The RTOG 94-13 trial provided evidence that pts. with high risk of pelvic node involvement (estimated risk ⬎ 15%) benefit from an additional radiotherapy to the pelvic nodes combined with concomitant hormonal ablation. Since the physiological lymphatic drainage is highly variable, the optimal target volume definition for the adjuvant nodes is problematic. To overcome this limitation, we tried to optimize our target volume definition by including information derived from pelvic sentinel nodes (SN) identification. Materials/Methods: Pts. with histologically proven high risk PC, but cN0 stage, were included. To permit a three-dimensional (3D) localisation of SN transmission- and emission data were acquired using a double-headed gamma camera with an integrated X-Ray device (Millennium VG & Hawkeye®, GE) 1.5-3 hours after injection of 250 MBq 99mTc-Nanocoll. Numbers and 3D-localisations of SN were analysed. IMRT planning was done with Hyperion® (University of Tuebingen, Germany) based on 3 CT’s, definition of clinical/planning target volumes (CTV/PTV) and risk organs (rectum, colon, small bowel, bladder, hips) with image fusion of 3 data sets. All SN localisations were included into the pelvic CTV additionally. Dose prescriptions were 50,4 Gy (1,8 Gy daily) to the pelvis and 70,0 Gy (2 Gy daily) to the prostate/seminal vesicles. Results: Since 08/2003 6 pts. with cT1c-3b stage were treated. No pt. had undergone a staging lymphadenectomy. All pts. had detectable SN, the numbers of SN per patient ranged from 2 to 9. A total of 29 SN could be identified for all 6 pts. together. Most common localisations were ext. iliac (9), followed by int. iliac (6), perirectal lymph. plexus (6), comm. iliac (2), sacral (2), int. pudendal (1), seminal vesicle lymph. plexus (1), superior rectal (1) and left paraaortic (1). IMRT planning could be completed in all pts. with acceptable doses to risk organs and prescribed doses to the target volumes. 4 of 6 pts. showed SN localisations (total 10 SN) that would not have been treated adequately with only CT-based planning (”geographical miss”). The comparison between dose-volume-histograms of IMRT- and conventional CT-planning in regard to the risk organs demonstrated clear superiority of IMRT when all SN were included. No gastrointestinal or genitourinary acute toxicity Grade 3 or 4 (RTOG) occurred. Conclusions: IMRT based on sentinel lymph node identification is feasible and reduces the probability of a geographical miss. Furthermore IMRT allows a pronounced sparing of normal tissue irradiation. Thus the chosen approach will help to increase the curative potential of radiotherapy in high risk prostate cancer patients.

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Combination of Fast Neutron Irradiation and Permanent Prostate Brachytherapy in Intermediate and High Risk Localized Prostate Cancer

D.J. Perry,1 R.J. Patel,1 C.L. Zuniga,1 M.L. Cher,2 M.C. Joiner,1 Z. Lai,1 J.W. Ager,1 J.D. Forman1 Radiation Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, 2Urology, Karmanos Cancer Institute/Wayne State University, Detroit, MI

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Purpose/Objective: This study was designed to evaluate the combination of two effective radiation treatments in patients with intermediate and high risk prostate cancer. Materials/Methods: Between 8/1996 - 4/2003, 70 patients were treated with a permanent I-125 implant (median dose, 100 Gy) followed one month later by external-beam fast neutron therapy (median dose 12 NGy, range 8-12 NGy). Implants were performed with modified peripheral loading. Both freehand and template transrectal ultrasound guided techniques were utilized. The external-beam fast neutron irradiation was delivered by a superconducting cyclotron using a six-field axial technique with dose defined as the minimum dose to the prostate and seminal vesicles. The median age of the patients was 65 years (range 42– 80). Four patients (5.7%) were low risk, 55 (78.6%) intermediate risk and 11 (15.7%) high risk. The median pre-irradiation PSA level was 7 ng/ml (range 1–56). The median follow-up was 3.5 years (range 1.5– 8). Results: At the time of last follow-up, 67 patients (95.7%) were alive and free of recurrence by the Houston definition (BCF ⫽ PSA nadir ⫹ 2). Fifty-five patients (78.6%) had no chronic GU complications and 61 patients (87.1%) were free of chronic GI morbidity. The actuarial rate of chronic GU and GI complications ⱖ Grade 2 was 24.8% and 26.0% respectively, at 5 years. Moderate to severe complications (Grade 3 & 4) occurred in 3 patients (4.3%). One patient had a urethral stricture and two patients developed a recto-vesical fistula requiring cystoprostatectomy, urinary diversion and colostomy. Conclusions: This novel combination of permanent brachytherapy and external-beam fast neutron irradiation was highly effective in patients with intermediate and high risk localized prostate cancer. Completion of treatment in 11 visits or less offers

Proceedings of the 47th Annual ASTRO Meeting

logistical and cost advantages. Although the 2 severe complications seen thus far are concerning, further investigation in to maintaining the efficacy and reducing the toxicity of this treatment is warranted. It is not clear whether the complications were a consequence of the total dose delivered, the sequencing of the two treatment modalities, or technical aspects (e.g., hot spots from the implant).

