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Abstract Background The aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed. Methods Fourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m2) was administered to 8 (57.1%) patients. Results Five (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036). Conclusions Salvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.

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., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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., (© 2022. Italian Society of Medical Radiology.)

The prognosis of lung cancer patients has improved in the last few years. Despite definitive therapy, local recurrence or a second primary tumour can occur in many patients within previously irradiated areas. Recent developement of more accurate techniques in radiation oncology allows delivery of high radiation dose to the tumor with the aim of improving local control, delaying disease progression and in some cases even curing. Nevertheless, the use of high dose in the reirradiation setting is not without risks, especially when treatment volumes overlap with previously irradiated tissues. The risk of adverse effects must be balanced with the choice of an effective treatment by selecting suitable candidates and the best radiation technique. In this systemic review efficacy and toxicity of reirradiation in locoregionally recurrent non-small-cell lung cancer is extensively discussed. Results indicate that reirradiation might be beneficial in well-selected patients. Prospective and high quality studies are necessary in this field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed., Methods: Fourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m 2 ) was administered to 8 (57.1%) patients., Results: Five (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036)., Conclusions: Salvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.

Locally advanced non-small cell lung cancer (NSCLC) represents approximately one third of presentations at diagnosis. Most patients are judged non-surgical due to disease extension, and chemo-radiotherapy still represents the standard therapeutic option, with unsatisfactory results in terms of overall survival (OS) despite advances in staging and radiation therapy planning and delivery. Immunotherapy, and in particular immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis, gained wide popularity for NSCLC in light of the positive findings of several trials in metastatic disease. Stage III unresectable NSCLC is a remarkably interesting setting for the combined use of chemo-radiation and immunotherapy, also considering the multiple experimental evidences in favor of a synergistic effect between radiation and immune checkpoint inhibitors, with the potential of enhancing immuno-modulating effects and overcoming resistance. We here summarized the biological rationale and the initial clinical experiences testing for this combination, and we briefly discussed ongoing trials and future options in this field., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Oral mucositis (OM) is a common acute side effect during radiotherapy treatments for head and neck cancer (HNC), with a potential impact on patient's compliance to therapy, quality of life (QoL) and clinical outcomes. Its timely and appropriate management is of paramount importance. Several quantitative scoring scales are available to properly assess OM and its influence on patient-reported outcomes (PROs) and QoL. We prospectively assessed OM in a cohort of HNC patients submitted to radiation using the Oral Mucositis Assessment Scale (OMAS), while its impact on PROs and QoL was evaluated employing the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN) and the Functional Assessment of Cancer Therapy-Head and Neck Cancer (FACT-HN). Evaluation of OMAS scores highlighted a progressive increase in OM during treatment and a partial recovery after the end of radiation. These trends were correlated to PROs and QoL as evaluated with OMWQ-HN and FACT-HN questionnaires. In the present study, we provided a quantitative assessment of OM, PROs and QoL in HNC patient undergoing radiotherapy, potentially useful for future comparison.

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6-124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good-excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.

Aim: The purpose of the study was to assess outcomes of locally advanced head and neck (LAHNC) treated with induction chemotherapy (ICT) and subsequent concurrent chemo-radiation., Patients and Methods: A total of 71 LAHNC patients were treated with 2-3 cycles of docetaxel, cisplatin and 5-fluorouracil as induction chemotherapy and subsequent concurrent chemoradiation with weekly cisplatin or carboplatin. Definitive radiotherapy was delivered with intensity-modulated radiation and a simultaneous integrated boost approach up to a total dose of 70 Gy in 35 fractions to the macroscopic primary and nodal disease., Results: Actuarial 2-year OS, CSS, DFS, MFS, LC were 55.3% (95%CI=39.3-68.6), 58.6% (95%CI=41.9-72), 60.5% (95%CI=47.3-71.4), 87.3% (95%CI=76.2-93.5) and 74.7% (95%CI=61.5-83.9), respectively. On multivariate analysis undergoing to 3 vs. 2 cycles of TPF (HR=22.31; 95%CI=2.68-185.66; p=0.004) and radiotherapy treatment break >4 days (HR=1.28; 95%CI=1.06-1.55; p=0.01) negatively affected cancer-specific survival (CSS) with statistical significance. Achieving complete remission after ICT had a statistically significant impact on CSS (HR=0.9; 95%CI=0.01-0.54; p=0.009). Patients undergoing ICT with 3 cycles had more frequently treatment breaks compared to those submitted to 2 cycles (HR=1.36; 95%CI=1.06-1.73; p=0.01), and had statistically significant longer treatment break time (5.9+1.8 vs. 3+0.36; p=0.02)., Conclusion: A shorter ICT phase may be a better option enhancing patients' tolerance during concurrent chemoradiation and affecting clinical outcomes., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.