Proton therapy for pediatric malignancies: Indications and challenges focusing on the oncological landscape.

Advances in therapeutic techniques and multimodal approaches have significantly improved the success rates of treatment for pediatric malignancies, with cure rates now close to 80%. This has led to an increase in long-term survival, with 0.10-0.15% of the general population being survivors of childhood cancer. In Italy, cancer registry data suggest that 75% of treated children become long-term survivors. However, these survivors face significant risks of late adverse events, including chronic diseases and severe conditions, highlighting the need for specialized follow-up care.Radiotherapy, a cornerstone of pediatric cancer treatment, contributes to late toxicities due to the susceptibility of growing tissues. Proton therapy offers advantages in reducing treatment-related toxicity, reducing the risk of secondary cancers, and allowing dose escalation for radioresistant tumors. Comparative studies suggest that proton therapy is superior in sparing healthy tissues and reducing long-term toxicities.Despite these benefits, challenges such as the high cost, limited proton therapy centers, and the need for clinical trials hinder the widespread adoption of proton therapy. Efforts to centralize care in high-ranking centers and ensure equitable access to proton therapy are crucial. In Italy, pediatric solid tumors are now eligible for proton therapy under national health policies, ensuring free access for all children.Dedicated proton therapy centers must provide comprehensive care involving multidisciplinary teams and supportive environments for pediatric patients and their families. Addressing current limitations and enhancing care environments are essential for improving outcomes for pediatric oncology patients.

MDT-BRIDGE: Neoadjuvant Durvalumab Plus Chemotherapy Followed by Either Surgery and Adjuvant Durvalumab or Chemoradiotherapy and Consolidation Durvalumab in Resectable or Borderline-resectable Stage IIB-IIIB NSCLC.

INTRODUCTION: In the AEGEAN trial, neoadjuvant durvalumab plus platinum-based chemotherapy (D+CT) followed by adjuvant durvalumab, versus neoadjuvant chemotherapy alone, significantly improved pathological complete response (pCR) rate and event-free survival (EFS) in patients with resectable NSCLC. In the PACIFIC trial, consolidation durvalumab significantly improved progression-free (PFS) and overall survival (OS) for patients with unresectable stage III NSCLC after chemoradiotherapy. Strong pathological and clinical outcomes with chemoimmunotherapy have generated interest in its use to enable patients with borderline-resectable NSCLC to undergo surgery. Additionally, for patients initially deemed resectable but who later become unresectable/inoperable during neoadjuvant treatment, consolidation immunotherapy after chemoradiotherapy should be explored. PATIENTS AND METHODS: MDT-BRIDGE (NCT05925530) is a multicenter, phase II, non-randomized study in ∼140 patients with EGFR/ALK wild-type, stage IIB-IIIB (N2) NSCLC. Following baseline multidisciplinary team (MDT) assessment to determine resectable/borderline-resectable status, all patients receive 2 cycles of neoadjuvant D+CT every 3 weeks, followed by MDT reassessment of resectability. Patients deemed resectable receive 1-2 additional cycles of D+CT followed by surgery (Cohort 1). Patients deemed unresectable receive standard-of-care chemoradiotherapy (Cohort 2). Cohort 1 patients who become ineligible for surgery can enter Cohort 2. Following surgery or chemoradiotherapy, patients receive adjuvant or consolidation durvalumab for 1 year. The primary endpoint is resection rate in all patients. Additional endpoints include resection rates by baseline resectable/borderline-resectable status, resection outcomes, EFS/PFS, OS, pCR rate, circulating tumor DNA dynamics pre- and post-surgery (including correlation with clinical outcomes), and safety. CONCLUSION: Enrollment began in February 2024; primary completion is anticipated in April 2026.

Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study.

INTRODUCTION: The phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS). METHODS: PACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan-Meier method). RESULTS: As of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1-24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease. CONCLUSIONS: Consolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy.

Consolidation durvalumab is standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression following chemoradiotherapy (the 'PACIFIC regimen'). However, many patients with poor performance status, older age or comorbidities may be ineligible for chemotherapy due to expected high toxicity. These patients typically receive radiotherapy alone, with poor survival outcomes. Based on the PACIFIC trial data, and the strong biological rationale for combining radiotherapy with anti-programmed cell death ligand-1 therapy, durvalumab following radiotherapy could provide additional survival benefit versus radiotherapy alone. Here, we describe the DUART trial, a Phase II, open-label, single-arm study assessing the safety and tolerability of durvalumab following radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy (ClinicalTrials.gov Identifier: NCT04249362).

