Prevention and management of radiotherapy-related toxicities in gynecological malignancies. Position paper on behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology).

Multi-modal therapies for gynecological cancers management may determine a wide range of side effects which depend on therapy-related factors and patient characteristics and comorbidities. Curative or adjuvant pelvic radiotherapy is linked with acute and late toxicity due to irradiation of organs at risk, as small and large bowel, rectum, bladder, pelvic bone, vagina and bone marrow. Successful toxicity management varies with its severity, Radiation Centre practice and experience and skills of radiation oncologists. This position paper was designed by the Italian Association of Radiation and Clinical Oncology Gynecology Study Group to provide radiation oncologists with evidence-based strategies to prevent and manage acute and late toxicities and follow-up recommendations for gynecological cancer patients submitted radiotherapy. Six workgroups of radiation oncologists with over 5 years of experience in gynecologic cancers were setup to investigate radiotherapy-related toxicities. For each topic, PubMed database was searched for relevant English language papers from January 2005 to December 2022. Titles and abstracts of results were checked to verify suitability for the document. Reference lists of selected studies and review papers were added if pertinent. Data on incidence, etiopathogenesis, prevention, treatment and follow-up of acute and late side effects for each organ at risk are presented and discussed.

Definitive chemoradiation in vulvar squamous cell carcinoma: outcome and toxicity from an observational multicenter Italian study on vulvar cancer (OLDLADY 1.1).

BACKGROUND: Vulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT. METHODS: The primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale. RESULTS: Retrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010-November 2021). Median age at diagnosis was 72 years (range 32-89). With a median follow-up of 19 months (range 1-114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1-53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded. CONCLUSION: In the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management.

Observational multicenter Italian study on vulvar cancer adjuvant radiotherapy (OLDLADY 1.2): a cooperation among AIRO Gyn, MITO and MaNGO groups.

BACKGROUND: Adjuvant radiotherapy (aRT) has been shown to reduce the risk of local relapse in vulvar cancer (VC). In this multicentre study (OLDLADY-1.2), several Institutions have combined their retrospective data on VC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of aRT. METHODS: The primary study end-point was the 2-year-local control, secondary end-points were the 2-year-metastasis free-survival, the 2-year-overall survival and the rate and severity of acute and late toxicities. Participating centres were required to fill data sets including age, stage, tumor diameter, type of surgery, margin status, depth of invasion, histology, grading as well technical/dosimetric details of radiotherapy. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. RESULTS: One hundred eighty-one patients with invasive VC from 9 Institutions were retrospectively identified. The majority of patients were stage III (63%), grade 2 (62.4%) squamous carcinoma (97.2%). Positive nodes were observed in 117 patients (64.6%), moreover tumor diameter > 4 cm, positive/close margins and depth of invasion deeper than 5 mm were found in 59.1%, 38.6%, 58% of patients, respectively. Sixty-one patients (33.7%) received adjuvant chemoradiation, and 120 (66.3%) received radiotherapy alone. aRT was started 3 months after surgery in 50.8% of patients. Prescribed volumes and doses heterogeneity was recorded according to margin status and nodal disease. Overall, 42.5% locoregional recurrences were recorded. With a median follow-up of 27 months (range 1-179), the 2-year actuarial local control rate, metastasis free and overall survival were 68.7%, 84.5%, and 67.5%, respectively. In term of safety, aRT leads to a prevalence of acute skin toxicity with a low incidence of severe toxicities. CONCLUSIONS: In the context of aRT for VC the present study reports a broad spectrum of approaches which would deserve greater standardization in terms of doses, volumes and drugs used.

Intraluminal Brachytherapy in Unresectable Extrahepatic Biliary Duct Cancer: An Italian Pooled Analysis.

BACKGROUND/AIM: To evaluate the outcome of patients with unresectable extrahepatic cholangiocarcinoma (CC) treated with external-beam radiotherapy (EBRT) and concurrent chemotherapy (CT) with or without intraluminal brachytherapy (ILBT) boost or with definitive ILBT. PATIENTS AND METHODS: A pooled analysis of patients with non-metastatic unresectable CC was performed. They were treated in three different institution with EBRT plus CT with or without an ILBT boost. Some patients received only ILBT with curative dose. RESULTS: Seventy-three patients were included in the analysis. Thirty-nine patients (53%) received EBRT treatment with ILBT boost (18 patients with CT during EBRT), while 28 patients (38%) were treated with EBRT (CT in 26 patients) and 6 patients (8.2%) with definitive ILBT (2 patients with CT). CT was administered including either the use of gemcitabine or 5-fluorouracil. With a median follow-up of 16 month (range=1-94 months), median overall survival (OS) was 16 months. Overall median LC was 16 months and patients who underwent ILBT had a better local control (LC) (p=0.018). CONCLUSION: The role of ILBT in unresectable CC is not yet supported by robust evidence in the literature. However, within this limit, preliminary results seem to suggest an improved local control in patients treated with ILBT, almost comparable to the ones of standard chemo-radiotherapy (CRT).

