Brachytherapy: An overview for clinicians.

Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high-level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high-risk prostate cancer to perform dose escalation and improve progression-free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.

Image-guided adaptive brachytherapy for advanced cervical cancer spreading to the bladder and/or rectum: Clinical outcome and prognostic factors.

INTRODUCTION: Refinements of brachytherapy techniques have led to better local control of locally advanced cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT). Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the experience of our institution in the treatment of these advanced tumors with IGABT. MATERIALS AND METHODS: Medical records of patients treated for a LACC spreading to the bladder and/or rectum between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk target volume (D90 CTVHR) and intermediate-risk target volume (D90 CTVIR), as well as the dose received by the most exposed 2 cm3 of the organs at risk. A Cox regression model was used to study the potential associations between clinical and dosimetric factors with survival endpoints and fistula formation. RESULTS AND STATISTICAL ANALYSIS: A total of 81 patients were identified. All patients received pelvic+/- para-aortic radiotherapy, 45 Gy in 25 fractions +/- boost to gross lymph nodes. Concomitant platinum-based chemotherapy was administered in 93.8% of cases. The median D90 CTVHR dose was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and median CTVHR volume was 47.6 cm3 (SD: 27.9 cm3). Median bladder and rectal D2cm3 dose were 75.04 GyEQD2 (SD: 8.72 GyEQD2) and 64.07 GyEQD2 (SD: 6.68 GyEQD2). After a median follow-up of 27.62 ± 25.10 months, recurrence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25). Use of a combined interstitial/intracavitary technique and D90 CTVHR ≥ 75.1 GyEQD2 were prognostic factors for OS in univariate analysis (HR = 0.24, 95%IC: 0.057-1, p = 0.023; HR = 0.2, 95%IC: 0.059-0.68, p = 0.0025, respectively). In multivariate analysis, a D90 CTVHR ≥ 75.1 GyEQD2 was significant for OS (HR = 0.23; 95%IC: 0.07, 0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence (HR = 4.6, 95%CI: 1.5-14, p = 0.01). CONCLUSION: Advances in brachytherapy modalities improved local control and survival while reducing toxicities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy techniques is a major factor in patients cure probability, together with systemic intensification to better control distant events.

Long-term urological complications after conservative local treatment (surgery and brachytherapy) in children with bladder-prostate rhabdomyosarcoma: A single-team experience.

BACKGROUND: Outcome of children with bladder-prostate rhabdomyosarcoma (RMS) has improved with multimodal therapies, including surgery and/or radiotherapy for local treatment. Our aim was to report long-term urological complications after a conservative approach combining conservative surgery and brachytherapy. PATIENTS AND METHODS: Eighty-six patients, free of disease, were retrospectively reviewed. Symptoms related to urinary tract obstruction, incontinence, infection, and lithiasis were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Only symptomatic patients underwent urodynamic studies. Risk factors for complications were analyzed. RESULTS: There were 76 males and 10 females. The median follow-up was 6.3 years (18 months to 24 years). Complications occurred after a median follow-up of 5 years (0-21). Twenty-two patients (26%) had long-term urological complications. Urinary tract obstruction was found in 15 patients (17%) and urinary incontinence in 14 patients (16%). Recurrent urinary tract infection occurred in four patients and urinary lithiasis in four (5%). The underlying physiopathology included bladder dysfunction in 15 patients (17%), urethral stenosis in six (7%), and ureterovesical junction stenosis in five (6%). On univariate analysis, posterior bladder wall dissection (p = .001), bladder neck trigone dissection (p = .010), and partial prostatectomy (p = .023) were significantly associated with an increased risk of bladder dysfunction; on multivariate analysis, only age ≤2 years (p = .028) at operation and posterior bladder wall dissection (p = .006) were found to be significant. CONCLUSION: The conservative surgical approach combined with brachytherapy for bladder-prostate RMS leads to long-term urological complications in 26% of survivors. Optimizing brachytherapy doses for young children and establishing a clear and long-term follow-up protocol could help to reduce these complications.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

BACKGROUND: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. METHODS: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FINDINGS: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. INTERPRETATION: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. METHODS: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. RESULTS: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. INTERPRETATION: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

A score combining baseline neutrophilia and primary tumor SUVpeak measured from FDG PET is associated with outcome in locally advanced cervical cancer.

