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The risk of survivors developing a secondary bone sarcoma after being treated for pediatric cancers is well established. The aim of this study was to examine the clinical characteristics and outcomes of patients with secondary osteosarcoma (SOS).The study concerns survivors of childhood and adolescence primary neoplasms (PN) treated with chemotherapy, with or without radiotherapy and surgery, subsequently diagnosed with SOS.We identified 26 patients (13 females, 13 males) who developed SOS a median 7.3 years after being diagnosed with a PN (5/7 of these patients tested for Li-Fraumeni and found positive for the syndrome). The sample's median age was 8.0 and 15.0 years when their PN and SOS were diagnosed, respectively. To treat their PN, 24 out of 26 patients had been given radiotherapy, and 19 had received chemotherapy including doxorubicin. A considerable number of SOS occurred at unfavorable sites (nine hip bone, six skull). All but one patient received chemotherapy with tailored schedules, omitting doxorubicin in 19 cases. Eighteen of the 26 patients underwent surgery. The 5- and 10-year overall survival and probabilities after the diagnosis of SOS (95% confidence interval) were 50% (32.7-76.5%) and 38.9% (22.4-67.4%); 5- and 10-year progression-free survival was 47% (29.9-73.7%) and 35.2% (19.3-64.4%), respectively.The survival rates after SOS are lower than in patients with primary osteosarcoma, but not negligible. It is therefore mandatory to discuss the best choice of treatment for such patients at a referral center, in terms of their chances of cure and quality of life.

This study reports the treatment feasibility and efficacy of a novel multiagent intensive treatment program for young patients with desmoplastic small round cell tumor. This small series includes three patients and should be seen as a first suggestion of integration of the dose density and the maintenance chemotherapy concept. The IrIVA regimen (irinotecan, ifosfamide, vincristine, and actinomycin-D) is added—used at a short interval between chemotherapy administrations—at more classic intensive ifosfamide–based regimens. The vinorelbine and low-dose oral cyclophosphamide maintenance therapy is added at the end of conventional chemotherapy to achieve an antiangiogenic effect.

AIM To evaluate the role of baseline neutrophil-to-lymphocyte ratio (NLR) as prognostic marker in squamous cell carcinoma of the oropharynx (OPC) treated with definitive chemoradiotherapy (CRT) in the era of HPV status. PATIENTS AND METHODS A retrospective analysis of 125 patients (pts) affected with locally advanced OPC was performed. Inclusion criteria were age >18 years, stage III or IV (TNM 7th ed.) and definitive CRT. Haematological marker for their independent role as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS). Logistic models were used to assess the association with downstage in TNM 8th ed. RESULTS Seventy-seven (61.6%) pts had HPV/p16 + related OPC. Therapeutic choice consisted in sequential and concurrent CRT. Median follow-up was 50 months. A value of NLR ≥3 was associated with poorer OS. Two-year OS was 91% and 81% in pts with NLR

Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches.We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010-2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed.Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6-16.2 months)/6.9 months (0.6-17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081).This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial.

The prognosis for patients with metastatic rhabdomyosarcoma (RMS) remains largely unsatisfactory despite the adoption of intensive multimodal therapy. To assess the role of different treatments adopted over the years, we retrospectively analyzed a cohort of patientslt;21 years old with metastatic RMS, treated from 1990 to 2020 at a referral center for pediatric sarcomas.Patients were treated using a multimodal approach that included surgery, radiotherapy, and chemotherapy (both high-dose chemotherapy and maintenance therapy in some cases). The type of radiotherapy administered was categorized as radical (to all sites of disease); partial (to at least one, but not all sites of disease); or none. A landmark analysis was used to examine the impact of radiotherapy on survival, that is, patients who had an event before day 221 were excluded from the analysis.The series included 80 patients. Event-free survival (EFS) and overall survival (OS) rates at 5 years were 17.3% and 21.3%, respectively. Survival was significantly associated with radiotherapy to metastatic sites, and with the radiotherapy category. In particular, 5-year EFS and OS rates were 70.6% and 76.0% for patients given radical radiotherapy, and 4.8% and 10.7%, respectively, for those given partial radiotherapy or none. Using the Cox multivariable analysis, OS correlated significantly with radiotherapy category.While confirming the poor overall outcome of patients with metastatic RMS, this study identified radiotherapy-when given to all sites of disease (including metastases)-as the main variable influencing survival.

