Prospective validation of stringent dose constraints for prostatic stereotactic radiation monotherapy: results of a single-arm phase II toxicity-oriented trial.

PURPOSE: There are no safety-focused trials on stereotactic body radiotherapy (SBRT) for localized prostate cancer. This prospective 3­year phase II trial used binomial law to validate the safety and efficacy of SBRT with stringent organ at risk dose constraints that nevertheless permitted high planning target volume doses. METHODS: All consecutive ≥ 70-year-old patients with localized prostate adenocarcinoma who underwent SBRT between 2014 and 2018 at the National Radiotherapy Center in Luxembourg were included. Patients with low Cancer of Prostate Risk Assessment (CAPRA) scores (0-2) and intermediate scores (3-5) received 36.25 Gy. High-risk (6-10) patients received 37.5 Gy. Radiation was delivered in 5 fractions over 9 days with Cyberknife-M6™ (Accuray, Sunnyvale, CA, USA). Primary study outcome was Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) genitourinary and rectal toxicity scores at last follow-up. Based on binomial law, SRBT was considered safe in this cohort of 110 patients if there were ≤ 2 severe toxicity (CTCAEv4 grade ≥ 3) cases. Secondary outcomes were biochemical progression-free survival (bPFS) and patient quality of life (QOL), as determined by the IPPS and the Urinary Incontinence QOL questionnaire. RESULTS: The first 110 patients who were accrued in a total cohort of 150 patients were included in this study and had a median follow-up of 36 months. Acute grade ≥ 3 toxicity never occurred. One transient late grade 3 case was observed. Thus, our SBRT program had an estimated severe toxicity rate of < 5% and was safe at the p < 0.05 level. Overall bPFS was 90%. QOL did not change relative to baseline. CONCLUSION: The trial validated our SBRT regimen since it was both safe and effective.

Safety of adjuvant intensity-modulated postoperative radiation therapy in endometrial cancer: Clinical data and dosimetric parameters according to the International Commission on Radiation Units (ICRU) 83 report.

AIM: To report a single-institution experience using postoperative pelvic Intensity Modulation Radiation Therapy (IMRT) using tomotherapy accelerators (TA) in postoperative endometrial cancer (EC) regarding ICRU 83 recommendations. BACKGROUND: IMRT in gynecological malignancies provides excellent dosimetric data, lower rates of adverse events and clinical data similar to historical series. MATERIAL AND METHODS: Seventy-six patients with EC were postoperatively treated with adjuvant IMRT using TA. The IMRT dose was 45 Gy for patients without positive lymph nodes and Type I histology and 50.4 Gy for patients with positive lymph nodes and/or type II histology. RESULTS: With a median follow-up of 29 months, the 12- and 24-month Overall Survival (OS) and Disease-Free Survival (DFS) were 96%, 93%, 87%, and 74%, respectively. Age of less than 60 years was associated with better OS (HR: 8.9; CI: 1.1-68) and DFS (HR: 3.5; CI: 1.2-10.2). Patients with Type II and Type I Grade III histology had a worse OS (HR: 3.3; CI: 1.1-11). Five women (6.6%) presented in-field local vaginal recurrence, 2 (2.6%) presented non-in-field vaginal recurrence, 4 (5.2%) presented pelvic node and distant recurrence and 11 (14.4%) presented only distant metastases. One patient stopped radiation treatment due to Grade III acute diarrhea. No Grade III late toxicity was observed. Planning Target Volume (PTV) coverage showed mean D2, D50, D95, and D98 of 51.64-46.23 Gy, 49.49-44.97 Gy, 48.62-43.96 Gy, and 48.47-43.58 Gy for patients who received 45 and 50.4 Gy, respectively. CONCLUSIONS: IMRT with TA in postoperative EC shows excellent conformity and homogeneity of PTV dose. Without Grade III late toxicity, data from this cohort demonstrated the utility of IMRT.

