Analysis of clinical outcomes from the START and START 40 trials: the efficacy of SR-90 radiation in the treatment of long lesion in stent restenosis

Analysis of clinical outcomes from the START and START 40 trials: the efficacy of SR-90 radiation in the treatment of long lesion in stent restenosis
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  252  Relationship of Prostate Biopsy Status to Radiotherapy Dose, PSA Nadir Level and Outcome inParticipants of a Randomized Dose Escalation Trial for Prostate Cancer A. Pollack, G.K. Zagars, J.A. Antolak, D.A. Kuban, A.C. Von Eschenbach, I.I. Rosen  Radiation Oncology, UT-MD Anderson cancer Center, Houston, TX  Purpose:  A positive biopsy 2-3 yr after external beam radiotherapy (RT) in patients free of treatment failure is a strongprognostic factor, but, is not synonymous with eventual recurrence. The analysis performed here is the first to measure theeffects of RT dose on biopsy status, in the setting of a randomized trial. Materials and Methods:  From 1993-1998 there were 305 men with T1-T3 prostate cancer who were randomized between 70Gy and 78 Gy. Of these, 170 were without evidence of failure when prospective sextant or greater prostate biopsies were doneat approximately 2 yr post-RT. Biopsies were classified as: no tumor, atypical cells not diagnostic of carcinoma, carcinoma withtreatment effect (CaTxEffect), and carcinoma without treatment effect (CaNoEffect). CaTxEffect or CaNoEffect wereconsidered biopsy positive. Treatment failure was defined as three rises in PSA on follow-up or clinical relapse. Kaplan-Meiercurves were calculated from the completion of RT. Median follow-up for those alive at last contact was 60 months (range 24-91mo). Results:  The rate of biopsy no tumor was 42%, atypical cells was 28%, CaTxEffect was 21%, and CaNoEffect was 9%. Biopsypositivity overall was 29%, and was 27% in the 70 Gy group and 32% in the 78 Gy group (p  0.7). The  Table  (top) shows 5yr freedom from failure (FFF) rates with patient numbers in parentheses. For the pooled biopsy negative patients (no tumor oratypical), 83% were FFF, which was higher than for those biopsy positive (65%, p  0.001). RT dose appeared to affect outcomein biopsy negative patients; 5 yr FFF was 77% for the 70 Gy group and 91% for the 78 Gy group (p  0.065). Dose did notinfluence FFF in biopsy positive patients. PSA nadir level was also a strong post-treatment prognostic factor ( Table  bottom).Significantly lower nadirs were found in the 78 Gy patients (p  0.024). A nadir of    0.5 ng/ml was associated with biopsynegativity in 66% of the 70 Gy group and 78% of the 78 Gy group (p  0.08). However, there was no such trend in 5 year FFFrates when nadir level was subdivided by dose arm. Multivariate analysis revealed that PSA level, stage, nadir level and biopsystatus were independent correlates of FFF; RT dose group was of borderline significance (p  0.07) when nadir level was notincluded. Conclusion:  Other investigators have reported a distinction in prognosis between CaTxEffect and CaNoEffect, and that dosereduces the rate of biopsy positivity. We found, in the setting of a randomized dose escalation trial, that CaTxEffect wasassociated with the same FFF rate as CaNoEffect, and that dose did not alter the incidence of biopsy positivity. Improvementin FFF secondary to dose escalation was related mainly to an effect on biopsy negative and not CaTxEffect patients. BiopsyGroups NNo Tumor:%5 yr FFF(n)Atypical Cells:%5 yr FFF(n)CaTxEffect:%5 yr FFF(n)CaNoEffect:%5 yr FFF(n)Log-rank P-valueAll 170 84%(72) 81%(48) 63%(35) 67%(15) 0.00370 Gy Arm 88 77%(34) 75%(30) 52%(15) ---(9) 0.11478 Gy Arm 82 90%(38) 93%(18) 71%(20) ---(6) 0.004Nadir Groups N   0.5 ng/ml   0.5-1.0 ng/ml   1.0-2.0 ng/ml   2.0 ng/ml Log-rank P-valueAll 170 82%(122) 69%(37) ---(9) ---(2) 0.0870 Gy Arm 88 77%(58) 61%(21) ---(7) ---(2) 0.0678 Gy Arm 82 86%(64) 80%(16) ---(2) ---(0) 0.15 253  Analysis of Clinical Outcomes from the START and START 40 Trials: The Efficacy of Sr-90 Radiation inthe Treatment of Long Lesion In Stent Restenosis M. Suntharalingam 1 , W. Laskey 1 , A. Lansky 2 , I. Crocker 3 , J. Popma 4 , R. Bonan 5 , R. Kuntz 4 1  Radiation Oncology, University