Outcome of patients with local recurrent gynecologic malignancies after resection combined with intraoperative electron radiation therapy (IOERT)

Background: Treatment of recurrent gynecologic cancer is a challenging issue. Aim of the study was to investigate clinical features and outcomes of patients with recurrent gynecologic malignancies who underwent resection including IOERT (intraoperative electron radiation therapy) with regard to clinical outcome and potential predictive factors or subgroups that benefit most from this radical treatment regime. Methods: A total of 36 patients with recurrent gynecologic malignancies (cervical (n = 18), endometrial (n = 12) or vulvar cancer (n = 6)) were retrospectively identified through hospital databases in accordance with institutional ethical policies. Patient characteristics and outcomes were assessed. Survival data was analyzed using the Kaplan-Meier-method and log-rank-test, categorical variables were analyzed with chi-square-method. Results: For the entire cohort 1-/2-/5-year Overall Survival (OS) was 65.3 %/36.2 %/21.7 %. Patients with endometrial, cervical, and vulvar carcinoma had a 1-/2-/5-year OS of 83.3 %/62.5 %/50 %, 44.5 %/25.4 %/6.4 %, and 83.3 %/16.7 %/16.7 %, respectively. Patients with endometrial carcinoma showed a significantly better OS (p = 0.038). 1-/2-/5-year Local Progression-free Survival (LPFS) for the entire cohort was 44.1 %/28 %/21 % with 76.2 %/61 %/40.6 % for endometrial, 17.2 %/0 %/0 % for cervical, and 40 %/20 %/20 % for vulvar cancer, respectively. Patients with endometrial cancer showed a significantly (p = 0.017) and older patients a trend (p = 0.059) for a better LPFS. 1-/2-/5-year Distant Progression-free Survival (DPFS) for the entire cohort was 53.1 %/46.5 %/38.7 % with 74.1 %/74.1 %/74.1 % for endometrial, 36.7 %/36.7 %/0 % for cervical, and 60 %/30 %/30 % for vulvar cancer, respectively. There was a significantly better DPFS for older patients (p = 0.015) and a trend for a better DPFS for patients with endometrial carcinoma (p = 0.075). Conclusion: The radical procedure of resection combined with IOERT seems to be a valid curative treatment option for patients with recurrent endometrial carcinoma with 5-year survival rates of 50 %. For patients with cervical or vulvar cancer this treatment should be considered a rather palliative one and must be weighted carefully against other treatment options like chemotherapy, targeted therapies or new highly conformal radiotherapy techniques

Prospective phase-II-study evaluating postoperative radiotherapy of cervical and endometrial cancer patients using protons – the APROVE-trial

Background: The prognosis for patients with cervical or endometrial cancer has improved over the last decades. Thus, reducing therapy-related toxicity and impact on quality of life have become more and more important. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy) the incidence of acute and chronic toxicities has already been reduced. Nevertheless, rates of complications requiring medical treatment range from 0.7–8% according to literature. 7.7% of patients develop severe complications after 5 years with an increasing risk for complications of 0.3%/year. Particularly, the volume of the small and large bowel receiving low doses (15 Gy) has been shown to be a predictive factor for the development of higher bowel toxicity. With the introduction of proton therapy into clinical practice, there are new opportunities for optimization of organ at risk-sparing thus possibly reducing toxicity. Methods/design: The APROVE study is a prospective single-center one-arm phase-II-study. Patients with cervical or endometrial cancer after surgical resection who have an indication for postoperative pelvic radiotherapy will be treated with proton therapy instead of the commonly used photon radiation. A total of 25 patients will be included in this trial. Patients will receive a dose of 45–50.4 GyE in 1.8 GyE fractions 5–6 times per week using active raster-scanning pencil beam proton radiation. Platinum-based chemotherapy can be administered if indicated. For treatment planning, rectum, sigma, large and small bowel, bladder and femoral heads are defined as organs at risk. The CTV is defined according to the RTOG consensus guidelines. Discussion: The primary endpoint of the study is the evaluation of safety and treatment tolerability of pelvic radiation using protons defined as the lack of any CTC AE Grade 3 or 4 toxicity. Secondary endpoints are clinical symptoms and toxicity, quality of life and progression-free survival. The aim is to explore the potential of proton therapy as a new method for adjuvant pelvic radiotherapy to decrease the dose to the bowel, rectum and bladder thus reducing acute and chronic toxicity and improving quality of life. Trial registration: Registered at https://clinicaltrials.gov , ClinicalTrials.gov Identifier: NCT03184350 , registered 09 June 2017, enrolment of the first participant 19 June 2017

