Long term toxicity and second malignancies in patients with testicular seminoma treated with radiotherapy

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I. J. Radiation Oncology

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● Biology ● Physics

Volume 54, Number 2, Supplement, 2002

Five Year Results Following Permanent Prostate Seed Implantation in Consecutive Patients Treated at Two Academic Institutions

M. Roach1,2, A.L. Zietman3, V. Weinberg1,2, U. Skowronski3, K. Shinohara2 1 Department of Radiation Oncology, University of California, San Francisco, CA, 2Department of Urology, University of California, San Francisco, CA, 3Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA Purpose/Objective: Most of the published results of permanent prostate seed implantation (PPI) have come from community based practices, and academic institutions whose treatment policies favored the use of PPI over external beam radiotherapy (EBRT). These reports frequently excluded patients due to a “learning curve” and separated out patients treated with EBRT and / or neoadjuvant hormonal therapy (NHT). This report summarizes the results of consecutive patients treated with PPI at 2 academic institutions (MGH and UCSF) where EBRT alone has generally been considered the treatment of choice for early prostate cancer. Materials/Methods: Patient selection and treatment were based on guidelines popularized by “the Seattle group”. All patients undergoing PPI with or without EBRT and or NHT (for “downsizing”) for localized prostate at MGH and UCSF treated between 6/96 and 6/97 were included in this analysis. A total of 69 patients were treated with a median follow-up of 52.1 months. The median age was 64 (50-76). Forty-two percent were treated with PPI alone, 41% received NHT, 7% EBRT, and 10% both. The distribution by T stage was 75% T1c-2a, 16% T2b and 9% T2c-T3, respectively. Thirty-nine percent had a Gleason score (GS) of ⬍ 3-5, 42% GS⫽6, and 19% a GS⫽7-9. The median pre-PPI PSA was 5.7 ng/ml and the median number of values obtained was 7.7. Results: Three deaths occurred at 13, 15 and 16 months without evidence of disease, 5 patients failed, 3 with documented local or distant disease (one Bx⫹ and two with metastatic disease) and 2 failed by the ASTRO definition. Using the ASTRO definition the 5-year freedom from PSA failure (FFPF) is 94% (87%–100%). The median nadir following treatment was 0.2 ng/ml for patients treated with PPI alone and 0.1 ng/ml for the remaining patients. The median last PSA ⫽ 0.2 ng/ml. Excluding the failing patients, 62% had PSAs ⬍ 0.2 ng/ml and 85% ⬍ or ⫽ 0.5 ng/ml with several patients having values that appeared to still be declining. Conclusions: These results are unique in that they reflect the pooled 5 year outcomes of consecutively treated patients using PPI from two major academic institutions well known for the use of EBRT. Despite the potential for a “learning curve” these results confirm the excellent 5-year results reported by other investigators using PPI in selected patients with localized disease. The PSA values at 5 years appear to be lower than generally seen after EBRT and may reflect a greater biological impact of PPI compared to EBRT. This raises the possibility that PPI may actually be a more effective/ablative treatment for early stage prostate cancer and could even be the treatment of choice.

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Differences in Prostate Volume Delineation on Post-Prostate Brachytherapy CT Scans Among Experienced Brachytherapists and Their Effect on Dosimetric Parameters

