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Background: Brain metastases are the most common intracranial malignancy and remain a substantial source of morbidity and mortality in cancer patients. Linear accelerator based stereotactic radiosurgery (SRS) is widely used and is frequently delivered by hypo-fractionnated volumetric modulated arc therapy using non-coplanar beams, where geometric accuracy and planning margins are a major concern., Purpose: To give a practical analysis of intrafraction patient motion for multi-target, single isocentre, brain SRS treatments and to derive adapted GTV-to-PTV margins., Methods: Data of 154 lesions, spread over 85 fractions from 56 patients treated in our institution with the Varian HyperArc  SRS solution was processed. Intrafraction patient motion were recorded using an Optical Surface Monitoring System during irradiation. The present study focuses on small tumor volumes, roughly equal or inferior to 1.5  cm 3 ${\rm cm}^3$ , and frameless mask-based immobilization. For each treatment session, a tumor displacement vector matrix was calculated from the patient drifts as a function of time. Data were combined together into a representative treatment scenario and the dosimetric impact of GTV displacement was calculated., Results: Recommended margins due to patient motion range between 0.3 and 1 mm, depending on the distance tumor-isocentre, and the desired GTV edge dose coverage. Those values should be added quadratically with other sources of uncertainty, such as mechanical isocentre and kV-MV misalignment., Conclusion: Thorough analysis of intrafraction patient motion was performed, the dosimetric impact was calculated for different scenarios, and adequate GTV-to-PTV margins were derived. These values vary according to the distance isocentre-to-GTV, as well as the desired dose coverage, and should be chosen adequately., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

In cancer treatment, mild hyperthermia (HT) represents an old, but recently revived opportunity to increase the efficacy of radiotherapy (RT) without increasing side effects, thereby widening the therapeutic window. HT disrupts cellular homeostasis by acting on multiple targets, and its combination with RT produces synergistic antitumoral effects on specific pathophysiological mechanisms, associated to DNA damage and repair, hypoxia, stemness and immunostimulation. HT is furthermore associated to direct tumor cell kill, particularly in higher temperature levels. A phenomenon of temporary resistance to heat, known as thermotolerance, follows each HT session. Cancer treatment requires innovative concepts and combinations to be tested but, for a meaningful development of clinical trials, the understanding of the underlying mechanisms of the tested modalities is essential. In this mini-review, we aimed to describe the synergistic effects of the combination of HT with RT as well as the phenomena of thermal shock and thermotolerance, in order to stimulate clinicians in new, clinically relevant concepts and combinations, which become particularly relevant in the era of technological advents in both modalities but also cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Righini, Durham and Tsoutsou.)

Aim: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario., Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology., Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR., Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints., Competing Interests: Conflict of interest statement A.I. declares the following relevant financial activities outside the submitted work: has received Grants from Transgene, Sanofi, Air Liquide, Nutritheragene; has received travel funding from Leo Pharma; Grant research support and travel funding from Carthera. J.G. declare the following financial personnal fees for activities outside the submitted work or served as consultant or advisory board/ has received symposium and travel funding from: Roche-Genentech, Novartis, Onxeo, Dachii Sankyo, MSD, Isai, Genomic Health, Ipsen, Macrogenics, Pfizer, Mylan, Lilly, Immunomedics, Sandoz. J.-P.S. declares the following financial personnal fees for activities outside the submitted work or served as consultant or advisory board/ has received Symposium and travel funding from: MSD, Lilly, Roche, Mylan, Pfizer, PFOncology, LeoPharma, Novartis, Biogaran, Astra Zeneca, Gilead, BMS. All the other authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The association of radiotherapy and immunotherapy has recently emerged as an exciting combination that might improve outcomes in many solid tumor settings. In the context of breast cancer, this opportunity is promising and under investigation. Given the heterogeneity of breast cancer, it might be meaningful to study the association of radiotherapy and immunotherapy distinctly among the various breast cancer subtypes. The use of biomarkers, such as tumor infiltrating lymphocytes, which are also associated to breast cancer heterogeneity, might provide an opportunity for tailored studies. This review highlights current knowledge of the association of radiotherapy and immunotherapy in the setting of breast cancer and attempts to highlight the therapeutic opportunities among breast cancer heterogeneity.