Laparoscopic radical hysterectomy after preoperative brachytherapy for stage IB1 cervical cancer: feasibility, results, and surgical implications in a large bicentric study of 162 consecutive cases.

PURPOSE: To examine the feasibility and to report the results of laparoscopic radical hysterectomy (LRH) after initial uterovaginal brachytherapy (BT) for stage IB1 cervical cancer. METHODS: We retrospectively reviewed patients at 2 comprehensive cancer centers who underwent initial BT followed 6-8 weeks later by LRH and lymph node dissection. RESULTS: Between 2003 and 2010, a total of 162 patients underwent LRH. The procedure was feasible via this approach in 160 cases (98.8%) (2 conversions to laparotomy). Eight perioperative complications occurred. Nineteen patients had nodal involvement. Peri- or postoperative ureteral morbidity occurred in 10 patients (6%). Twenty-four patients (15%) experienced postoperative dysuria. Histologically, only 9 patients had residual cervical disease ≥5 mm, and only 1 patient had parametrial lymphovascular space involvement (associated with nodal spread). No patient had vaginal disease or involved surgical margins. After a median follow-up of 39 (range 3-118) months, 9 patients experienced relapse. Five-year overall survival was 95% (range 88.2-97.9%). CONCLUSIONS: Radical hysterectomy using a laparoscopic approach is feasible and reproducible after initial BT for stage IB1 cervical cancer and is associated with excellent survival. Morbidity is close to that reported in patients treated with up-front surgery. In this large series, the morbidity associated with parametrial dissection and the fact that parametrial spread was observed in only 0.6% of the patients suggest that a simple extrafascial hysterectomy is perhaps sufficient in this context; the rate of urinary tract morbidity would then be reduced.

Benefit of robot-assisted laparoscopy in nerve-sparing radical hysterectomy: urinary morbidity in early cervical cancer.

OBJECTIVE: To evaluate the feasibility of nerve-sparing radical hysterectomy in early cervical cancer by robot-assisted laparoscopy and atonic bladder rate. METHODS: This was a retrospective study with consecutive patients in three gynecological oncology departments. Patients with <2 cm cervical cancer had nerve-sparing radical hysterectomy by robot-assisted laparoscopy and pelvic lymphadenectomy. Two days after surgery, we systematically removed the Foley bladder catheter. RESULTS: The median (range) age and body mass index of the 30 patients were 44 (33-68) years and 23.9 (17.7-39.4) kg/m(2), respectively. The median (range) tumor diameter at the time of surgery was 13 (4-38) mm. The median (range) operative time, blood loss, and number of pelvic lymph nodes (any common iliac lymph nodes) were 305 (180-405) min, 100 (30-1,500) ml, and 18 (7-28). The overall complication rate was 52.3 %, of which 6.7 % atonic bladder. Twenty-eight patients (93.3 %) were discharged 2 days after surgery with spontaneous voiding and no residual urine >100 ml. CONCLUSIONS: Nerve-sparing radical hysterectomy by robot-assisted laparoscopy is feasible in early cervical cancer (<2 cm). A total of 93.3 % of the patients were discharged 2 days after surgery with spontaneous voiding. The next step would be a prospective study with objective urodynamic investigations.

Stereotactic focal radiotherapy as an alternative treatment for low-risk prostate cancer: Results of a single-arm monocenter Phase-II trial.