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.

High-dose-rate brachytherapy for high-grade vaginal intraepithelial neoplasia: a dosimetric analysis.

PURPOSE: Due to the rarity of vaginal intraepithelial neoplasia (VAIN), it is impossible to define the best treatment approach or to assess vaginal morbidity. However, brachytherapy (BT) could be a valuable choice for VAIN grade 3 (VAIN3). The aim of this paper was to report a single-institution study of the application of high-dose-rate BT and to evaluate clinical outcomes as well as to investigate the dose-effect relationship for vaginal stenosis. MATERIAL AND METHODS: We retrospectively collected hospital records and treatment plans of 14 consecutive women treated in our department from August 2010 to August 2016, with HDR-BT delivered using iridium-192 by a remote after-loading system. Doses in 3D-planned treatment based on computed tomography (CT) were prescribed in high-risk clinical target volume (HR-CTV) at the vaginal wall. Vaginal stenosis was defined as vaginal shortening/narrowing according to CTCAE4.1. The International Commission on Radiation Units & Measurements (ICRU) bladder and rectal points were used for dose report analysis. The posterior-inferior border of the symphysis points was used to derive reference points. The median age of the enrolled women was 60 years, and the median total radiation dose delivered was 35 Gy. RESULTS: During a median period of 15 days, the treatment was well tolerated, and no interruption was necessary. Acute toxicity was minimal, whereas late toxicity appeared in 4 patients as G2 and in 3 patients as G3 vaginal stenosis. Patients with stenosis G ≥ 2 received a higher median dose to the rectal point and were mainly over 60 years old. CONCLUSIONS: Patients with VAIN3 seemed to benefit from BT. It is generally assumed that the vagina is radio-resistant, and no constraints have yet been set, but sexual dysfunction after BT is an important cause of long-term distress. Finding applicable dose limits to the vagina could improve patients' quality of life.

Combination of Immunotherapy and Brain Radiotherapy in Metastatic Melanoma: A Retrospective Analysis.

BACKGROUND: Up to 40% of patients with metastatic melanoma (MM) develop brain metastases. Radiotherapy (RT) may potentiate the effects of immunotherapy (IO), even on distant sites (abscopal effect). MATERIAL AND METHODS: We retrospectively analyzed all our MM patients treated with IO within 6 months before/after brain RT between 2012 and 2016. Progression-free (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with those of controls treated with IO during the same period. RESULTS: Thirty-six cases and 25 controls were identified. Among cases, 23 patients received an anti-CTLA4 agent and 13 an anti-PD1 agent. Eighteen cases were treated with stereotactic RT and 18 with whole-brain RT. Median PFS from the beginning of RT was 4 months in first-line and 2 months in second-line treatment. A third of the cases progressed at first evaluation after RT. Median OS from the beginning of RT was 7 months in first-line and 4 months in second-line treatment. Median PFS and OS of each treatment line showed a trend towards inferiority compared with those of controls. CONCLUSION: Synergism between RT and IO was not observed in our case series. No cases of abscopal effect were seen, and most patients underwent early systemic progression after RT.

An innovative gynecological HDR brachytherapy applicator system for treatment delivery and real-time verification.

The multichannel vaginal cylinder (MVC) applicator employed for gynecological high dose rate (HDR) brachytherapy increases dose delivery complexity, and thus makes the treatment more prone to errors. A quality assurance (QA) procedure tracking the source throughout dose delivery can detect dwell position and time errors in the multiple channels of the applicator. A new MVC system with integrated real time in vivo treatment delivery QA has been developed based on diodes embedded on the outer surface of the MVC. It has been pre-calibrated and verified using a non-clinical treatment plan with consecutive test positions and dwell times within each catheter, followed by the delivery of ten clinical plans of adjuvant vaginal cuff brachytherapy following hysterectomy for endometrial cancer. The non-clinical verification showed overall mean dwell position and time discrepancies between the nominal and measured treatment of -0.2 ±â€¯0.5 mm and -0.1 ±â€¯0.1 s (k = 1), respectively. The clinical plans showed mean positional discrepancies of 0.2 ±â€¯0.4 and 0.0 ±â€¯0.8 mm, for the central and peripheral catheters, respectively, and mean dwell time discrepancies of -0.1 ±â€¯0.2 and -0.0 ±â€¯0.1 s for central and peripheral catheters, respectively. The innovative prototype of the MVC system has shown the ability to track the source with sub-mm and sub-second accuracy, and demonstrated potential for its incorporation into the clinical routine.