PURPOSE: We investigated whether a score combining baseline neutrophilia and a PET biomarker could predict outcome in patients with locally advanced cervical cancer (LACC). METHODS: Patients homogeneously treated with definitive chemoradiation plus image-guided adaptive brachytherapy (IGABT) between 2006 and 2013 were analyzed retrospectively. We divided patients into two groups depending on the PET device used: a training set (TS) and a validation set (VS). Primary tumors were semi-automatically delineated on PET images, and 11 radiomics features were calculated (LIFEx software). A PET radiomic index was selected using the time-dependent area under the curve (td-AUC) for 3-year local control (LC). We defined the neutrophil SUV grade (NSG = 0, 1 or 2) score as the number of risk factors among (i) neutrophilia (neutrophil count >7 G/L) and (ii) high risk defined from the PET radiomic index. The NSG prognostic value was evaluated for LC and overall survival (OS). RESULTS: Data from 108 patients were analyzed. Estimated 3-year LC was 72% in the TS (n = 69) and 65% in the VS (n = 39). In the TS, SUVpeak was selected as the most LC-predictive biomarker (td-AUC = 0.75), and was independent from neutrophilia (p = 0.119). Neutrophilia (HR = 2.6), high-risk SUVpeak (SUVpeak > 10, HR = 4.4) and NSG = 2 (HR = 9.2) were associated with low probability of LC in TS. In multivariate analysis, NSG = 2 was independently associated with low probability of LC (HR = 7.5, p < 0.001) and OS (HR = 5.8, p = 0.001) in the TS. Results obtained in the VS (HR = 5.2 for OS and 3.5 for LC, p < 0.02) were promising. CONCLUSION: This innovative scoring approach combining baseline neutrophilia and a PET biomarker provides an independent prognostic factor to consider for further clinical investigations.

Dose-volume effects in pathologic lymph nodes in locally advanced cervical cancer.

OBJECTIVE: In cervical cancer patients, dose-volume relationships have been demonstrated for tumor and organs-at-risk, but not for pathologic nodes. The nodal control probability (NCP) according to dose/volume parameters was investigated. MATERIAL AND METHODS: Patients with node-positive cervical cancer treated curatively with external beam radiotherapy (EBRT) and image-guided brachytherapy (IGABT) were identified. Nodal doses during EBRT, IGABT and boost were converted to 2-Gy equivalent (α/ß = 10 Gy) and summed. Pathologic nodes were followed individually from diagnosis to relapse. Statistical analyses comprised log-rank tests (univariate analyses), Cox proportional model (factors with p ≤ 0.1 in univariate) and Probit analyses. RESULTS: A total of 108 patients with 254 unresected pathological nodes were identified. The mean nodal volume at diagnosis was 3.4 ±â€¯5.8 cm3. The mean total nodal EQD2 doses were 55.3 ±â€¯5.6 Gy. Concurrent chemotherapy was given in 96%. With a median follow-up of 33.5 months, 20 patients (18.5%) experienced relapse in nodes considered pathologic at diagnosis. Overall nodal recurrence rate was 9.1% (23/254). On univariate analyses, nodal volume (threshold: 3 cm3, p < .0001) and lymph node dose (≥57.5 Gyα/ß10, p = .039) were significant for nodal control. The use of simultaneous boost was borderline for significance (p = .07). On multivariate analysis, volume (HR = 8.2, 4.0-16.6, p < .0001) and dose (HR = 2, 1.05-3.9, p = .034) remained independent factors. Probit analysis combining dose and volume showed significant relationships with NCP, with increasing gap between the curves with higher nodal volumes. CONCLUSION: A nodal dose-volume effect on NCP is demonstrated for the first time, with increasing NCP benefit of additional doses to higher-volume nodes.