Systemic treatments are tailored to breast cancer (BC) heterogeneity, which is not yet taken into account for radiotherapy (RT) personalization. The primary objective of this review is to summarize existing data suggesting BC subtypes and genetic assays are prognostic and predictive biomarkers useful for RT decision-making and to provide implications for their incorporation into future translational and clinical research. The evidence suggesting that BC subtypes also exhibit distinct "locoregional recurrence (LRR)" patterns is retrospective but consistent and validated in over fifteen studies. The HER-2 positive and triple negative subtypes are the most susceptible to locoregional failure. The high risk of the HER-2 positive subtype can be reversed with trastuzumab administration. Very little is known on the subtypes' intrinsic radiosensitivity properties. Genetic assays have assessed retrospectively signatures' prognostic and predictive value in patients' cohorts (several coming from prospective studies) for LRR risk and radiotherapy (RT) benefit. Further confirmation is needed before their introduction into clinical routine. Evidence on the use of molecular biomarkers for adjuvant RT tailoring is emerging but needs validation and introduction into prospective studies. The plethora of modern RT options (partial breast irradiation, hypofractionation), as well as recent evidence pointing towards more extensive radiotherapy, demand introduction of biological features into clinical trials to improve therapeutic decisions. Open questions, such as tailoring of irradiation after neo-adjuvant chemotherapy in complete responders and the understanding of the interplay between local control, systemic recurrence and survival given modern systemic treatments, need to be addressed under the prism of biology within this heterogeneous disease. Intrinsic radiobiological properties within this heterogeneity need to be highlighted in order to further improve outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Due to the significant advances in the diagnosis and treatment of breast cancer seen in the last decades, increased survival rates and better outcomes of patients are being observed. The role of radiotherapy remains pivotal in the treatment of early breast cancer. In the adjuvant setting, whole breast irradiation remains the standard of care using a relatively well standardized radiation technique. The recent technology advances and 3D conformal radiotherapy allow for better volumes definition resulting to increased organ at risk--sparing and therefore treatment optimization. Sophisticated techniques and emerging options (such as accelerated partial breast irradiation) are not routinely used yet outside of a clinical trial. Moreover, new drugs and targeted therapies have recently been introduced to the clinical practice for treatment individualization according to the specific tumours' prognosis and/or prediction of the drugs' efficacy based on new biological tools. Regarding the synergistic effect of these molecules with ionizing radiation, rigorous prospective evaluation of combined therapy is important to ensure improved long-term benefit/risk ratio. In this review, the significant advances of radiotherapy and combined therapy in the new era of breast cancer management will be discussed., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Purpose: Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with amifostine, was herein investigated., Methods and Materials: Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m(2)/week) and cetuximab (standard weekly regimen) therapy. The dose of amifostine was individualized according to tolerance., Results: A high daily amifostine dose (750-1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) was tolerated by 34.9% of patients. A high amifostine dose was linked to reduced RT delays (p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.)., Conclusions: In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash. A high daily dose of amifostine allows completion of therapy with minor delays.

The adjuvant setting of early breast cancer treatment is an evolving field where different modalities must be combined to improve outcomes; moreover, quality of life of breast cancer survivors emerges as a new important parameter to consider, thus implying a better understanding of toxicities of these modalities. We have conducted a review focusing on the latest literature of the past 3 years, trying to evaluate the existing data on the maximum acceptable delay of radiotherapy when given as sole adjuvant treatment after surgery and the optimal sequence of all these modalities with respect to each other. It becomes evident radiotherapy should be given as soon as possible and within a time frame of 6-20 weeks. Chemotherapy is given before radiotherapy and hormone therapy. However, radiotherapy should be started within 7 months after surgery in these cases. Hormone therapy with tamoxifen might be given safely concomitantly or sequentially with radiotherapy although solid data are still lacking. The concurrent administration of letrozole and radiotherapy seems to be safe, whereas data on trastuzumab can imply only that it is safe to use concurrently with radiotherapy. Randomized comparisons of hormone therapy and trastuzumab administration with radiotherapy need to be performed.

