REPeated mAgnetic resonance Image-guided stereotactic body Radiotherapy (MRIg-reSBRT) for oligometastatic patients: REPAIR, a mono-institutional retrospective study.

BACKGROUND: Oligo-progression or further recurrence is an open issue in the multi-integrated management of oligometastatic disease (OMD). Re-irradiation with stereotactic body radiotherapy (re-SBRT) technique could represent a valuable treatment option to improve OMD clinical outcomes. MRI-guided allows real-time visualization of the target volumes and online adaptive radiotherapy (oART). The aim of this retrospective study is to evaluate the efficacy and toxicity profile of MRI-guided repeated SBRT (MRIg-reSBRT) in the OMD setting and propose a re-SBRT classification. METHODS: We retrospectively analyzed patients (pts) with recurrent liver metastases or abdominal metastatic lesions between 1 and 5 centimeters from liver candidate to MRIg-reSBRT showing geometric overlap between the different SBRT courses and assessing whether they were in field (type 1) or not (type 2). RESULTS: Eighteen pts completed MRIg-reSBRT course for 25 metastatic hepatic/perihepatic lesions from July 2019 to January 2020. A total of 20 SBRT courses: 15 Type 1 re-SBRT (75%) and 5 Type 2 re-SBRT (25%) was delivered. Mean interval between the first SBRT and MRIg-reSBRT was 8,6 months. Mean prescribed dose for the first treatment was 43 Gy (range 24-50 Gy, mean BEDα/ß10=93), while 41 Gy (range 16-50 Gy, mean BEDα/ß10=92) for MRIg-reSBRT. Average liver dose was 3,9 Gy (range 1-10 Gy) and 3,7 Gy (range 1,6-8 Gy) for the first SBRT and MRIg-reSBRT, respectively. No acute or late toxicities were reported at a median follow-up of 10,7 months. The 1-year OS and PFS was 73,08% and 50%, respectively. Overall Clinical Benefit was 54%. CONCLUSIONS: MRIg-reSBRT could be considered an effective and safe option in the multi-integrated treatment of OMD.

Efficacy of stereotactic body radiotherapy and response prediction using artificial intelligence in oligometastatic gynaecologic cancer.

PURPOSE: We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed. METHODS: A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS. RESULTS: 501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR. CONCLUSIONS: CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology.

Machine-learning prediction of treatment response to stereotactic body radiation therapy in oligometastatic gynecological cancer: A multi-institutional study.

BACKGROUND AND PURPOSE: We aimed to develop and validate different machine-learning (ML) prediction models for the complete response of oligometastatic gynecological cancer after SBRT. MATERIAL AND METHODS: One hundred fifty-seven patients with 272 lesions from 14 different institutions and treated with SBRT with radical intent were included. Thirteen datasets including 222 lesions were combined for model training and internal validation purposes, with an 80:20 ratio. The external testing dataset was selected as the fourteenth Institution with 50 lesions. Lesions that achieved complete response (CR) were defined as responders. Prognostic clinical and dosimetric variables were selected using the LASSO algorithm. Six supervised ML models, including logistic regression (LR), classification and regression tree analysis (CART) and support vector machine (SVM) using four different kernels, were trained and tested to predict the complete response of uterine lesions after SBRT. The performance of models was assessed by receiver operating characteristic curves (ROC), area under the curve (AUC) and calibration curves. An explainable approach based on SHapley Additive exPlanations (SHAP) method was deployed to generate individual explanations of the model's decisions. RESULTS: 63.6% of lesions had a complete response and were used as ground truth for the supervised models. LASSO strongly associated complete response with three variables, namely the lesion volume (PTV), the type of lesions (lymph-nodal versus parenchymal), and the biological effective dose (BED10), that were used as input for ML modeling. In the training set, the AUCs for complete response were 0.751 (95% CI: 0.716-0.786), 0.766 (95% CI: 0.729-0.802) and 0.800 (95% CI: 0.742-0.857) for the LR, CART and SVM with a radial basis function kernel, respectively. These models achieve AUC values of 0.727 (95% CI: 0.669-0.795), 0.734 (95% CI: 0.649-0.815) and 0.771 (95% CI: 0.717-0.824) in the external testing set, demonstrating excellent generalizability. CONCLUSION: ML models enable a reliable prediction of the treatment response of oligometastatic lesions receiving SBRT. This approach may assist radiation oncologists to tailor more individualized treatment plans for oligometastatic patients.