Extraosseous Ewing sarcoma is a rare entity and less is known about its clinical behavior and optimal treatment than for its counterpart in bone. This study is a retrospective analysis on a cohort of patients21 years treated according to a "soft tissue sarcoma approach."The "extraosseous" origin of the tumor was established on radiological findings, based on the lack of any bone involvement. Patients were treated using a multimodality approach including surgery, radiotherapy, and chemotherapy. All patients received chemotherapy with alkylating agents and anthracyclines for 25 weeks (nine courses). Radiotherapy (45-54.8 Gy) was required for all cases except those who had an initial R0 resection of tumors smaller than 5 cm.Fifty-seven patients (age 2-20 years, median 14) were treated from 1990 to 2020. Ten-year event-free survival (EFS) and overall survival (OS) were 77.5% and 85.5% in patients with localized disease, and 11.1% and 29.6% in those with metastatic disease (p .001) (follow-up 5-349 months, median 107 months). In patients with localized disease, the most recent IVADo-IVE regimen achieved excellent survivals, that is, 10-year EFS 95.5%.Our study showed that satisfactory results were achieved in patients with localized extraosseous Ewing sarcoma treated with a tailored approach derived from soft tissue sarcoma protocols, which was less intensive and shorter as compared to the standards utilized for the management of bone Ewing sarcoma. Our study suggests that the extraskeletal site might be considered as a variable to stratify patients and modulate treatment intensity accordingly in Ewing sarcoma protocol.

BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.

Background: The aim of this work is to evaluate pattern of care and clinical outcome in a large series of patients with in-breast recurrence (IBR), after quadrantectomy and intraoperative radiation therapy with electrons (IOERT) as partial breast irradiation. Patients and Methods: Patients with IBR after IOERT, treated with salvage surgery ± adjuvant reirradiation (re-RT), were selected from a multiinstitution database. Disease-free survival (DFS), overall survival (OS), cumulative incidence of second IBR, and distant metastases (DM) were estimated. Results: A total of 224/267 patients from seven institutions were included. Primary tumors received 21 Gy. Median time to first IBR was 4.3 years (range 2.6–6.1 years). Salvage mastectomy and repeat quadrantectomy were performed in 135 (60.3%) and 89 (39.7%) patients, followed by adjuvant re-RT in 21/135 (15.5%) and 63/89 (70.8%), respectively. Median follow-up after salvage treatment was 4.1 years. Overall, 5- and 8-year outcomes were as follows: cumulative incidence of second IBR: 8.4% and 14.8%; cumulative incidence of DM: 17.1% and 22.5%; DFS: 67.4% and 52.5%; OS: 89.3% and 74.7%. The risk of second IBR was similar in the salvage mastectomy and repeat quadrantectomy + RT groups [hazard ratio (HR) 1.41, p = 0.566], while salvage mastectomy patients had greater risk of DM (HR 3.15, p = 0.019), as well as poorer DFS (HR 2.13, p = 0.016) and a trend towards worse OS (HR 3.27, p = 0.059). Patients who underwent repeat quadrantectomy alone had worse outcomes (second IBR, HR 5.63, p = 0.006; DFS, HR 3.21, p = 0.003; OS, HR 4.38, p = 0.044) than those adding re-RT. Conclusions: Repeat quadrantectomy + RT represents an effective salvage approach and achieved local control comparable to that of salvage mastectomy.

Purpose To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children. Methods and materials Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients’ brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations. Results The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p Conclusion This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.

OBJECTIVE The space comprised between tumor and neck lymph nodes (T-N tract) is one of the main routes of tumor spread in oral cavity tumors. Aim of the study was to investigate the impact of T-N tract involvement on the postoperative radiotherapy (PORT) outcomes. MATERIALS AND METHODS Patients (pts) treated between 2000 and 2016 with indication to PORT were retrospectively retrieved. Inclusion criteria were: (a) locally advanced tumors of the oral cavity, (b) who received with indication to PORT (c) with a minimum follow-up of six months. RESULTS One hundred and fifty-seven pts met the inclusion criteria (136 pts treated with PORT and 21 pts not treated with PORT). In the PORT cohort, the T-N tract involvement had no impact on both OS (p = .09) and LRFS (p = .2). Among the non-PORT cohort, both OS (p = .007) and LRFS (p = .017) were worse for pts with positive T-N tract compared to those with negative T-N tract. PORT improved both OS (p = .008) and LRFS (p = .003) in pts with positive T-N tract but not in those with negative T-N tract (p = .36 and p = .37, respectively). CONCLUSIONS Our results suggest that involvement of T-N tract should be considered as prognostic factors informing the indication to PORT.