Introduction: Since radical treatments in low risk prostate cancer do not improve overall survival in comparison to active surveillance, preserving quality of life (QOL) remains the key objective. Active surveillance of indolent prostate cancer avoids curative treatment side-effects but necessitates repeated biopsies. Focal stereotactic body radiation therapy (focal SBRT) may be an alternative. This non-randomized Phase-II trial examined the feasibility and safety of focal SBRT for low and favorable intermediate-risk prostate cancer. Methods: Patients were recruited in 2016-2019 if they had: localized CAPRA ≤ 3 prostate adenocarcinoma; an isolated PIRADS≥4 macroscopic tumor on MRI; WHO Performance Status 0-1; and no major urinary symptoms. 36.25 Gy (80% isodose prescription) were delivered in 5 fractions every other day. Primary outcome was delay between focal SBRT and salvage-treatment initiation. Secondary outcomes were: acute/late genitourinary/rectal toxicity; biological, clinical and MRI local control; and change in QOL measures. Results: Over a median follow-up of 36 months, salvage prostatectomy in the 24 eligible patients was never required. Three-year biochemical progression-free survival was 96%. The single biochemical recurrence was a small (2-mm) Gleason 6 (3 + 3) lesion in the non-irradiated lobe. All 19 patients with ≥1 post-treatment MRI evaluations demonstrated complete radiological response. Acute/late grade ≥3 toxicities did not occur: all acute toxicities were grade-1 genitourinary (38% patients), grade-2 genitourinary (8%), or grade-1 rectal (13%) toxicities. There was one (4%) late grade-1 genitourinary toxicity. QOL was unchanged at last follow-up, as shown by IPSS (2.86 to 3.29, p>0.05), U-QOL (0.71 to 0.67, p>0.05), and IIEF5 (the 14 initially potent patients maintained potency (IIEF5 > 16)). Conclusion: Focal SBRT is feasible, well-tolerated, and preserves QOL. This innovative robotized approach challenges active surveillance.

A Multicenter Phase 2 Study of Ultrahypofractionated Stereotactic Boost After External Beam Radiotherapy in Intermediate-risk Prostate Carcinoma: A Very Long-term Analysis of the CKNO-PRO Trial.

Background: Genitourinary (GU) or gastrointestinal (GI) complications and tumor relapse can occur in the long term after radiotherapy for prostate cancer. Objective: To assess the late tolerance and relapse-free survival (RFS) in patients undergoing hypofractionated stereotactic boost therapy after external beam radiotherapy (EBRT) for intermediate-risk prostate cancer. Design setting and participants: Seventy-six patients with intermediate-risk prostate carcinoma between August 2010 and April 2013 were included. The first course delivered a dose of 46 Gy by conventional fractionation; the second course was a boost of 18 Gy (3 × 6 Gy) within 10 d. Outcome measurements and statistical analysis: GU and GI toxicities were evaluated as the primary outcomes. The secondary outcomes were overall survival and RFS. The cumulative incidence of toxicity was calculated using a competing-risk approach. Overall survival and RFS were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up period was 88 mo (range, 81-99 mo). Sixty (79%) patients were treated with the CyberKnife and 16 (21%) using a linear accelerator. The cumulative incidences of GU and GI grade ≥2 toxicities at 120 mo were 1.4% (95% confidence interval [CI]: 0.1-6.6%) and 11.0% (95% CI: 5.1-19.4%), respectively. The overall survival and RFS rates at 8 yr were 89.1% (95% CI: 77-95%) and 76.9% (95% CI: 63.1-86.1), respectively. Conclusions: A very long follow-up showed low GU and GI toxicities after a hypofractionated stereotactic boost after EBRT for intermediate-risk prostate cancer. Dose escalation of the boost delivered by hypofractionated radiation therapy appears safe for use in future trials. Patient summary: We found low toxicity and good survival rates after a short and high-precision boost after external beam radiotherapy for intermediate-risk prostate cancer, with a long-term follow-up of 88 mo. This long-term treatment is safe and should be considered in future trials.

A Multicenter Phase 2 study of Hypofractionated Stereostatic Boost in Intermediate Risk Prostate Carcinoma: A 5-Year Analysis of the CKNO-PRO Trial.