The Impact of HAPPY (Humanity Assurance Protocol in Interventional Radiotherapy) on the Psychological Well-being of Gynecological Cancer Patients.

BACKGROUND: HAPPY (Humanity Assurance Protocol in interventional radiotherapy) reports the necessity for gynecological cancer patients to undergo interventional radiotherapy (IRT, also called brachytherapy). The present paper has evaluated how some precautions may improve the psychological well-being of the patients during IRT. METHODS: Patients with gynecological cancer undergoing IRT-HDR were analyzed. Patients answered three questionnaires before the IRT procedure (T0) and at the end of IRT (T1): Distress Thermometer (DT), Numerical Rating Scale for IRT procedure distress (NRS), and Hospital Anxiety and Depression Scale (HADS). Correlations have been calculated pairwise through pandas. corrwith with a Pearson algorithm, and the p-values have been calculated through scipy.stats.pearsonr. Plots have been generated through seaborn and matplotlib. A Wilcoxon test was used. RESULTS: 55 patients were selected for this study. The median age of the patients was 64 (range, 39-84) years. 52 patients were with stage I endometrial cancer, whereas 3/3 patients with cervical cancer had locally advanced stages (IIB-IVA). 26 patients had a high education level (47.3%), and 38 were married or with a partner (69.1%). Only 14/55 (25.45%) patients were working. The HADS, DT, and NRS averages before the IRT procedure (T0) were 10.2, 3.8, and 4.3, respectively. After applying the HAPPY protocol, the HADS, DT, and NRS averages after IRT (T1) were 9.4, 3.4, and 2.6, respectively. The Wilcoxon signed rank test analysis showed a significant improvement in NRS (p < 0.00001) and HADS (p = 0.034). Living with a partner, parents or relatives was the only parameter statistically significantly associated with better DT pre-IRT (p = 0.04), HADS pre-IRT (p = 0.01), DT post-IRT (p = 0.01), and HADS post-IRT (p = 0.04). CONCLUSION: In our study, the HAPPY protocol was associated with a significant reduction in patients' distress, anxiety, and discomfort.

Efficacy and Safety of Stereotactic Body Radiation Therapy in Oligometastatic Uterine Cancer (MITO-RT2/RAD): A Large, Real-World Study in Collaboration With Italian Association of Radiation Oncology, Multicenter Italian Trials in Ovarian Cancer, and Mario Negri Gynecologic Oncology Group Groups.

PURPOSE: This retrospective, multicenter study analyzes the efficacy and safety of stereotactic body radiation therapy in a large cohort of patients with oligometastatic/persistent/recurrent uterine cancer. METHODS AND MATERIALS: Clinical and radiation therapy data from several radiation therapy centers treating patients by stereotactic body radiation therapy between March 2006 and October 2021 were collected. Objective response rate was defined as complete and partial response, and clinical benefit included objective response rate plus stable disease. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer and Common Terminology Criteria for Adverse Events scales were used to grade toxicities. Primary endpoints were the rate of complete response to stereotactic body radiation therapy, and the 2-year actuarial local control rate "per-lesion" basis. Secondary endpoints were progression-free survival and overall survival, as well as toxicity. RESULTS: In the study, 157 patients with oligometastatic/persistent/recurrent uterine cancer bearing 272 lesions treated by stereotactic body radiation therapy at 14 centers were analyzed. Lymph node metastases (137, 50.4%) were prevalent, followed by parenchyma lesions (135, 49.6%). Median total dose was 35 Gy (10-75.2), in 5 fractions (range, 1-10). Complete and partial responses were 174 (64.0%), and 54 (19.9%), respectively. Stable disease was registered in 29 (10.6%), and 15 (5.5%) lesions progressed. Type of lesion (lymph node), volume (≤13.7 cc) and total dose (BED10 >59.5 Gy) were significantly associated with a higher probability of achieving complete response. Patients achieving complete response (CR) "per-lesion" basis experienced a 2-year actuarial local control rate of 92.4% versus 33.5% in lesions not achieving complete response (NCR; P < .001). Moreover, the 2-year actuarial progression-free survival rate in patients with CR was 45.4%, and patients with NCR had a 2-year rate of 17.6% (P < .001). Finally, patients who had a CR had a 2-year overall survival rate of 82.7%, compared with 56.5% for NCR patients (P <.001). Severe acute toxicity was around 2%, including one toxic death due to gastric perforation, and severe late toxicity around 4%. CONCLUSIONS: The efficacy of stereotactic body radiation therapy in this setting was confirmed. The low toxicity profile and the high local control rate in complete responder patients encourage the wider use of this approach.

