[Molecular-integrated risk profile: An opportunity for therapeutic de-escalation in intermediate and high-intermediate risk endometrial cancer]. / Cancer de l'endomètre de stade localisé : la perspective d'une désescalade thérapeutique guidée par la classification moléculaire.

In Europe, endometrial cancer is the fourth most common cancer among women. The majority of patients are diagnosed at a localized stage. For these patients, the standard of care is based on an hysterectomy with salpingo oophorectomy±lymph node staging. Through the assessment of histopathologic features, risk groups are determined: low, intermediate, high-intermediate, and high risk. Adjuvant strategies are guided by these risk groups. While the prognosis of low-risk and high-risk is well known, that of intermediate and high-intermediate risk is more heterogeneous, and the therapeutic index of adjuvant treatments is more questionable. Several trials (PORTEC [Post Operative Radiation Therapy in Endometrial Carcinoma] I, GOG [Gynecologic Oncology Group] 99, ASTEC [A Study in the Treatment of Endometrial Cancer] EN.5, PORTEC II, Sorbe et al trial) have assessed observation, vaginal cuff brachytherapy and/or pelvic external beam radiotherapy in this population. Vaginal cuff brachytherapy reduces the local recurrence rate, and pelvic external beam radiotherapy the pelvic recurrence rate. However, no benefit in terms of overall survival or occurrence of distant metastases is highlighted. Compared to observation, brachytherapy and above all external beam radiotherapy are associated with an increased morbidity, and with a decreased quality of life. In order to improve the therapeutic ratio and to optimize medico-economic decisions, therapeutic de-escalation strategies, based on the molecular profiles, are emerging in clinical trials, and in the recommendations for the management of intermediate and high-intermediate risk endometrial cancers. The four main molecular profiles highlighted by the genomic analyzes of The Cancer Genome Atlas (TCGA) - POLE (polymerase epsilon) mutation, non-specific molecular profile, MMR (MisMatch repair) deficiency, and p53 mutation - but also the quantification of lymphovascular space invasion (absent, focal or substantial), and the assessment of L1CAM (L1 cell adhesion molecule) overexpression represent growing concerns. Thus, the use of molecular-integrated risk profile to determine the best adjuvant treatment represent a major way to personalize adjuvant treatment of endometrial cancers, with therapeutic de-escalation opportunity for around half of the high-intermediate risks. However, in the absence of prospective data, inclusion in clinical trials assessing molecular profile-based treatment remains the best therapeutic opportunity.

Role of radiotherapy in the treatment of primary vaginal cancer: Recommendations of the French society for radiation oncology.

Primary vaginal cancers are rare tumours, for which external beam radiotherapy and brachytherapy are major treatment tools. Given the complexity of brachytherapy techniques, the treatment should be performed in specialised centres. We present the recommendations of the French society for radiation oncology on the indications and techniques for external beam radiotherapy and brachytherapy for primary vaginal cancer.

Radiotherapy of cervical cancer.

External beam radiotherapy and brachytherapy are major treatments in the management of cervical cancer. For early-stage tumours with local risk factors, brachytherapy is a preoperative option. Postoperative radiotherapy is indicated according to histopathological criteria. For advanced local tumours, chemoradiation is the standard treatment, followed by brachytherapy boost, which is not optional. We present the update of the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for cervical cancer.

Radiotherapy for endometrial cancer.

The first intent upfront treatment of endometrial cancer is surgery. External radiotherapy and brachytherapy; however, are important tools in adjuvant setting, according to histopathological risk factors for locoregional recurrence or in the event of an inoperable tumor. We present the update of the recommendations of the French society of oncological radiotherapy on the indications and technical methods of performing radiotherapy and brachytherapy for endometrial cancer.

Use of an intravaginal spacer in young girls treated with brachytherapy for bladder neck rhabdomyosarcoma: Dosimetric impact for organs at risk sparing and acute tolerance.