PURPOSE: The aim of this analysis was to assess the 5-year tolerance and survival in patients undergoing hypofractionated stereotactic boost after external beam radiation therapy (EBRT) for intermediate-risk prostate cancer. METHODS AND MATERIALS: Between August 2010 and April 2013, 76 patients with intermediate-risk prostate carcinoma were included in the study. A first course delivered 46 Gy using conventional fractionation. The second course delivered a boost of 18 Gy (3 × 6 Gy) within 10 days using stereotactic body radiation therapy (SBRT). Gastrointestinal and genitourinary toxicities were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Secondary outcome measures were overall, biochemical relapse-free, and relapse-free survival; prostate-specific antigen kinetics; and patient functional status (urinary and sexual) according to the International Index of Erectile Function and International Prostate Symptom Score questionnaires. RESULTS: Sixty patients (79%) were treated by CyberKnife and 16 (21%) by linear accelerator. Median follow-up was 62 months (range, 29-69). The cumulative incidence of genitourinary and gastrointestinal grade ≥2 toxicities at month 60 after the end of radiation therapy was 1.4% (95% confidence interval [CI], 0.1%-6.6%) and 9.3% (95% CI, 4.1%-17.1%), respectively. Biochemical relapse-free and relapse-free survival rates at 5 years were 87.4% (95% CI, 77.1%-93.2%) and 86.2% (95% CI, 75.8-92.3), respectively. The mean (standard deviation) prostate-specific antigen variation within 3 months and 5 years post-radiation therapy was -1.20 ng/mL/mo (0.79) and -1.30 ng/mL/y (1.05), respectively. There was no significant difference between the International Prostate Symptom quality of life score between inclusion and month 60. For the International Index of Erectile Function, there was a significant difference between inclusion and month 60 (P = .005), with a higher proportion of severe/noninterpretable disorders at 60 months. CONCLUSIONS: The results of the trial demonstrate that the EBRT and SBRT combination is well tolerated and yields good efficacy results. These data provide a good basis for comparing EBRT and brachytherapy boost to EBRT and SBRT boost in future prospective studies.

Tumor Size Matters-Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

A dosimetric selectivity intercomparison of HDR brachytherapy, IMRT and helical tomotherapy in prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: Dose escalation in order to improve the biochemical control in prostate cancer requires the application of irradiation techniques with high conformality. The dosimetric selectivity of three radiation modalities is compared: high-dose-rate brachytherapy (HDR-BT), intensity-modulated radiation radiotherapy (IMRT), and helical tomotherapy (HT). PATIENTS AND METHODS: Ten patients with prostate adenocarcinoma treated by a 10-Gy HDR-BT boost after external-beam radiotherapy were investigated. For each patient, HDR-BT, IMRT and HT theoretical treatment plans were realized using common contour sets. A 10-Gy dose was prescribed to the planning target volume (PTV). The PTVs and critical organs' dose-volume histograms obtained were compared using Student's t-test. RESULTS: HDR-BT delivers spontaneously higher mean doses to the PTV with smaller cold spots compared to IMRT and HT. 33% of the rectal volume received a mean HDR-BT dose of 3.86 + or - 0.3 Gy in comparison with a mean IMRT dose of 6.57 + or - 0.68 Gy and a mean HT dose of 5.58 + or - 0.71 Gy (p < 0.0001). HDR-BT also enables to better spare the bladder. The hot spots inside the urethra are greater with HDR-BT. The volume of healthy tissue receiving 10% of the prescribed dose is reduced at least by a factor of 8 with HDR-BT (p < 0.0001). CONCLUSION: HDR-BT offers better conformality in comparison with HT and IMRT and reduces the volume of healthy tissue receiving a low dose.

Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PURPOSE: Glioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies. METHODS AND MATERIALS: A number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration. RESULTS: Various immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials. CONCLUSIONS: This review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response.

Salvage Stereotactic Body Radiation Therapy for Local Prostate Cancer Recurrence After Radiation Therapy: A Retrospective Multicenter Study of the GETUG.

