Sexual health in Belgian cervical cancer survivors: an exploratory qualitative study.

PURPOSE: To assess experiences of sexuality and of receiving sexual healthcare in cervical cancer (CC) survivors. METHODS: A qualitative phenomenological study using semistructured one-on-one interviews was conducted with 15 Belgian CC survivors recruited in 5 hospitals from August 2021 to February 2022. The interviews were audiotaped and transcribed verbatim. Data were analyzed using inductive thematic analysis. COREQ and SRQR reporting guidelines were applied. RESULTS: Most participants experienced an altered sexuality after CC treatment with often long-term loss/lack of sex drive, little/no spontaneity, limitation of positions to avoid dyspareunia, less intense orgasms, or no sexual activity at all. In some cases, emotional intimacy became more prominent. Physical (vaginal bleeding, vaginal dryness, dyspareunia, menopausal symptoms) and psychological consequences (guilt, changed self-image) were at the root of the altered sexuality. Treatment-induced menopause reduced sex drive. In premenopausal patients, treatment and/or treatment-induced menopause resulted in the sudden elimination of family planning. Most participants highlighted the need to discuss their altered sexual experience with their partner to grow together toward a new interpretation of sexuality. To facilitate this discussion, most of the participants emphasized the need for greater partner involvement by healthcare providers (HPs). The oncology nurse or sexologist was the preferred HP with whom to discuss sexual health. The preferred timing for information about the sexual consequences of treatment was at treatment completion or during early follow-up. CONCLUSION: Both treatment-induced physical and psychological experiences were prominent and altered sexuality. Overall, there was a need for HPs to adopt proactive patient-tailored approaches to discuss sexual health.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Vaginal morbidity, sexual functioning, and health-related quality of life in cervical cancer survivors: a cross-sectional multicenter study (VAMOS).

PURPOSE: To compare sexual/vaginal functioning between early cervical cancer (ECC) and locally advanced cervical cancer (LACC) survivors. METHODS: VAMOS was a multicenter, cross-sectional, questionnaire, noninferiority study including ECC patients treated with surgery and, if clinically indicated, adjuvant (chemo)radiotherapy and LACC patients treated with neoadjuvant (chemo)radiotherapy followed by surgery. Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-CX24, and Female Sexual Functioning Index (FSFI) questionnaires. Clinical reported outcomes (ClinROs) consisted of vaginal morbidity scored according to the CTCAE v4.0 scoring system. RESULTS: One hundred forty-three patients were included. Compared to ECC patients (n = 97), LACC patients (n = 46) were significantly less sexually active in the 4 weeks prior to completion of the questionnaires (65% vs. 41%; p = .005). The primary endpoint was not met: LACC patients reported a higher mean score (more problems) for sexual/vaginal functioning than ECC patients, with a non-clinically relevant mean difference of 6.38 ([95% CI: - 6.41, 19.17]; p = .570 for noninferiority). Regarding the secondary endpoints, the prevalence of sexual dysfunction between the two groups did not differ significantly (p = 0.124). Compared to ECC patients, LACC patients did not have significantly more vaginal morbidity (adjusted odds ratio [OR] 1.51 [95% CI: 0.22, 10.29]; p = .674). Moreover, there was poor agreement between any vaginal morbidity and sexual dysfunction (Cohen's kappa of 0.17). CONCLUSION: Compared to ECC survivors, LACC survivors were significantly less sexually active and reported equivalent or worse sexual/vaginal functioning, although the proportion of patients with sexual dysfunction was similar. Clinical assessment of vaginal morbidity was poorly correlated with sexual dysfunction.

Completion surgery after intensity-modulated arc therapy for locally advanced cervical cancer: long-term follow-up and update on surgical outcome and oncologic results of a unique tertiary care single-center retrospective cohort.