PURPOSE: Interstitial brachytherapy is indicated as part of a conservative strategy for children with bladder and/or prostate rhabdomyosarcoma (RMS), providing high local control probability with acceptable functional results. Vaginal and/or rectal complications were however reported, due to the close proximity to the implanted volume. We investigated the dosimetric impact of a vaginal spacer in terms of rectal and vaginal doses. METHODS AND PATIENTS: Medical records of 12 consecutive female patients with bladder neck RMS, median age 32 months (range: 1.3-6 years), were reviewed. Five patients were treated prior to 2017 without a vaginal spacer and seven patients treated after 2017 had their brachytherapy delivered with a vaginal spacer placed at time of implant. RESULTS: Minimal doses delivered to the most exposed 2cm3, 1cm3, and 0.5cm3 of the rectum were all statistically significantly lower among patients treated with a vaginal spacer, as compared to those treated without a spacer. Median rectal D2cm3 was 22GyEQD2 versus 38GyEQD2 (P=0.02), D1cm3 was 29GyEQD2 versus 51GyEQD2 (P=0.013), and D0.5cm3 was 32GyEQD2 versus 61GyEQD2 (P=0.017), with and without the vaginal spacer, respectively. The posterior vaginal wall D0.5cm3 dose was also significantly decreased, with median D0.5cm3 of 92GyEQD2 versus 54GyEQD2 (P<0.0001), with and without the spacer, respectively. Acute tolerance was excellent in all patients, with no need for replanning and no acute complication. CONCLUSIONS: The use of vaginal spacers in brachytherapy of female pediatric patients with bladder neck RMS resulted in significantly decreased doses to the rectum and the posterior vaginal wall. Though the clinical impact of such dose reduction remains undemonstrated, routine utilization of a vaginal spacer could be a method to decrease long-term morbidity in these patients.

Radiotherapy Quality Assurance in the PORTEC-3 (TROG 08.04) Trial.

AIMS: Quality assurance in radiotherapy (QART) is essential to ensure the scientific integrity of a clinical trial. This paper reports the findings of the retrospective QART assessment for all centres that participated in PORTEC-3; a randomised controlled trial that compared pelvic radiotherapy with concurrent chemoradiotherapy to the pelvis followed by adjuvant chemotherapy. The trial showed an overall survival benefit for the addition of the chemotherapy in the management of women with high-risk endometrial cancer. MATERIALS AND METHODS: Clinicians were invited to upload a randomly selected case/s treated at each of the participating sites. Panel reviewers analysed the contours to certify that the target volumes and organ at risk structures were contoured according to guidelines. The results were categorised into acceptable, minor variation, major variation or unevaluable. The radiotherapy plans were dosimetrically evaluated using the well-established Trans-Tasman Radiation Oncology Group (TROG) protocol. RESULTS: Between August 2010 and January 2018, data from 146 patients of 686 consecutively treated patients were retrospectively reviewed. All 16 Australia and New Zealand and 71 of 77 international centres uploaded data for evaluation. In total, 3514 dosimetric and contour variables were reviewed. Of these, 3136 variables were deemed acceptable (89.2%), with 335 minor (9.6%) and 43 major variations (1.2%). Major contour variations included the clinical target volume vaginal vault, clinical target volume parametria and differential planning target volume vault expansion. CONCLUSION: The results of the QART assessment confirmed high uniformity and low rates of both minor and major deviations in contouring and dosimetry in all sites. This supports the safe introduction of the PORTEC-3 treatment protocol into routine clinical practice.

Role of radiotherapy in the management of vulvar cancer: Recommendations of the French society for radiation oncology.

Primary vulvar carcinomas are rare gynaecological cancers, for which surgery is the mainstay of treatment. There is however a major place for external beam radiotherapy in the situation of inoperable locally advanced tumours and/or as adjuvant therapy, when there are risk factors for locoregional relapse. We present the recommendations of the French society for radiation oncology on the indications and techniques for radiotherapy in the treatment of primary vulvar cancer.

Radiotherapy for penile cancers.