PURPOSE: To assess the efficacy and safety of salvage stereotactic body radiation therapy (SBRT) in patients with biopsy-proven local prostate cancer recurrence after radiation therapy. METHODS AND MATERIALS: Between April 2010 and January 2017, 100 patients were included in 7 centers. Disease extension was assessed by pelvic multiparametric magnetic resonance imaging and choline positron emission tomography in 87% and 94% of patients, respectively. The median time interval between the 2 treatments was 7.5 years (range, 2-18). Median prostate-specific antigen at recurrence was 4.3 ng/mL (range, 2-38). Median SBRT dose was 36 Gy (range, 25-36.25) in 6 fractions (range, 5-6), every other day. Thirty-four percent of patients were treated by androgen deprivation therapy for a median duration of 12 months. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03. RESULTS: Median follow-up was 29.3 months (range, 4-91). Second biochemical recurrence-free survival rate at 3 years was 55% (95% confidence interval [CI], 42%-66%). The initial D'Amico group, time interval after first radiation therapy, and SBRT dose were prognostic factors of biochemical recurrence-free survival in multivariate analysis (P = .09, P = .025, P = .018, respectively). No patient developed acute gastrointestinal toxicity of grade >1; rates of acute genitourinary toxicity of grade 2 and 3 were 8% and 1%, respectively. The actuarial 3-year grade ≥2 genitourinary and gastrointestinal toxicity was 20.8% (95% CI, 13%-29%) and 1% (95% CI, 0.1%-5.1%), respectively. One patient presented with neuritis of grade 3. CONCLUSIONS: With a short follow-up, this study shows that salvage SBRT allows for encouraging control and acceptable toxicity. Further prospective studies are necessary to confirm these preliminary results and to determine late toxicity.

NHL-ChirEx: An interprofessional cross-border education initiative in the Greater Region with a focus on radiation morbidity and patient safety.

NHL-ChirEx is an interprofessional cross-border education project that addresses the potential excess of radiation induced morbidity throughout the radiation planning and treatment process. NHL-ChirEx is supported by ESTRO and the University of the Greater Region and has been recently approved and funded under INTERREG VA Programme.

Adjuvant stereotactic permanent seed breast implant: a boost series in view of partial breast irradiation.

PURPOSE: The aim of this study was to use permanent seed implants in the breast and describe our experience with 15 cases, using iodine seed implants as a tumor bed boost. METHODS AND MATERIALS: Breasts were fixed with a thermoplastic sheet, a template bridge applied, the thorax scanned and the images rotated to be perpendicular to the implant axis. Skin, heart, and lung were delineated. A preplan was made, prescribing 50 Gy to the clinical target volume (CTV), consisting in this boost series of nearly a quadrant. Iodine (125) seeds were stereotactically implanted through the template, and results were checked with a postplan computed tomographic (CT) scan. RESULTS: The breast was immobilized reproducibly. Simulation, scanning, and implant were performed without difficulties. Preplan CTV D90% (the dose delivered to 90% of the CTV) was 66 Gy, and postoperative fluoroscopic or CT scan checks were satisfactory. Pre- and postplan dose-volume histogram showed good organ sparing: mean postplan skin, heart, and lung V30 Gy (the organ volume receiving a dose of 30 Gy) of 2 +/- 2.2 mL, 0.24 +/- 0.34 mL, and 3.5 +/- 5 mL, respectively. No short-term toxicity above Grade 1 was noted, except for transient Grade 3 neuropathy in 1 patient. CONCLUSIONS: Seeds remained in the right place, as assessed by fluoroscopy, absence of significant pre- to postplan dose-volume histogram change for critical organs, and total irradiated breast volume. The method could be proposed as a boost when high dosimetric selectivity is required (young patients after cardiotoxic chemotherapy for left-sided cancer). This boost series was a preliminary step before testing partial breast irradiation by permanent seed implant in a prospective trial.

Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy.

The aim of this paper is to supplement the GEC/ESTRO/EAU recommendations for permanent seed implantations in prostate cancer to develop consistency in target and volume definition for permanent seed prostate brachytherapy. Recommendations on target and organ at risk (OAR) definitions and dosimetry parameters to be reported on post implant planning are given.

Salvage robotic SBRT for local prostate cancer recurrence after radiotherapy: preliminary results of the Oscar Lambret Center.