Recurrent Endometrial Cancer: Which Is the Best Treatment? Systematic Review of the Literature.

BACKGROUND: Endometrial cancer is the most common gynaecological tumour in developed countries. The overall rate of relapse has remained unchanged in recent decades. Recurrences occur in approximately 20% of endometrioid and 50% of non-endometrioid cases. The aim of this systematic review is to compare different therapeutic strategies in the treatment of endometrial cancer recurrence to evaluate their prognostic and curative effects based on site and type of recurrence. METHODS: This systematic review of literature was conducted in accordance with the PRISMA guidelines. The study protocol was registered on PROSPERO (CRD42020154042). PubMed, Embase, Chocrane and Cinahl databases were searched from January 1995 to September 2021. Five retrospective studies were selected. RESULTS: A total of 3571 studies were included in the initial search. Applying the screening criteria, 299 articles were considered eligible for full-text reading, of which, after applying the exclusion criteria, 4 studies were selected for the final analysis and included in the systematic review. No studies were included for a quantitative analysis. We divided the results according to the location of the recurrence: locoregional recurrence, abdominal recurrence and extra abdominal recurrence. CONCLUSION: the treatment of choice should be assessed according to the relapse location and to the presence of single or multiple lesions. A crucial role in the decision-making algorithm is also the type of adjuvant treatment received at the time of the first diagnosis.

Evaluation of early regression index as response predictor in cervical cancer: A retrospective study on T2 and DWI MR images.

BACKGROUND AND PURPOSE: Early Regression Index (ERITCP) is an image-based parameter based on tumor control probability modelling, that reported interesting results in predicting pathological complete response (pCR) after pre-operative chemoradiotherapy (CRT) in rectal cancer. This study aims to evaluate this parameter for Locally Advanced Cervical Cancer (LACC), considering not only T2-weighted but also diffusion-weighted (DW) Magnetic Resonance (MR) images, comparing it with other image-based parameters such as tumor volumes and apparent coefficient diffusion (ADC). MATERIALS AND METHODS: A total of 88 patients affected by LACC (FIGO IB2-IVA) and treated with CRT were enrolled. An MRI protocol consisting in two acquisitions (T2-w and DWI) in two times (before treatment and at mid-therapy) was applied. Gross Tumor Volume (GTV) was delineated and ERITCP was calculated for both imaging modalities. Surgery was performed for each patient after nCRT: pCR was considered in case of absence of any residual tumor cells. The predictive performance of ERITCP, GTV volumes (calculated on T2-w and DW MR images) and ADC parameters were evaluated in terms of area (AUC) under the Receiver Operating Characteristic (ROC) curve considering pCR and two-years survival parameters as clinical outcomes. RESULTS: ERITCP and GTV volumes calculated on DW MR images (ERIDWI and Vmid_DWI) significantly predict pCR (AUC = 0.77 and 0.75 respectively) with results superior to those observed considering T2-w MR images or ADC parameters. Significance was also reported in the prediction of 2-years local control and disease free-survival. CONCLUSION: This study identified ERITCP and Vmid as good predictor of pCR in case of LACC, especially if calculated considering DWI. Using these indicators, it is possible to early identify not responders and modifying the treatment, accordingly.

Postoperative treatment of intermediate-risk early stage cervical cancer: results of a survey from the Gynecology Study Group in the AIRO Gyn and MITO Groups.