Lay abstract The current standard treatment for patients with stage III non-small-cell lung cancer whose cancer cannot be removed by surgery is chemotherapy plus radiotherapy; if their disease gets no worse after this, patients also receive durvalumab ­ altogether this is known as the 'PACIFIC regimen'. However, some patients who are older or who have existing health conditions cannot tolerate chemotherapy, so instead of the PACIFIC regimen they receive radiotherapy only. The DUART study described here is an ongoing, Phase II clinical trial looking at the safety and tolerability of durvalumab after radiotherapy in patients with stage III non-small-cell lung cancer who are unsuitable for chemotherapy and whose cancer cannot be removed by surgery. Clinical Trial Registration: NCT04249362.

Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20-40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis. METHODS: Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance. RESULTS: The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine. CONCLUSION: A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.

Total marrow and total lymphoid irradiation in bone marrow transplantation for acute leukaemia.

The use of total body irradiation as part of conditioning regimens for acute leukaemia is progressively declining because of concerns of late toxic effects and the introduction of radiation-free regimens. Total marrow irradiation and total marrow and lymphoid irradiation represent more targeted forms of radiotherapy compared with total body irradiation that have the potential to decrease toxicity and escalate the dose to the bone marrow for high-risk patients. We review the technological basis and the clinical development of total marrow irradiation and total marrow and lymphoid irradiation, highlighting both the possible advantages as well as the current roadblocks for widespread implementation among transplantation units. The exact role of total marrow irradiation or total marrow and lymphoid irradiation in new conditioning regimens seems dependent on its technological implementation, aiming to make the whole procedure less time consuming, more streamlined, and easier to integrate into the clinical workflow. We also foresee a role for computer-assisted planning, as a way to improve planning and delivery and to incorporate total marrow irradiation and total marrow and lymphoid irradiation in multi-centric phase 2-3 trials.

COVID-19: Global radiation oncology's targeted response for pandemic preparedness.

As the global COVID-19 pandemic escalates there is a need within radiation oncology to work to support our patients in the best way possible. Measures are required to reduce infection spread between patients and within the workforce. Departments need contingency planning to create capacity and continue essential treatments despite a reduced workforce. The #radonc community held an urgent online journal club on Twitter in March 2020 to discuss these issues and create some consensus on crucial next steps. There were 121 global contributors. This document summarises these discussions around themes of infection prevention, rationalisation of workload and working practice in the presence of infection.

Management of the axilla in patients with breast cancer and positive sentinel lymph node biopsy: An evidence-based update in a European breast center.

The surgical approach to the axilla in breast cancer has been a controversial issue for more than three decades. Data from recently published trials have provided practice-changing recommendations in this scenario. However, further controversies have been triggered in the surgical community, resulting in heterogeneous diffusion of these recommendations. The development of clinical guidelines for the management of the axilla in patients with breast cancer is a work in progress. A multidisciplinary team discussion was held at the research hospital Policlinico San Matteo from the Università degli Studi di Pavia with the aim to update recommendations for the management of the axilla in patients with breast cancer. An evidence-based approach is presented. Our multidisciplinary panel determined that axillary dissection after a positive sentinel lymph node biopsy may be avoided in cN0 patients with micro/macrometastasis to ≤2 sentinel nodes, with age ≥40y, lesions ≤3 cm, who have not received neoadjuvant chemotherapy and have planned breast conservation (BCS) with whole breast radiotherapy (WBRT). Cases with gross (>2 mm) ECE in SLNs are evaluated on individual basis for completion ALND, axillary radiotherapy or omission of both. Patients fulfilling the criteria listed above who undergo mastectomy, may also avoid axillary dissection after multidisciplinary discussion of individual cases for consideration of axillary irradiation. Women 70 years or older with hormone receptors positive invasive lesions ≤3 cm, clinically negative nodes, and serious or multiple comorbidities who undergo BCS with WBRT, may forgo axillary staging/surgery (if mastectomy or larger tumor, comorbidities and life expectancy are taken into account).