Lymphadenectomy in women with endometrial cancer: aspiration and reality from a radiation oncologist’s point of view

Background: To investigate the meaning of lymphadenectomy (LNE) in women with endometrial cancer (EC) for clinical outcome and secondly to determine the impact of the method of adjuvant radiotherapy (RT) on survival as well as to define prognostic factors. Methods: 322 patients (pts) underwent adjuvant RT for endometrioid EC at our department from 2004 until 2012 and were included in this retrospective study. Chi-square test, LogRank test and Cox regression were used for statistical analyses. Results: Median age at diagnosis: 66 years. FIGO stages: FIGO I 69.4 %, FIGO II 15.3 %, FIGO III 14.5 %, FIGO IV 0.9 %. Surgical staging: 30.6 % pelvic/paraaortic LNE, 45 % sole pelvic LNE, 8.8 % sampling of suspicious lymph nodes, 15.6 % no LNE. Adjuvant chemotherapy (ChT): 3.2 %. Sole intravaginal brachytherapy (IVB): 60.2 %. IVB + external beam radiotherapy (EBRT): 39.8 %. 5-year local recurrence free survival (LRFS): 90.6 %, distant metastases free survival (DMFS): 89.8 %, overall survival (OS):79.3 %. In multivariate analysis age (p = .007), pT stage (p = .029), lymph node status (p = .003), grading (p = .011) and lymphovascular space invasion (LVSI; p = .008) remained as independent prognostic factors for OS. Resection status (p = .01) and LVSI (p = .014) were independent prognostic factors for LRFS and LVSI (p = .008) was the only independent prognostic factor for DMFS. There was no statistically significant survival benefit from LNE in LRFS (p = .561), DMFS (p = .981) or OS (p = .791). 5-year LRFS in stage I and II: 96.0 and 82.9 % after sole IVB, 90.8 and 81.6 % after combined IVB/EBRT (p = .105; p = .970). 5-year OS rates for stage I and II: 86.5 and 71.3 % after sole IVB, 84.2 % and 69.2 % after combined IVB/EBRT (p = .153; p = .619). Conclusion: Comprehensive surgical staging is rarely performed and may be omitted in women with endometrioid EC in stages I-II. Sole IVB delivers equally good local control as combined IVB/EBRT in pts with FIGO stage I and II disease. LVSI deserves more attention as a prognostic factor and these pts may require a combined local and systemic therapy

Linear accelerator-based stereotactic fractionated photon radiotherapy as an eye-conserving treatment for uveal melanoma

Background: The purpose of this retrospective analysis is to analyze clinical outcome, visual acuity and enucleation rates after linear accelerator-based stereotactic fractionated photon radiotherapy for primary uveal melanoma. Methods: Twenty-four patients with primary uveal melanoma treated at the Department of Radiation and Oncology of the University Hospital Heidelberg between 1991 and 2015 were analyzed regarding survival and treatment-related toxicity including eye- and sight-preservation. Results: Photon radiotherapy (RT) offered good overall local control rates with a local progression-free survival (LPFS) of 82% after 5 years and a median LPFS of 5.5 years at a median follow-up time of 5.2 years. Gender had a significant impact on LPFS yielding a mean LPFS of 8.1 years for women and 8.7 years for men (p = 0.04). Of all local progressions, 80% occurred within the first 5 years after RT. In one case, enucleation as final therapy option was necessary. Enucleation-free survival (EFS) was related to the radiotherapy dose (p < 0.0001). Thus, higher prescribed doses led to a significantly higher enucleation rate. T-stage had no significant impact on EFS, but affected the enucleation rate (p = 0.01). The overall survival (OS) rate was 100% after 2 years and 70% after 5 years with a median OS of 5.75 years. Age (p = 0.046), T stage (p = 0.019), local control rate (p = 0.041) and the time between diagnosis and the first radiation session (p = 0.01) had a significant effect on OS. Applied biologically effective dose (BED) did not significantly influence OS or PFS. A 2-year sight preservation rate of 75% could be achieved. In all patients, irradiation could be applied safely without any interruptions due to side effects. Six significant late toxicities with consequential blindness could be observed, making a secondary enucleation necessary in four patients. An impairment of visual acuity due to chronic optic nerve atrophy was identified in five patients within 2 years after treatment. Conclusions: Linear accelerator-based stereotactic fractionated photon radiotherapy is an effective method in the treatment of uveal melanoma with excellent local control rates and a 2-year vision retention rate comparable to brachytherapy (BRT) or proton beam radiotherapy, even available in small centers and easy to implement. Interdisciplinary decision making is necessary to guarantee best treatment for every patient

Treatment planning for MLC based robotic radiosurgery for brain metastases: plan comparison with circular fields and suggestions for planning strategies

To evaluate the possible range of application of the new InCise2 MLC for the CyberKnife M6 system in brain radiosurgery, a plan comparison was made for 10 brain metastases sized between 1.5 and 9cm3 in 10 patients treated in a single fraction each. The target volumes consist of a PTV derived by expanding the GTV by 1mm and were chosen to have diversity in the cohort regarding regularity of shape, location and the structures needed to be blocked for beam transmission in the vicinity. For each case, two treatment plans were optimized: one using the MLC and one using the IRIS-collimator providing variable circular fields. Plan re-quirements were: dose prescription to the 70% isodose line (18 or 20Gy), 100% GTV coverage, ≥98% PTV coverage, undisturbed central high dose region (95% of maximum dose) and a conformity index as low as possible. Plan com-parison parameters were: conformity index (CI), high-dose gradient index (GIH), low-dose gradient index (GIL), total number of monitor units (MU) and expected treatment time (TT). For all cases, clinically acceptable plans could be gen-erated with the following results (mean±SD) for CI, GIH, GIL, MU and TT, respectively for the MLC plans: 1.09±0.03, 2.77±0.26, 2.61±0.08, 4514±830MU and 27±5min and for the IRIS plans: 1.05±0.01, 3.00±0.35, 2.46±0.08, 8557±1335MU and 42±7min. In summary, the MLC plans were on average less conformal and had a shallower dose gradient in the low dose region, but a steeper dose gradient in the high dose region. This is accompanied by a smaller vol-ume receiving 10Gy. A plan by plan comparison shows that usage of the MLC can spare about one half of the MUs and one third of treatment time. From these experiences and results suggestions for MLC planning strategy can be de-duced

Adjuvant intensity modulated whole-abdominal radiation therapy for high-risk patients with ovarian cancer FIGO stage III: final results of a prospective phase 2 study

Background: To assess late toxicity, quality of life and oncological outcome after consolidative whole abdominal radiotherapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high risk patients with advanced ovarian cancer FIGO stage III using IMRT (Intensity modulated radiation therapy). Methods: The OVAR-IMRT-02 study is a multi-center single-arm phase-II-trial. Twenty patients with optimally debulked ovarian cancer stage FIGO III with complete remission after chemotherapy were treated with intensity modulated WART. A total dose of 30 Gy in 20 fractions was applied to the entire peritoneal cavity. Primary endpoint was treatment tolerability; secondary objectives were acute and chronic toxicities, quality of life, rates of therapy disruption/abortion, progression-free survival (PFS) and overall survival (OS). Results: All patients completed treatment and 10/20 patients (50%) reached the final study follow-up of 36 months. Late side effects consisted of °1-°2 lower limb edema (44.5%), with one patient (5.6%) showing °3 edema. Three patients (16.7%) showed elevated gamma-Glutamyltransferase. There were no severe late side effects regarding renal or hepatic function or any gastrointestinal toxicity greater than °2. During WART, mean global health status decreased by 18.1 points (95%-CI: 7.1–29.0), but completely normalized after 6 months. The same trend was observed for the function scale scores. Kaplan-Meier-estimated 1-, 2- and 3-year PFS was 74, 51 and 40%, respectively. 1-, 2- and 3-year OS was 89, 83 and 83%, respectively. Conclusions: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late toxicity and minor impact on long-term quality of life. Together with the promising results for PFS and OS, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer. Trial registration: The study is registered with ClinicalTrials.gov (NCT01180504). Registered 12 August 2010 – retrospectively registered

Adjuvant Intensity Modulated Whole-Abdominal Radiation Therapy for High-Risk Patients With Ovarian Cancer (International Federation of Gynecology and Obstetrics Stage III): First Results of a Prospective Phase 2 Study

Purpose: To assess treatment tolerance and toxicity rates of consolidative whole-abdominal radiation therapy (WART) following cytoreductive surgery and carboplatin/ paclitaxel chemotherapy in high-risk patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III) using intensity modulated radiation therapy. Methods and Materials: The OVAR-IMRT-02 study is a multicenter, single-arm, phase 2 trial. Twenty patients with optimally debulked ovarian cancer (International Federation of Gynecology and Obstetrics stage III) with complete remission after chemotherapy were treated with intensity modulated WART as a consolidation therapy. A total dose of 30 Gy in 20 fractions of 1.5 Gy was applied to the entire peritoneal cavity. The primary endpoint was treatment tolerability, defined as lack of any Common Terminology Criteria for Adverse Events grade 4 toxicity within 10 weeks after start of treatment; secondary objectives were acute and chronic toxicity, quality of life, rates of therapy disruption and abortion, and progression-free and overall survival. Results: Intensity modulatedWART resulted in excellent coverage of the whole peritoneal cavity, with effective sparing of all organs at risk. The primary analysis included all 20 enrolled patients, of whom 19 did not experience Common Terminology Criteria for Adverse Events grade 4 toxicity. Only 1 patient experienced acute grade 4 hematologic toxicity. Thus, the tolerability rate of intensity modulated WART was significantly higher than 70%. No gastrointestinal acute toxicities higher than grade 2 have been observed. During WART, mean global health status decreased by 18.1 points (95% confidence interval 7.1, 29.0). Six weeks afterWART, global health status had already increased, with a mean score difference of 4.6 (95% confidence interval - 11.1, 20.4) compared with baseline. Similar characteristics were observed for all function scale scores. Conclusion: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute toxicity and a treatment tolerability rate significantly higher than 70%. Together with our knowledge about clinical feasibility, meaning excellent coverage of the planning target volume and effective sparing of organs at risk, intensity modulatedWART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer. (C) 2017 Elsevier Inc. All rights reserved

Additional file 1: Figure S1. of Outcome of patients with local recurrent gynecologic malignancies after resection combined with intraoperative electron radiation therapy (IOERT)

Kaplan-Meier curves of OS [A], LPFS [B] and DPFS [C] by different clinical parameters like histology, time to recurrence, lymphonodal status, lymphangiosis carcinomatosa, organinfiltration, resection status, and applied dose of IOERT. Further statistical analysis of possible predictive factors was performed. Histology, time to recurrence, lymphonodal status, lymphangiosis carcinomatosa, organinfiltration, resection status, and applied dose of IOERT were assessed. None of the mentioned parameters showed a statistically significant influence on OS, LPFS or DPFS. (PDF 357 kb