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Therapeutic Effects of Combination Radiation and Suicide Gene Therapy Using a Chimeric Adenovirus Vector for Bladder Cancer

K. Matsumoto,1 B.S. Teh,2,3 N. Okuno,1 C.T. Freund,1 J.X. Zhu,2 M.T. Vlachaki,2 A.R. Davis,1 E. Butler,2,3 S. Lerner1 Scott Department of Urology, Baylor College of Medicine, Houston, TX, 2Radiology / Section of Radiation Oncology, Baylor College of Medicine, Houston, TX, 3Radiation Oncology, The Methodist Hospital, Houston, TX 1

Purpose/Objective: Radiation therapy is an established therapeutic modality for invasive bladder cancer. Recently, radiation therapy has been shown to improve both transduction efficiency and transgene expression. However, alteration of the coxsackie and adenovirus receptor (CAR) poses a barrier to adenovirus-mediated gene therapy. In addition, loss of CAR expression is associated with higher grade and stage bladder cancers with potential for metastasis and impaired prognosis. We have previously demonstrated the efficacy of a CAR-independent Ad vector (Ad5/F35) expressing HSV-tk with GCV in CARnegative and CAR-positive human bladder cancer models. In the present study, we test the hypothesis that independently of CAR status, combination radiogene therapy is more effective than gene therapy alone in bladder cancer and minimizes treatment-related toxicity. Materials/Methods: In preparation for combination therapy, a subcutaneous tumor was exposed to increasing doses of radiation (2.5, 5 and 10Gy), and 2.5 Gy was selected for use in the combination treatment. Therapeutic efficacy of gene therapy using Ad5/F35(1⫻10e8, 5⫻10e8 PFU) or Ad5 (5⫻10e8 PFU) HSVtk/GCV were evaluated in bladder cancer xenografts either as a single treatment or combination with radiation. Tumors were established in nude mice by subcutaneous inoculation of 1⫻10e7 TCCSUP (CAR-negative) and 5637 (CAR-positive) human bladder cancer cells. Ad vector was injected when the tumor diameter was approximately 5mm. 48h later, a single dose of 2.5 Gy was administered. GCV was injected intraperitoneally every 12h for 6 days from the next day after injected Ad vector. Visceral organs and xenograft tumor were analyzed pathologically and apoptosis status assessed. Results: In both CAR-negative and -positive bladder cancer models, combination therapy significantly increased anti-tumor effect as compared to gene therapy alone. Combination of radiation with either Ad5/F35HSV-tk or Ad5HSV-tk vector with GCV suppressed tumor growth more effectively than controls. There were no significant adverse effects. In pathologic examination, combination therapy showed higher induction of apoptosis than gene therapy alone. This combination strategy provided similar therapeutic effects in CAR-negative and -positive bladder cancer utilizing the Ad5F35 chimeric vector. Conclusions: In both CAR-negative and -positive bladder cancer xenografts, combination of radiation and suicide gene therapy using the CAR-independent Ad5F35 vector yielded significantly greater anti-tumor effects than gene therapy alone. These data provide the potential for enhanced local-regional control which would be especially valuable in the setting of a bladder-sparing approach for invasive bladder cancers.

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Preliminary Toxicity and Quality of Life (QoL) Data From a Randomized Phase III Trial Investigating the Optimal Method of Sequencing Radiation (XRT) and Short Course Total Androgen Blockade (TAB) in Prostate Cancer (PC)

S. Malone, L. Eapen, C. E, R. MacRae, R. Samant, W. Kendall, S. Bowen, S. Grimes, S. Robertson, C. Addison, V. Gallant Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada Purpose/Objective: Currently, there is limited published toxicity and QoL data on TAB in PC. In patients (pts) with recurrent metastatic PC there is controversy regarding TAB vs. LHRH monotherapy because of toxicity concerns associated with steroidal and non-steroidal anti-androgens. Casodex is a newer non-steroidal anti-androgen with a more favourable side effect profile when compared to other oral anti-androgens. We are currently performing a randomized phase III trial of the optimal method of sequencing XRT and 6 months of TAB in PC. To date 220 pts have been entered on study. We report the acute toxicity and QoL for the first 100 pts. Materials/Methods: Pts with intermediate risk PC (cT1-T3, Gleason 7 or less, PSA ⬍ 30) were randomized to delayed XRT (after 4 months TAB, Arm A) versus upfront (XRT day 1 of TAB, Arm B). Pts were treated with 3D conformal radiation therapy (6 field technique 7,600 cGy/38 fractions). TAB consists of Casodex 50 mg po od ⫻ 6 months and Zoladex 10 .8 mg SQ Q3mo ⫻ 2. Pts were evaluated clinically q2mo during treatment, 1 mo post therapy, and q 4mo to year 2, then q6mo. Clinical follow-up includes toxicity scoring using RTOG-EORTC toxicity scale and NCIC CTG Scale. In addition the EORTC QLQ-C30 version 3.0, an integrated system for assessing the health-related QoL incorporating 5 functional subscales (physical, role, cognitive, emotional, and social), 3 symptom subscales (fatigue, pain, and nausea and vomiting) and an overall general health profile was administered at each visit. In addition the EORTC QLQ-PR 25 was also administered at each visit. Results: 50 pts were randomized to each treatment arm; one pt in Arm B withdrew consent following randomization. There were no differences between the arms in terms of age, stage, Gleason, initial PSA or in length of follow-up time. 6 pts had non-compliance issues: 2 pts did not receive Casodex because of elevated liver enzymes pretreatment and 4 pts discontinued Casodex (3 secondary to elevated liver enzymes and 1 secondary to nausea/emesis). The 3 cases of hepatopathy, 2 grade 3 and 1 grade 4 were reversible. For pts who completed the full treatment, the frequency of grade 1, 2 and 3 toxicity was 23%, 17% and 17%, respectively. The most frequently reported toxicities included grade 1 and 2 hot flushes (48% of patients), grade 1 fatigue (41%), grade 3 erectile impotence (20%) and grade 2 decreased libido (18%). Lesser reported toxicities included diarrhea, (6%) and gynecomastia (5%). 95% of the pts completed the QoL questionnaire over the first year of treatment and follow-up. For the functional scales, there was a reduction from baseline in self-reported social and role functioning. For the

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