Purpose: The optimal sequence of modalities involved in breast cancer treatment with respect to radiotherapy and the maximum acceptable interval between radiotherapy and surgery need to be determined., Design: This review attempts a critical reading of the literature., Results: A delay of radiotherapy more than 8-12 weeks after surgery adversely affects local recurrence. Radiotherapy should be administered within 7 months after surgery, when chemotherapy is administered first. Several chemotherapy regimens can be safely administered concurrently with radiotherapy. The concurrent use of tamoxifen with chemotherapy should be avoided, but not with radiotherapy. Data is insufficient with regard to concurrent use of aromatase inhibitors with radiotherapy. The use of trastuzumab concomitantly with radiotherapy may enhance toxicities but may also improve its efficacy., Conclusions: Although the issue of radiotherapy delay and that of sequence with chemotherapy or tamoxifen are clarified, the sequence of radiotherapy with aromatase inhibitors and trastuzumab needs to be defined. Individual radiosensitivity may influence toxicity. New biologic markers have to be determined in the future for tailoring radiotherapy in breast cancer.

Purpose: Short radiotherapy schedules might be more convenient for patients and overloaded radiotherapy departments, provided late toxicity is not increased. We evaluated the efficacy and toxicity of a hypofractionated and highly accelerated radiotherapy regimen supported with cytoprotection provided by amifostine in breast cancer patients treated with breast-conserving surgery., Methods and Materials: A total of 92 patients received 12 consecutive fractions of radiotherapy (3.5 Gy/fraction for 10 fractions) to the breast and/or axillary/supraclavicular area and 4 Gy/fraction for 2 fractions to the tumor bed). Amifostine at a dose of 1,000 mg/d was administered subcutaneously. The follow-up of patients was 30-60 months (median, 39)., Results: Using a dose individualization algorithm, 77.1% of patients received 1,000 mg and 16.3% received 750 mg of amifostine daily. Of the 92 patients, 13% interrupted amifostine because of fever/rash symptoms. Acute Grade 2 breast toxicity developed in 6.5% of patients receiving 1,000 mg of amifostine compared with 46.6% of the rest of the patients (p < .0001). The incidence of Grade 2 late sequelae was less frequent in the high amifostine dose group (3.2% vs. 6.6%; p = NS). Grade 1 lung fibrosis was infrequent (3.3%). The in-field relapse rate was 3.3%, and an additional 2.2% of patients developed a relapse in the nonirradiated supraclavicular area. c-erbB-2 overexpression was linked to local control failure (p = .01). Distant metastasis appeared in 13% of patients, and this was marginally related to more advanced T/N stage (p = .06)., Conclusion: Within a minimal follow-up of 2.5 years after therapy, hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection has proved a well-tolerated and effective regimen. Longer follow-up is required to assess the long-term late sequelae.

