Guilhem Roubaud

Dynamic contrast enhanced MRI-derived parameters are potential biomarkers of therapeutic response in bladder carcinoma

OBJECTIVES To evaluate the performance of dynamic contrast enhanced (DCE) magnetic resonance (MR) imaging to assess the histological response after chemotherapy on bladder carcinoma. METHODS From 2008 to 2010, 12 patients presenting localized urothelial carcinoma of the bladder were prospectively evaluated by DCE-MR imaging before and after two courses of cisplatin-based neoadjuvant chemotherapy. Size and thickness of tumours were measured. Relative enhancement at the arterial (rSI35s) and venous phases (rSI80s) of each tumour was obtained. Histological response was assessed and outcomes were recorded. RESULTS Histological examination after neoadjuvant chemotherapy concluded as pathological complete response (pCR) for 6 out of 12 patients. Five patients developed recurrences (4/6 no pCR and 1/6 pCR). Significant differences, between before and after treatment, were found for patients with complete pathological response after chemotherapy for all MR quantitative values. Tumours decreased in size and thickness (both P=0.03). After treatment, rSI80s was significantly different between pCR and non-pCR patients (P=0.04) with a cut-off value of 40%. For this cut-off, sensitivity, specificity and accuracy were 83.33%. Similar recurrence free survivals were obtained if applying the MR cut-off value or the histopathological findings. CONCLUSION Our results suggest that DCE-MR imaging may be a useful biomarker for patients with localized bladder carcinoma, improving selection before surgery.

Standard or accelerated methotrexate, vinblastine, doxorubicin and cisplatin as neoadjuvant chemotherapy for locally advanced urothelial bladder cancer: Does dose intensity matter?

BACKGROUND There is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer. PATIENTS AND METHODS We performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004-May 2013. RESULTS The median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56-79) and 72% (95% CI, 59.5-88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens. CONCLUSION Similar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC.

Adjuvant radiotherapy after radical cystectomy for muscle-invasive bladder cancer: A retrospective multicenter study

Objectives Radical cystectomy (RC) and pelvic lymph-node dissection (LND) is standard treatment for non-metastatic muscle-invasive urothelial bladder cancer (MIBC). However, loco-regional recurrence (LRR) is a common early event associated with poor prognosis. We evaluate 3-year LRR-free (LRRFS), metastasis-free (MFS) and overall survivals (OS) after adjuvant radiotherapy (RT) for pathological high-risk MIBC. Material and methods We retrospectively reviewed data from patients in 3 institutions. Inclusion criteria were MIBC, histologically-proven urothelial carcinoma treated by RC and adjuvant RT. Patients with conservative surgery were excluded. Outcomes were evaluated by Kaplan-Meier method. Acute toxicities were recorded according to CTCAE V4.0 scale. Results Between 2000 and 2013, 57 patients [median age 66.3 years (45–84)] were included. Post-operative pathological staging was ≤pT2, pT3 and pT4 in 16%, 44%, and 39%, respectively. PLND revealed 28% pN0, 26% pN1 and 42% pN2. Median number of lymph-nodes retrieved was 10 (2–33). Forty-eight patients (84%) received platin-based chemotherapy. For RT, clinical target volume 1 (CTV 1) encompassed pelvic lymph nodes for all patients. CTV 1 also included cystectomy bed for 37 patients (65%). CTV 1 median dose was 45 Gy (4–50). A boost of 16 Gy (5–22), corresponding to CTV 2, was administered for 30 patients, depending on pathological features. One third of patients received intensity-modulated RT. With median follow-up of 40.4 months, 8 patients (14%) had LRR. Three-year LRRFS, MFS and OS were 45% (95%CI 30–60), 37% (95%CI 24–51) and 49% (95%CI 33–63), respectively. Five (9%) patients had acute grade ≥3 toxicities (gastro-intestinal, genito-urinary and biological parameters). One patient died with intestinal fistula in a septic context. Conclusions Because of poor prognosis, an effective post-operative standard of care is needed for pathological high-risk MIBC. Adjuvant RT is feasible and may have oncological benefits. Prospective trials evaluating this approach with current RT techniques should be undertaken.

Oncological and functional results of robotic salvage radical prostatectomy after permanent brachytherapy implants

PURPOSE To evaluate the feasibility of robotic salvage prostatectomy for local recurrence after permanent brachytherapy implants for prostate cancer. PATIENTS AND METHODS Seven patients were operated by robotic salvage prostatectomy with or without pelvic lymph node dissection between October 2007 and March 2012, for a local recurrence after iodine 125 permanent brachytherapy implants. Local recurrence was proved by prostate biopsies, once biochemical relapse was diagnosed and imaging assessment performed. RESULTS The average age of a patient at the time of diagnosis was 66 years (62-71 years). The median nadir prostate specific antigen (PSA) serum concentration after brachytherapy was 1.29ng/mL (0.6-2.1ng/mL), obtained after a median of 12 months (7-21 months). The average [PSA] before robotic salvage prostatectomy was 6.60ng/mL (4.17-13.80ng/mL). [PSA] at 1 and 3 months after prostatectomy was less than 0.05ng/mL in five patients. [PSA] remained below 0.05ng/mL for six patients at 12 and 24 months. One month after robotic salvage prostatectomy, all patients had at least partial urinary incontinence. At 12 and 24 months after robotic salvage prostatectomy four patients have regained full urinary continence. In terms of erectile function at 24 months, three patients retained erectile function with possible sexual intercourse. CONCLUSION Robotic salvage prostatectomy appears to be a reliable treatment in terms of oncological outcome with convincing results both for urinary continence and erectile function for selected patients with local recurrence after permanent brachytherapy implants.

