Erectile function preservation after radiotherapy using a dose-optimization approach on sexual structures for localized prostate cancer.

PURPOSE: Erectile function preservation is an important quality of life factor in patients treated for prostate cancer. A dose-optimization approach on sexual structures was developed and evaluated to limit erectile dysfunction after radiotherapy. MATERIALS AND METHODS: Twenty-three men with localized prostate cancer and no erectile dysfunction were enrolled in the study. All patients received a prescription dose between 76 and 78Gy. Computed tomography/magnetic resonance image registration was used to delineate the prostatic volume and the sexual structures: internal pudendal arteries (IPA), penile bulb and corpus cavernosum. Erectile function was evaluated using the 5-items International Index of Erectile Function (IIEF-5) score every 6 months during the 2 years after radiotherapy and once a year afterwards. No erectile dysfunction, mild erectile dysfunction and severe erectile dysfunction were defined if the IIEF-5 scores were 20-25, 17-19 and < 17, respectively. RESULTS: The mean follow-up was 4.5 years. The mean age of the patients was 66.3 years. At 2 years, 67% of the patients had no erectile dysfunction, 11% had mild erectile dysfunction and 22% had severe erectile dysfunction. No significant difference was found between the patients with and without erectile dysfunction (IIEF-5≥20 and IIEF-5<20, respectively) for any of the parameters: dosimetric values (internal pudendal arteries, penile bulb, corpus cavernosum), age, comorbidity and smoking status. The biochemical-relapse free survival was 100% at 2 years. CONCLUSION: This approach with dose-optimization on sexual structures for localized prostate cancer found excellent results on erectile function preservation after radiotherapy, with 78% of the patients with no or mild erectile dysfunction at 2 years.

The role of radiation therapy for de novo metastatic bladder and renal cancers.

Metastatic bladder and renal cancers account respectively for 2.1% and 1.8% of cancer deaths worldwide. The advent of immune checkpoint inhibitors has revolutionized the management of metastatic disease, by demonstrating considerable improvements in overall survival. However, despite initial sensitivity to immune checkpoint inhibitors for most patients, both bladder and renal cancer are associated with short progression-free survival and overall survival, raising the need for further strategies to improve their efficacy. Combining systemic therapies with local approaches is a longstanding concept in urological oncology, in clinical settings including both oligometastatic and polymetastatic disease. Radiation therapy has been increasingly studied with either cytoreductive, consolidative, ablative or immune boosting purposes, but the long-term impact of this strategy remains unclear. This review intends to address the impact of radiation therapy with either curative or palliative intent, for synchronous de novo metastatic bladder and renal cancers.

Indication and perspectives of radiation therapy in the setting of de-novo metastatic prostate cancer.

Prostate cancer is the most common cancer and the third leading cause of cancer mortality in men. Each year, approximately 10% of prostate cancers are diagnosed metastatic at initial presentation. The standard treatment option for de-novo metastatic prostate cancer is androgen deprivation therapy with novel hormonal agent or with chemotherapy. Recently, PEACE-1 trial highlighted the benefit of triplet therapy resulting in the combination of androgen deprivation therapy combined with docetaxel and abiraterone. Radiotherapy can be proposed in a curative intent or to treat local symptomatic disease. Nowadays, radiotherapy of the primary disease is only recommended for de novo low-burden/low-volume metastatic prostate cancer, as defined in the CHAARTED criteria. However, studies on stereotactic radiotherapy on oligometastases have shown that this therapeutic approach is feasible and well tolerated. Prospective research currently focuses on the benefit of intensification by combining treatment of the metastatic sites and the primary all together. The contribution of metabolic imaging to better define the target volumes and specify the oligometastatic character allows a better selection of patients. This article aims to define indications of radiotherapy and perspectives of this therapeutic option for de-novo metastatic prostate cancer.

[Relationship between doses to anatomical structures and erectile dysfunction after radiotherapy for prostate cancer: A systematic review]. / Relations entre doses dans les structures anatomiques et dysfonction érectile après radiothérapie pour un cancer de la prostate : revue systématique de la littérature.