This survey investigated prognostic factors, treatment modalities, references followed and radiation oncologists' opinions to prescribe adjuvant therapy in early intermediate-risk cervical cancer. All but one recommended pelvic radiotherapy ± vaginal boost (45%) with or without chemotherapy (20%). 88% believed other prognostic factors could integrate classic risk criteria. 66% considered chemo-radiation indicated in case of lymphovascular invasion and suboptimal node dissection, high grade, size ≥ 4 cm, non squamous histology and risk factors combination. This wide heterogeneity of treatments reflects the different guideline options due to the lack of defined indications. The need of integrating the classic prognostic factors with others factors was unanimously expressed by radiation oncologists. The best local and systemic therapy should be established through new studies. These results highlighted the need of a position paper to standardize adjuvant treatment in Italy and to design collaborative studies to clarify the controversial aspects.

Neoadjuvant Chemoradiotherapy With Simultaneous Integrated Boost in Locally Advanced Cervical Cancer: Long Term Results of a Single-Center Experience.

Aim of this study was to analyze the efficacy and tolerability of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) associated with cisplatin-based chemotherapy in preoperative setting of patients with locally advanced cervical cancer (LACC). From June 2013 to September 2019, we analyzed patients with LACC who had undergone neoadjuvant chemoradiation (CRT). A radiation dose of 39.6 Gy, 1.8 Gy/fraction was delivered to the pelvis plus a radiation dose to the primary tumor delivered with SIB-VMAT strategy for a total of 50.6Gy, 2.3Gy/fraction in 25 fractions. Cisplatin-based chemotherapy was delivered combined with radiotherapy. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 7 to 8 weeks from CRT. One hundred forty-eight patients (median age: 49.5 years; FIGO stage IB2: 7, IIA: 8, IIB: 106, IIIA: 5; IIIB: 16; IVA: 5, IVB: 1; N0: 56, N1: 92) were analyzed. The treatment was well tolerated with good compliance: no grade 3/4 gastrointestinal or genitourinary toxicity was reported; grade 3 neutropenia was described in five cases. Pathological complete response (pCR) was documented in 68 cases (46%) and 32 patients (21.6%) had microscopic residual disease. Pathological nodal involvement was observed in 23 patients (15.5%). At median follow-up of 59 months (range: 27-100), the 3-year local control was 78.5%, whereas the 3-year metastasis-free survival was 70.5%. The 3-year overall survival rate was 89.0%. Neoadjuvant CRT with SIB-VMAT followed by radical surgery results in a high rate of pathologically assessed complete response and a very encouraging local control rate, with acceptable toxicity.

Radiomics-based prediction of two-year clinical outcome in locally advanced cervical cancer patients undergoing neoadjuvant chemoradiotherapy.

PURPOSE: The aim of this study is to determine if radiomics features extracted from staging magnetic resonance (MR) images could predict 2-year long-term clinical outcome in patients with locally advanced cervical cancer (LACC) after neoadjuvant chemoradiotherapy (NACRT). MATERIALS AND METHODS: We retrospectively enrolled patients with LACC diagnosis who underwent NACRT followed by radical surgery in two different institutions. Radiomics features were extracted from pre-treatment 1.5 T T2w MR images. The predictive performance of each feature was quantified in terms of Wilcoxon-Mann-Whitney test. Among the significant features, Pearson correlation coefficient (PCC) was calculated to quantify the correlation among the different predictors. A logistic regression model was calculated considering the two most significant features at the univariate analysis showing the lowest PCC value. The predictive performance of the model created was quantified out using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 175 patients were retrospectively enrolled (142 for the training cohort and 33 for the validation one). 1896 radiomic feature were extracted, 91 of which showed significance (p < 0.05) at the univariate analysis. The radiomic model showing the highest predictive value combined the features calculated starting from the gray level co-occurrence-based features. This model achieved an AUC of 0.73 in the training set and 0.91 in the validation set. CONCLUSIONS: The proposed radiomic model showed promising performances in predicting 2-year overall survival before NACRT. Nevertheless, the observed results should be tested in larger studies with consistent external validation cohorts, to confirm their potential clinical use.

Stereotactic body radiotherapy in oligometastatic cervical cancer (MITO-RT2/RAD study): a collaboration of MITO, AIRO GYN, and MaNGO groups.