BACKGROUND: Currently, there is no standard option for local salvage treatment for local prostate cancer recurrence after radiotherapy. Our objective was to investigate the feasibility and efficiency of Robotic Stereotactic Body Radiation Therapy (SBRT) in this clinical setting. METHODS/MATERIALS: We retrospectively reviewed patients who were treated at our institution with SBRT for local prostate cancer recurrence after External Beam Radiation Therapy (EBRT) or brachytherapy. Multidisciplinary staff approved the treatment, and recurrence was biopsy-proven when feasible. A dose of 36 Gy was prescribed in six fractions. Treatment was delivered every other day. RESULTS: Between August 2011 and February 2014, 23 patients were treated with SBRT for intra-prostate cancer recurrence with a median follow up of 22 months (6 to 40). Twenty patients had biopsy-proven recurrence. For 19 patients, EBRT was the initial treatment and in four patients, brachytherapy was the initial treatment; the median relapse-time from initial treatment was 65 months (28 to 150). At relapse, 10 patients had an extra-capsular extension. Fourteen patients were treated with androgen deprivation that could be stopped after a median of 1 month after SBRT (range 0-24). A PSA decrease occurred in 82.6% of the patients after SBRT. The 2-year disease-free survival and overall survival rates were 54 and 100%, respectively. Disease progression was observed for nine patients (39.1%) (five local, three metastatic and one nodal progression) after a median of 20 months (7-40 months). The median nadir PSA was 0.35 ng/ml and was achieved after a median of 8 months (1 to 30) after treatment. We observed no grade 4 or 5 toxicity. Two patients presented with grade 3 toxicities (two Cystitis and one neuralgia). Other toxicities included urinary toxicities (five grade 2 and nine grade 1) and rectal toxicities (two grade 2 and two grade 1). CONCLUSION: SBRT for local prostate cancer recurrence seems feasible and well tolerated with a short follow up. Prospective evaluation is needed.

Hypofractionated stereotactic boost in intermediate risk prostate carcinoma: Preliminary results of a multicenter phase II trial (CKNO-PRO).

PURPOSE: Dose escalation may improve curability in intermediate-risk prostate carcinoma. A multicenter national program was developed to assess toxicity and tumor response with hypofractionated stereotactic boost after conventional radiotherapy in intermediate-risk prostate cancer. METHODS AND MATERIAL: Between August 2010 and April 2013, 76 patients with intermediated-risk prostate carcinoma were included in the study. A first course delivered 46 Gy by IMRT (68.4% of patients) or 3D conformal radiotherapy (31.6% of patients). The second course delivered a boost of 18 Gy (3x6Gy) within 10 days. Gastrointestinal (GI) and genitourinary (GU) toxicities were evaluated as defined by NCI-CTCAE (v4.0). Secondary outcome measures were local control, overall and metastasis-free survival, PSA kinetics, and patient functional status (urinary and sexual) according to the IIEF5 and IPSS questionnaires. RESULTS: The overall treatment time was 45 days (median, range 40-55). Median follow-up was 26.4 months (range, 13.6-29.9 months). Seventy-seven per cent (n = 58) of patients presented a Gleason score of 7. At 24 months, biological-free survival was 98.7% (95% CI, 92.8-99.9%) and median PSA 0.46 ng/mL (range, 0.06-6.20 ng/mL). Grade ≥2 acute GI and GU toxicities were 13.2% and 23.7%, respectively. Grade ≥2 late GI and GU toxicities were observed in 6.6% and 2.6% of patients, respectively. No grade 4 toxicity was observed. CONCLUSIONS: Hypofractionated stereotactic boost is effective and safely delivered for intermediate-risk prostate carcinoma after conventional radiation. Mild-term relapse-free survival and tolerance results are promising, and further follow-up is warranted to confirm the results at long term. TRIAL REGISTRATION: ClinicalTrials.gov NCT01596816.