PURPOSE: During prostatic radiotherapy, damage to several anatomical structures could be the cause of erectile dysfunction: corpora cavernosa, internal pudendal arteries, penile bulb, and neurovascular bundles. Numerous studies have analysed the correlations between the dose received by these structures and erectile function. The objective of this article is to make a systematic review on current knowledge. MATERIALS AND METHODS: A systematic review was performed in the Medline database using the search engine PubMed. Keywords for the search included: erectile dysfunction, penile bulb, corpora cavernosa, cavernosum, neurovascular bundles, radiation therapy, cancer, prostate cancer. The selected articles must study a correlation between erectile dysfunction and the dose received by anatomical structures. A total of 152 articles were identified. Of these 152 articles, 45 fulfilled the defined selection criteria. RESULTS: For corpora cavernosa, seven studies were identified, only two studies demonstrated a significant correlation between the dose received by corpora cavernosa and the occurrence of erectile dysfunction. For penile bulb, only 15 of 23 studies showed a correlation. A mean dose on the penile bulb greater than 20Gy was found to be predictive of erectile dysfunction. None of the eight trials concerning neurovascular bundles succeeded to show a correlation between dose and erectile dysfunction. Only one study evaluated the relationship between the dose received by internal pudendal arteries and erectile dysfunction but was found to be negative. However, vessels-sparing studies showed good results on erectile function preservation without compromising the target volume. CONCLUSION: We currently have little data to show a correlation between erectile dysfunction and sexual structures. It would be necessary to have additional prospective studies evaluating the impact of an optimization on these sexual structures on erectile dysfunction.

[Stereotactic body radiation therapy for primary kidney cancer]. / Radiothérapie stéréotaxique des carcinomes rénaux primitifs.

The incidence of primary renal cancer is increasing, particularly in elderly patients who may have comorbidities and/or a surgical contraindications. Stereotactic body radiotherapy has primarily been evaluated retrospectively to date. The most commonly used dose schedules are 40Gy in five fractions, 42Gy in three fractions, and 26Gy in one fraction. The results in terms of local control and toxicity are very encouraging. The advantages of stereotactic body radiotherapy compared to thermal ablative treatments are its non-invasive nature, absence of general anesthesia, ability to treat larger lesions, and those close to the renal hilum. Prospective evaluations are still necessary.

External radiotherapy for prostatic cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on external radiotherapy of prostate cancer. External radiotherapy is intended for all localized prostate cancers, and more recently for oligometastatic prostate cancers. The irradiation techniques are detailed. Intensity-modulated radiotherapy combined with prostate image-guided radiotherapy is the recommended technique. A total dose of 74 to 80Gy is recommended in case of standard fractionation (2Gy per fraction). Moderate hypofractionation (total dose of 60Gy at a rate of 3Gy per fraction over 4 weeks) in the prostate has become a standard of therapy. Simultaneous integrated boost techniques can be used to treat lymph node areas. Extreme hypofractionation (35 to 40Gy in five fractions) using stereotactic body radiotherapy can be considered a therapeutic option to treat exclusively the prostate. The postoperative irradiation technique, indicated mainly in case of biological recurrence and lymph node involvement, is detailed.

Recommendations for stereotactic body radiation therapy for spine and non-spine bone metastases. A GETUG (French society of urological radiation oncolgists) consensus using a national two-round modified Delphi survey.

Background and purpose: The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) remains to be demonstrated through phase III trials. Multiple SBRT procedures have been published potentially resulting in a disparity of practices. Therefore, the french society of urological radiation oncolgists (GETUG) recognized the need for joint expert consensus guidelines for metastasis-directed SBRT in order to standardize practice in trials carried out by the group. Materials and methods: After a comprehensive literature review, 97 recommendation statements were created regarding planning and delivery of spine bone (SBM) and non-spine bone metastases (NSBM) SBRT. These statements were then submitted to a national online two-round modified Delphi survey among main GETUG investigators. Consensus was achieved if a statement received ≥ 75 % agreements, a trend to consensus being defined as 65-74 % agreements. Any statement without consensus at round one was re-submitted in round two. Results: Twenty-one out of 29 (72.4%) surveyed experts responded to both rounds. Seventy-five statements achieved consensus at round one leaving 22 statements needing a revote of which 16 achieved consensus and 5 a trend to consensus. The final rate of consensus was 91/97 (93.8%). Statements with no consensus concerned patient selection (3/19), dose and fractionation (1/11), prescription and dose objectives (1/9) and organs at risk delineation (1/15). The voting resulted in the writing of step-by-step consensus guidelines. Conclusion: Consensus guidelines for SBM and NSBM SBRT were agreed upon using a validated modified Delphi approach. These guidelines will be used as per-protocole recommendations in ongoing and further GETUG clinical trials.

Candidates to salvage therapy after external-beam radiotherapy of prostate cancer: Predictors of local recurrence volume and metastasis-free survival.

