Stéphane Guerif

Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial

BACKGROUND How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. METHODS This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. FINDINGS Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. INTERPRETATION Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. FUNDING French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

DNA-PKcs expression predicts response to radiotherapy in prostate cancer.

PURPOSE Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. METHODS Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. RESULTS The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). CONCLUSIONS The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.

Postoperative brachytherapy alone for T1-2 N0 squamous cell carcinomas of the oral tongue and floor of mouth with close or positive margins

PURPOSE To evaluate the efficacy of postoperative brachytherapy alone (brachy) for Stage T1-2 squamous cell carcinomas (SCC) of the floor of mouth (FM) and the oral tongue (OT) with close or positive margins. METHODS AND MATERIALS Between 1979 and 1993, 36 patients with T1-2 N0 (24 T1, 12 T2) OT (19), and FOM (17) SCC with close or positive margins following surgery underwent postoperative brachy. Mean patient age was 56 years (range 37-81) and sex ratio was 3.5:1 male:female. Mean surgery to brachy interval was 36 days (range 16-68). The technique used was interstitial Iridium-192 ((192)Ir) brachytherapy with plastic tubes and manual afterloading. Mean total dose was 60 Gy (range 50-67.4) at a mean dose rate of 0.64 Gy/h (range 0.32-0.94). Mean patient follow-up was 80 months. RESULTS The 5-year actuarial overall and cause-specific survivals of the entire group were 75% and 85%, respectively. The local control was 88.5% at 2 years, with a plateau apparent after 23 months. Of the 4 local relapses, 2 were salvaged with surgery and external beam radiotherapy (EBR). No tumor or treatment factors, including tumor size, margin status, disease site, or radiation dose, were correlated with local control. The 2 head and neck second primaries underwent curative treatment on nonirradiated tissue. One patient developed a grade 3 sequelae (bone and soft tissue necrosis). Grade 2-3 chronic sequelae were seen in 7 of 17 and 3 of 19 FOM and OT tumors, respectively (p = 0.09). CONCLUSION Postoperative brachy is a promising approach in T1-2 N0 OT and FOM SCC with close or positive margins. This approach is associated with high rate of locoregional control and low risk of chronic sequelae, obviates major surgery, avoids potential sequelae of EBR (xerostomia, dysgueusia, fibrosis), and avoids treatment of second head and neck primary on nonirradiated tissues.

Curved angiocatheter metal guide for the implantation in velo-tonsillar carcinomas.

Brachytherapy in velo-tonsillar region is not applied in all the institutions because of difficulties to learn it. For the implantation of wires in the soft palate, the Reverdin needle is replaced by a curved guide of angiocatheter 14 Gauge. This technique is easy and reduces the risk of tear mucosa.

Post-Prostatectomy Image-Guided Radiotherapy: The Invisible Target Concept

In the era of intensity-modulated radiation therapy, image-guided radiotherapy (IGRT) appears crucial to control dose delivery and to promote dose escalation while allowing healthy tissue sparing. The place of IGRT following radical prostatectomy is poorly described in the literature. This review aims to highlight some key points on the different IGRT techniques applicable to prostatic bed radiotherapy. Furthermore, methods used to evaluate target motion and to reduce planning target volume margins will also be explored.

Evaluation of tumor hypoxia prior to radiotherapy in intermediate-risk prostate cancer using 18 F-fluoromisonidazole PET/CT: a pilot study

Purpose Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of 18F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment. Materials and Methods Intermediate-risk prostate cancer patients about to receive high-dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and 18F-choline-PET. 18F-choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation. Results Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUVmax and SUVmax tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO-positive volume was 1.1 ml. Conclusions This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO-positive volume was detected in one third of intermediate-risk prostate cancer patients.