BACKGROUND: Chemoradiotherapy (CRT) followed by brachytherapy (BT) is the standard treatment for locally advanced cervical cancer (LACC), but replacement of BT by surgery (CRT-S) could be an acceptable alternative. The main concern is the risk of operative morbidity. The aim is to report on therapeutic morbidity, OS, PC, and LC of CRT-S. METHODS: This was a single tertiary center retrospective cohort study in patients treated with CRT-S. A type II Wertheim hysterectomy was performed 6-8 weeks after CRT. Acute and chronic radiotherapy-related and surgical morbidity was classified according to the CTCAE v4.0. OS, and DFS, PC, and LC were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were performed to determine variables with a prognostic role. RESULTS: A total of 130 consecutive LACC patients were treated with CRT, and 119 underwent completion surgery. The median follow-up was 53 months. Five-year OS rate, local control, pelvic control, and 5-year DFS rate were 73%, 93%, 90%, and 74%, respectively. The 5-year OS rate was 92%/72%/67%/56% for FIGO (2009) stage I/II/III/IV, respectively. The five-year OS rate was 79% and 71% for adenocarcinoma and squamous cell carcinoma (p > 0.05), respectively. There was no intra- and perioperative mortality. Intraoperative and early postoperative complication rates were 7% and 20% (3% ≥ G3), respectively; they resolved within 3 months. The late postoperative complication rate was 9% (7% ≥ G3). Acute/late radiotherapy-related G3 side effects were 5%/3% for gastrointestinal and 3%/7% for genitourinary side effects. CONCLUSIONS: CRT-S is safe with an acceptable rate of complications for both the CRT and completion surgery and shows encouraging outcome data for stage III/IV and adenocarcinoma patients.

Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment.

We investigated the potential of tumor-infiltrating immune cells (ICs) as predictive or prognostic biomarkers for cervical cancer patients. In total, 38 patients treated with (chemo)radiotherapy and subsequent surgery were included in the current study. This unique treatment schedule makes it possible to analyze IC markers in pretreatment and posttreatment tissue specimens and their changes during treatment. IC markers for T cells (CD3, CD4, CD8 and FoxP3), macrophages (CD68 and CD163) and B cells (CD20), as well as IL33 and PD-L1, were retrospectively analyzed via immunohistochemistry. Patients were grouped in the low score or high score group based on the amount of positive cells on immunohistochemistry. Correlations to pathological complete response (pCR), cause-specific survival (CSS) and metastasis development during follow-up were evaluated. In analysis of pretreatment biopsies, significantly more pCR was seen for patients with CD8 = CD3, CD8 ≥ CD4, positive IL33 tumor cell (TC) scores, IL33 IC < TC and PD-L1 TC ≥5%. Besides patients with high CD8 scores, also patients with CD8 ≥ CD4, CD163 ≥ CD68 or PD-L1 IC ≥5% had better CSS. In the analysis of posttreatment specimens, less pCR was observed for patients with high CD8 or CD163 scores. Patients with decreasing CD8 or CD163 scores between pretreatment and posttreatment samples showed more pCR, whereas those with increasing CD8 or decreasing IL33 IC scores showed a worse CSS. Meanwhile, patients with an increasing CD3 score or stable/increasing PD-L1 IC score showed more metastasis during follow-up. In this way, the intratumoral IC landscape is a promising tool for prediction of outcome and response to (chemo)radiotherapy.

Splenic 18F-FDG uptake on baseline PET/CT is associated with oncological outcomes and tumor immune state in uterine cervical cancer.

OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.

PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.

BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer.

BACKGROUND: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. METHODS: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. DISCUSSION: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017.

EXclusion of non-Involved uterus from the Target Volume (EXIT-trial): an individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques.

BACKGROUND: Definitive chemoradiotherapy is standard of care in locally advanced cervical cancer (LACC). Both toxicity and local relapse remain major concerns in this treatment. We hypothesize that a magnetic resonance imaging (MRI) based redefining of the radiotherapeutic target volume will lead to a reduction of acute and late toxicity. In our center, chemoradiotherapy followed by hysterectomy was implemented successfully in the past. This enables us to assess the safety of reducing the target volume but also to explore the biological effects of chemoradiation on the resected hysterectomy specimen. METHODS: The EXIT-trial is a phase II, single arm study aimed at LACC patients. This study evaluates whether a MRI-based exclusion of the non-tumor-bearing parts of the uterus out of the target volume results in absence of tumor in the non-high doses irradiated part of the uterus in the hysterectomy specimen. Secondary endpoints include a dosimetric comparison of dose on normal tissue when comparing study treatment plans compared to treatment of the whole uterus at high doses; acute and chronic toxicity, overall survival, local relapse- and progression-free survival. In the translational part of the study, we will evaluate the hypothesis that the baseline apparent diffusion coefficient (ADC) values of diffusion weighted MRI and its evolution 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on the hysterectomy specimen. DISCUSSION: Although MRI is already used to guide target delineation in brachytherapy, the EXIT-trial is the first to use this information to guide target delineation in external beam radiotherapy. Early therapy resistance prediction using DW-MRI opens a window for early treatment adaptation or further dose-escalation on tumors/intratumoral regions at risk for treatment failure. TRIAL REGISTRATION: Belgian Registration: B670201526181 (prospectively registered, 26/11/2015); ClinicalTrials.gov Identifier: NCT03542942 (retrospectively registered, 17/5/2018).