Penile cancers are uncommon and should be treated in expert center. Radiotherapy indications are mainly limited to exclusive brachytherapy for early stage penile glans cancer. Brachytherapy yields to excellent outcome for disease control and organ and function preservation. Only scarce data are available for external beam radiation therapy. It could be considered as palliative setting for irradiation of the primary tumor. For lymph node irradiation, external beam radiation therapy (with or without chemotherapy) could be discussed either as neoadjuvant approach prior to surgery for massive inguinal lymph node invasion or as adjuvant approach in case of high-risk of relapse. However, these cases should be discussed on an individual basis, as the level of evidence is poor. We present the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for penile glans cancer.

Glassy cell carcinoma of the uterine cervix: 20-year experience from a comprehensive cancer center.

PURPOSE: Glassy cell carcinoma (GCC) of the uterine cervix is a rare entity. This study aims at describing the clinical characteristics and outcomes of cervical GCC patients treated in a comprehensive cancer center. MATERIAL AND METHODS: We retrospectively reported patients and tumors characteristics, therapeutic management, overall survival (OS), progression-free progression (PFS), relapse rates, and toxicities. RESULTS: Between 1994 and 2014, 55 patients were treated with curative intent. The median age at diagnosis was 41 years (range, 20-68). Among 22 patients with early stage tumors (IA2-IB1-IIA1), 17 had preoperative brachytherapy, followed by radical hysterectomy. Among 33 patients with locally advanced disease (≥IB2), 32 underwent chemoradiation±brachytherapy boost. After a median follow-up of 5.4 years (range, 0.15-21.7 years), 18/55 (33%) patients experienced tumor relapse. Local recurrence occurred in 2/22 (9%) patients with early disease (treated with upfront surgery) and in 3/32 (9%) patients with locally advanced disease. Most frequent relapses were distant, occurring in a total of 11/55 patients (20%). PFS rates at 5-year were 86.4% (95% CI: 63.4-95.4) for early stage versus 75.9% (95% CI: 55.2-89.2) for locally advanced stages, respectively (P=0.18). CONCLUSION: Large cohort data are warranted to guide the optimal management of GCC. From this retrospective analysis, a multimodal approach yielded to good disease control in early stages tumors. Given the high-risk of distant failure, consideration should be given to adjuvant chemotherapy in locally advanced disease.

Evaluation of adjuvant vaginal vault brachytherapy in early stage cervical cancer patients.

PURPOSE: Adjuvant external beam radiotherapy (EBRT) was shown to decrease pelvic relapses in patients with an early stage cervical cancer and intermediate-risk histopathological prognostic factors, at the cost of increased bowel morbidity. We examined the feasibility and results of adjuvant brachytherapy alone as an alternative to EBRT in this situation. PATIENTS AND METHODS: Medical records of consecutive patients receiving adjuvant brachytherapy between 1991 and 2018 for an early stage cervical cancer were examined. Patients were included if they presented a pT1a2N0 or pT1b1N0 disease following radical colpohysterectomy. Adjuvant vaginal wall brachytherapy (without EBRT) was indicated because of a tumor size≥2cm and/or presence of lymphovascular space invasion (LVSI). Patients received 60Gy to 5mm of the vaginal wall, through low-dose or pulse-dose rate technique. Patients' outcome was examined for disease control, toxicities and prognostic factors. RESULTS: A total of 40 patients were included. Eight patients (20%) had LVSI, 26 patients (65%) had a tumor size≥2cm. With median follow-up time of 42.0 months, 90% of patients were in complete remission and four patients (10%) experienced tumor relapse, all in the peritoneal cavity, and associated with synchronous pelvic lymph node failure in 2/4 patients. No vaginal or isolated pelvic nodal failure was reported. At 5 year, overall survival was 83.6% (CI95%: 67.8-100%) and disease-free survival was 85.1% (CI95%: 72.6-99.9%). In univariate analysis, probability of relapse correlated with tumor size≥3cm (P=0.004). No acute or late toxicity grade more than 2 was reported. CONCLUSION: Brachytherapy alone was a well-tolerated adjuvant treatment for selected patients with intermediate risk factors. The risk of relapse in patients with tumor size≥3cm was however high, suggesting that EBRT is more appropriate in this situation.