Pre-implant magnetic resonance and transrectal ultrasound imaging in high-dose-rate prostate brachytherapy: comparison of prostate volumes, craniocaudal extents, and contours.

PURPOSE: The purpose of this study was to compare the prostate contours drawn by two radiation oncologists and one radiologist on magnetic resonance (MR) and transrectal ultrasound (TRUS) images. TRUS intra- and inter-fraction variability as well as TRUS vs. MR inter-modality and inter-operator variability were studied. MATERIAL AND METHODS: Thirty patients affected by localized prostate cancer and treated with interstitial high-dose-rate (HDR) prostate brachytherapy at the National Cancer Institute in Milan were included in this study. Twenty-five patients received an exclusive two-fraction (14 Gy/fraction) treatment, while the other 5 received a single 14 Gy fraction as a boost after external beam radiotherapy. The prostate was contoured on TRUS images acquired before (virtual US) and after (real US) needle implant by two radiation oncologists, whereas on MR prostate was independently contoured by the same radiation oncologists (MR1, MR2) and by a dedicated radiologist (MR3). Absolute differences of prostate volumes (│ΔV│) and craniocaudal extents (│Δdz│) were evaluated. The Dice's coefficient (DC) was calculated to quantify spatial overlap between MR contours. RESULTS: Significant difference was found between Vvirtual and Vlive (p < 0.001) for the first treatment fractions and between VMR1 and VMR2 (p = 0.043). Significant difference between cranio-caudal extents was found between dzvirtual and dzlive (p < 0.033) for the first treatment fractions, between dzvirtual of the first treatment fractions and dzMR1 (p < 0.001) and between dzMR1 and dzMR3 (p < 0.01). Oedema might be responsible for some of the changes in US volumes. Average DC values resulting from the comparison MR1 vs. MR2, MR1 vs. MR3 and MR2 vs. MR3 were 0.95 ± 0.04 (range, 0.82-0.99), 0.87 ± 0.04 (range, 0.73-0.91) and 0.87 ± 0.04 (range, 0.72-0.91), respectively. CONCLUSIONS: Our results demonstrate the importance of a multiprofessional approach to TRUS-guided HDR prostate brachytherapy. Specific training in MR and US prostate imaging is recommended for centers that are unfamiliar with HDR prostate brachytherapy.

Locally Advanced Cervical Cancer: Is a Trimodality Treatment a Safe and Effective Approach?

BACKGROUND: Chemoradiotherapy (CRT) is the standard of care for locally advanced cervical cancer (LACC). Pre-treatment lymph nodes (LN) assessment may have an important therapeutic role. CRT followed by adjuvant chemotherapy increased progression free survival (PFS) and overall survival (OS). Our study evaluated the feasibility and the effectiveness of a trimodality strategy in patients with LACC and positive LN. METHODS: Consecutive patients with LACC treated at the National Cancer Institute of Milan were enrolled. All patients underwent pelvic and para-aortic extraperitoneal laparoscopic lymphadenectomy to assess the nodal status. After surgery, patients received radiotherapy followed by chemotherapy according to the stage of disease. RESULTS: Between April 2012 and October 2013, 19 cervical cancer patients were enrolled. Overall, 10 (52.6%) patients presented with positive LN: 6 in the pelvic area and 4 both in the pelvic and para-aortic area. No perioperative major complications occurred. The most common surgical-related adverse events were bleeding (26%), respiratory distress (5%), infection (5%) and the development of lymphoceles (25%). Overall, 15 (78.9%) complete responses and 2 (10.5%) partial responses were registered. After a median follow-up of 43.3 months, 89.5% of patients were alive at the last visit, and 3-year PFS was 63%. CONCLUSIONS: Trimodality treatment appears feasible, well tolerated and promising in terms of oncologic outcome.

Maternal Exposure to Pesticides, Paternal Occupation in the Army/Police Force, and CYP2D6*4 Polymorphism in the Etiology of Childhood Acute Leukemia.

Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1.87; 95% confidence intervals [CI], 1.04-3.33), with subjects living <100 m from pesticide-treated fields (OR=3.21; 95% CI, 1.37-7.53) and with a paternal occupation as traffic warden/policeman (OR=4.02; 95% CI, 1.63-9.87). Associations were found between CAL and genetic polymorphism of CYP2D6*4 for homozygous alleles (mutant type/mutant type: OR=6.39; 95% CI, 1.17-34.66). In conclusion, despite the small sample size, maternal prenatal exposure to pesticides, paternal occupation as a traffic warden/police officer, and CYP2D6*4 polymorphism could play a role in the etiology of CAL.