OBJECTIVE: This retrospective, multicenter study analyzes the efficacy and safety of stereotactic body radiotherapy in a large cohort of patients with oligometastatic/persistent/recurrent cervical cancer. METHODS: A standardized data collection from several radiotherapy centers that treated patients by stereotactic body radiotherapy between March 2006 and February 2021 was set up. Clinical and stereotactic body radiotherapy parameters were collected. Objective response rate was defined as a composite of complete and partial response, while clinical benefit included objective response rate plus stable disease. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer and Common Terminology Criteria for Adverse Events scales were used to grade toxicities. The primary endpoints were the rate of complete response to stereotactic body radiotherapy, and the 2 year actuarial local control rate on a 'per lesion' basis. The secondary end points were progression-free survival and overall survival, as well as toxicity. RESULTS: A total of 83 patients with oligometastatic/persistent/recurrent cervical cancer bearing 125 lesions treated by stereotactic body radiotherapy at 15 different centers were selected for analysis. Of the sites of metastatic disease, lymph node metastases were most common (55.2%), followed by parenchyma lesions (44.8%). Median total dose was 35 Gy (range 10-60), in five fractions (range 1-10), with a median dose/fraction of 7 Gy (range 4-26). Complete, partial, and stable response were found in 73 (58.4%), 29 (23.2%), and 16 (12.8%) lesions, respectively, reaching 94.4% of the clinical benefit rate. Forty-six (55.4%) patients had a complete response. Patients achieving complete response on a 'per lesion' basis experienced a 2 year actuarial local control rate of 89.0% versus 22.1% in lesions not achieving complete response (p<0.001). The 2 year actuarial progression-free survival rate was 42.5% in patients with complete response versus 7.8% in patients with partial response or stable or progressive disease (p=0.001). The 2 year actuarial overall survival rate was 68.9% in patients with complete response versus 44.3% in patients with partial response or stable or progressive disease (p=0.015). Fifteen patients (18.1%) had mild acute toxicity, totaling 29 side events. Late toxicity was documented in four patients (4.8%) totaling seven adverse events. CONCLUSION: Our analysis confirmed the efficacy of stereotactic body radiotherapy in oligometastatic/persistent/recurrent cervical cancer patients. The low toxicity profile encourages the wider use of stereotactic body radiotherapy in this setting.

EROS 2.0 study: evaluation of two interventional radiotherapy (brachytherapy) schedules for endometrial cancer: a comparison of late vaginal toxicity rates.

BACKGROUND: To compare the late toxicity rates after two different high dose rate (HDR) adjuvant intravaginal interventional radiotherapy (IRT-brachytherapy) dose schedules in stage I-II endometrial cancer. METHODS: Stage I-II patients with endometrial cancer treated with surgery (with or without lymphadenectomy) and adjuvant HDR-IRT between 2014 and 2020 were included in this analysis. Patients were treated with two schedules. In the first cohort (C1), 21 Gy were delivered in three weekly fractions (7 Gy) prescribed 0.5 cm from the applicator surface. In the second cohort (C2), 24 Gy were delivered in four weekly fractions (6 Gy). The clinical target volume was the upper third of the vagina for C1 and the upper 3 cm for C2. HDR-IRT technique and point prescription (5 mm depth from the applicator surface) were the same for all patients. Vaginal toxicity was scored according to the CTCAE 5.0 scale in terms of the presence versus absence of any toxicity grade. The correlation among toxicity and clinical covariates (age, lymphadenectomy, fractionation, stage) was tested by Pearson correlation test (univariate) and by logistic regression (multivariable). RESULTS: 114 stage I and three stage II patients, median age 62 (range: 32-85) years, were included in this analysis. The mean follow-up was 56.3 months in C1 (40-76) and 20 months in C2 (8-42). Vaginal late toxicity was recorded in 40 and 15 patients in C1 and 2, respectively. Age, lymphadenectomy, and fractionation were significantly correlated with toxicity at univariate analysis (p value = 0.029, 0.006, and 0.002, respectively), while stepwise logistic regression confirmed only age and fractionation as significantly correlated parameters (p value = 0.02 and 0.001, respectively). Three-year local relapse-free, distant metastasis-free and cause-specific survival rates were 96.6%, 94.8%, and 99.1%, respectively. CONCLUSIONS: This analysis showed lower vaginal late toxicity rate in C2 compared to C1.