Localized vaginal/uterine rhabdomyosarcoma-results of a pooled analysis from four international cooperative groups.

BACKGROUND: Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed. PROCEDURE: From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty-eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG). RESULTS: Ten-year event-free (EFS) and overall survival (OS) were 74% (95% CI, 67-79%) and 92% (95% CI, 88-96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery. CONCLUSIONS: About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.

Multimodal Management of Locally Advanced Neuroendocrine Cervical Carcinoma: A Single Institution Experience.

OBJECTIVE: The aim of this study was to report our institutional experience of a multimodal approach for treatment of locally advanced high-grade neuroendocrine cervical cancer. METHODS AND MATERIALS: Patients with primary locally advanced neuroendocrine cervical cancer diagnosed between 2001 and 2014 were included. The scheduled treatment sequence was as follows: pelvic +/- para-aortic radiotherapy (according to tumor stage), associated with chemotherapy based on platine-derivate and etoposide regimen, followed with a brachytherapy boost, then completion surgery if there was no progression +/- consolidation etoposide chemotherapy (for a total of 5-6 cycles). Disease-free survival (DFS) and overall survival (OS) were reported and prognostic factors were searched. RESULTS: A total of 24 patients fulfilled inclusion criteria. Median age was 48 (range 22-77 years). Fourteen patients (58%) had pelvic lymph node metastases. After chemoradiation/brachytherapy, a radical hysterectomy could be performed in 18 of 24 patients (75%). Histologically complete resection was achieved in 14 (78%) of 18 patients. Complete pathological response was reported in 7 (39%) of 18. With median follow-up of 29.7 months, 10 (42%) of 24 patients experienced tumor relapse, all associated with distant failure, including one local failure. The DFS and OS rates estimated at 3 years were 55% and 63%, respectively. Lymph node metastases and tumor stage were prognostic for DFS (P = 0.016 and P = 0.022, respectively). Complete resection was associated with a lower incidence of relapses, as compared with microscopically incomplete resection (P = 0.04). A total of 12 (86%) of 14 patients with histologically complete resection were in complete remission at last follow-up. Apart from manageable acute hematological toxicities, most treatment complications were mild to moderate. CONCLUSIONS: This series based on a multimodal management compares favorably with previously published data. Most patients could be eligible to surgery, and complete remission was achieved in 85% of those amenable to complete resection.

The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients With Cervical Cancer.

BACKGROUND: Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. OBJECTIVE: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. METHODS: The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. RESULTS: The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.

Optimizing Local Control in High-Grade Uterine Sarcoma: Adjuvant Vaginal Vault Brachytherapy as Part of a Multimodal Treatment.

PURPOSE: The phase III European Organization for Research and Treatment of Cancer 55874 study has shown that external beam radiotherapy (EBRT) given as adjuvant treatment decreased locoregional recurrences from 40% to 20% in patients (pts) with localized uterine sarcomas (US). No data exist, however, on the place of brachytherapy (BT). MATERIAL AND METHODS: We conducted a single-center retrospective analysis of pts receiving adjuvant BT of the vaginal vault based on the vaginal mold technique as part of their multimodal adjuvant treatment for a high-grade US from 1985 to 2015. Treatment characteristics, patterns of relapse, and toxicity were examined. RESULTS: Median follow-up time was 5.5 years. A total of 98 pts with high-grade US were identified: 81 leiomyosarcomas and 17 undifferentiated sarcomas. Postoperative chemotherapy was delivered in 53 pts. Median dose of EBRT was 45 Gy in 25 fractions. High-dose rate, low-dose rate, and pulsed-dose rate techniques were used in 66, 31, and 1 pts, respectively. At last follow-up, six pts (6.1%) experienced a locoregional relapse as first event. The International Federation of Gynecology and Obstetrics stage and the tumor size were associated with a higher probability of local relapse. When focusing on pts with stage I-III disease, 5-year overall survival was 77% (95% confidence interval: 67%-87%) and 5-year survival without locoregional failure was 91% (83%-98%). Toxicities were mild to moderate, with only four acute grade 3 toxicities and two grade 3 late effects. CONCLUSION: Vaginal vault BT as part of a multimodal adjuvant treatment was associated with a high locoregional control rate and with acceptable side effects in localized high-grade US. The Oncologist 2017;22:182-188Implications for Practice: This study suggests that an aggressive adjuvant treatment combining chemotherapy and pelvic external beam radiotherapy followed with a brachytherapy of the vaginal vault is associated with a high locoregional control rate and an acceptable toxicity rate in patients with high grade uterine sarcoma. Adding a brachytherapy boost could also allow deescalating the total dose of pelvic external beam radiotherapy, in order to decrease the side effects of adjuvant treatment in these patients without increasing the risk of local relapse. However, the prognosis remains determined by a high frequency of systemic relapses.