PURPOSE: The purpose of this study was to assess the predictors of metastasis-free survival (MFS) and of the volume of the local recurrence in patients with rising prostate-specific antigen (PSA) serum level after radiotherapy for prostate cancer and referred for prostate magnetic resonance imaging (MRI) and biopsy in view of salvage treatment. MATERIALS AND METHODS: A total of 132 consecutive men (median age, 70 years; IQR, 66-77 years) with rising PSA after prostate radiotherapy who underwent prostate MRI and biopsy in view of salvage treatment between January 2010 and July 2017 were retrospectively evaluated at a single center. MFS predictors were assessed with Cox models. Predictors of the volume of the local recurrence (number of invaded prostate sectors at biopsy) were assessed using Poisson regression among variables available at PSA relapse. RESULTS: At multivariate analysis, an initial Gleason score≥8 (OR=7 [95% confidence interval (CI): 1.2-40]; P=0.03), a recent radiotherapy (OR=17 [95% CI: 3.9-72]; P<0.0001), the use of androgen deprivation therapy at PSA relapse (OR=12.5 [95% CI: 2.8-57]; P=0.001) and the number of invaded prostate sectors (OR=1.5 [95% CI: 1.1-2]; P=0.007) and maximum cancer core length (OR=0.7 [95%CI: 0.6-0.9]; P=0.002) at biopsy performed at PSA relapse were significant MFS predictors. The PSA level at relapse was significant independent predictor of the volume of local recurrence only when used as a continuous variable (P=0.0002) but not when dichotomized using the nadir+2 threshold (P=0.41). CONCLUSION: Pathological and clinical factors can help predict MFS in patients with rising PSA after prostate radiotherapy and candidates to salvage treatment. The PSA level at relapse has strong influence on the local recurrence volume when used as a continuous variable.

Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial.

BACKGROUND: In resectable rectal cancer trials, pathological parameters are early preoperative treatment efficacy measures. Their validation as surrogate end points for long-term clinical outcomes would allow to reduce trial duration. The aim was to evaluate potential surrogates for overall survival (OS) and local control (LC) in preoperative T3/T4 rectal cancer trials. Candidate variables included ypT and ypN stages, T downstaging, tumor regression grade (TRG), and circumferential resection margin (CRM) status. PATIENTS AND METHODS: In the Fédération Francophone de Cancérologie Digestive (FFCD) 9203 trial, 742 eligible patients were randomly assigned to receive preoperative radiotherapy with or without concurrent chemotherapy. Surrogacy was evaluated using Prentice criteria and the proportion of treatment effect (PTE) explained by each potential surrogate. RESULTS: None of the candidate surrogates fulfilled all Prentice criteria. Data analyses did not provide interpretable PTE measures for OS. Regarding LC, the highest PTE was reached by TRG, which explained 12% of the effect on local recurrence. This proportion may not exceed 41% [95% confidence interval (CI) -1% to 41%]. PTE explained by the CRM status was associated with a wide uncertainty (95% CI -81% to 105%), which does not exclude a potentially high degree of surrogacy. CONCLUSION: In the FFCD 9203 trial, pathological parameters were not surrogate for OS or LC.

[Indications and outlooks of radiohormonal therapy of high-risk prostate cancers]. / Indications et perspectives de l'hormonoradiothérapie des cancers de prostate à haut risque.

Prostate cancer is a sensitive adenocarcinoma, in more than 80% of cases, to chemical castration, due to its hormone dependence. Locally advanced and/or high-risk cancer is defined based on clinical stage, initial prostate specific antigen serum concentration value or high Gleason score. Hormone therapy associated with radiation therapy is the standard of management and improves local control, reduces the risk of distant metastasis and improves specific and overall survival. Duration of hormone therapy, dose level of radiation therapy alone or associated with brachytherapy are controversial data in the literature. The therapeutic choice, multidisciplinary, depends on the age and comorbidity of the patient, the prognostic criteria of the pathology and the urinary function of the patient. Current research focuses on optimizing local and distant control of these aggressive forms and incorporates neoadjuvant or adjuvant chemotherapy and also new hormone therapies.

Patterns of practice of androgen deprivation therapy combined to radiotherapy in favorable and unfavorable intermediate risk prostate cancer. Results of The PROACT Survey from the French GETUG Radiation Oncology group.