B.H. Han1, K.E. Wallner1, K.R. Badiozamani2, G.S. Merrick3 1 Department of Radiation Oncology, Seattle VA Medical Center, Seattle, WA, 2Department of Radiation Oncology, Swedish Medical Center, Seattle, WA, 3Department of Radiation Oncology, Schiffler Cancer Center, Wheeling, WV Purpose/Objective: To investigate the differences in prostate volume delineation on post-prostate brachytherapy CT scans among experienced brachytherapists and their effect on dosimetric parameters. Materials/Methods: Post-implant pelvic CT scans with axial cuts at 3 mm intervals were obtained within 4 hours after the completion of the implant procedure on 20 consecutive prostate brachytherapy patients treated in August and September, 2001. The DICOM data from the CT scans were imported to Variseed prostate brachytherapy dosimetry software version 6.7 (Varian/MMS, Charlottesville, VA) loaded on a high-end laptop computer to be shipped to the investigators. Four experienced brachytherapists delineated the prostate gland, and an analysis of different prostate volumes and dosimetry was performed. Results: The average prostate volumes of the 20 cases for the four investigators, KB, KW, BH, and GM, were 61, 54, 52, and 43 cc’s, respectively (ANOVA, P ⫽ 0.18). The average standard deviation in prostate volume among investigators was 8 cc’s. Much of the difference in the volume stemmed from the difference in superior-inferior extent of the delineated prostate which had an average standard deviation of 0.6 cm compared to 0.3 and 0.2 cm for anterior to posterior and right to left lateral extents, respectively. The average V100 for KB, KW, BH, and GM were 85.8, 88.9, 90.7, and 92.8%, respectively (ANOVA, P ⫽ 0.008). The average standard deviation was 3.6%. The average D90 for KB, KW, BH, and GM were 95.3, 103.0, 107.4, and 115.1%, respectively (ANOVA, P ⫽ 0.05). The average standard deviation was 10.1%. Anterior, posterior, right lateral, and left lateral treatment margins were measured for the different investigators at KW’s mid-gland slice. The average standard deviation for anterior margin was 2.1 mm, the posterior margin, 1.1 mm, right lateral margin 1.3 mm, and left lateral margin, 1.1 mm. Conclusions: The differences in prostate volume delineations among experienced brachytherapists can lead to significant differences in V100, D90, and treatment margins. Dosimetric studies of prostate brachytherapy should be viewed with caution as the results can be skewed by the brachytherapist’s contouring style.

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Long Term Toxicity and Second Malignancies in Patients with Testicular Seminoma Treated with Radiotherapy

V.M. Venkatesan, A. Cheung, G.S. Bauman Department of Radiation Oncology, London Regional Cancer Centre, London, ON, Canada

Proceedings of the 44th Annual ASTRO Meeting

Purpose/Objective: Stage 1 and 2a/b testicular seminoma treated with adjuvant radiotherapy has excellent cure rates. That fact combined with the relative young age of this patient population, has shifted the focus towards the evalution and prevention of the long term sequelae of radiotherapy. In this retrospective study, we report our experience with patients treated with post-orchidectomy radiotherapy. Materials/Methods: Between 1950 and 1995, 212 patients received adjuvant radiotherapy following orchidectomy for stage 1(169) and 2(43) seminoma at the London Regional Cancer Centre. The median folloW-up was 7.5 years. We reviewed patient records, focusing on late toxicity and second malignancies occuring after radiotherapy. All patients were treated with mega voltage machines (Cobalt 60,6mv,18mv). Results: 5/212 patients developed late g.i. complications post radio therapy. 4/212 patients developed second malignancies (actuarial; 1%, 1%, 4% at 5, 10, 15 years respectively). Progression free, cause specific and overall survival were 95%, 98% and 95% at 5 years and 94%, 98% and 94% at 10 years respectively. There was a trend towards increased acute complications for patients treated with larger volumes of radiation. No prognostic factors associated with increased risk of late toxicity or second malignancywere identified, likely a consequence of the small number of events. Conclusions: Overall the data suggest that the risk of late toxicity post treatment is minimal for patients with seminoma receiving adjuvant radiotherapy. Our rates of late G.I. toxicity and second malignancy were comparable to that reported in the literature. This reaffirms post-operative radiotherapy as a safe and effective adjuvant treatment for stage 1 and 2a/b seminoma.