Neo-adjuvant treatment of adenocarcinoma and squamous cell carcinoma of the cervix results in significantly different pathological complete response rates.

BACKGROUND: Previous studies on cervical cancer reported a worse outcome for adenocarcinoma (AC) compared with squamous cell carcinoma (SCC). Nevertheless, standard treatment remains identical. Insight in the impact of histological types on biological behavior and pathological complete response rates might result in a treatment paradigm shift. METHODS: Clinicopathological characteristics, survival rates and relapse patterns were compared between AC (n = 36) and SCC (n = 143) cervical cancer patients. Pathological response to treatment was evaluated in the patient subgroup treated with neo-adjuvant chemoradiation followed by surgery (NA-CRT group; n = 84). RESULTS: In the entire cohort, 5y Disease Specific Survival (DSS) was 97.1 and 84% for AC and SCC respectively (p = 0.150). In the NA-CRT group 5y DSS was 100 and 75.5% for AC and SCC respectively (p = 0.059). Relapse patterns did not differ significantly between AC and SCC in the entire cohort, or in the NA-CRT group. Adenocarcinoma patients treated with NA-CRT showed significantly less pathological complete response compared with SCC patients (AC = 7%, SCC = 43%, p = 0.027). CONCLUSIONS: There were no statistically significant differences regarding relapse and DSS rates between SCC and AC in the entire cohort, or the NA-CRT group. However, a trend to better 5y DSS of AC in the NA-CRT group was observed. This analysis showed significant differences in treatment responses after NA-CRT: patients with AC responded remarkably less to chemoradiation, resulting in a significantly lower pathological complete response rate. These findings imply a need for a paradigm shift in the treatment of cervical AC patients.

External partial breast irradiation in prone position: how to improve accuracy?

INTRODUCTION: In view of the limited incremental benefit between whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) and omission of radiotherapy in favorable early-stage breast cancer (ESBC), APBI can only be justified if it combines adequate target coverage with the lowest achievable toxicity. Interobserver exercises demonstrated the difficulty of precise target delineation, especially in prone position; information on accuracy is even scarcer. We tested the impact of inserting an additional indicator clip, marking the depth of the tumor in the breast, and the added value of a preoperative CT in treatment position on precision and accuracy. MATERIAL AND METHODS: In 12 patients, tumor bed delineation was performed by four radiation oncologists, with CTVstandard (clinical target volume) based on standard delineation guidelines, CTVclip resulting from a 1-2-cm symmetrical expansion with the indicator clip as center and CTVclip_CT expanding from the midpoint between the indicator clip and preoperative gross tumor volume (GTV) as center. Precision was measured as the mean pairwise Jaccard index (JIpairs) between observers, accuracy as the mean overlap between GTV and respective CTVs. RESULTS: JIpairs was 0.38 for CTVstandard, 0.75 for CTVclip and 0.59 for CTVclip_CT. Overlap rate of GTV with CTVs was respectively 0.48, 0.67 and improved further to 0.88 for CTVclip_CT. High-dose coverage of GTV (D95 and D90) improved with an indicator clip, but the most optimal result was reached when preoperative CT was added. CONCLUSIONS: If EB-APBI in prone position is aimed for, an indicator clip intended to mark the depth of the tumor increases the probability of accurate target coverage, but cannot entirely replace the added value of a preoperative CT in treatment position. Avoiding the cost and effort of such CT implies a risk of missing the target, especially when small volumes are aimed for. Increasing target volumes to reduces this risk, questions the concept of APBI.

Advanced Ovarian Cancer: Primary or Interval Debulking? Five Categories of Patients in View of the Results of Randomized Trials and Tumor Biology: Primary Debulking Surgery and Interval Debulking Surgery for Advanced Ovarian Cancer.