Of Maryland School of Medicine, Baltimore, MD,  2 Cardiology, Lenox Hill Hospital, NewYork, NY,  3  Radiation Oncology, Emory University, Atlanta, GA,  4 Cardiology, Brigham&Womens Hospital, Boston, MA, 5 Cardiology, Montreal heart Institute, Montreal, ON, Canada Purpose:  to compare the results of the START 40 registry to data from the START trial to evaluate the efficacy of treating instent restenosis (ISR) with a 40 mm source train. A secondary analysis was also performed to identify any differences in efficacyor increased toxicities associated with treating patients presenting with long lesions. Materials and Methods:  The START trial was a triple masked, randomized trial which included 476 patients. From 6/99 to2/00 the START 40 registry trial enrolled 207 patients. The eligibility criteria was the same for both studies, and included singlelesion , ISR within native vessels between 2.7 and 4.0 mm. Lesion length criteria was identical on both studies, and was definedby the ability to treat the restenotic region with a 20 mm balloon. Patients randomized to radiation on the START trial weretreated with a 30 mm 90 Sr/Y 90 source train while those enrolled onto START 40 received therapy with a 40 mm source train.RT doses were 18.4 Gy for reference vessel diameters of   2.7 mm and  3.3 mm and 23 Gy for vessels  3. 3 mm to 4.0mm. Routine angiographic follow up was performed at 8 months.The three patient groups analyzed included the placebo arm of START (n  232) {ST p}, treated group of START (n  244){ST 30} and the START 40 pts (n  207) {ST40}. The primary efficacy endpoint was 8 month target vessel failure (TVF),and the safety endpoints included 8- month MACE and aneurysm formation. An analysis was performed comparing thethree groups in order to determine if treating with a longer source train improved the rates of geographic miss and edgerestenosis. A secondary analysis was performed on the 348 pts who had lesions lengths  15 mm and the 189 who were  20mm.142 I. J. Radiation Oncology  ●  Biology  ●  Physics Volume 51, Number 3, Supplement 1, 2001  Results:  Analysis of baseline demographics revealed that patients in ST 40 group were older (mean age 64.4 ST40 vs 61.1 STpand 61.5 ST30) [p  0.003], presented more frequently with unstable angina (85% ST 40 vs 73.8 % ST 30) [p  0.004], and hada history of more prior interventions for ISR ( 61% ST 40 vs 43 % ST p and 48% ST 30) [p  0.0002]. The average lesionlength was 16 mm ST p, 16.3 mm ST 30 and 17.4 mm ST Use of the 40 mm source train was associated with a lowerincidence of geographic miss (34% ST 30 vs. 7 % ST 40% [p  0.001]. There were no significant differences seen in the8 month thrombosis rates (0% vs 1%). The 8 month target vessel revascularization (TVR) rate was significantly lower inST 40 (16%) and ST 30(16%) pts vs ST p (24%) [p  0.03]. This reduction was also seen in TVR (11% vs 22%) [p  0.002].The MACE rate was decreased by 26% with the use of the 40 mm source train.There were 237 pts treated with RT who had lesions greater than 15 mm in length. Angiographic and clinical outcomes werecompared to the 111 STp pts . No differences were seen in the baseline demographics of the two groups. The mean lesion lengthin the treated group was 22.2   6.3 mm vs 22.1   5.5 mm. There was a significant reduction in the TVR (14% vs29%)[p  0.001], and a similar decrease in the rate of MACE (17% vs 30%)[p  0.004]. The restenosis rate was improved by46% ( 29% for those SR/Y 90 vs 53% for placebo) [p  0.0001]. No significant differences were seen in rates of aneurysmformation or total occlusions. Similar results were achieved when the analysis was performed on those patients with lesionsgreater than 20 mm in length. Conclusion:  The results of the START 40 registry trial support the continued use of Sr-90, beta radiation for the treatment of ISR. The additional treatment length led to a decrease in the rate of geographic miss with no deleterious effects. The secondaryanalysis revealed that the beneficial treatment effect was maintained throughout all lesion lengths analyzed without increasedtoxicity. 