Permanent prostate brachytherapy and short-term androgen deprivation for favorable and unfavorable intermediate risk: Clinical results for median 5 year follow-up.

e554Background: The option of prostate brachytherapy for intermediate risk is discuss. We present mature results of permanent prostate brachytherapy and short-term androgen deprivation for favourable and unfavourable intermediate risk. Methods: From 01/2006 through 12/2012, 707 patient were treated by real time iodine brachytherapy. 135 intermediate risk, 72% favourable and 28% unfavourable were include. Unfavourable was define as a gleason 7 (4+3) or > 50 % positive biopsy or 2 intermediate factors. Neoadjuvant with or without adjuvant androgen deprivation therapy was administered to 94% patients. 91 % of patients have a duration of hormone ≤ 6 mouths. 40% had vesicle seminal biopsy. 62 % had a lymph node dissection. 75 % had a bone scan. 95% had a MpMRI with tumour index in 72 %. All patients with DIL on MpMRI had a focused real time image guided brachytherapy. Tumour control was measure with phoenix definition and death with Kaplan-Meier method. The GU and GI toxicity were measure with IPSS and CTCAE V...

Multimodal image and mapping guided focal salvage high-dose-rate brachytherapy for local recurrent prostate cancer.

122Background: Image guided brachytherapy and mapping biopsy could reduce the toxicity of the total salvage brachytherapy. This study evaluate the tumor control and the tolerance of a focal real time salvage high-dose-rate (HDR) brachytherapy to treat the local relapse as defined on transperineal mapping biopsy, multipara-metric MRI and Choline PETSCAN on the same treatment planning. Methods: Between October 2013 and June 2016, Twenty-nine patients with local relapse on Choline PET Scan after a primary irradiation had a salvage HDR Brachytherapy (2 fractions of 10 Gy within 4-6 hours in one implant) without hormone. One month before brachytherapy All patients had real time transperineal randomized European regions standardised magnetic resonance imaging (MRI) prostate biopsies and targeted biopsies with a fusion of T2 MRI sequence /CholinePETscan (50 % SUV) to intraoperative transrectal ultrasound one month before brachytherapy. We used Flex Focus 400 ultrasound machine BK, Vitesse 3.0 and 3 D navigation ...

Delineation of the Prostate Bed: The “Invisible Target” Is Still an Issue?

For pathological high-risk prostate cancer, adjuvant irradiation has shown a survival benefit. Phase III studies have highlighted that half men would face biochemical relapse and would be candidate for radiotherapy at adjuvant or salvage times. Despite at least four published international contouring guidelines from different collaborative groups, discrepancies remain for volumes, delineation, and margins to be considered in order to optimize radiotherapy planning. This article from “Groupe d’Etude des Tumeurs UroGénitales (GETUG)” members will focus on controversies to help clinicians to create best volume delineation for adjuvant or salvage post prostatectomy radiotherapy.

Traitement à domicile par l’acide zolédronique chez des patients atteints de tumeurs solides : observance et satisfaction du patient et de l’infirmier

PURPOSE To explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of a bisphosphonate. METHODS Prospective 1-year survey of home zoledronic acid therapy (4 mg, 15-min intravenous, every three to four weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered. RESULTS Physician participation rate: 56.5% (87/154); 818 patients included; 381 predominantly community nurses; 763/788 case report forms meeting inclusion criteria. PATIENT CHARACTERISTICS median age, 68 years (30-95); M/F, 40/60; ECOG-PS 0 or 1, 78.6%; primary tumour site: breast (55.2%), prostate (28.4%), lung (7.2%), other (9.4%). Nurse satisfaction rates: 90.9% (organization of home ZOL therapy); 96.7% (ease of infusion); 97.5% (patient-nurse relationship); 73% (relationship with hospital staff). Patient satisfaction rates: 95.3% overall; 57.6% (quality of the nurse-patient relationship); 68.8% (less travel/waiting); 52.9% (consideration for home environment). Treatment tolerance: 33.63% (discontinuation due to adverse events); 0.6% (osteonecrosis of the jaw); 0.2% fractures. Practitioner compliance with best practice: 76.7% to 83.7% (recommended and/or tolerated dosage), 73% (dental hygiene checks at inclusion; 48 to 56% thereafter); 66% (pre-infusion hydration); often undocumented for calcium/vitamin D supplementation. CONCLUSION Home zoledronic acid treatment was well tolerated. There was a very high level of both patient and nurse satisfaction with home therapy. However, better compliance with best practice should be encouraged.