Clinical and imaging findings in cervical cancer and their impact on FIGO and TNM staging - An analysis from the EMBRACE study.

OBJECTIVE: To investigate differences in local tumour staging between clinical examination and MRI and differences between FIGO 2009, FIGO 2018 and TNM in patients with primary cervical cancer undergoing definitive radio-chemotherapy. METHODS: Patients from the prospective observational multi-centre study "EMBRACE" were considered for analysis. All patients had gynaecological examination and pelvic MRI before treatment. Nodal status was assessed by MRI, CT, PET-CT or lymphadenectomy. For this analysis, patients were restaged according to the FIGO 2009, FIGO 2018 and TNM staging system. The local tumour stage was evaluated for MRI and clinical examination separately. Descriptive statistics were used to compare local tumour stages and different staging systems. RESULTS: Data was available from 1338 patients. For local tumour staging, differences between MRI and clinical examination were found in 364 patients (27.2%). Affected lymph nodes were detected in 52%. The two most frequent stages with FIGO 2009 are IIB (54%) and IIIB (16%), with FIGO 2018 IIIC1 (43%) and IIB (27%) and with TNM T2b N0 M0 (27%) and T2b N1 M0 (23%) in this cohort. CONCLUSIONS: MRI and clinical examination resulted in a different local tumour staging in approximately one quarter of patients. Comprehensive knowledge of the differential value of clinical examination and MRI is necessary to define one final local stage, especially when a decision about treatment options is to be taken. The use of FIGO 2009, FIGO 2018 and TNM staging system leads to differences in stage distributions complicating comparability of treatment results. TNM provides the most differentiated stage allocation.

Implementation of image-guided brachytherapy as part of non-surgical treatment in inoperable endometrial cancer patients.

OBJECTIVE: This study assessed outcomes of inoperable endometrial cancer (IEC) patients treated with definitive external beam radiation therapy (EBRT) followed by a 3D image-guided brachytherapy boost. METHODS: All consecutive patients treated with EBRT followed by 3D image-guided brachytherapy for IEC were retrospectively included. EBRT delivered a dose of 45Gy. Then, patients had an uterovaginal brachytherapy guided by 3D imaging. Clinical target volume (CTVBT) included the whole uterus and the initial disease extent. Gross tumour volume (GTVres) included the residual disease at time of brachytherapy. RESULTS: Twenty-seven patients were identified. Causes of inoperability were comorbidities (37%) or tumour loco regional extent (63%). Including EBRT and brachytherapy, the median D90 (minimal dose delivered to 90% of the volume) was 60.7 GyEQD2 (IQR = 56.4-64.2) for the CTVBT, and was 73.6 GyEQD2 (IQR = 64.1-83.7) for the GTVres. The median overall treatment time was 50 days (IQR = 46-54). The mean follow-up was 36.5 months (SD = 30.2). The cumulative incidence of local, pelvic and distant failures was 19% (n = 5), 7% (n = 2) and 26% (n = 7), respectively. Five-year overall survival was 63% (95% CI = 43-91). Late urinary and gastro intestinal toxicities ≥ grade 2 were reported in four (15%) and two patients (7%) respectively. No vaginal toxicity ≥ grade 2 was reported. CONCLUSIONS: EBRT followed by intracavitary brachytherapy seems to be an effective option for IEC. The implementation of 3D concepts at time of brachytherapy may contribute to high local control probability and low toxicity profile. Large scale retrospective or prospective data are needed to confirm these early data.

Comprehensive analysis of patient outcome after local recurrence of locally advanced cervical cancer treated with concomitant chemoradiation and image-guided adaptive brachytherapy.

