The purpose of our study was to compare acute and late toxicities of high dose rate (HDR) brachytherapy and low dose rate (LDR) permanent iodine or palladium seeds as monotherapy in patients with low and favorable intermediate risk prostate cancer. Materials/Methods: We retrospectively examined patients with biopsy proven, low to favorable intermediate risk prostate cancer treated with interstitial brachytherapy monotherapy from 1998-2016 at a single institution. Patients selected were restricted to T stage T2c, Gleason score 7, and prostate specific antigen (PSA) less than 20 ng/ml. For each case of prostate brachytherapy, needles/seeds were implanted transperineally via trans-rectal ultrasound guidance. Dose for LDR was 145 Gy and HDR was 27 Gy in 2 fractions. The Common Toxicity Criteria scale, version 2.0 and 3.0 were used to score the acute (<12 months after brachytherapy) and late (! 12 months after brachytherapy) toxicities. Chi square analysis tested for associations between toxicity and treatment technique. Logistic regression was used in multivariable analyses (MVA). Results: A total of 572 patients were included, including 97 treated with HDR using 192 iridium (192 Ir), and 475 treated with LDR using 125 iodine (125 I) or 103 palladium (103 Pd). The median follow up time was 9.2months (range 3.1-145.3) for HDR patients and 53.1 months (range 0.2-198.6) for LDR patients. The two treatment groups were well-balanced with respect to age, T stage, ethnicity, and implanted prostate gland volume. A majority of patients had T1c disease and pretreatment PSA less than 10 ng/ml. 69% of HDR patients had Gleason score of 7 while 2.5% of LDR patients had Gleason score of 7. On univariate analysis, HDR brachytherapy was associated with lower rate of grade 2+ acute GU toxicity (14% vs 38%, p <0.0001) and grade 2+ late GU toxicity (10% vs 31%, p< 0.0001). Acute GI toxicity was low at 3% for both HDR and LDR; late GI toxicity were 6% and 7% (pZ 0.63) for HDR and LDR, respectively. In MVA, only LDR was independently associated with increased risk of grade 2+ acute GU toxicity (OR 2.4, 95% CI 1.1-5.3), but it was no longer associated with increased risk of grade 2+ late GU toxicity (OR 1.0, 95% CI 0.5-2.3). MVA demonstrated no difference between the two treatment methods with regard to acute or late GI toxicity. Conclusion: Acute and late GI toxicity was rare in patients treated with brachytherapy. The use of HDR brachytherapy as monotherapy was associated with a significantly lower risk of grade 2+ acute GU toxicity but similar grade 2+ late GU toxicity compared to LDR. Our results suggest HDR may be the preferred brachytherapy option in patients with clinically localized prostate cancer due to the better acute safety profile.
264 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS can detect carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy. Results: AMS detected Pt-DNA damage when cancer cells and mice with tumor xenografts were exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage were linearly proportional to the DNA damage caused by the therapeutic drug dose (R2=0.92, p<0.001); and these levels of DNA damage correlated with chemoresistance. Low DNA damage predicts chemoresistance. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some resistance mechanisms. We have opened a phase 0 microdosing trial to study patients with bladder cancer who are scheduled to receive Pt-based chemotherapy. One subtoxic microdose of 14C-carboplatin will be administered to these patients before biopsy. Pt-induced DNA damage and repair in left-over tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Molecular analysis of genes such as ERCC1 and RRM1 will be analyzed and compared with this phase 0 results. We have opened a similar phase 0 trial in dog patients with bladder cancer. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The clinical data of the phase 0 trial will be presented. No significant financial relationships to disclose.
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