Erratum: Stella, G.M. et al. Brain Metastases from Lung Cancer: Is MET an Actionable Target? Cancers 2019, 11, 271.

The authors wish to make the following corrections to this paper [...].

Brain Metastases from Lung Cancer: Is MET an Actionable Target?

The process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d'Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach.

Treatment of metastatic melanoma: a multidisciplinary approach.

The prognosis of stage IV metastatic melanoma is poor. An overall 1-year survival of 25.5% and a median survival of 6.2 months were reported without any significant improvement during the last 30 years before the introduction of new drugs (immune checkpoint inhibitors and targeted therapies) which completely modified the therapeutic approach and induced an overwhelming improvement on the survival rates of these patients. This review will analyze the therapeutic tools available for the treatment of patients with metastatic melanoma, including adjuvant interferon and locoregional therapies (surgery, radiotherapy and electrochemotherapy) and will mainly focus on the presentation of results obtained by the new treatments (checkpoint inhibitors and targeted therapies).

Radiation therapy planning for early-stage Hodgkin lymphoma: experience of the International Lymphoma Radiation Oncology Group.

PURPOSE: Early-stage Hodgkin lymphoma (HL) is a rare disease, and the location of lymphoma varies considerably between patients. Here, we evaluate the variability of radiation therapy (RT) plans among 5 International Lymphoma Radiation Oncology Group (ILROG) centers with regard to beam arrangements, planning parameters, and estimated doses to the critical organs at risk (OARs). METHODS: Ten patients with stage I-II classic HL with masses of different sizes and locations were selected. On the basis of the clinical information, 5 ILROG centers were asked to create RT plans to a prescribed dose of 30.6 Gy. A postchemotherapy computed tomography scan with precontoured clinical target volume (CTV) and OARs was provided for each patient. The treatment technique and planning methods were chosen according to each center's best practice in 2013. RESULTS: Seven patients had mediastinal disease, 2 had axillary disease, and 1 had disease in the neck only. The median age at diagnosis was 34 years (range, 21-74 years), and 5 patients were male. Of the resulting 50 treatment plans, 15 were planned with volumetric modulated arc therapy (1-4 arcs), 16 with intensity modulated RT (3-9 fields), and 19 with 3-dimensional conformal RT (2-4 fields). The variations in CTV-to-planning target volume margins (5-15 mm), maximum tolerated dose (31.4-40 Gy), and plan conformity (conformity index 0-3.6) were significant. However, estimated doses to OARs were comparable between centers for each patient. CONCLUSIONS: RT planning for HL is challenging because of the heterogeneity in size and location of disease and, additionally, to the variation in choice of treatment techniques and field arrangements. Adopting ILROG guidelines and implementing universal dose objectives could further standardize treatment techniques and contribute to lowering the dose to the surrounding OARs.

Outcomes of single fraction stereotactic ablative radiotherapy for lung metastases.

Stereotactic Ablative Radiotherapy (SABR) has been previously investigated as an alternative to thoracic surgery in patients with a limited number of pulmonary nodules from different primary tumors. We here report the clinical outcomes of a series of consecutive patients homogeneously selected and treated with single dose SABR in our Institution. Eligibility criteria were: 1-5 lung metastases, maximum tumor diameter <50 mm, absent or controlled extra-thoracic disease, adequate pulmonary function, no prior radiotherapy, performance status ECOG 0-1. All patients were treated with a single dose of 26 Gy prescribed to the 80% isodose, by 3D-CRT or by IGRT-VMAT. Follow-up consisted of clinical evaluation and periodic CT scans. Primary endpoints were Local Control (LC), toxicity and Progression-Free Survival (PFS). Secondary endpoints were Cancer-Specific Survival (CSS) and Overall Survival (OS). Out of 102 patients treated with SABR between october 2003 and october 2011, we selected 67 patients for a total of 90 lesions. Main primary tumor sites were lung and colon-rectum (37.3% and 43.3% of lesions, respectively). Median follow up time was 24 months. Treated metastasis progression at SABR site was observed in 10 lesions (11.1%), and actuarial LC rates at 1 and 2 years were respectively 93.4% and 88.1%. Systemic failure occurred in 37 patients (55.2%) at a median interval of 8 months after SABR. PFS rates were 72% and 55.4% at 1 and 2 year. Seven patients had grade 1 (10.4%) and 8 grade 2-3 late radiological toxicity (11.9%), while 6 experienced late chest wall toxicity (2 rib fractures, 4 chronic chest pain, 8.9%). CSS rates at 1 and 2 years were 90% and 76%, while OS rates were 85.1% and 70.5%, respectively. Median survival time was 40 months. On multivariate analysis, a disease-free interval longer than 24 months was close to significance for a benefit in CSS (p = 0.07; HR 0.34 [95% CI 0.1-1.12]). The study includes a cohort of patients treated with single fraction 26 Gy SABR followed for a prolonged time interval. Single fraction SABR appears to be an effective treatment option, with little observed acute toxicity and limited late toxicity (<15%); its advantages also include a high patients' compliance, a short overall treatment time and an easy combination with systemic therapies. These results might provide supportive evidence to the use of single fraction SABR as a valid and acceptable alternative to surgery for pulmonary metastases from different primary tumors.