A standardized multidisciplinary step-by-step approach to improve the compliance of young (or difficult) children having to undergo radiotherapy was described and applied. The procedure is called SIESTA, which stands for show-imagination-evaluation-support-treatment-anesthesia. Preliminary assessments suggest that the SIESTA approach was effective: the rate of young patients (≤6 years) requiring anesthesia decreased from 27% (14/52 cases) in 2011-2012 (before the procedure was adopted) to 13% (6/46) in 2018.

To evaluate the incidence and predictors for late toxicity and tumor outcome after hypofractionated radiotherapy using three different image-guided radiotherapy (IGRT) systems (hypo-IGRT) compared with conventional fractionation without image guidance (non-IGRT). We compared the late rectal and urinary toxicity and outcome in 179 prostate cancer patients treated with hypo-IGRT (70.2 Gy/26 fractions) and 174 non-IGRT patients (80 Gy/40 fractions). Multivariate analysis was performed to define predictors for late toxicity. 5- and 8-year recurrence-free survival (RFS) and overall survival (OS) were analyzed. Mean follow-up was 81 months for hypo-IGRT and 90 months for non-IGRT group. Mainly mild late toxicity was observed: Hypo-IGRT group experienced 65 rectal (30.9% G1/G2; 6.3% G3/G4) and 105 urinary events (56% G1/G2; 4% G3/G4). 5- and 8-year RFS rates were 87.5% and 86.8% (hypo-IGRT) versus 80.4% and 66.8% (non-IGRT). 5- and 8-year OS rates were 91.3% and 82.7% in hypo-IGRT and 92.2% and 84% in non-IGRT group. Multivariate analysis showed that hypo-IGRT is a predictor for late genitourinary toxicity, whereas hypo-IGRT, acute urinary toxicity and androgen deprivation therapy are predictors for late rectal toxicity. Advanced T stage and higher Gleason score (GS) were correlated with worse RFS. A small increase in mild late toxicity, but not statistically significant increase in severe late toxicity in the hypo-IGRT group when compared with conventional non-IGRT group was observed. Our study confirmed that IGRT allows for safe moderate hypofractionation, offering a shorter overall treatment time, a good impact in terms of RFS and providing potentially more economic health care.

Soft tissue sarcomas (STS) are uncommon, heterogeneous malignant tumors of mesodermal origin. Other than conservative surgery (CS), neoadjuvant or adjuvant radiotherapy (RT) is recommended when the risk of local recurrence is high. The aim of this study is to present our Institutional experience in adjuvant RT for treatment of STS of extremities and trunk (with either brachytherapy (BRT), external beam RT (EBRT), or both) and to provide an insight of toxicity and oncological outcomes for each RT modality. According to the RT treatment approach, patients were divided into three categories: 1) BRT alone; 2) EBRT alone; 3) combined BRT+EBRT. Differences among the three groups were assessed by the Chi-squared test. Patients' follow-up was performed every 6 months for the first two years after the end of RT and then once a year. Data from 90 patients were analyzed. The overall 3-year distant relapse-free survival (DRFS), progression-free survival (PFS), and overall survival (OS) were 84%, 80%, and 97%, respectively. Acute erythema was the most frequent side effect, although severe grade 3 toxicity was present in 5 patients. Chronic toxicity of any grade was reported in 14 patients. The incidence of chronic toxicity did not show any association with treatment modality. Multivariate analysis suggested a significant correlation between acute toxicity and tumor size, RT modality, and RT dose. In conclusion, good local control and toxicity profile were observed, despite negative patients' selection at baseline. Further investigation on wider series is warranted in order to define the optimal combination with systemic therapy.

Pediatric radiotherapy (RT) is a highly specialized field, requiring great experience to delineate correctly tumor targets and organs at risk. To reduce treatment failures related to planning inaccuracies and to obtain robust clinical results despite the limited numbers of enrolled pediatric patients, the SIOP PNET5MB clinical trial on medulloblastoma requires a real-time, pre-radiation review of the RT treatment (craniospinal irradiation and boost plan) under the direct responsibility of the national coordinator center. Here we describe the centralized radiotherapy quality assurance (QA) program developed in Italy for this purpose. Using the software package VODCA (MSS, Hagendorn, Switzerland, www.vodca.ch ), we developed a cloud platform able to handle computed tomography (CT) images and RT objects and to support the complete workflow required by the review process in the context of the SIOP PNET5 trial. All Italian centers participating in the PNET5 trial adopted the proposed QA system. 24 patients were successfully enrolled and reviewed. For 15 patients (62.5%), one or more plan revisions were requested for the craniospinal irradiation plan and for 11 patients (45.8%) plan revisions were requested for the boost. RT was delivered after the plan was centrally approved for all enrolled patients. So far, in Italy, no patients have been excluded from PNET5 due to dosimetric incompliance to the protocol or for exceeding the RT starting time limit. The cloud platform successfully supported the trial workflow, producing official review documents. This efficient QA was crucial to guarantee optimized treatments and protocol compliance for all pediatric patients enrolled in the SIOP protocol.