BACKGROUND: Standard treatment of stage III and IV advanced ovarian cancer (AOC) consists of primary debulking surgery (PDS) followed by chemotherapy. Since the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial, clinical practice has changed and many AOC patients are now treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The best option remains unclear. Ovarian cancer is a heterogenic disease. Should we use the diversity in biology of the tumor and patterns of tumor localization to better stratify patients between both approaches? METHODS: This analysis was based on results of five phase III randomized controlled trials on PDS and IDS in AOC patients, three Cochrane reviews, and four meta-analyses. RESULTS: There is still no evidence that NACT-IDS is superior to PDS. Clinical status, tumor biology, and chemosensitivity should be taken into account to individualize surgical approach. Nonserous (type 1) tumors with favorable prognosis are less chemosensitive, and omitting optimal PDS will lead to less favorable outcome. For patients with advanced serous ovarian cancer (type 2) associated with severe comorbidity or low performance status, NACT-IDS is the preferred option. CONCLUSION: We propose stratifying AOC patients into five categories according to patterns of tumor spread (reflecting the biologic behavior), response to chemotherapy, and prognosis to make a more rational decision between PDS and NACT-IDS. IMPLICATIONS FOR PRACTICE: Trial results regarding effect and timing of debulking surgery on survival of patients with advanced ovarian cancer have been inconsistent and hence difficult to interpret. This review examines all randomized trials on primary and interval debulking surgery in advanced ovarian cancer, including the results of the newly published CHORUS (chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer) trial. On the basis of findings presented in this review and in view of recent molecular data on the heterogeneity of ovarian tumors, we propose prognostic categorization for patients with advanced ovarian cancer to better distinguish those who would optimally benefit from primary debulking from those who would better benefit from interval debulking following neoadjuvant chemotherapy.

Immunogenic Apoptotic Cell Death and Anticancer Immunity.

For many years it has been thought that apoptotic cells rapidly cleared by phagocytic cells do not trigger an immune response but rather have anti-inflammatory properties. However, accumulating experimental data indicate that certain anticancer therapies can induce an immunogenic form of apoptosis associated with the emission of damage-associated molecular patterns (DAMPs), which function as adjuvants to activate host antitumor immune responses. In this review, we will first discuss recent advances and the significance of danger signaling pathways involved in the emission of DAMPs, including calreticulin, ATP, and HMGB1. We will also emphasize that switching on a particular signaling pathway depends on the immunogenic cell death stimulus. Further, we address the role of ER stress in danger signaling and the classification of immunogenic cell death inducers in relation to how ER stress is triggered. In the final part, we discuss the role of radiotherapy-induced immunogenic apoptosis and the relationship of its immunogenicity to the fraction dose and concomitant chemotherapy.

Adaptive radiotherapy for locally advanced non-small cell lung cancer, can we predict when and for whom?

BACKGROUND: Adaptive radiotherapy (ART) could be a tool to reduce toxicity and to facilitate dose escalation in stage III NSCLC. Our aim was to identify the most appropriate time and potential benefit of ART. MATERIAL AND METHODS: We analyzed volume reduction and dosimetric consequences of 41 patients who were treated with concurrent (cCRT) (n = 21) or sequential (sCRT) chemoradiotherapy to a median dose of 70 Gy, 2 Gy/F. At every treatment fraction a cone-beam CT (CBCT) was performed. The gross tumor volume (GTV-T) was adapted (exclusion of lymph nodes) to create the GTV-T-F1. Every fifth fraction (F5-F30), the GTV-T-F1 was adapted on the CBCT to create a GTV-T-Fx. Dose volume histograms were recalculated for every GTV-T-Fx, enabling to create lookup tables to predict the theoretical dosimetric advantage on common lung dose constraints. RESULTS: The average GTV reduction was 42.1% (range 4.0-69.3%); 50.1% and 33.7% for the cCRT and sCRT patients, respectively. A linear relationship between GTV-T-F1 volume and absolute volume decrease was found for both groups. The mean V5, V20, V30 and mean lung dose increased by 0.8, 3.1, 5.2 and 3.4%, respectively. A larger increase (p < 0.05) was observed for peripheral tumors and cCRT. Lookup tables were generated. CONCLUSION: ART offers the most beneficial dosimetric effects when performed around fraction 15, especially for patients with a large initial GTV-T treated by cCRT.