INTRODUCTION: Since dose escalation allowed by image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer (LACC), local relapses have become a rare event. Only scarce data are available on the outcome of patients experiencing a local relapse after IGABT. METHODS: Between 2004 and 2016, all consecutive patients treated at Gustave Roussy Institute for LACC and receiving concomitant chemoradiation and IGABT were analysed. Clinical and treatment-related prognostic factors for survival after local relapse were searched, in order to potentially identify patients requiring salvage treatment. RESULTS: Two hundred and fifty-nine patients were treated during this period. With a median follow-up of 4.1 years, 10.8% (n = 28) had a local relapse. Among these patients, 53.6% had synchronous lymph nodes or distant metastatic relapse and only 13 patients (5% of all patients) had isolated local relapse. After local relapse, median survival was 47 months and three patients were alive at last follow-up. Only three patients with local relapse could receive salvage surgery (10.7%). Metastases occurrence and pelvic wall involvement were the main contraindications (67.9%) for salvage surgery. Among the three patients treated with surgery, two are still alive at last follow-up without significant complication. Improved survival was observed among the two patients who could have surgery (p = .02). Local progression led to serious symptoms in 75% of patients. Only the time interval between brachytherapy and relapse (<1 year) was prognostic for 2-year overall survival (p = .005). CONCLUSION: Salvage surgery is feasible in a very low number of highly selected patients with local relapse following IGABT. Local failure is a major cause of severe local symptoms, confirming that every effort should be done to achieve long-term local control through dose escalation.

[Multimodal imaging guided brachytherapy: the example of cervical cancer]. / Curiethérapie guidée par imagerie multimodale : l'exemple du cancer du col utérin.

Image-guided brachytherapy is crucial in the management of locally advanced cervical cancers and has benefited from advances in imaging over recent decades. The recommendations of the European Brachytherapy - European Society for Radiation Oncology (GEC-ESTRO) have resulted in harmonized practices and improved clinical outcomes in terms of efficacy and toxicity. Post-implant magnetic resonance imaging (MRI) has become the reference imaging modality to guide brachytherapy. There is an increasing interest for other multimodal imaging in these patients. The metabolic information provided by Positrons Emission Tomography/computed tomodensitometry (PET/CT) is also very promising approach to guide personalized dose escalation strategies. The prognostic values of MRI and PET scanner before brachytherapy make it possible to consider personalizing the dose delivered in brachytherapy and to propose a dose escalation to patients who really need it and to possibly consider a deescalation strategy in patients with a very good prognosis. However, further studies are needed to confirm this approach.

[Place of radiotherapy and surgery in the treatment of cervical cancer patients]. / Places respectives de la radiothérapie et de la chirurgie dans les cancers du col utérin.

The treatment of cervical cancer patients relies on surgery and radiotherapy (according to the stage) and requires a multimodal discussion before any treatment to avoid adding the morbidities of each individual intervention and to optimize functional and oncological outcomes. The places of surgery and radiotherapy have been highlighted in recent international guidelines. For early stage tumors, an exclusive surgery with or without fertility sparing (according to well defined criteria) is the therapeutic standard. For tumors with risk factors (measuring more than 2cm in size and/or presence of lymphovascular invasion) a preoperative brachytherapy can be proposed to minimize the need for postoperative external beam radiotherapy and optimize local control. For locally advanced disease, the standard treatment relies on chemoradiation followed by a brachytherapy boost. A primary paraaortic lymph node dissection may guide radiotherapy volumes and is useful to identify patients requiring a para-aortic radiotherapy. The technical evolutions of surgical approaches and technological improvement of radiotherapy and brachytherapy should be analyzed in the context of prospective studies. We review the literature on the respective places of radiotherapy and surgery for the treatment of cervical cancer.

Correlation between pelvic bone marrow radiation dose and acute hematological toxicity in cervical cancer patients treated with concurrent chemoradiation.