Brachytherapy or external beam radiotherapy as a boost in locally advanced cervical cancer: a Gynaecology Study Group in the Italian Association of Radiation and Clinical Oncology (AIRO) review.

This review analyzes the experience and trends in external beam radiotherapy for delivering a boost in locally advanced cervical cancer, identifying whether radiation therapy modalities impact clinical outcomes with the ultimate aim of evaluating alternatives to brachytherapy. Three independent Italian radiation oncologists conducted a literature search on different external beam radiotherapy boost modalities in locally advanced cervical cancer. The search yielded 30 studies. Eight dosimetric studies, evaluating target coverage and dose to organs at risk, and nine clinical investigations, reporting clinical outcomes, were analyzed. Dosimetric studies comparing external beam radiotherapy boost with brachytherapy produced divergent results, while clinical studies were limited by their retrospective nature, heterogeneous doses, radiation schedules, volumes and techniques, diverse follow-up times, and small cohorts of patients. Evidence emerged that high-tech external beam radiotherapy seemed no better than image-guided brachytherapy for delivering a boost in locally advanced cervical cancer. Prospective clinical studies comparing high-tech external beam radiotherapy and image-guided brachytherapy should be encouraged.

Cervical cancer patterns of care in Italy: A radiation oncology survey of MITO and AIRO GYN groups.

Large heterogeneity in therapeutic approaches to cervical cancer (CC) patients has been registered worldwide; a national survey exploring practice settings and equipments in CC treatment was distributed to radiation oncologists. Questionnaires were compiled in 90 of 194 Centers (compliance: 46.3 %). Most of respondents reported the presence of multidisciplinary tumor board, and modern equipments/techniques; 55.5 % of centers reported >1 brachytherapy (BT) equipment, thus implying the need to refer their patients outside for the remaining centers. Post-surgery radiotherapy was performed in 96.7 % of early CC (ECC) cases with pathological high risk factors. Exclusive chemoradiation with concomitant platinum schedules was referred to be used by 84.4 % of centers in locally advanced CC. Alternative options were reported with a range between 4.4 and 28.9 %. The present survey reports a broad spectrum of therapeutic options for CC in Italy. Availability and use of modern techniques is quite diffuse, but the distribution of BT resources and skills remains a challenge.

Low Tesla magnetic resonance guided radiotherapy for locally advanced cervical cancer: first clinical experience.

OBJECTIVE: Magnetic resonance-guided radiotherapy (MRgRT) represents an innovative approach for personalized radiotherapy treatments and its applications are being explored in various anatomical sites to fully understand its potential advantages. This study describes the first clinical experience of MRgRT application in patients with locally advanced cervical cancer (LACC) undergoing neoadjuvant chemoradiotherapy. The feasibility of the technique is evaluated and its toxicity profile and clinical outcomes are reported. METHODS: Patients with LACC (International Federation of Gynecology and Obstetrics stage IIA-IVA) undergoing neoadjuvant chemoradiotherapy (CRT) on a 0.35T Tri-60-Co hybrid unit (ViewRay) were retrospectively compared with randomly selected patients treated with a standard linear accelerator. Total prescribed dose was 50.6 Gy (2.3 Gy/fraction) to planning target volume 1 (PTV1) and 39.6 Gy (1.8 Gy/fraction) to PTV2, delivered using a simultaneous integrated boost. Surgery was performed 8 weeks after the end of CRT. The effect of magnetic resonance guidance on replanning approaches, treatment-related toxicities, and pathologic response were assessed for each patient. Patient outcomes were noted and dosimetric comparisons performed between the 2 arms. RESULTS: Nine patients with LACC treated from May 2018 to November 2018 were retrospectively enrolled and their records compared with the records of an equivalent cohort of randomly selected patients. Five replanning cases were performed in the MRgRT group and 0 in the linear accelerator group. Acute G1-G2 gastrointestinal toxicities were observed in 33.3% of MRgRT patients and in 55.5% of linear accelerator patients; acute G1-G2 genitourinary toxicities in 22.2% and 33.3%, respectively. No G3 toxicity was found except for neutropenia in 2 patients. No differences were observed in pathologic response between the 2 groups. CONCLUSIONS: Despite the retrospective nature of the observations and the low number of enrolled patients, the application of MRgRT in LACC appears to be safe and feasible with a favorable toxicity profile and response rates comparable to gold standard, supporting the setup of larger prospective studies to investigate the potentialities of this new technology.