Reliability and accuracy assessment of Radiation Therapy Oncology Group-endorsed guidelines for brachial plexus contouring.

PURPOSE: The goal of this work was to validate the Radiation Therapy Oncology Group (RTOG)-endorsed guidelines for brachial plexus (BP) contouring by determining the intra- and interobserver agreement. Accuracy of the delineation process was determined using anatomically validated imaging datasets as a gold standard. MATERIALS AND METHODS: Five observers delineated the right BP on three cadaver computed tomography (CT) datasets. To assess intraobserver variation, every observer repeated each delineation three times with a time interval of 2 weeks. The BP contours were divided into four regions for detailed analysis. Inter- and intraobserver variation was verified using the Computerized Environment for Radiation Research (CERR) software. Accuracy was measured using anatomically validated fused CT-magnetic resonance imaging (MRI) datasets by measuring the BP inclusion of the delineations. RESULTS: The overall kappa (κ) values were rather low (mean interobserver overall κ: 0.29, mean intraobserver overall κ: 0.45), indicating poor inter- and intraobserver reliability. In general, the κ coefficient decreased gradually from the medial to lateral BP regions. The total agreement volume (TAV) was much smaller than the union volume (UV) for all delineations, resulting in a low Jaccard index (JI; interobserver agreement 0-0.124; intraobserver agreement 0.004-0.636). The overall accuracy was poor, with an average total BP inclusion of 38%. Inclusions were insufficient for the most lateral regions (region 3: 21.5%; region 4: 12.6%). CONCLUSION: The inter- and intraobserver reliability of the RTOG-endorsed BP contouring guidelines was poor. BP inclusion worsened from the medial to lateral regions. Accuracy assessment of the contours showed an average BP inclusion of 38%. For the first time, this was assessed using the original anatomically validated BP volume. The RTOG-endorsed BP guidelines have insufficient accuracy and reliability, especially for the lateral head-and-neck regions.

Incidence and radiotherapy treatment patterns of complicated bone metastases.

Background: Despite the encouraging results of the SCORAD trial, single fraction radiotherapy (SFRT) remains underused for patients with complicated bone metastases with rates as low as 18-39%. We aimed to evaluate the incidence and treatment patterns of these metastases in patients being referred to a tertiary centre for palliative radiotherapy. Materials and methods: We performed a retrospective review of all bone metastases treated at our centre from January 2013 until December 2017. Lesions were classified as uncomplicated or complicated. Complicated was defined as associated with (impending) fracture, existing spinal cord or cauda equina compression. Our protocol suggests using SFRT for all patients with complicated bone metastases, except for those with symptomatic neuraxial compression and a life expectancy of ≥28 weeks. Results: Overall, 37 % of all bone metastases were classified as complicated. Most often as a result of an (impending) fracture (56 %) or spinal cord compression (44 %). In 93 % of cases, complicated lesions were located in the spine, most commonly originating from prostate, breast and lung cancer (60 %). Median survival of patients with complicated bone metastases was 4 months. The use of SFRT for complicated bone metastases increased from 51 % to 85 % over the study period, reaching 100 % for patients with the poorest prognosis. Conclusions: Approximately 37 % of bone metastases are classified as complicated with the majority related to (impending) fracture. Patients with complicated bone metastases have a median survival of 4 months and were mostly treated with SFRT.

Performance of MRI for Detection of ≥pT1b Disease in Local Staging of Endometrial Cancer.

Magnetic resonance imaging (MRI) can be used for the preoperative local staging of endometrial cancer (EC). The presence of ≥pT1b disease (i.e., tumor invasion in ≥50% of the myometrium, into the cervical stroma or spread outside the uterus) has important prognostic value and implications for the decision to perform lymphadenectomy. The purpose of this study was to assess the performance of MRI for the detection of ≥pT1b disease and to evaluate whether tumor size measured via MRI was predictive for ≥pT1b disease, independent of imaging signs of deep invasion. MRI T-staging and tumor diameter and volume were correlated with histopathology of the hysterectomy specimen in 126 patients. MRI had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 70.0%, 83.3%, 79.2%, 75.3% and 77.0%, respectively, for the detection of ≥pT1b disease. A tumor diameter of ≥40 mm and volume of ≥20 mL measured via MRI were predictive for ≥pT1b disease at rates of 78.3% and 87.1%, respectively. An EC size of at least 5 mm upon MRI was predictive for ≥pT1b disease in more than 50% of cases. Our results support the use of MRI in the preoperative staging of EC and suggest including size criteria in EC staging guidelines.