PURPOSE: The intermediate-risk (IR) prostate cancer (PCa) group is heterogeneous in terms of prognosis. For unfavorable or favorable IR PCa treated by radiotherapy, the optimal strategy remains to be defined. In routine practice, the physician's decision to propose hormonal therapy (HT) is controversial. The PROACT survey aimed to evaluate pattern and preferences of daily practice in France in this IR population. MATERIALS AND METHODS: A web questionnaire was distributed to French radiotherapy members of 91 centers of the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG). The questionnaire included four sections concerning: (i) the specialists who prescribe treatments and multidisciplinary decisions (MTD) validation; (ii) the definition of IR subsets of patients; (iii) radiotherapy parameters; (iv) the pattern of practice regarding cardiovascular (CV) and (iv) metabolic evaluation. A descriptive presentation of the results was used. RESULTS: Among the 82 responses (90% of the centers), HT schedules and irradiation techniques were validated by specific board meetings in 54% and 45% of the centers, respectively. Three-fourths (76%) of the centers identified a subset of IR patients for a dedicated strategy. The majority of centers consider PSA>15 (77%) and/or Gleason 7 (4+3) (87%) for an unfavorable IR definition. Overall, 41% of the centers performed systematically a CV evaluation before HT prescription while 61% consider only CV history/status in defining the type of HT. LHRH agonists are more frequently prescribed in both favorable (70%) and unfavorable (98%) IR patients. Finally, weight (80%), metabolic profile (70%) and CV status (77%) of patients are considered for follow-up under HT. CONCLUSION: To the best of our knowledge, this is the first survey on HT practice in IR PCa. The PROACT survey indicates that three-quarters of the respondents identify subsets of IR-patients in tailoring therapy. The CV status of the patient is considered in guiding the HT decision, its duration and type of drug.

[Dosimetric impact of breath-hold in the treatment of hepatocellular carcinoma by conformal radiation therapy]. / Impact dosimétrique du blocage respiratoire dans le traitement du carcinome hépatocellulaire par irradiation de conformation.

OBJECTIVE: To evaluate the dosimetric impact of breath-hold during radiotherapy of hepatocellular carcinoma (HCC) and to determinate the optimal respiratory phase for treatment (exhale or inhale). PATIENTS AND METHODS: Two CT scans were performed in inhale and in exhale in 20 patients with HCC. The GTV was delineated slice by slice on the inspiration breath hold acquisition (GTV(insp)) and on the expiration breath hold acquisition (GTV(exp)). The superposition of two GTV allowed to obtain the global GTV (free respiration). PTV was defined by adding a margin of 1cm around each GTV. The liver, the duodenum, the two kidneys, the stomach and the spinal cord were delineated on each acquisition as organs at risk (OAR). Three dosimetric plans were created on inspiration, expiration and on global PTV. RESULTS: The mean reduction in the volume of PTV with conformal radiation therapy (3D-CRT) in the hold-breath group compared to the free respiration group was of 33.5+/-11.9%. The average difference of V50%, V20, V30, V40 and V50 were around 4% in favor of the breath hold. The average value of NTCP was 8.9% in free respiration, 4.5% in expiration and 3.2% in inspiration. Further improvement in the OARs dosimetric parameters for the breath hold was observed. CONCLUSION: Compared to the conformal radiotherapy with free respiration, the breath-hold allows reducing the volume of the PTV and the doses to the healthy liver and organs at risk. The use of this modality during different radiotherapy techniques (3D-CRT, IMRT and stereotactic) may be recommended. No difference in dosimetric value has been observed between the breath hold in expiratory and inspiratory phases.

[Treatment of primary disease (breast, non-small cell lung and prostate cancers) with irradiation in case of de novo metastatic cancer]. / Traitement de la maladie primitive (cancers du sein, du poumon non à petites cellules et de la prostate), par irradiation, au stade d'emblée métastatique.

The basis of treatment of primary disease in case of metastatic cancer at diagnosis is based on the knowledge of the natural history of the disease, the biology of the primary tumour and its metastases, advances in modern radiotherapy techniques (modulated intensity, stereotactic radiotherapy) in order to improve the survival of patients with advanced disease. The clinical concept of oligometastatic disease at diagnosis has repositioned the interest of local treatment for primitive disease because these patients have a slower evolutionary profile than metastatic disease extended from the outset. This article reviews the indication of radiotherapy as a local treatment for primary cancer in a de novo metastatic diagnosed disease in the case of breast cancer, non-small cell lung cancer and prostate cancer.

[Stereotactic ablative body radiotherapy: Which machine for which therapeutic indication? A focus on prostate cancer]. / Radiothérapie stéréotaxique extracrânienne : quelle machine pour quelle indication ? Stéréotaxie prostatique.

For the last decade, stereotactic body radiotherapy has become a leading treatment for localized prostate cancer. It can be delivered using a wide array of radiotherapy machines. However, although numerous clinical studies, both prospective and retrospective, have been published, the different techniques have never been properly compared. This article aims at giving an overview of the published trials, and at pointing out the major differences between the machines, from a clinical (efficacy end toxicity), technical and radiobiological point of view.