The role of 18F-FDG-PET/CT in predicting the histopathological response in locally advanced cervical carcinoma treated by chemo-radiotherapy followed by radical surgery: a prospective study.

PURPOSE: This prospective study aimed to evaluate whether 18F-FDG-PET/CT performed before, during and after neoadjuvant chemo-radiotherapy (CRT) could predict histopathological response in patients with locally advanced cervical cancer (LACC) treated with CRT followed by radical surgery. METHODS: Between October 2010 and June 2014, 88 patients with LACC were enrolled. For each patient, three 18F-FDG-PET/CT scans (baseline, early and final) were acquired and evaluated by qualitative and quantitative analysis. Maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured as absolute values and their percentage variation (delta) (early vs. baseline and final vs. baseline). The role of 18F-FDG-PET/CT in predicting lymph node (LN) residual disease was evaluated by qualitative analysis only. Histopathology was the reference standard. RESULTS: At histopathology, 40 patients had complete response (CR, pR0), 48 had partial response (PR: 21 microscopic [pR1] and 27 macroscopic [pR2]). At baseline, SUVmax and SUVmean were significantly higher in pR0 than in pR1-pR2 patients. At early evaluation, MTV and TLG were significantly higher in pR1-pR2 than in pR0 patients. At final evaluation, SUVmax, SUVmean and TLG were significantly higher in pR1-pR2 than in pR0 patients. Delta SUV parameters and delta TLG were significantly lower in PR group both during and after CRT. Delta MTV was significantly lower in patients with PR in the early phase only. In receiver operating characteristic (ROC) curve analysis, baseline SUVmean, early delta TLG, and final delta SUVmax better discriminated PR, providing 83.3%, 67.6% and 85% positive predictive value (PPV) and 60.3%, 90% and 70.8% negative predictive value (NPV), respectively. For LN assessment, high NPV was observed at early and final 18F-FDG-PET/CT (93.5% and 92.3%, respectively). CONCLUSION: In LACC patients treated with CRT followed by surgery, early variations in metabolic parameters effectively discriminate histopathological PR of the primary tumor, suggesting the potential role of 18F-FDG-PET/CT in early personalized treatment. The high NPV of early and final PET/CT could enable "tailored surgery" by avoiding lymphadenectomy in selected patients.

EROS study: evaluation between high-dose-rate and low-dose-rate vaginal interventional radiotherapy (brachytherapy) in terms of overall survival and rate of stenosis.

PURPOSE: To compare the survival and toxicity outcomes in patients with endometrial cancer treated with either high-dose-rate (HDR) or low-dose-rate (LDR) vaginal brachytherapy (VBT) following external beam radiotherapy (EBRT). MATERIAL AND METHODS: From January 2000 to December 2014, patients with endometrial cancer after radical hysterectomy with/without pelvic and/or para-aortic lymphadenectomy were treated with adjuvant EBRT (45 Gy, 1.8 Gy/day to the whole pelvis) and subsequent VBT boost (HDR dose of 7 Gy in one fraction or LDR VBT dose of 25 Gy). The dose was prescribed at 0.5 cm from the surface of the applicator and the proximal half to two-thirds of the vagina was irradiated. The outcomes of patients were evaluated in terms of local control (LC), overall survival (OS), and rates of adverse events. RESULTS: We analyzed data of 200 patients treated with EBRT followed by HDR VBT boost in 78 patients and LDR VBT boost in 122 patients. With a median follow-up of 25 months (range, 6-163), 5-year OS was 98% and 97% in the LDR and HDR groups, respectively (p = 0.37). The 5-year LC was similar (93% in both groups) (p = 0.81). In multivariate analyses, none of the factors assessed (age, stage, grade) impacted OS (p = 0.37) or LC (p = 0.81). Patients treated with LDR VBT after EBRT had higher rates of acute gastrointestinal toxicity. No differences were found in acute genitourinary or hematological toxicities. Late toxicity such as vaginal stenosis was registered during regular follow-up visits and was similar in the two groups (p = 0.67). CONCLUSIONS: In our analysis, there were no differences in terms of OS and late toxicity outcomes for patients receiving LDR or HDR VBT. HDR VBT is a safe technique in comparison to LDR VBT.