Exclusion of non-Involved uterus from the target volume (EXIT-trial): An individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques followed by completion surgery.

Background and purpose: Chemoradiotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer (LACC). In this study, we postulate that omitting an iconographical unaffected uterus (+12 mm distance from the tumour) from the treatment volume is safe and that no tumour will be found in the non-targeted uterus (NTU) leading to reduction of high-dose volumes of surrounding organs at risk (OARs). Material and Methods: In this single-arm phase 2 study, two sets of target volumes were delineated: one standard-volume (whole uterus) and an EXIT-volume (exclusion of non-tumour-bearing parts of the uterus with a minimum 12 mm margin from the tumour). All patients underwent chemoradiotherapy targeting the EXIT-volume, followed by completion hysterectomy. In 15 patients, a plan comparison between two treatment plans (PTV vs PTV_EXIT) was performed. The primary endpoint was the pathological absence of tumour involvement in the non-targeted uterus (NTU). Secondary endpoints included dosimetric impact of target volume reduction on OARs, acute and chronic toxicity, overall survival (OS), locoregional recurrence-free survival (LRFS), and progression-free survival (PFS). Results: In all 21 (FIGO stage I: 2; II: 14;III: 3; IV: 2) patients the NTU was pathologically negative. Ssignificant reductions in Dmean in bladder, sigmoid and rectum; V15Gy in sigmoid and rectum, V30Gy in bladder, sigmoid and rectum; V40Gy and V45Gy in bladder, bowel bag, sigmoid and rectum; V50Gy in rectum were achieved. Median follow-up was 54 months (range 7-79 months). Acute toxicity was mainly grade 2 and 5 % grade 3 urinary. The 3y- OS, PFS and LRFS were respectively 76,2%, 64,9% and 81 %. Conclusion: MRI-based exclusion of the non-tumour-bearing parts of the uterus at a minimum distance of 12 mm from the tumour out of the target volume in LACC can be done without risk of residual disease in the NTU, leading to a significant reduction of the volume of surrounding OARS treated to high doses.

Completion surgery after intensity-modulated arc therapy in the treatment of locally advanced cervical cancer: feasibility, surgical outcome, and oncologic results.

INTRODUCTION: Since the addition of chemotherapy to radiotherapy, the survival rates of locally advanced cervical cancer (LACC) have improved but are still disappointing. Therefore, the idea of surgery after chemoradiation in case of LACC or bulky disease was adopted. One of the concerns regarding surgery following chemoradiotherapy is surgery-related morbidity. AIM: The objectives of this study were to investigate the feasibility of surgery after advanced radiotherapy techniques such as intensity-modulated arc therapy (IMAT) and to describe the morbidity. METHODS: This was a prospective study of primary inoperable LACC patients primary treated with IMAT, in most cases combined with weekly cisplatin. Then the resectability was reevaluated. If resectable patients were treated with Wertheim type 2 surgery ± pelvic lymphadenectomy (on positron emission tomography-computed tomography indication). If tumor is not resectable, patients were treated with brachytherapy. RESULTS: Since 2006, 41 consecutive patients were included. After neoadjuvant IMAT, 34 were considered resectable and underwent surgery, whereas 7 proceeded with brachytherapy. The operative mortality rate was nil. There were no major perioperative complications. No ureter, bladder, or bowel injuries occurred. No postoperative urinary/digestive fistulae or stenoses were noted. Eleven patients had postoperatively urinary retention problems. At the time of discharge, 5 patients still needed self-catheterization. All problems resolved within 3 months. In 4 cases, we saw significant lymphoceles. In all patients intended to treat, overall survival and disease-free survival at 3 years were 63% and 74%. In the Wertheim group, overall survival and disease-free survival at 3 years were 81% and 91%. CONCLUSIONS: Completing surgery after chemoradiation therapy (with IMAT) for LACC or bulky disease is feasible, and complication rates are comparable with those of primary surgery for cervical cancer.