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The Dose-Volume Conundrum in Low Dose-Rate Prostate Implants: Is it Better to Moderately Underdose a Large Volume, or Grossly Underdose a Small Volume

W.D. D’Souza1, H.D. Thames2 1 Department of Radiation Physics, UT M.D. Anderson Cancer Center, Houston, TX, 2Department of Biomathematics, UT M.D. Anderson Cancer Center, Houston, TX Purpose/Objective: To characterize the interdependence of moderately underdosed large volumes and grossly underdosed small volumes, and the corresponding changes in the estimated tumor control probability (TCP) of highly inhomogeneous dose distributions from low dose-rate I-125 prostate implants alone. Materials/Methods: Fifty patients who had undergone I-125 prostate implants alone at our clinic were selected for this study. For each patient, post-implant CT scans were obtained the day of (CT1) and approximately one month after (CT2) the implant. Dose distribution information was obtained from CT2 using the Variseed Planning System (Varian). The percent volume of prostate receiving a specified dose was recorded from the respective differential DVHs in 10 Gy bins (from 65 Gy to 275 Gy). Subvolumes receiving in excess of 275 Gy were assumed to have received 275 Gy since these were determined to contribute less than a 0.1% decrease (a little higher in 3 patients) in the surviving fraction of tumor clonogens. The volume of prostate underdosed at various fractions of the prescription dose was determined (e.g., v100 –volume of prostate receiving less than 100% of the prescription dose, v90, v80, etc.) along with the minimum prostate dose. We assumed log-normal distributions for the radiobiological parameters (RB) ln(K) (log clonogen number), a, and a/b, and constructed a dose-response curve for external beam radiation therapy with doses ranging from 56-78 Gy in 2 Gy fractions. Mean individual values and standard deviations of these parameters were adjusted iteratively to obtain population values in the neighborhood of published values. Mean individual K, a, and a/b values were chosen to be 5e⫹8, 0.15 Gy-1 and 1.5 Gy, respectively, for the distribution. TCP was then calculated for the 50 patients using fixed ln(K), a, and a/b from the log-normal distribution. This was repeated 50 times, each time using a randomly chosen fixed set of RB parameters. TCP was then averaged over the 50 trials. Dose values obtained from the 50 patients were scaled by factors ranging from 0.6 to 1.5 to fill the dose-response curve as a function of volume underdosed (this would be the equivalent of changing the source activity by the above factors). Results: The volume of prostate severely underdosed (⬍ 80% of the prescription dose) was related to the volume that was moderately underdosed (⬍ 100% of the prescription dose). For a given level of moderate underdosing, the corresponding level of severe underdosing was bounded above and below. The spread in the bounds increased for increasing volumes of moderate underdosing. A clinician can therefore determine a priori the possible extent of severe underdosing for a given moderate level of underdosing. However, it is not possible to determine for a specific patient the volume of prostate that would be severely underdosed for a given volume of prostate that is moderately underdosed. This is important because TCP is driven to a greater extent by severe underdosing than by moderate underdosing. TCP was found to be linearly dependent on minimum dose. For v100 in the range (0-15%) of clinically acceptable target coverage, the TCP was found to be in the range of 0.5-0.9. However, the TCP is greatly dependent on the inhomogeneous dose distribution. Dosimetric indices (such as V100, V90, etc.) by themselves may not indicate the quality of the implant. Our data show that for a higher value of V100, the TCP may be lower than for another implant, which has a lower V100 value. Thus, TCP can vary for patients having equal values for dosimetric indices. Conclusions: TCP is strongly dependent on minimum prostate dose, regardless of the doses to sub-volumes of the prostate. The volume of severe underdosing is bounded for a given volume of moderate underdosing. For the data used here, no single dosimetric index can predict the comparative TCP between two prostates and one must consider the totality of the dose distribution to evaluate the dosimetric quality of a low dose-rate implant.

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Short and Long Term Toxicity After Transperineal Permanent Seed Implantation (TPSI) of 120 Patients with Low Risk Prostate Cancer and “High Activity Seeds”

T. Block1, U. Maurer2, H. Czempiel1, M. Eble2 1 Department of Urology, Vaterstetten, Vaterstetten, Germany, 2Department of Radiooncology, RWTH Aachen, Aachen, Germany

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