Aims and Background: Adjuvant external beam radiotherapy is highly recommended for uterine carcinomas invading beyond the inner half of the myometrium or cervical stage IIa carcinomas. The addition of a booster intracavitary dose is widely used., Methods: We assessed the feasibility and toxicity of a hypofractionated accelerated conformal radiotherapy scheme (2.7 Gy per fraction, for 14 consecutive fractions to the pelvis) supported with the cytoprotective agent amifostine (HypoARC). The amifostine dose was individualized (500-1000 mg daily subcutaneously). A booster dose of radiation was given to the vagina and stump using a 6-field 3D-conformal technique (3 x 4 Gy or 4 x 3 Gy) instead of intracavitary radiotherapy., Results: Grade 2 diarrhea appeared in 9/25 (36%) and grade 1 cystitis in 7/25 (28%) cases. Analysis according to the amifostine dose level clearly showed reduced toxicity in patients receiving a daily dose of 750-1000 mg (P < 0.009). Within a median follow-up of 31 months (range, 11-52), there was only one case with grade 2 colitis (the patient had received no amifostine). None of the patients treated has relapsed locally or to distant organs within a median of 31 months of follow-up., Conclusions: It is concluded that HypoARC followed by 3D-conformal booster dose to the vagina is feasible and convenient for patients and for busy radiotherapy departments, as it reduces the overall time by 50%. When supported by high-dose daily amifostine, it has an impressively low rate of early and late radiation toxicity.

Objectives: Lung fibrosis is a severe complication after radiotherapy in patients with nonsmall cell lung cancer and is the main undesirable late complication limiting the therapeutic ratio of thoracic radiation treatment. Here we evaluated the lung fibrosis using computed tomography scan mediated assessment of lung tissue density in long-term survivals treated with hypofractionated and accelerated radiotherapy supported with amifostine (HypoARC)., Methods: Out of 45 patients with locally advanced nonsmall cell lung cancer treated with conformal HypoARC (3.5 Gy x 15 fractions in 4 weeks) and concurrent chemotherapy, 14 are alive 16 to 47 months (median 20) after radiotherapy. Patients received 500 to 1000 mg of amifostine before each radiotherapy fraction, according to a previously described dose individualization algorithm., Results: Early pneumonitis was absent in all patients, whereas lung density assessed with computed tomography scan in Hounsfield units (HU), within a median of 20 months after radiotherapy, showed marked increase in 2/6 and 0/8 patients who received 500 to 750 mg and 1000 mg of amifostine, respectively. The HU in these 2 patients increased to values below -550 HU, from initial values of -700 to -800 HU. Only one of these 2 patients had mild exertional dyspnoea., Conclusions: Given the good tolerance of daily high-dose amifostine administration and the encouraging very low rates of pneumonitis and lung fibrosis noted, despite the aggressiveness of the radio-chemotherapy regimen applied, it is suggested that the value of amifostine in chest radiotherapy should be re-evaluated in properly designed randomized clinical trials.

Background: Combined radiochemotherapy is the gold standard for patients with locally advanced non-small cell lung cancer (LA-NSCLC). In the present study, the feasibility of hypofractionated accelerated radiotherapy with cytoprotection (HypoARC) in combination with vinorelbine and liposomal doxorubicin was evaluated., Patients and Methods: Fourteen patients (pts) with LA-NSCLC (PS 0-2) were recruited. Patients received 15 fractions for 3.5 Gy within four consecutive weeks (1 week split after the 10th fraction), supported with subcutaneously administered amifostine (500-1000 mg/day). Pegylated liposomal doxorubicin was administered at a standard dose of 20 mg/m2 every two weeks, for 3 consecutive cycles. Vinorelbine was administered at 3 dose levels: a) 20 mg/m2 every week (5 pts), b) 25 mg/m2 thrice every two weeks (5 pts) and c) 30 mg/m2 thrice every two weeks (4 pts)., Results: Grade 3 neutropenia enforcing chemotherapy delays was noted in 2/5 and 2/4 patients in the groups b and c respectively. Fatigue was a common but not dose-defining feature. Radiation grade 2 esophagitis was noted in 6/14 patients. No case of severe radiation pneumonitis was noted. Partial response was documented in 9/14 patients, minimal response in 3/14 and stable disease in 2/14. The median local progression-free survival was 12 months and the median overall survival was 8 months., Conclusion: It is concluded that the administration of 25 mg/m2 of vinorelbine thrice a week together with liposomal doxorubicin and thoracic radiotherapy is feasible for patients with LA-NSCLC, providing high response rates. Further studies are required to better assess benefits in terms of local and distant control of the disease.