A retrospective cohort study to assess adjuvant concurrent chemoradiation (CCRT) compared to adjuvant radiation therapy (RT) in the treatment of grade 2 and 3 extremity soft tissue sarcomas.

PURPOSE: To evaluate the efficacy and tolerance of adjuvant concurrent chemoradiation (CCRT) as treatment of grade 2 and 3 (G2-3) localized extremity soft tissue sarcomas (STS) by comparing CCRT with standard adjuvant radiation therapy (RT). PATIENTS AND METHODS: This monocentric retrospective study included non-pediatric patients (>16years) treated by adjuvant RT with or without chemotherapy (CT) after conservative resection of non-recurrent G2-3 extremity STS. RESULTS: A total of 80 patients were treated between 1990 and 2012: 51 by RT and 29 by CCRT. Of the 29 CCRT patients, 25 received doxorubicin monotherapy (75mg/m2/3weeks). The CCRT group contained a greater proportion of grade 3 extremity STS (p<0.001). Median follow up was 68months (9-284). Multivariate analysis revealed greater local control in the CCRT group (1 local recurrence vs 8 in the RT group; HR=0.082, 95% CI 0.011-0.321) and incomplete resection as the major risk factor of local recurrence (HR=25.2, 95% CI 4.767-133.226). The two groups exhibited no differences in distant failure-free survival (HR=1.469, 95% CI 0.668-3.228), disease-free survival (HR=1.096, 95% CI 0.519-2.315) or overall survival (HR=1.378, 95% CI 0.498-3.814). Grade 3 was an adverse prognostic factor for overall survival (HR=3.11, 95% CI 1.04-9.32). Our analyses also revealed that CCRT tended to increase the risk of both grade ≥3 acute dermatitis (14 events vs 6 in the RT group; OR=6.99, 95% CI 2.28-21.47) and grade ≥2 late toxicity (6 events vs 3 in the RT group; p=0.0572). CONCLUSION: CCRT could improve local control as part of a limb-preservation strategy. However, with a limited number of patients, CCRT showed no improvement in either distant control or survival and increased toxicity.

Prognostic value of PSA nadir < or =4 ng/mL within 4 months of high-dose radiotherapy for locally advanced prostate cancer.

PURPOSE: To investigate early prostate-specific antigen (PSA) kinetics after high radiation doses of 85 Gy on locally advanced prostate cancer. METHODS AND MATERIALS: A total of 201 patients were prospectively and consecutively treated with external beam radiotherapy and a brachytherapy boost. Of the 201 patients, 104 received concomitant hormonal therapy on the decision of the referring urologist and were excluded, yielding a study population of 97 patients. The first posttreatment PSA analysis was performed not earlier than 1 month after treatment completion but within the first 4 months, and then every 4 months. Analysis of PSA kinetics included the PSA nadir (nPSA) at values of < or =4 ng/mL to < or =0.5 ng/mL. The nPSA at < or =4 ng/mL within 4 months (nPSA < or =4/4m) was the variable of interest. RESULTS: We established highly significant associations between an nPSA of < or =1 and < or =0.5 ng/mL and the nPSA < or =4/4m (p <0.0001). A hazard ratio of 0.33 (95% Confidence Interval (CI), 0.12-0.91) underlined the lower risk of recurrence related to nPSA < or =4/4m achievement (p = 0.033). Using time-dependent covariate models for patients who did not reach an nPSA < or =4/4m, an nPSA of < or =1 ng/mL remained without prognostic significance (p = 0.06). However, for patients who reached an nPSA < or =4/4m, an nPSA of < or =1 ng/mL did significantly improve the prognosis (p <0.001), but much later after treatment. The same analysis was repeated for nPSA < or =0.5 ng/mL with similar conclusions as when nPSA < or =4/4m was obtained (p <0.01). CONCLUSION: The nPSA < or =4/4m has been demonstrated to be a significant predictor of biochemical no evidence of disease after high radiation doses of 85 Gy. Its major advantage is that it was available earlier than the other nadirs.