Outcome of early stage cervical cancer patients treated according to a radiosurgical approach: Clinical results and prognostic factors.

OBJECTIVE: To report clinical results of a multimodal strategy based on preoperative brachytherapy followed with surgery in early stage cervical cancer. MATERIALS/METHODS: The outcome of consecutive patients receiving brachytherapy in our Institution for an early stage IB1-IIA1 invasive cervical cancer with risk factors (lymphovascular embols and/or tumor >2cm) between 2000 and 2013 was analyzed. The treatment consisted of preoperative low dose or pulse dose-rate utero-vaginal brachytherapy followed, 6-8weeks later, by a radical hysterectomy/bilateral salpingo-oophorectomy plus pelvic±para-aortic lymph node dissection. A postoperative chemoradiation was delivered in patients with histological evidence of lymph nodes metastases. RESULTS: 182 patients were identified. Histological examination of hysterectomy specimen showed the presence of a tumor residuum in 55 patients (30.2%). One patient (0.5%) had residual tumor cells in the parametria. With a median follow-up of 5.3years, 14 patients (7.7%) presented tumor relapse, including three (1.6%) local relapses. Five-year disease-free survival (DFS) rate was 93.6% (95%CI: 91.6-95.6%). In log-rank analysis, presence of pelvic nodal metastases at time of lymphadenectomy (p=0.001) and tumor size ≥3cm (p=0.003) correlated with a poorer DFS. Presence of a tumor residuum on hysterectomy specimen correlated with a higher risk of pelvic or para-aortic failure (p=0.035). A time interval>10weeks between brachytherapy and surgery correlated with a higher risk of failure outside the pelvis (p=0.003). Significant postoperative complications were reported in 16 patients (8.8%). All delayed toxicities were mild to moderate. CONCLUSIONS: A preoperative brachytherapy is a safe and effective option in early stage cervical cancer.

Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: About 15% of patients with endometrial cancer have high-risk features and are at increased risk of distant metastases and endometrial cancer-related death. We designed the PORTEC-3 trial to investigate the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone for women with high-risk endometrial cancer. METHODS: PORTEC-3 was a multicentre, open-label, randomised, international trial. Women with high-risk endometrial cancer were randomly allocated (1:1) to radiotherapy alone (48·6 Gy) in 1·8 Gy fractions five times a week or chemoradiotherapy (two cycles concurrent cisplatin 50 mg/m(2) and four adjuvant cycles of carboplatin area under the curve [AUC] 5 and paclitaxel 175 mg/m(2)) using a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The primary endpoints of the PORTEC-3 trial were overall survival and failure-free survival analysed in the intention-to-treat population. This analysis focuses on 2-year toxicity and health-related quality of life as secondary endpoints; analysis was done according to treatment received. Health-related quality of life was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) the cervix cancer module and chemotherapy and neuropathy subscales of the ovarian cancer module at baseline, after radiotherapy and at 6, 12, 24, 36, and 60 months after randomisation. Adverse events were graded with Common Terminology Criteria for Adverse Events version 3.0. The study was closed on Dec 20, 2013, after achieving complete accrual, and follow-up remains ongoing for the primary outcomes analysis. This trial is registered with ISRCTN.com, number ISRCTN14387080, and with ClinicalTrials.gov, number NCT00411138. FINDINGS: Between Sept 15, 2006, and Dec 20, 2013, 686 women were randomly allocated in the PORTEC-3 trial. Of these, 660 met eligibility criteria, and 570 (86%) were evaluable for health-related quality of life. Median follow-up was 42·3 months (IQR 25·8-55·1). At completion of radiotherapy and at 6 months, EORTC QLQ-C30 functioning scales were significantly lower (worse functioning) and health-related quality of life symptom scores higher (worse symptoms) for the chemoradiotherapy group compared with radiotherapy alone, improving with time. At 12 and 24 months, global health or quality of life was similar between groups, whereas physical functioning scores remained slightly lower in patients who received chemoradiotherapy compared with patients who received radiotherapy alone. At 24 months, 48 (25%) of 194 patients in the chemoradiotherapy group reported severe tingling or numbness compared with 11 (6%) of 170 patients in the radiotherapy alone group (p<0·0001). Grade 2 or worse adverse events were found during treatment in 309 (94%) of 327 patients in the chemoradiotherapy group versus 145 (44%) of 326 patients in the radiotherapy alone group, and grade 3 or worse events were found in 198 (61%) of 327 patients in the chemoradiotherapy group versus 42 (13%) of 326 patients in the radiotherapy alone group (p<0·0001), with most of the grade 3 adverse events being haematological (45%). At 12 and 24 months, no significant differences in grade 3 or worse adverse events were found between groups; only grade 2 or higher sensory neuropathy adverse events persisted at 24 months (25 [10%] of 240 patients in the chemoradiotherapy group vs one [<1%] of 247 patients in the radiotherapy alone group; p<0·0001). INTERPRETATION: Despite the increased physician and patient-reported toxicities, this schedule of adjuvant chemotherapy given during and after radiotherapy in patients with high-risk endometrial cancer is feasible, with rapid recovery after treatment, but with persistence of patient-reported sensory neurological symptoms in 25% of patients. We await the analysis of primary endpoints before final conclusions are made. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and Canadian Cancer Society Research Institute.

Image-guided adaptive brachytherapy in locally advanced cervical cancer: recent advances and perspectives.

PURPOSE OF REVIEW: Image-guided adaptive brachytherapy (IGABT) is a high-precision radiation that allows defining accurately treatment targets and optimizing their coverage whereas sparing efficiently the surrounding organs at risk. Ten years ago, in a will of harmonizing the reporting of brachytherapy, the Groupe Européen de Curiethérapie - European Society for Radiation Oncology (GEC-ESTRO) published recommendations on target definitions and dosimetric parameters. During the last years, clinical and dosimetric studies supporting their relevance led the International Commission on Radiation Units and Measurements to propose a report on prescribing and reporting. This review aims to highlight the recent advances in IGABT and its future developments. RECENT FINDINGS: Clinical evidence demonstrating the superiority of IGABT over radiographs-based brachytherapy is accumulating. In parallel, dose-volume effects have been established between dose-volume parameters and tumor response or the occurrence of late radiation morbidity. Preliminary studies indicate that planning aims could be adapted to clinical situations and cofactors. The first publications from the large studies led by the GEC-ESTRO enforce these findings. SUMMARY: A trend emerges toward a personalization of treatment with the adaptation of planning aims to prognostic features and the development of individualized applicators. Image-guidance modalities are developed with a better use of MRI or conversely the use of more accessible modalities such as transrectal ultrasound.

Prognostic significance of an early decline in serum alpha-fetoprotein during chemotherapy for ovarian yolk sac tumors.