Radiation pneumonitis and subsequent radiation pulmonary fibrosis are the two main dose-limiting factors when irradiating the thorax that can have severe implications for patients' quality of life. In this article, the current concepts about the pathogenetic mechanisms underlying radiation pneumonitis and fibrosis are presented. The clinical course of fibrosis, a postulated acute inflammatory stage, and a late fibrotic and irreversible stage are discussed. The interplay of cells and the wide variety of molecules orchestrating the immunologic response to radiation, their interactions with specific receptors, and the cascade of events they trigger are elucidated. Finally, the implications of this knowledge with respect to the therapeutic interventions are critically presented.

Background: Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder. Cytokines contribute an important but yet undefined role to its pathogenesis., Objectives: The present study aims to compare serum levels of cytokines involved in Th-1 and Th-2 immunity, such as interleukins (IL) IL-2, IL-4, IL-8, IL-10, interferon-gamma (IFN-gamma) and IL-12 (p40) in patients with IPF and healthy volunteers. Twenty patients with IPF and 40 healthy controls (HC) participated., Methods: Cytokines were assessed by enzyme-linked immunoabsorbent assay (ELISA)., Results: Median values of serum IL-2, IL-8, IL-10, IL-12 (p40) were higher in the IPF than the control group: IPF group: 1.05 U/ml, 12.55, 10.13, 44.17 pg/ml; control group: 0.05 U/ml, 6.91, 0.75, 4.51 pg/ml, respectively (P<0.05). IFN-gamma serum levels were lower in the IPF (0.19 pg/ml) than in the control group (0.49 pg/ml). IL-4 values did not differ in a statistically significant way among the groups: 8.40 pg/ml in the IPF group, and 7.46 pg/ml in the control group (P>0.05). IL-4 positively correlated to fast expiratory volume in 1s (FEV1%) and forced vital capacity (FVC%), while IL-8 negatively correlated to the respective values (P<0.005)., Conclusions: IL-2, IL-8, IL-10 and IL-12 (p40) were found to be elevated in the sera of patients with IPF. IFN-gamma was found to be decreased in the sera of patients with IPF.

During the last half of century considerable research on radiosensitivity biomarkers has been published. However, to date there is no non-invasive marker of cellular radiosensitivity identified for clinical routinely use. In this review, the main functional and metabolic imaging isotopic techniques for tumor radiosensitivity that have been explored over the last years are being described. This indirect evaluation fall into 3 topics associated with tumor proliferation rate or apoptosis, tumor hypoxic fraction, neoangiogenesis and the intrinsic radiosensitivity of clonogenic tumor cells. The final objective of the radiosensitivity monitoring during radiotherapy would be to adapt treatment strategy for overcoming the identified radioresistance mechanism such as hypoxia by the addition of radiosensitisers for example. This would allow better tumor control rather than continue inefficient and costly treatment delivery, which in addition could compromise outcome.

In order to test the serum levels of ICAM-1, ICAM-2 and ICAM-3 in patients with idiopathic pulmonary fibrosis (IPF), twenty patients with IPF and eleven with secondary interstitial fibrosis (SIF), as well as forty healthy volunteers (HV) were studied. Serum intracellular adhesion molecules (ICAM) 1, 2 and 3 were assessed by ELISA. Functional respiratory tests, which included spirometry and lung diffusing capacity were simultaneously performed. Median values of serum ICAM-1 and ICAM-2 were higher in the patients' than in the healthy volunteers' (HV) group: IPF group: 946.60 ng/ml and 400.14 ng/ml; SIF group: 901.58 ng/ml and 378.27 ng/ml; HV group: 308.40 ng/ml and 217.55 ng/ml, respectively (p<0.05). ICAM-3 serum levels were equal between the three groups. ICAM-2 negatively correlated to DLCO values. (p<0.005). It can be concluded that ICAM 1 and 2 are elevated in the sera of patients with pulmonary fibrosis. ICAM-2 might be associated with a more impaired clinical status.