254  Potential Pitfalls of Simplistic Fixed Dosimetry Prescriptions Currently used in IntravascularBrachytherapy L.B. Harrison 1 , N.S. Patel 1 , A. Maehara 2 , N.J. Weissman 2 , R. Waksman 2 , G.S. Mintz 2 , T. Duckworth 1 , T.L. McMillan 2 , H.Xie 3 , S. Chiu-Tsao 1 1  Radiation Oncology, Beth Israel Medical Center & St.Luke’s-Roosevelt Hospital Center, New York, NY,  2 Cardiovascular  Research Institute, Washington Hospital Center, Washington, DC,  3  National Cancer Institute, National Institute of Health, Bethesda, MD Purpose:  We undertook the current study of 3D treatment planning and dose-volume histogram (DVH) analysis to assess theactual radiation doses delivered when fixed dosimetry methods are employed in an example randomized trial. Monte Carlosimulations and radiochromic film measurements of a  192 Ir multiple seed train (Best Industries) were also performed to showthe high doses delivered by  192 Ir electrons between seeds. Materials and Methods:  Treatment Planning : We examined the intravascular ultrasound (IVUS) and angiographic measure-ments of 20 cases from the WRIST randomized trial that employed a fixed dosimetry prescription: 15 Gy @ 2mm from thesource for vessels smaller than 4mm in diameter and 15 Gy @ 2.4mm for larger vessels. The adventitial and intimal tissue layerswere contoured using volumetric IVUS. Angiographic review of these patients provided longitudinal source placementinformation. DVHs, and their associated parameters (e.g., D90, D50, D10, D1), were calculated at the intimal and adventitiallayers. To examine the doses at the stent edges, DVHs were also calculated for the proximal, central, and distal 5mm of theadventitia. Centering/noncentering issues were examined by assuming (a) seeds were centered on the IVUS tip and (b) seedswere localized in the geographic center of the lumen.  Monte Carlo simulations : Using the MCNP4C code, Monte Carlo simulations were performed for a 5-seed train used in earlyclinical trials of intravascular brachytherapy, including WRIST. Less than 5% standard deviation was reached for energiesscored within 1 mm from the interseed air gap axis.  Radiochromic film : GAFchromic film measurements were performed for a  192 Ir 6-seed train to verify the dose distributions atradial distance of 0.5mm to  2mm. Results:  The actual doses received at the adventitia and intima were very heterogeneous. The table indicates that the majorityof patients did not receive the prescription dose of 15Gy to a large percent of the adventitial volume. The doses become evenmore heterogeneous in proximal and distal adventitial segments, potentially explaining the edge effect. The D90, D50, D10, andD1 values (averaged over patients receiving 15Gy @ 2mm) for the intima (stented segment) are 12, 19, 34, and 58 Gy,respectively. The adventitial values for the same cohort are 7, 11, 16, and 23 Gy for D90, D50, D10, and D1, respectively.Monte Carlo and film results indicate that high doses were deposited by  192 Ir electrons between seeds for a multiple seed trainused in intravascular brachytherapy clinical trials. At very close distances, the electron dose exceeded the dose from  192 Irgammas. The total dose near the interseed air gap delivered at 0.5 mm and 0.8 mm can be 160 Gy and 58 Gy, respectively,when 15 Gy is delivered to 2mm. Conclusion:  DVH analysis shows that fixed dosimetry prescription results in a wide range of actual delivered doses to both theadventitia and the intima. This type of analysis can be very critical to the assessment of success/failure as well as adverseoutcomes. Centering results in a more homogenous dose to the adventitia and intima, associated with a higher D90 value.Geographic miss patients show lower distal or proximal adventitial segment D90 values than the central adventitial portion.High electron doses delivered to shallow tissue layers may lead to adverse outcomes despite the small volume receiving suchdoses. Improved seed/source train design is needed to contain the high interseed electron dose from  192 Ir seed trains. % adventitial volumereceiving 15Gy 90-100 80-90 70-80 60-70 50-60 40-50 30-40 20-30 10-20 0-10# patients (n  20) 0 0 0 1 0 0 1 2 2 14 143Proceedings of the 43rd Annual ASTRO Meeting


Feb 24, 2019
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