Comparison of different treatment planning optimization methods for vaginal HDR brachytherapy with multichannel applicators: A reduction of the high doses to the vaginal mucosa is possible.

PURPOSE: A direct planning approach with multi-channel vaginal cylinders (MVCs) used for HDR brachytherapy of vaginal cancers is particularly challenging. Purpose of this study was to compare the dosimetric performances of different forward and inverse methods used for the optimization of MVC-based vaginal treatments for endometrial cancer, with a particular attention to the definition of strategies useful to limit the high doses to the vaginal mucosa. METHODS: Twelve postoperative vaginal HDR brachytherapy treatments performed with MVCs were considered. Plans were retrospectively optimized with three different methods: Dose Point Optimization followed by Graphical Optimization (DPO + GrO), Inverse Planning Simulated Annealing with two different class solutions as starting conditions (surflPSA and homogIPSA) and Hybrid Inverse Planning Optimization (HIPO). Several dosimetric parameters related to target coverage, hot spot extensions and sparing of organs at risk were analyzed to evaluate the quality of the achieved treatment plans. Dose homogeneity index (DHI), conformal index (COIN) and a further parameter quantifying the proportion of the central catheter loading with respect to the overall loading (i.e., the central catheter loading index: CCLI) were also quantified. RESULTS: The achieved PTV coverage parameters were highly correlated with each other but uncorrelated with the hot spot quantifiers. HomogIPSA and HIPO achieved higher DHIs and CCLIs and lower volumes of high doses than DPO + GrO and surflPSA. CONCLUSIONS: Within the investigated optimization methods, HIPO and homoglPSA showed the highest dose homogeneity to the target. In particular, homogIPSA resulted also the most effective in reducing hot spots to the vaginal mucosa.

In vivo rectal wall measurements during HDR prostate brachytherapy with MOSkin dosimeters integrated on a trans-rectal US probe: Comparison with planned and reconstructed doses.

BACKGROUND AND PURPOSE: To study if MOSkin detectors coupled to a trans-rectal ultrasound (TRUS) probe may be used for in vivo dosimetry on the rectal wall surface during US-based HDR prostate brachytherapy and to quantify possible discrepancies between planned and delivered doses. MATERIALS AND METHODS: MOSkins are a specific type of MOSFET dosimeter optimized to measure dose in steep dose gradients on interfaces. Two MOSkins were assembled on a TRUS probe used for on-line treatment planning. Measurements of the dose to the rectal wall were performed over 18 treatment sessions and compared to the doses calculated on the pre-treatment plan (DPRE) and reconstructed on post-treatment images (DPOST). RESULTS: Averages of the absolute differences between MOSkin readings and DPRE, MOSkin readings and DPOST and DPRE and DPOST were 6.7 ± 5.1%, 3.6 ± 1.9% and 6.3 ± 4.7%, respectively. Agreement between measurements and DPOST was significantly better than between measurements and DPRE (p=0.002) and DPRE and DPOST (p=0.004). Discrepancy between DPOST and DPRE correlated with the time required for treatment planning. CONCLUSION: MOSkin dosimeters integrated to the TRUS probe proved to be an accurate instrument for measuring the dose delivered to the rectal wall in HDR prostate brachytherapy. The delivered doses may differ significantly from those calculated in the treatment plan.

Ionizing radiations increase the activity of the cell surface glycohydrolases and the plasma membrane ceramide content.

We detected significant levels of ß-glucosidase, ß-galactosidase, sialidase Neu3 and sphingomyelinase activities associated with the plasma membrane of fibroblasts from normal and Niemann-Pick subjects and of cells from breast, ovary, colon and neuroblastoma tumors in culture. All of the cells subjected to ionizing radiations showed an increase of the activity of plasma membrane ß-glucosidase, ß-galactosidase and sialidase Neu3, in addition of the well known increase of activity of plasma membrane sphingomyelinase, under similar conditions. Human breast cancer cell line T47D was studied in detail. In these cells the increase of activity of ß-glucosidase and ß-galactosidase was parallel to the increase of irradiation dose up to 60 Gy and continued with time, at least up to 72 h from irradiation. ß-glucosidase increased up to 17 times and ß-galactosidase up to 40 times with respect to control. Sialidase Neu3 and sphingomyelinase increased about 2 times at a dose of 20 Gy but no further significant differences were observed with increase of radiation dose and time. After irradiation, we observed a reduction of cell proliferation, an increase of apoptotic cell death and an increase of plasma membrane ceramide up to 3 times, with respect to control cells. Tritiated GM3 ganglioside has been administered to T47D cells under conditions that prevented the lysosomal catabolism. GM3 became component of the plasma membranes and was transformed into LacCer, GlcCer and ceramide. The quantity of ceramide produced in irradiated cells was about two times that of control cells.