PURPOSE: To evaluate the association between pelvic bone marrow (BM) dose volume parameters and probability of acute hematological toxicity (HT), a cohort of cervical cancer patients receiving definitive chemoradiation (CRT) was assessed. MATERIALS AND METHODS: Medical records of patients treated by CRT (45 Gy in 25 fractions, without dose constraints applied to the BM) were reviewed. Baseline and weekly hematological parameters were collected. BM was retrospectively delineated and divided into sub-sites: iliac crests, lower pelvis, lumbosacral region. BM volumes (V) receiving 5, 10, 20, 30, 40 Gy (V5, V10, V20, V30, V40, respectively) and mean dose (Dm) were calculated. Logistic regression was used to analyze associations between HT and dose-volume histograms parameters. RESULTS: 114 patients were included. 75.4% were treated with 3D radiation therapy and 24.6% were receiving intensity modulated radiation therapy (IMRT). Neither age, chemotherapy regimen (cisplatin vs carboplatin), number of chemotherapy cycles, performance status, body mass index, or para-aortic irradiation were associated with HT. In univariate analysis, more frequent grade 3+ leukopenia was found in the IMRT group (odds ratio [OR]: 3.5; 95% CI, 1.4-9.1; p=0.007). In multivariate analysis, grade 4 HT was associated with lower pelvis V5>95% (OR 4.1; 95% CI, 1.6-14. p=0.02), lower pelvis V20>45% (OR 3.5; 95% CI, 1.1-13.4; p=0.05), total pelvic bone V20>65%, and iliac crests Dm >31 Gy (OR 4.5; 95% CI, 1.4-14.7; p=0.02). CONCLUSION: The following dose constraints could be proposed to decrease acute HT risk: lower pelvis V5<95%, lower pelvis V20≤45%, total pelvic bone V20<65%, and iliac crests Dm <31 Gy.

[Recent data in cervical cancer: Radiation oncologist's perspective]. / Cancers du col utérin : nouveautés dans la prise en charge en oncologie radiothérapie.

During the recent past years, the therapeutic management of locally advanced cervical cancer patients has consistently improved, with the integration of image guided brachytherapy and dose escalation strategies leading to an improvement of local control rates. In parallel, the evolution of external beam radiotherapy techniques and the better control of organs at risk doses in brachytherapy have contributed to decrease the probability of severe normal tissue complication. In case of advanced disease, patients prognosis remains however marked by a high risk of distant failure, and this finding has encouraged the assessment of various research pathways in order to better predict and/or prevent tumor relapse. Major studies are being conducted or have been published, and the place of chemoradiation and brachytherapy has been confirmed as first intent treatment in case of locally advanced disease. Numerous prospective or retrospective data, few of which are reviewed there, have been integrated as part of a strategy aimed at being more and more personalized. Next steps of therapeutic optimization will include the assessment of multiparameters radiological tools, but will also rely on a better understanding of radiobiological pathways involved in local or systemic response to irradiation, and the most promising of those is probably the anti-tumor immune response.

Radiobiology of brachytherapy: The historical view based on linear quadratic model and perspectives for optimization.

Most preclinical studies examining the radiobiology of brachytherapy have focused on dose rate effects. Scarcer data are available on other major parameters of therapeutic index, such as cell cycle distribution, repopulation or reoxygenation. The linear quadratic model describes the effect of radiotherapy in terms of normal tissue or tumour response. It allows some comparisons between various irradiation schemes. This model should be applied cautiously for brachytherapy, because it relies on cell death analysis only, and therefore partially reflects the biological effects of an irradiation. Moreover, the linear quadratic model validity has not been demonstrated for very high doses per fraction. A more thorough analysis of mechanisms involved in radiation response is required to better understand the true effect of brachytherapy on normal tissue. The modulation of immune response is one promising strategy to be tested with brachytherapy. A translational approach applied to brachytherapy should lead to design trials testing pharmacological agents modulating radiation response, in order to improve not only local control, but also decrease the risk of distant failure. Here we review the radiobiology of brachytherapy, from the historical view based on linear quadratic model to recent perspectives for biological optimization.

[Why is brachytherapy still essential in 2017?] / Pourquoi la curiethérapie reste-t-elle indispensable en 2017 ?

These recent years, brachytherapy has benefited from imaging modalities advances. A more systematic use of tomodensitometric, ultrasonographic and MRI images during brachytherapy procedures has allowed an improvement in target and organs at risk assessment as well as their relationship with the applicators. New concepts integrating tumor regression during treatment have been defined and have been clinically validated. New applicators have been developed and are commercially available. Optimization processes have been developed, integrating hypofractionation modalities leading to tumor control improvement. All these opportunities led to further development of brachytherapy, with indisputable ballistic advantages, especially compared to external irradiation.