[Irradiation of hepatocellular carcinoma: impact of breathing on motions and variations of volume of the tumor, liver and upper abdominal organs]. / L'irradiation des carcinomes hépatocellulaires: impact de la respiration sur les mouvements et variations de volume de la tumeur, du foie et des organes intra-abdominaux.

PURPOSE: To evaluate the amplitude of motion and the variations of volume of the tumor, the liver and upper abdominal organs induced by breathing during the irradiation of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Two scanners were performed in inhale and in exhale not forced in 20 patients with a HCC. The liver (left/right lobes), the tumor, the duodenum, the two kidneys and the pancreas were delineated on each acquisition. The superposition of the two spirals made it possible to measure the displacements and variations of volume of these structures in the craniocaudal (CC), lateral (Lat), and anteroposterior (AP) directions. RESULTS: The mean displacement of the tumour in CC, Lat and AP was of 19.7+/-8.3 mm, 4.5+/-2.3 mm, and 8.9+/-6.5 mm. The greatest amplitude of movement was obtained in CC for the right and left hepatic lobes (19+/-6.5 mm, 10+/-5.6 mm), the duodenum(12.6+/-6.4 mm), the kidneys right and left (15.5+/-6.1 mm, 16.2+/-10 mm) and the pancreas (13.2+/-6 mm). No significant variation of volume was observed for these organs. CONCLUSION: The movements of the tumour, the liver and the abdominal organs, induced by breathing are significant. The respiratory gating appears essential in particular with the development of new techniques of irradiation such as the intensity-modulated radiotherapy (IMRT) or the stereotactic body radiation therapy (SBRT).

[Radiation-induced sequelae: toward an individual profile]. / Séquelles radio-induites et tests prédictifs.

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivery is limited by the tolerated dose of the surrounding healthy tissues. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced sequelae due to their irreversibility and the potential impact on daily quality of life. In a population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, lymphocytes seem to be the tissue of choice due to easy accessibility. Recently, low percentage of CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of sequelae. In addition, recent data suggest that patients with severe radiation-induced late side effects possess four or more SNP in candidate genes (ATM, SOD2, TGFB1, XRCC1 et XRCC3) and low radiation-induced CD8 lymphocyte apoptosis in vitro.

French experience with contact X-ray endocavitary radiation for early rectal cancer.

This paper is an overview of the French experience with contact X-ray radiation for rectal cancer. The analysis was mainly carried out on 50 years of experience in Lyon or since 1980 in the Centre Hospitalier Universitaire Lyon Sud. The results obtained in Dijon and Nancy are also reported. In early rectal cancer, contact X-ray radiation can play an important role in three different situations: (1) small T1 less than 2 cm: adjuvant contact X-ray radiotherapy after local excision; (2) T2 N0 or large T1: first-line contact X-ray radiotherapy combined with external beam radiotherapy (+/- chemotherapy) followed by surgery (anterior resection or local excision); (3) early T3 N0 in frail patients: the same approach as for T2 N0 with, in case of clinical complete response, local excision or follow-up.

[Acute and late toxicities in thoracic irradiation]. / Complications aiguës et tardives des irradiations thoraciques.

Radiotherapy of lung cancer is often complexe because of several organs at risk such as lung, heart, esophagus or spinal cord. An accurate balance needs to be defined between the necessities to reach a local control and to limit the risks of toxicities for each of them. Several parameters were significantly correlated with radiation induced lung toxicities (V13, V20, 30, Mean Dose) and esophagitis (V40 to V60). However no parameters are clearly defined for heart toxicities. The large number of parameters described for lung and esophagus highlights the necessity to perform an overall analysis of the DVHs that could be possible by using Nomal Tissue Complication Probability models.

[Combination external beam radiation and brachytherapy boost for prostate cancer]. / Association de radiothérapie externe et de curiethérapie pour les cancers de la prostate.

Brachytherapy as sole treatment is standard of care for D'Amico classification low-risk prostate cancer. For intermediate and high-risk patients, brachytherapy can be associated to external beam radiation therapy to better take into account the risk of extracapsular effraction and/or seminal vesicle involvement. Three randomized studies have shown that this association increases freedom from relapse survival compared to exclusive external beam radiation therapy. This benefit is not shown for overall survival. The addition of a hormonal therapy to this association is most likely mandatory for high-risk patients, and needs to be confirmed for intermediate risk patients. Both high-dose rate and low-dose rate brachytherapy are suitable with similar biochemical disease free survival rates. High-dose rate brachytherapy seems to have a better genitourinary tolerance profile, while low-dose rate brachytherapy is an easier process and has a more widespread expertise.

[Adjuvant radiotherapy for bladder cancer in patients with risk of locoregional recurrence: Who, what and how?] / 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.