BACKGROUND: The ovarian yolk sac tumor (OYST) is a very rare malignancy arising in young women. Our objective was to determine whether an early decline in serum alpha-fetoprotein (AFP) during chemotherapy has a prognostic impact. METHODS: This retrospective study is based on prospectively recorded OYST cases at Gustave Roussy (Cancer Treatment Center). Survival curves were estimated using the Kaplan-Meier method. The serum AFP decline was calculated with the formula previously developed and validated in male patients with poor prognosis non-seminomatous germ cell tumors. Univariate and multivariate analyses were performed using the log-rank test and logistic regression, respectively. RESULTS: Data on AFP were available to calculate an early AFP decline in 57 patients. All patients had undergone surgery followed by chemotherapy. The 5-year overall survival (OS) and event-free survival (EFS) rates were 86% (95% CI: 74%-93%) and 84% (95% CI: 73%-91%), respectively. The disease stage, presence of ascites at presentation, use of the BEP regimen, serum AFP half-life and an early AFP decline were significantly predictive factors for OS and EFS in the univariate analysis. The OS rate was 100% and 49% (95% CI: 26%-72%) in patients with a favorable AFP decline and in those with an unfavorable decline, respectively (p<0.001). In the multivariate analysis, only the presence of ascites at diagnosis (RR=7.3, p=0.03) and an unfavorable early AFP decline (RR=16.9, p<0.01) were significant negative predictive factors for OS. CONCLUSIONS: An early AFP decline during chemotherapy is an independent prognostic factor in patients with OYSTs. CONFLICT OF INTEREST STATEMENT: No conflict of interest.

Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer.

OBJECTIVE: To report the outcomes and late toxicities of patients with locally advanced cervical cancer treated with concomitant chemoradiation (CRT) followed by intracavitary image-guided adaptive brachytherapy (IGABT). METHODS: Data from consecutive patients with histologically proven stage IB-IVA cervical cancer treated with curative intent in a single institution were analyzed. After pelvic +/- para-aortic external-beam radiation therapy, they received pulsed-dose rate IGABT following GEC-ESTRO recommendations. RESULTS: Two hundred and twenty-five patients were enrolled. Sixty-five percent were stage≥IIB according to FIGO classification. Ninety-five percent received CRT. Mean D90 to HR and IR-CTV were 80.4+/-10.3Gy and 67.7+/-6.1Gy. After a median follow-up of 38.8months, 3-year local control and overall survival rates were 86.4% and 76.1%, respectively. A trend for a detrimental effect of tumor stage on local control rates was observed with 3-year local control rates of 100% for stages IB1 and IIA, 90.5 for IB2, 85.8% for IIB, 50% for IIIA, 77.1 for IIIB, and 66.7% for IVA tumors (p=0.06). Local control rates at 3years were 95.6% in the group of patients with D90 of HR-CTV≥85Gy, 88.8% in those with D90 between 80 and 85Gy, and 80% when D90<80Gy (p=0.018). Eighteen severe late gastrointestinal and urinary effects affecting 14 patients were reported corresponding with a crude incidence of 6.6%. CONCLUSIONS: CRT followed by IGABT provides high local control rates with limited toxicity. Reaching high doses is mandatory to achieve local control and interstitial brachytherapy is necessary in advanced diseases.