192Ir or 125I prostate brachytherapy as a boost to external beam radiotherapy in locally advanced prostatic cancer: a dosimetric point of view.

PURPOSE: This work aims at comparing the dosimetric possibilities of 125I or 192Ir prostate brachytherapy (Bt) as a boost to external beam radiotherapy in the treatment of locally advanced adenocarcinoma. METHODS AND MATERIALS: From 1/1997 to 12/2002, 260 patients were treated. Until 12/2001 a low dose rate (LDR) treatment with 192Ir wires was used, later replaced by a high dose rate (HDR) delivered with an 192Ir stepping source technology. For the present work, we selected 40 patients including the last 20 treated, respectively, by LDR and HDR. The planning CT Scans of all these 40 patients were transferred into the 3D Prowess system for 125I permanent implants design according to the Seattle method. The reference data for dosimetric comparisons were the V100 and the prescribed dose for 192Ir as well as the dose delivered with 125I techniques to the 192Ir V100. We compared V100-150 data as well as doses to the organs at risks (OR) and cold spots (CS). RESULTS: The V100 is 85.3+/-8% for 192Ir LDR and 96+/-2% for HDR techniques (P < 0.0001). In comparison with 125I, the 192Ir LDR mode induces higher hyperdosage volumes inside the CTV but also more CS, while maximal doses to urethra and rectum are, respectively, 17 and 39% less with 125I (P < 0.0001). In comparison with the 192Ir HDR mode, 125I Bt induces higher hyperdosage volumes and slightly more CS deliberately planned around the bladder neck. If delivered doses to urethra are identical, those to the 20% anterior part of the rectum are 33% less with 125I (P < 0,0001). The 125I Bt technique was only possible in 24 out of the 40 patients studied due to pelvic bone arch interference. CONCLUSIONS: At the present time, there is no evident dosimetric superiority of one Bt method when all the criteria are taken into account. However, improving Bt techniques to implant any prostatic size could found the superiority of the 125I or permanent implants. 125I indeed allows large hyperdosage volumes inside the CTV in comparison with 192Ir HDR techniques while lowering doses to OR and minimizing CS.

192Ir low dose rate brachytherapy for boosting locally advanced prostate cancers after external beam radiotherapy: a phase II trial.

BACKGROUND AND PURPOSE: To evaluate on 201 locally advanced prostatic cancers prospectively treated in a phase II trial, the efficacy of a combination of external beam radiotherapy (39.6 Gy) and (192)Ir low dose rate brachytherapy (Bt) (40-45 Gy). PATIENTS AND METHODS: Sixty-four patients were included in the intermediate prognosis group with only one of the following adverse factors (PSA > 10 ng/ml, Gleason score > or = 7 or clinical stage > or =T2b) and 137 in the unfavourable group when at least two of these factors were present. RESULTS: The actuarial 4 years biochemical no evidence of disease is 82.8% for the entire population. It is, respectively, 97 and 76% in the intermediate and unfavourable prognosis groups (P < 0.0001). Grade > or =3 late urinary complications occurred in 13 patients (6.5%). Eight patients (4%) presented late grade 2 rectal complications but no grades 3-5 was observed. CONCLUSIONS: Even if an alpha/beta of 1.5-3 Gy theoretically favours the use of a high dose rate mode of irradiation, the early results presented here are as good as those reported for similar groups of patients with high dose rate treatments. Late toxicity is identical but our urinary toxicity is within the less favourable and rectal toxicity within the most favourable results. We can postulate that while inducing very high hyperdosage regions (V150) mainly focused on the peripheral zone, most of the Bt techniques consist of a more ablative treatment. Many of the radiobiological studies on Bt did not in fact take into account the heterogeneity of irradiation inside the CTV. This study highlights the need to explore pulsed dose rate therapies, permanent implant and new available radioisotopes such as (169)Ytterbium that will offer the safety of low and lower dose rates. The actual late toxicity of the different Bt techniques is not yet inexistent indeed.