INTERACTS (INTErventional Radiotherapy ACtive Teaching School) guidelines for quality assurance in choroidal melanoma interventional radiotherapy (brachytherapy) procedures.

Eye plaque brachytherapy represents a safe and effective therapeutic approach for choroidal melanoma, combining clinical outcomes with an eye and visual preservation. As it represents a complex procedure, a specific quality assurance program is strongly suggested to improve patients and operators safety, and to reduce possible complications linked to surgical procedure and radiation exposure. The aim of this paper is to describe the INTERACTS (Interventional Radiotherapy Active Teaching School) guidelines for quality assurance in choroidal melanoma interventional radiotherapy (brachytherapy) used in our institution.

Circulating human papillomavirus DNA detected using droplet digital PCR in the serum of patients diagnosed with early stage human papillomavirus-associated invasive carcinoma.

Specific human papillomavirus genotypes are associated with most ano-genital carcinomas and a large subset of oro-pharyngeal carcinomas. Human papillomavirus DNA is thus a tumour marker that can be detected in the blood of patients for clinical monitoring. However, data concerning circulating human papillomavirus DNA in cervical cancer patients has provided little clinical value, due to insufficient sensitivity of the assays used for the detection of small sized tumours. Here we took advantage of the sensitive droplet digital PCR method to identify circulating human papillomavirus DNA in patients with human papillomavirus-associated carcinomas. A series of 70 serum specimens, taken at the time of diagnosis, between 2002 and 2013, were retrospectively analyzed in patients with human papillomavirus-16 or human papillomavirus-18-associated carcinomas, composed of 47 cases from the uterine cervix, 15 from the anal canal and 8 from the oro-pharynx. As negative controls, 18 serum samples from women with human papillomavirus-16-associated high-grade cervical intraepithelial neoplasia were also analyzed. Serum samples were stored at -80°C (27 cases) or at -20°C (43 cases). DNA was isolated from 200 µl of serum or plasma and droplet digital PCR was performed using human papillomavirus-16 E7 and human papillomavirus-18 E7 specific primers. Circulating human papillomavirus DNA was detected in 61/70 (87%) serum samples from patients with carcinoma and in no serum from patients with cervical intraepithelial neoplasia. The positivity rate increased to 93% when using only serum stored at -80°C. Importantly, the two patients with microinvasive carcinomas in this series were positive. Quantitative evaluation showed that circulating viral DNA levels in cervical cancer patients were related to the clinical stage and tumour size, ranging from 55 ± 85 copies/ml (stage I) to 1774 ± 3676 copies/ml (stage IV). Circulating human papillomavirus DNA is present in patients with human papillomavirus-associated invasive cancers even at sub-clinical stages and its level is related to tumour dynamics. Droplet digital PCR is a promising method for circulating human papillomavirus DNA detection and quantification. No positivity was found in patients with human papillomavirus-associated high grade cervical intraepithelial neoplasia.

Standardized data collection to build prediction models in oncology: a prototype for rectal cancer.

The advances in diagnostic and treatment technology are responsible for a remarkable transformation in the internal medicine concept with the establishment of a new idea of personalized medicine. Inter- and intra-patient tumor heterogeneity and the clinical outcome and/or treatment's toxicity's complexity, justify the effort to develop predictive models from decision support systems. However, the number of evaluated variables coming from multiple disciplines: oncology, computer science, bioinformatics, statistics, genomics, imaging, among others could be very large thus making traditional statistical analysis difficult to exploit. Automated data-mining processes and machine learning approaches can be a solution to organize the massive amount of data, trying to unravel important interaction. The purpose of this paper is to describe the strategy to collect and analyze data properly for decision support and introduce the concept of an 'umbrella protocol' within the framework of 'rapid learning healthcare'.