Multimodal treatment with doxorubicin, cisplatin, and ifosfamide for the treatment of advanced or metastatic uterine leiomyosarcoma: a unicentric experience.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy characterized by a poor prognosis due to a high rate of local and metastatic recurrences. Chemotherapy with doxorubicin or ifosfamide or both is associated with a 10% to 30% objective response rate. We report a monocentric experience with doxorubicin, cisplatin, and ifosfamide (API) combination in the setting of multimodal treatment of advanced or metastatic ULMS. PATIENTS AND METHODS: This monocentric retrospective study included patients with metastatic or locally advanced ULMS with a physiological age younger than 65 years treated in first line with a multimodal aggressive approach with API chemotherapy. Treatment consisted of doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2 per day d1d2 plus mesna, cisplatin 75 mg/m2 d3, plus G-CSF; every 3 weeks up to 6 cycles. Surgery, radiation therapy, or radiofrequency ablation therapy of metastatic sites was associated whenever possible. RESULTS: Thirty-eight patients received API for metastatic or locally advanced ULMS. Median age was 51 years (40-64 years); 4 (11%) patients were treated for a locally advanced disease and 34 (89%) for metastatic disease. Sixteen patients responded (4 complete responses+12 partial responses) among 33 evaluable patients (objective response rate, 48%); 8 and 9 patients had, respectively, stable and progressive disease. Twelve patients had surgeries with 9 surgical complete responses and 3 surgical partial responses. Median progression-free and overall survival in the whole population were 9.8 and 27 months, respectively. Main grade 3-4 toxicities in 38 patients were neutropenia (74%), thrombocytopenia (60%), anemia (55%), fatigue (18%), and vomiting (13%). Febrile neutropenia was observed in 37% of patients. CONCLUSIONS: Despite the toxicity observed, API is an effective treatment which compares favorably with other first-line therapies for patients with metastatic or advanced ULMS.

Brachytherapy in children with rhabdomyosarcomas of the nasolabial fold.

BACKGROUND: Rhabdomyosarcomas (RMS) of the nasolabial fold can be difficult to manage surgically due to functional and cosmetic limitations. Therefore, brachytherapy (BT) has been proposed to improve local control while limiting the volume of irradiation as well as the extent of the surgical excision. MATERIALS AND METHODS: Sixteen pediatric cases with RMS of the nasolabial fold treated from 1971 to 2005 were retrospectively reviewed. RESULTS: Median follow-up was 4.4 years (1.7-33). Half of the patients were male and their age at diagnosis ranged from 4 months to 13.5 years. Histological subtypes included 10 embryonal and 6 alveolar RMS. Initial treatment consisted of induction multi-agent chemotherapy in all cases. In 12 patients, BT was combined with local excision (4 complete resections, 1 with macroscopic residual disease, and 7 with microscopic disease). Low dose-rate brachytherapy was performed in all cases according to the Paris system, using plastic catheters implanted per-operatively. The doses delivered ranged from 50 to 70 Gy, depending on chemotherapy response, and surgical margin status. 10 patients relapsed: 4 local, 6 regional, and 2 metastatic failures were reported. The median time to relapse was 6.5 months. At the time of analysis eight patients were alive and four had died. Four cases, under palliative care at last check-up, were lost to follow-up. CONCLUSION: BT provided an acceptable local control rate, but the poor regional control of these cases may suggest a need for more aggressive management of cervical regional lymph node regions in RMS of the nasolabial fold.

Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95.

BACKGROUND: The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event-free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP). PROCEDURE: The combined dataset of 172 patients with BP RMS treated on the SIOP MMT 84, 89 and 95 studies was reviewed to determine tumour characteristics, details of treatment and outcome. RESULTS: Median age at diagnosis was 2.5 years (range 2 months-17.8 years) and 138 (79%) were males. Median follow-up was 11.4 years (range 3 months-22 years). The 5-year overall survival of the combined cohort was 77% (CI 70-83%). The 5-year event-free survival was 63% and included 7 patients (4%) who did not achieve complete remission (CR), and 57 (33%) who relapsed. Age ≥ 10 years (RR 3.7) and alveolar pathology (RR 3.3) were identified as independent prognostic factors on multivariate analysis. Fifty-nine (50%) of the 119 survivors were cured without significant local therapy, improving from 31% in MMT84 study to 61% in MMT95 study. CONCLUSION: The clinical strategy of the MMT studies aims to minimise the burden of therapy whilst maintaining survival rates. Overall survival is comparable to that of other international groups, despite the lower use of radiotherapy and or radical surgery, although number of events experienced is higher. Further assessment of the late effects of therapy is required to confirm whether this approach results in lower morbidity in the long-term.