To report toxicity and efficacy outcome of moderately hypofractionated image-guided external-beam radiotherapy in a large series of patients treated for prostate cancer (PCa). Between 10/2006 and 12/2015, 572 T1-T3N0M0 PCa patients received 70.2 Gy in 26 fractions at 2.7 Gy/fraction: 344 patients (60%) with three-dimensional conformal radiotherapy (3D-CRT) and 228 (40%) with intensity-modulated radiotherapy (IMRT). Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median age was 74 years (interquartile range 69-77). Compared with 3D-CRT, in IMRT group more high-risk patients (29% vs 18%; P = 0.002) and more high-volume target (75% vs 60%; P 0.001) were included. Acute gastro-intestinal (GI) toxicity G 1 were registered in 8% and in 11% IMRT and 3D-CRT patients, respectively, whereas late GI G 1 were observed in 2% and 16% IMRT and 3D-CRT patients, respectively. Acute genito-urinary (GU) toxicity G 1 were registered in 26% and 40% IMRT and 3D-CRT patients, respectively, whereas late GU G 1 occurred in 5% IMRT and 15% 3D-CRT patients. Multivariate proportional hazard Cox models confirmed significantly greater risk of late toxicity with 3D-CRT compared to IMRT for GU 1 (P = 0.004) and for GI 1 (P 0.001). With a median 4-year follow-up, overall survival (OS), clinical progression-free survival (cPFS) and biochemical PFS (bPFS) for the whole series were 91%, 92% and 91%, respectively. cPFS and bPFS were significantly different by risk groups. Multivariate Cox models for bPFS and cPFS showed no difference between irradiation techniques and a significant impact of risk group and initial PSA. Moderately hypofractionated radiotherapy is a viable treatment option for localized PCa with excellent tumour control and satisfactory toxicity profile. IMRT seems associated with a reduction in toxicity, whereas tumour control was equal between IMRT and 3D-CRT patients and depended mainly on the risk category.

As a result of aging, the number of patients with cardiac implantable electronic device (CIED) requiring radiotherapy (RT) continues to rise. The aim of this work was to evaluate RT-related malfunctions of CIED in a cohort of patients who underwent RT in our clinic from June 2010 to December 2016. We retrospectively analyzed 93 RT treatments in 63 patients with CIEDs. Patients were treated with 3D conformal RT, intensity-modulated RT and stereotactic RT. We collected clinical characteristics of cancer, models of CIEDs, total RT dose to tumor and radiation energy. Radiation dose delivered to CIED and its dysfunctions after RT was evaluated. Subgroup analysis of 48 RT treatments (32 patients) on chest and neck plus on 13 RT treatments (12 patients) with 18 MV neutron-producing photon energy considered as high risk was performed. The number of treatments of patients with CIEDs increased from 0.3% in 2011 to 1.2% in 2016. Two patients, treated with 18 MV photon beam, with implantable cardioverter–defibrillators (ICDs) that received a maximum dose of around 2.1 Gy, experienced adverse events: a reprogramming of ICD when the patient reached a delivered dose to the tumor of 32 Gy, and an altered sensing function requiring replacement after 11 months from the end of RT. Nearly 2% of patients with CIEDs from high-risk patients subgroup had experienced a damage of the device. Close cooperation between radiation oncologists, cardiologists, medical physicists and radiation technologists is needed to achieve the best practice management in these patients.

Unfortunately, the denomination of the IEO was incorrectly published in the affiliation of this original.

The prognosis of patients with metastatic melanoma is changing owing to the introduction of selective BRAF inhibitors combined with MEK inhibitors. Management of these patients continues to be a challenge, especially when systemic therapy has to be combined with concomitant radiotherapy, particularly owing to skin toxicity. Here we report a case of a patient who underwent concomitant treatment for two vertebral sites using two different radiotherapy techniques. An unexpected acute skin toxicity was reported at one of the treated sites. This finding might be owing to the different absorbed dose to the subcutaneous tissues linked with the technique of irradiation.