Révision de l’index thérapeutique des thérapies ciblées dans le cancer du rein : le mieux peut-il être l’ennemi du bien ? La toxicité peut-elle prédire l’efficacité ?

Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy.

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study

Background About one‐third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti‐angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal‐related events (SREs) can be prevented with bone‐targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination. Patients and Methods We conducted a multicenter retrospective study among centers from the French Groupe d’Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study. Results A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination. Conclusion The incidence of ONJ was high in this real‐life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population. Micro‐Abstract The aim of this multicenter retrospective study is to analyze the toxicity profile (mainly osteonecrosis of the jaw) of patients with metastatic renal cell carcinoma treated with denosumab and anti‐angiogenic combination. Of 41 patients enrolled in this study, 7 patients developed osteonecrosis of the jaw. This toxicity signal should warn physicians about this combination in the population with metastatic renal cell carcinoma.

Posterior reversible encephalopathy syndrome with colitis in a patient treated with panitumumab

journals.sagepub.com/home/taw 133 Posterior reversible encephalopathy syndrome (PRES) associates headaches, encephalopathy, seizures and visual disturbances with typical magnetic resonance imaging (MRI) findings. PRES is reversible and benign in most of cases, although sequels may exist, and fatal outcomes have been described in up to 19% [Alhilali et al. 2014; Fugate and Rabinstein, 2015]. Some PRES were associated to targeted therapies [Fugate and Rabinstein, 2015], including cetuximab [KamiyaMatsuoka et al. 2016; Palma et al. 2011], a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab is a fully human recombinant monoclonal antibody with a high binding affinity to human EGFR. Here we report and discuss the occurrence of a PRES in a patient presenting with colitis and treated with panitumumab. Patient consent was obtained and patient confidentiality was maintained.

Staged radiofrequency ablation and surgical resection for multiple lung metastases of germ cell tumors

Purpose: To evaluate the morbidity and efficacy of percutaneous radiofrequency ablation (RFA) performed before surgical resection for multiple residual lung metastases of germ cell tumors with negative tumor markers. Materials and Methods: This Review Board-approved retrospective study was carried out on five consecutive patients (mean age: 31 years, range: 22–41) treated successively with percutaneous RFA and surgery for multiple lung metastases of germ cell tumors. Mean number of lung metastases before treatment was 9.4. Staged procedures were performed on an average of 7.2 months (range: 1–16) after the primitive tumor resection. Results: The median clinical and imaging follow-up was 26 months (range: 24–36). Percutaneous RFA was technically feasible in one session under general anesthesia and CT guidance in all cases. On average, 2.8 tumors were ablated per patient (range: 1–6), and three of five procedures were bilateral. Three patients developed pneumothorax requiring drainage, but no severe complications were reported. Mean time between RFA and surgical resection of residual tumors was 2.5 months (range: 1–5). No local recurrences were noted, but one patient died due to metastatic evolution. Conclusion: Staged percutaneous RFA and surgical resection could be efficient with low morbidity for the management of multiple lung metastases of germ cell tumors.

Radiothérapie adjuvante des tumeurs de vessie à risque de rechute locorégionale : pour qui, pourquoi et comment ?

Radical cystectomy with extended pelvic lymph node dissection remains the standard of care for non-metastatic muscle-invasive bladder cancer. Locoregional control is a key factor in the outcome of patients since it is related to overall survival, metastasis-free survival and specific survival. Locoregional recurrence rate is directly correlated to pathological results and the quality of lymphadenectomy. In addition, while pre- or postoperative chemotherapy improved overall survival, it showed no impact on locoregional recurrence-free survival. Several recent publications have led to the development of a nomogram that predicts the risk of locoregional recurrence, in order to identify patients for which adjuvant radiotherapy could be beneficial. International cooperative groups have then come together to provide the rational for adjuvant radiotherapy, reinforced by recent technical developments limiting toxicity, and to develop prospective studies to reduce the risk of relapse. The aim of this critical literature review is to provide an overview of the elements in favor of adjuvant radiation for patients treated for muscle-invasive bladder cancer.

Révision de l’index thérapeutique des thérapies ciblées dans le cancer du rein : le mieux peut-il être l’ennemi du bien ? La toxicité peut-elle prédire l’efficacité ?Revision of therapeutic index for targeted treatment in kidney cancer: What if toxicity could predict efficacy?

Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy.