Bone Marrow Sparing by Intensity Modulated Proton Beam Therapy in Postoperative Irradiation of Gynecologic Malignancies.

Purpose: The aim of this matched-pair cohort study was to evaluate the potential of intensity-modulated proton therapy (IMPT) for sparring of the pelvic bone marrow and thus reduction of hematotoxicity compared to intensity-modulated photon radiotherapy (IMRT) in the setting of postoperative irradiation of gynaecological malignancies. Secondary endpoint was the assessment of predictive parameters for the occurrence of sacral insufficiency fractures (SIF) when applying IMPT. Materials and Methods: Two cohorts were analyzed consisting of 25 patients each. Patients were treated with IMPT compared with IMRT and had uterine cervical (n = 8) or endometrial cancer (n = 17). Dose prescription, patient age, and diagnosis were matched. Dosimetric parameters delivered to the whole pelvic skeleton and subsites (ilium, lumbosacral, sacral, and lower pelvis) and hematological toxicity were evaluated. MRI follow-up for evaluation of SIF was only available for the IMPT group. Results: In the IMPT group, integral dose to the pelvic skeleton was significantly lower (23.4GyRBE vs 34.3Gy; p < 0.001), the average V5Gy, V10Gy, and V20Gy were reduced by 40%, 41%, and 28%, respectively, compared to the IMRT group (p < 0.001). In particular, for subsites ilium and lower pelvis, the low dose volume was significantly lower. Hematotoxicity was significantly more common in the IMRT group (80% vs 32%; p = 0009), especially hematotoxicity ≥ CTCAE II (36% vs 8%; p = 0.037). No patient in the IMPT group experienced hematotoxicity > CTCAE II. In the IMPT cohort, 32% of patients experienced SIF. Overall SIF occurred more frequently with a total dose of 50.4 GyRBE (37.5%) compared to 45 GyRBE (22%). No significant predictive dose parameters regarding SIF could be detected aside from a trend regarding V50Gy to the lumbosacral subsite. Conclusion: Low-dose exposure to the pelvic skeleton and thus hematotoxicity can be significantly reduced by using IMPT compared to a matched photon cohort. Sacral insufficiency fracture rates appear similar to reported rates for IMRT in the literature.

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

Incidence and Risk Assessment of Capsular Contracture in Breast Cancer Patients following Post-Mastectomy Radiotherapy and Implant-Based Reconstruction.

Our study aims to identify the risk factors and dosimetry characteristics associated with capsular contracture. METHODS: We retrospectively analyzed 118 women with breast cancer who underwent PMRT following an IBR between 2010 and 2022. Patients were treated with PMRT of 50.0-50.4 Gy in 25-28 fractions. Capsular contracture was categorized according to the Baker Classification for Reconstructed Breasts. RESULTS: After a median follow-up of 22 months, the incidence of clinically relevant capsular contracture (Baker III-IV) was 22.9%. Overall, capsular contracture (Baker I-IV) occurred in 56 patients (47.5%) after a median of 9 months after PMRT. The rate of reconstruction failure/implant loss was 25.4%. In the univariate analysis, postoperative complications (prolonged pain, prolonged wound healing, seroma and swelling) and regional nodal involvement were associated with higher rates of capsular contracture (p = 0.017, OR: 2.5, 95% CI: 1.2-5.3 and p = 0.031, respectively). None of the analyzed dosimetric factors or the implant position were associated with a higher risk for capsular contracture. CONCLUSION: Postoperative complications and regional nodal involvement were associated with an increased risk of capsular contracture following breast reconstruction and PMRT, while none of the analyzed dosimetric factors were linked to a higher incidence. Additional studies are needed to identify further potential risk factors.

Noninferiority of Local Control and Comparable Toxicity of Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Breast Cancer: 5-Year Results of the IMRT-MC2 Phase III Trial.

PURPOSE: The IMRT-MC2 trial was conducted to demonstrate the noninferiority of conventionally fractionated intensity modulated radiation therapy with a simultaneous integrated boost to 3-dimensional conformal radiation therapy with a sequential boost for adjuvant breast radiation therapy. METHODS AND MATERIALS: A total of 502 patients were randomized between 2011 and 2015 for the prospective, multicenter, phase III trial (NCT01322854). Five-year results of late toxicity (late effects normal tissue task force-subjective, objective, management, and analytical), overall survival, disease-free survival, distant disease-free survival, cosmesis (Harvard scale), and local control (noninferiority margin at hazard ratio [HR] of 3.5) were analyzed after a median follow-up of 62 months. RESULTS: The 5-year local control rate for the intensity modulated radiation therapy with simultaneous integrated boost arm was non-inferior to the control arm (98.7% vs 98.3%, respectively; HR, 0.582; 95% CI, 0.119-2.375; P = .4595). Furthermore, there was no significant difference in overall survival (97.1% vs 98.3%, respectively; HR, 1.235; 95% CI, 0.472-3.413; P = .6697), disease-free survival (95.8% vs 96.1%, respectively; HR, 1.130; 95% CI, 0.487-2.679; P = .7758), and distant disease-free survival (97.0% vs 97.8%, respectively; HR, 1.667; 95% CI, 0.575-5.434; P = .3601). After 5 years, late toxicity evaluation and cosmetic assessment further showed no significant differences between treatment arms. CONCLUSIONS: The 5-year results of the IMRT-MC2 trial provide strong evidence that the application of conventionally fractionated simultaneous integrated boost irradiation for patients with breast cancer is both safe and effective, with noninferior local control compared with 3-dimensional conformal radiation therapy with sequential boost.

Palliative Radiotherapy for Symptomatic Locally Advanced Breast Cancer.

Objective: Women with locally advanced breast cancer (LABC) or inoperable local recurrence often suffer from a significantly reduced quality of life (QOL) due to local tumor-associated pain, bleeding, exulceration, or malodorous discharge. We aimed to further investigate the benefit of radiotherapy (RT) for symptom relief while weighing the side-effects. Materials and methods: Patients who received symptom-oriented RT for palliative therapy of their LABC or local recurrence in the Department of Radiation Oncology at Heidelberg University Hospital between 2012 and 2021 were recorded. Clinical, pathological, and therapeutic data were collected and the oncological and symptomatic responses as well as therapy-associated toxicities were analyzed. Results: We retrospectively identified 26 consecutive women who received palliative RT with a median total dose of 39 Gy or single dose of 3 Gy in 13 fractions due to (impending) exulceration, pain, local hemorrhage, and/or vascular or plexus compression. With a median follow-up of 6.5 months after initiation of RT, overall survival at 6 and 12 months was 60.0% and 31.7%, and local control was 75.0% and 47.6%, respectively. Radiation had to be discontinued in 4 patients due to oncological clinical deterioration or death. When completed as initially planned, symptom improvement was achieved in 95% and WHO level reduction of analgesics in 28.6% of patients. In 36% (16%) of patients, local RT had already been indicated >3 months (>6 months) before the actual start of RT, but was delayed or not initiated among others in favor of drug alternatives or systemic therapies. RT-associated toxicities included only low-grade side-effects (CTCAE I°-II°) with predominantly skin erythema and fatigue even in the context of re-RT. Conclusion: Palliative RT in symptomatic LABC or locoregional recurrence is an effective treatment option for controlling local symptoms with only mild toxicity. It may thus improve QOL and should be considered early in palliative patient care management.

Treatment Tolerability and Toxicity of Postoperative Proton Beam Therapy for Gynecologic Malignancies: Results of the Prospective Phase 2 APROVE Trial.

PURPOSE: The APROVE study is a prospective one-arm phase-2 study investigating the safety and treatment tolerability of postoperative proton beam therapy in women with uterine cervical or endometrial cancer. In this analysis, we report the primary study endpoint of safety and treatment tolerability as well as toxicity rates and progression-free survival (PFS). METHODS AND MATERIALS: 25 patients were treated with postoperative proton beam therapy with a total dose of 45 to 50.4 Gy (RBE) in 5 to 6 × 1.8 Gy (RBE) fractions weekly using active raster-scanning intensity modulated proton beam therapy (IMPT). Sequential or simultaneous platinum-based chemotherapy was administered if indicated. The primary endpoint was defined as the lack of any acute ≥grade 3 gastrointestinal (GI) or urogenital (GU) toxicity according to the Common Terminology Criteria for Adverse Events v 4.0 or premature treatment abortion. Secondary endpoints were clinical symptoms and toxicity, quality of life, and PFS. RESULTS: All patients completed IMPT according to the protocol, with a median treatment duration of 43 days (range, 33 to 51 days). No patient developed gastrointestinal or genitourinary toxicity ≥grade 3, and the treatment tolerability rate was 100%. Therefore, the null hypothesis H0: Tolerability Rate ≤80% could be rejected in favor of the alternative hypothesis H1: Tolerability rate >80% using an exact binomial test with a one-sided significance level of α = 10% (one-sided P value P = .0059). The median follow-up time after the end of IMPT was 25.1 months (range, 20.2 to 50.3 months). 18 of 25 (75%) patients completed the study follow-up of 24 months. 7 patients had progressive disease. Kaplan-Meier-estimated mean PFS was 39.9 months (95% confidence interval: 33.37 to 46.5 months). CONCLUSIONS: Postoperative IMPT is a safe treatment option for cervical and endometrial cancer patients, with only low-grade acute and late toxicities. Larger randomized trials are necessary to further assess the potential of IMPT and improve patient selection.

Health-related quality of life and patient-reported symptoms after postoperative proton beam radiotherapy of cervical and endometrial cancer: 2-year results of the prospective phase II APROVE-trial.

INTRODUCTION: The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. METHODS: 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. RESULTS: Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. CONCLUSION: Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. TRIAL REGISTRATION: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).

Vaginal cancer treated with curative radiotherapy with or without concomitant chemotherapy: oncologic outcomes and prognostic factors.

BACKGROUND: Vaginal cancer is a rare disease for which prospective randomized trials do not exist. We aimed to assess survival outcomes, patterns of recurrence, prognostic factors, and toxicity in the curative treatment using image-guided radiotherapy (RT). METHODS: In this retrospective review, we identified 53 patients who were treated at a single center with external beam radiotherapy and brachytherapy with or without concomitant chemotherapy from 2000 to 2021. RESULTS: With a median follow-up of 64.5 months, the Kaplan-Meier 2-, 5-, and 7-year overall survival (OS) was found to be 74.8%, 62.8%, and 58.9%, respectively. Local and distant control were 67.8%, 65.0%, and 65.0% and 74.4%, 62.6%, and 62.6% at 2, 5, and 7 years, respectively. In univariate Cox proportional hazards ratio analysis, OS was significantly correlated to FIGO stage (hazard ratio [HR] 1.78, p = 0.042), postoperative RT (HR 0.41, p = 0.044), and concomitant chemotherapy (HR 0.31, p = 0.009). Local control rates were superior when an equivalent dose in 2-Gy fractions (EQD2) of ⩾65 Gy was delivered (HR 0.216, p = 0.028) and with the use of concurrent chemotherapy (HR 0.248, p = 0.011). Not surprisingly, local control was inferior for patients with a higher TNM stage (HR 3.303, p = 0.027). Minimal toxicity was observed with no patients having documentation of high-grade toxicity (CTCAE grade 3+). CONCLUSION: In treatment of vaginal cancer, high-dose RT in combination with brachytherapy is well tolerated and results in effective local control rates, which significantly improve with an EQD2(α/ß=10) ⩾65 Gy. Multivariate analyses revealed concomitant chemotherapy was a positive prognostic factor for overall and progression-free survival.

Age-Dependent Hematologic Toxicity Profiles and Prognostic Serologic Markers in Postoperative Radiochemotherapy Treatment for Uterine Cervical Cancer.

Introduction: In the adjuvant setting for cervical cancer, classical risk factors for postoperative radiochemotherapy have been established. However, data on laboratory changes during therapy and the prognostic value of serological markers are limited and further knowledge is needed to optimize the toxic trimodal regimen. Methods: We retrospectively identified 69 women who underwent weekly postoperative radiochemotherapy with 40 mg/m2 of cisplatin for cervical cancer between 2010 and 2021 at a single center. Laboratory parameters were recorded before, at each cycle and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to calculate and compare survival, groups were compared using the Mann-Whitney U, χ2, and variance tests. Results: With a median follow-up of 17.7 months, the 1- and 5-year local control rates were 94.0% and 73.7%, respectively, with significantly better rates for more chemotherapy cycles and negative resection margins. Only 68.1% of patients completed all cycles. The most common reasons for early discontinuation were persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting infections in women aged > 50 years. Leukopenia was more likely to occur after the third cycle. Significantly worse survival was observed for post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase levels, low pre-radiochemotherapy nutritional index, and raised C-reactive-protein-levels; the latter were also predictable for local control. The Glasgow prognostic score did not reliably predict survival. Conclusion: Incomplete application of simultaneous chemotherapy leads to inferior local control, and age-dependent limiting factors should be identified at an early stage. In addition to classical risk factors, serological markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show prognostic significance.

Methods of Esthetic Assessment after Adjuvant Whole-Breast Radiotherapy in Breast Cancer Patients: Evaluation of the BCCT.core Software and Patients' and Physicians' Assessment from the Randomized IMRT-MC2 Trial.

The present analysis compares the esthetics assessment by the BCCT.core software in relation to patients' and physicians' ratings, based on the IMRT-MC2 trial. Within this trial, breast cancer patients received breast-conserving surgery (BCS) and adjuvant radiotherapy. At the baseline, 6 weeks, and 2 years after radiotherapy, photos of the breasts were assessed by the software and patients' and physicians' assessments were performed. Agreement rates of the assessments and their correlation with breast asymmetry indices were evaluated. The assessments of the software and the physicians were significantly correlated with asymmetry indices. Before and 6 weeks after radiotherapy, the patients' self-assessment was only correlated with the lower breast contour (LBC) and upward nipple retraction (UNR), while after 2 years, there was also a correlation with other indices. Only a slight agreement between the BCCT.core software and the physicians' or patients' assessment was seen, while a moderate and substantial agreement was detected between the physicians' and the patients' assessment after 6 weeks and 2 years, respectively. The BCCT.core software is a reliable tool to measure asymmetries, but may not sufficiently evaluate the esthetic outcome as perceived by patients. It may be more appropriate for a long-term follow-up, when symmetry appears to increase in importance.

Return to Work, Fatigue and Cancer Rehabilitation after Curative Radiotherapy and Radiochemotherapy for Pelvic Gynecologic Cancer.

Pain, fatigue, and depression are a common cluster of symptoms among cancer patients that impair quality of life and daily activities. We aimed to evaluate the burden of cancer rehabilitation and return-to-work (RTW) rates. Tumor characteristics, lifestyle and household details, treatment data, the use of in-house social services and post-treatment inpatient rehabilitation, and RTW were assessed for 424 women, diagnosed with cervical, uterine, or vaginal/vulvar cancer, receiving curative radio(chemo)therapy. Progression-free RTW rate at 3 months was 32.3%, and increased to 58.1% and 63.2% at 12 and 18 months, respectively. Patients with advanced FIGO stages and intensified treatments significantly suffered more from acute pain and fatigue. A higher Charlson-Comorbidity-Index reliably predicted patients associated with a higher risk of acute fatigue during RT. Aside from the presence of children, no other household or lifestyle factor was correlated with increased fatigue rates. Women aged ≤ 45 years had a significantly higher risk of developing depression requiring treatment during follow-up. Post-treatment inpatient cancer rehabilitation, including exercise and nutrition counseling, significantly relieved fatigue symptoms. The burdens for recovery from cancer therapy remain multi-factorial. Special focus needs to be placed on identifying high-risk groups experiencing fatigue or pain. Specialized post-treatment inpatient cancer rehabilitation can improve RTW rates.

Quality of life after simultaneously integrated boost with intensity-modulated versus conventional radiotherapy with sequential boost for adjuvant treatment of breast cancer: 2-year results of the multicenter randomized IMRT-MC2 trial.

BACKGROUND: We recently published 2-year results of the prospective, randomized IMRT-MC2 trial, showing non-inferior local control and cosmesis in breast cancer patients after conventionally fractionated intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB), compared to 3D-conformal radiotherapy with sequential boost (3D-CRT-seqB). Here, we report on 2-year quality of life results. PATIENTS AND METHODS: 502 patients were enrolled and randomized to IMRT-SIB (50.4 Gy in 1.8 Gy fractions with a 64.4 Gy SIB to the tumor bed) or to 3D-CRT-seqB (50.4 Gy in 1.8 Gy fractions, followed by a sequential boost of 16 Gy in 2 Gy fractions). For quality of life (QoL) assessment, patients completed the QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks and 2 years after radiotherapy. RESULTS: Significant differences between treatment arms were seen 6 weeks after radiotherapy for pain (22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; p = 0.033) and arm symptoms (18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; p = 0.013), both favoring IMRT-SIB. Compared to baseline values, both arms showed significant improvement in global score (IMRT: p = 0.009; 3D-CRT: p = 0.001) after 2 years, with slight deterioration on the role (IMRT: p = 0.008; 3-D-CRT: p = 0.001) and social functioning (IMRT: p = 0.013, 3D-CRT: p = 0.001) as well as the future perspectives scale (IMRT: p = 0.003; 3D-CRT: p = 0.0034). CONCLUSION: This is the first randomized phase III trial demonstrating that IMRT-SIB was associated with slightly superior QoL compared to 3-D-CRT-seqB. These findings further support the clinical implementation of SIB in adjuvant breast cancer treatment.

Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).

PURPOSE: In the modern era, improvements in radiation therapy techniques have paved the way for simultaneous integrated boost irradiation in adjuvant breast radiation therapy after breast conservation surgery. Nevertheless, randomized trials supporting the noninferiority of this treatment to historical standards of care approach are lacking. METHODS: A prospective, multicenter, randomized phase 3 trial (NCT01322854) was performed to analyze noninferiority of conventional fractionated intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) to 3-D conformal radiation therapy with sequential boost (3-D-CRT-seqB) for breast cancer patients. Primary outcomes were local control (LC) rates at 2 and 5 years (noninferiority margin at hazard ratio [HR] of 3.5) as well as cosmetic results 6 weeks and 2 years after radiation therapy (evaluated via photo documentation calculating the relative breast retraction assessment [pBRA] score [noninferiority margin of 1.25]). RESULTS: A total of 502 patients were randomly assigned from 2011 to 2015. After a median follow-up of 5.1 years, the 2-year LC for the IMRT-SIB arm was noninferior to the 3-D-CRT-seqB arm (99.6% vs 99.6%, respectively; HR, 0.602; 95% CI, 0.123-2.452; P = .487). In addition, noninferiority was also shown for cosmesis after IMRT-SIB and 3-D-CRT-seqB at both 6 weeks (median pBRA, 9.1% vs 9.1%) and 2 years (median pBRA, 10.4% vs 9.8%) after radiation therapy (95% CI, -0.317 to 0.107 %; P = .332). Cosmetic assessment according to the Harvard scale by both the patient and the treating physician as well as late-toxicity evaluation with the late effects normal tissues- subjective, objective, management, analytic criteria, a score for the evaluation of long-term adverse effects in normal tissue, revealed no significant differences between treatment arms. In addition, there was no difference in overall survival rates (99.6% vs 99.6%; HR, 3.281; 95% CI: -0.748 to 22.585; P = .148) for IMRT-SIB and 3-D-CRT-seqB, respectively. CONCLUSIONS: To our knowledge, this is the first prospective trial reporting the noninferiority of IMRT-SIB versus 3-D-CRT-seqB with respect to cosmesis and LC at 2 years of follow-up. This treatment regimen considerably shortens adjuvant radiation therapy times without compromising clinical outcomes.

Adjuvant Radiation Therapy for Male Breast Cancer-A Rare Indication?

Due to its rarity, there are no randomized trials investigating the outcome of adjuvant radiotherapy in MBC. This study reports on patient and tumor characteristics of 41 consecutive MBC patients treated between 1990 and 2018 and on clinical outcomes after surgical resection of tumors and adjuvant radiotherapy of the chest wall or breast. Local control (LC), locoregional control (LRC), overall survival (OS), disease-free survival (DFS), and toxicity were evaluated. After a median follow-up of 80 months (95% CI: 14.6-213.8 months) there was only one recurrence, in a patient's locoregional lymph nodes 17 months after start of radiotherapy, resulting in an LC rate of 100% at 5 years and a 5-year LRC rate of 97.4% (standard deviation (SD): 0.025). Five-year DFS and OS rates were 64.6% (SD: 0.085) and 57.2% (SD: 0.082), respectively. Adjuvant radiotherapy was tolerated well without high-grade (CTCAE grade > II) adverse events. After tumor resection and adjuvant radiotherapy, LC and LRC rates in MBC patients are excellent and comparable to results found for female breast cancer (FBC) patients. However, as patients are often diagnosed with locally advanced, higher-risk tumors, distant recurrences remain the major failure pattern.

Validation of Nine Different Prognostic Grading Indexes for Radiosurgery of Brain Metastases in Breast Cancer Patients and Development of an All-Encompassing Prognostic Tool.

Purpose: Several prognostic indexes for overall survival (OS) after radiotherapy of brain metastases in breast cancer patients exist but are mainly validated for whole-brain radiotherapy or not specifically for breast cancer patients. To date, no such index provides information beyond mere OS. Methods: We retrospectively analyzed 95 breast cancer patients treated with stereotactic radiosurgery for 203 brain metastases. The Kaplan-Meier method with log-rank test was used to assess OS, local control (LC), distant cranial control (DCC), and extracranial control (EC). Cox regression was applied to detect prognostic outcome factors. A point scoring system was designed to stratify patients based on outcome. Nine established prognostic indexes were analyzed using the concordance index (c-index). Results: Two out of nine analyzed prognostic indexes for OS showed a significant c-index, the breast graded prognostic assessment (bGPA; 0.631; 95% CI, 0.514-0.748; p = 0.037) and the modified bGPA (mod-bGPA; 0.662; 95% CI, 0.547-0.777; p = 0.010). Significant results from multivariate analysis (Karnofsky Performance Score, Her2/neu receptor status, extracranial control) were used to generate a new point system: the breast cancer stereotactic radiotherapy score (bSRS), which discriminated three significantly different prognostic groups, for LC, DCC, EC, and OS, respectively. However, the c-index was only significant for OS (0.689; 95% CI, 0.577-0.802; p = 0.003). Conclusions: The new bSRS score was superior to the bGPA and mod-bGPA scores for prognosis of OS. The bSRS is easy to use and the first tool, which might also provide outcome assessment beyond mere OS. Future studies need to validate these findings.

Acute toxicity of normofractionated intensity modulated radiotherapy with simultaneous integrated boost compared to three-dimensional conformal radiotherapy with sequential boost in the adjuvant treatment of breast cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) improves dose homogeneity and late toxicity compared to simple tangential techniques in adjuvant whole-breast radiotherapy for patients with breast cancer. Simultaneous-integrated boost (SIB) radiotherapy shortens the overall treatment time and improves dose homogeneity. However, prospective randomized trials regarding IMRT with SIB for adjuvant radiotherapy in breast cancer are lacking. METHODS: The IMRT-MC2 (MINT) trial is a phase III prospective randomized controlled trial comparing IMRT with SIB (Arm A: whole breast 28 × 1.8 Gy, Boost 28 × 2.3 Gy) to 3D-conformal radiotherapy with a sequential boost (Arm B: whole breast 28 × 1.8 Gy, boost 8 × 2 Gy) in patients with breast cancer after BCS. Indication for boost radiotherapy was defined as age < 70 years or age > 70 years with presence of additional risk factors. This is a retrospective analysis of acute toxicity at one of two trial sites. RESULTS: Five hundred two patients were randomized, of which 446 patients were eligible for this analysis. There was no statistically significant difference in terms of any grade radiation dermatitis between the two treatment arms at the end of treatment (p = 0.26). However, radiation dermatitis grade 2/3 (29.1% vs. 20.1 and 3.5% vs. 2.3%) occurred significantly more often in Arm A (p = 0.02). Breast/chest wall pain at the first follow-up visit was significantly more common in patients treated on Arm B (p = 0.02). CONCLUSIONS: Treatment on both arms was well tolerated, however there were some differences regarding radiodermatitis and breast pain. Further analyses are ongoing. TRIAL REGISTRATION: clinicaltrials.gov , NCT01322854 , registered 24th March 2011.

Evaluation of Uterine Brachytherapy as Primary Treatment Option for Elderly Patients with Medically Inoperable Endometrial Cancer-A Single-Center Experience and Review of the Literature.

We aimed to gain more evidence regarding the feasibility, toxicity, and oncological outcome of primary brachytherapy in patients with medically inoperable endometrial cancer. Thirteen patients receiving primary brachytherapy ± external beam radiotherapy (EBRT) for endometrial cancer due to medical inoperability were identified. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS). Univariate outcome analyses were performed using the log-rank test. Peri-interventional complications, acute and chronic toxicities were evaluated. Additionally, we performed a Pubmed search and review of the literature of the last 10 years. Mean age at time of diagnosis was 73.9 years (60.4-87.1 years). Eleven patients were staged FIGO IA/B and one patient each with FIGO IIIA and IIIC. Kaplan-Meier-estimated 2-/5-year LFFS were 76.2%/56.4%, respectively. High grading correlated with a worse LFFS (p = 0.069). Kaplan-Meier-estimated 2-/5-year PFS were 76.9%/53.8% and 2-/5-year-OS were 76.9%/69.2%, respectively. No acute toxicities > grade II and only two late toxicities grade II/III occurred. We observed three peri-interventional complications. The available evidence suggests high rates of local control after definitive brachytherapy for inoperable endometrial cancer with a favorable toxicity profile. Definitive brachytherapy +/- EBRT should be considered as the preferred approach for this patient group.

Intrafractional vaginal dilation in anal cancer patients undergoing pelvic radiotherapy (DILANA) - a prospective, randomized, 2-armed phase-II-trial.

BACKGROUND: The incidence of anal cancer is rising in the last decades and more women are affected than men. The prognosis after chemoradiation is very good with complete remission rates of 80-90%. Thus, reducing therapy-related toxicities and improving quality of life are of high importance. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy), the incidence of acute and chronic gastrointestinal toxicities has already been reduced. However, especially in female anal cancer patients genital toxicities like vaginal fibrosis and stenosis are of great relevance, too. Up to now, there are no prospective data reporting incidence rates, techniques of prevention or impact on quality of life. The aim of the DILANA trial is to evaluate the incidence and grade of vaginal fibrosis, to optimize radiotherapy by reducing dose to the vaginal wall to minimize genital toxicities and improve quality of life of anal cancer patients. METHODS: The study is designed as a prospective, randomized, two-armed, open, single-center phase-II-trial. Sixty patients will be randomized into one of two arms, which differ only in the diameter of a tampon used during treatment. All patients will receive standard (chemo) radiation with a total dose of 45-50.4 Gy to the pelvic and inguinal nodes with a boost to the anal canal up to 54-60 Gy. The primary objective is the assessment of the incidence and grade of vaginal fibrosis 12 months after (chemo) radiation depending on the extent of vaginal dilation. Secondary endpoints are toxicities according to the CTC AE version 5.0 criteria, assessment of clinical feasibility of daily use of a tampon, assessment of compliance for the use of a vaginal dilator and quality of life. DISCUSSION: Prospective studies are needed evaluating the incidence and grade of vaginal fibrosis after (chemo) radiation in female anal cancer patients. Furthermore, the assessment of techniques to reduce the incidence of vaginal fibrosis like intrafractional vaginal dilation as well as other radiotherapy-independent methods like using a vaginal dilator are essential. Additionally, implementation of a systematic assessment of vaginal stenosis is necessary to grant reproducibility and comparability of future data. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov (NCT04094454, 19.09.2019).

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.

Overexpression of p16INK4a Serves as Prognostic Marker in Squamous Cell Vulvar Cancer Patients Treated With Radiotherapy Irrespective of HPV-Status.

Purpose: We aimed to evaluate the impact of HPV-driven carcinogenesis on outcome in vulvar squamous cell carcinoma patients (VSCC) treated with radiotherapy. Methods and Materials: Analysis of clinical, pathological, and treatment data, HPV DNA-detection and -genotyping as well as p16INK4a immunohistochemistry were performed in 75 VSCC patients. Kaplan-Meier-method was used to estimate locoregional control (LC), Progression-free survival (PFS), and Overall Survival (OS). Univariate survival time comparisons were performed using the log-rank-test. Chi-square/Fisher exact test was used to assess correlations between HPV DNA and p16INK4a data, pathological, clinical, and treatment characteristics. Results: 23/75 (30.67%) of all women had locoregional relapse, 7/75 (9.3%) systemic recurrence, and 35/75 (46.67%) died after a median follow-up of 26.4 months. 21.3% of the tumors were HPV DNA-positive, mostly (93.75%) for the high-risk (HR) HPV type 16. 25.3% showed p16INK4a-overexpression. 17.3% showed concomitant HPV DNA- and p16INK4a-positivity (cHPPVC). Patients with p16INK4a-overexpression, irrespective of the HPV DNA status, showed significantly better PFS (5-year-PFS 69.3 vs. 39.2%, p = 0.045), LC (5-year-LC 86.7 vs. 56.7%, p = 0.033) and a strong trend for better OS (5-year-OS 75.6 vs. 43.9%, p = 0.077). Patients with cHPPVC showed a trend for better PFS (5-year-PFS 72.7 vs. 41.3%, p = 0.082) and OS (5-year-OS 81.1 vs. 45.7%, p = 0.084) but no significant benefit for LC. Conclusions: Patients with cHPPVC, indicating an etiological relevance of HPV in the respective tumors, showed a better, albeit not significant, prognosis. The sole detection of p16INK4a-overexpression is a prognostic factor for survival in vulvar cancer and indicates better prognosis after radiotherapy, independent of detection of HPV DNA. p16INK4a should be used as surrogate marker for HPV-driven carcinogenesis in vulvar cancer with caution.