Prostate cancer as a paradigm of multidisciplinary approach? Highlights from the Italian young radiation oncologist meeting.

AIMS AND BACKGROUND: The diagnostic and therapeutic approach to prostate cancer has evolved rapidly in last decades. Young professionals need an update about these recent developments in order to improve the care of patients treated in their daily clinical practice. METHODS: On May 18, 2013, AIRO Giovani (the young section of the Italian Association of Radiation Oncology) organized a multidisciplinary meeting involving, as speakers, several young physicians from many parts of Italy actively involved in the diagnostic and therapeutic approach to prostate cancer. The meeting was specifically addressed to young physicians (radio-oncologists, urologists, medical oncologists) and presented the state-of-the-art of the diagnostic/therapeutic approach based on the latest evidence on the issue. Highlights of the congress are summarized and presented in this report. RESULTS: The large participation in the meeting (more than 120 participants were present) confirmed the interest of young radiation oncologists in improving their skills in prostate cancer management. The contributions of the speakers confirmed the need for regular updates, considering the promising results of recently published studies and the many new ongoing trials, on the diagnostic and therapeutic approaches to prostate cancer. CONCLUSIONS: Multidisciplinary meetings are helpful to improve the skills of young professionals.

Postoperative radiotherapy for patients with completely resected pathologic n2 non-small-cell lung cancer: a retrospective analysis.

BACKGROUND: Adjuvant radiotherapy in non-small-cell lung cancer (NSCLC) is still controversial. The purpose of this retrospective study was to evaluate the role of postoperative radiotherapy (PORT) in terms of local control and survival in pathologic N2 NSCLC. PATIENTS AND METHODS: From January 2003 to December 2008, 66 patients with pathologic N2 NSCLC received PORT. Mediastinal lymph node metastases were classified into single (12 patients) or multiple (54 patients) stations. All patients received conformal radiation therapy, with a median total dose of 50.4 Gy. Target volumes included the bronchial stump, ipsilateral hilum, all pathologically involved lymph node regions, and all the lymph nodes between 2 noncontiguous pathologic nodal stations. The pattern of failure was considered as locoregional or systemic, or a combination of both. Locoregional failure was defined as in field or out of field. RESULTS: Median follow-up time was 34.9 months (range 3.5-62.8 months). Local control was 80% at 12 months, 77.2% at both 24 and 36 months, and 72.1% at 60 months. The pattern of failure was locoregional in 3 patients (1 out of field and 2 in field) and systemic in 25 patients, with 12 patients presenting both locoregional and distant disease. Overall survival at 12, 36, and 60 months was 77%, 44%, and 37%, respectively. Median survival time was 34 months. The number of pathologically involved lymph node stations was a prognostic factor for local control (P = .05), cancer-specific survival (CSS) (P = .04), and disease-free survival (DFS) (P = .04). CONCLUSION: Despite the limitations of the present study, mainly represented by its retrospective nature, our data support the role of PORT in terms of locoregional control and overall survival benefit; the number of involved mediastinal lymph nodes represents a significant prognostic factor in patients with pathologic N2 NSCLC.