Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Post-operative flank irradiation using conformal versus highly conformal radiotherapy techniques for paediatric renal tumours: Results from the French registry PediaRT.

PURPOSE: Three-dimensional conformal RT (3D-RT) techniques are gold standard for post-operative flank radiotherapy (RT) in paediatric renal tumours. Recently, highly conformal RT (HC-RT) techniques have been implemented without comparative clinical data. The main objective of this multicentre study was to compare locoregional control (LRC) in children treated either with HC-RT or 3D-RT techniques. METHODS: Patients treated with post-operative flank RT for renal tumour registered in the national cohort PediaRT between March 2013 and September 2019 were included. Treatment and follow-up data, including toxicities and outcomes, were retrieved from the database. LRC was calculated, and dose reconstruction was performed in case of an event. RESULTS: Seventy-nine patients were included. Forty patients were treated with HC-RT and 39 with 3D-RT. Median follow-up was 4.5 years. Three patients had locoregional failure (LRF; 4%). HC-RT was not associated with a higher risk of LRF. Three-year LRC were 97.4% and 94.7% in the HC-RT and 3D-RT groups, respectively. The proportion of planning target volumes receiving 95% or more of the prescribed dose did not significantly differ between both groups (HC-RT 88%; 3D-RT 69%; p = .05). HC-RT was better achieving dose constraints, and a significant mean dose reduction was observed in the peritoneal cavity and pancreas associated with lower incidence of acute gastrointestinal toxicity. CONCLUSION: LRF after post-operative flank RT for renal tumours was rare and did not increase using HC-RT versus 3D-RT techniques. Dose to the pancreas and the peritoneal cavity, as well as acute toxicity, were reduced with HC-RT compared to 3D-RT.

Brain radiotherapy in patients treated for a newly diagnosed primary central nervous system lymphoma: professional practice evaluation in 19 French centers.

INTRODUCTION: The objective of this study was a multicentric evaluation of professional practices, analyzing the irradiation technique itself and its impact on survival and recurrence sites, in primary central nervous system lymphomas (PCNSLs). METHODS: We retrospectively analyzed the technical and clinical records of 79 PCNSL patients included in the database of the national expert network for oculocerebral lymphoma ('LOC') who were treated with brain radiotherapy as first-line treatment for newly diagnosed primary central nervous system lymphoma between 2011 and 2018. RESULTS: The number of patients treated with brain radiotherapy gradually decreased over time. The heterogeneity of radiotherapy prescriptions was significant, and 55% of them did not comply with published recommendations in terms of irradiation dose and/or volume. The proportion of complete responders to induction chemotherapy treated with reduced-dose radiotherapy increased over time. Partial brain radiotherapy was associated with significantly lower overall survival in univariate analysis. In partial responders to induction chemotherapy, increasing the total dose to the brain >30 Gy and adding a boost to the WBRT induced a trend toward improved progression-free and overall survival. Five recurrences (13%) occurred exclusively in the eyes, all in patients whose eyes had been excluded from the irradiation target volume and including 2 patients without ocular involvement at diagnosis. CONCLUSION: The visibility of recommendations for prescribing brain radiotherapy for the treatment of newly diagnosed primary central nervous system lymphoma needs to be improved to harmonize practices and improve their quality. We propose an update of the recommendations.

Locoregional failure after postoperative flank irradiation for nephroblastoma: Results from the French cohort of the SIOP-2001 trial.

OBJECTIVE: To describe locoregional failure (LRF) after postoperative flank radiotherapy (RT) among French patients with nephroblastoma included in the Société Internationale d'Oncologie Pédiatrique (SIOP)-2001 protocol. PATIENTS AND METHODS: In selected SIOP-2001 patients, planning with simulation computed tomography (CT) scan and posttreatment CT scan demonstrating LRF were registered and analyzed. LRF was contoured and classified as in-field, marginal or out-of-field according to dose distribution. RESULTS: Total 316 French SIOP-2001 patients were treated with postoperative RT. Three patients with nephroblastoma developed LRF after flank RT. All failures were located within the retroperitoneum. In two patients, the relapse was within the RT field and in one it was classified as marginal. CONCLUSION: LRF after postoperative flank RT for nephroblastoma was rare and exclusively situated in the retroperitoneum. These results point out this region as the most at risk of local relapse. A prospective evaluation of a target volume restricted to the retroperitoneum allowing the use of modern and highly conformal radiation techniques in order to decrease dose to normal tissues shall be encouraged.

[National meetings for complex cases in pediatric radiation oncology: Back on six years experience]. / Réunions nationales de cas complexes en radiothérapie pédiatrique : retour sur six années d'expérience.

INTRODUCTION: Pediatric cancers are rare, representing almost 2,500 new cases each year in France meaning 1% of all cancers. Since 2012, a twice-monthly national web-based conference was held in France. Any patient with a pediatric type cancer requiring radiotherapy can be discussed. It aims at answering the physician with specific radiation therapy questions on rare and complex indications, at promoting the use of referential and the inclusion into clinical protocols. RESULTS: From 2012 to 2018, 1,078 cases were discussed for 940 patients in 142 meetings. Mean age was 10 years old (4 months to 45 years). The mean number of attendants was 6 (2 to 32). We review in this paper the main clinical features discussed in the web-conference and the decision of the web-conference. In 85% cases, the first treatment proposed was mostly accepted, but in 15%, other proposals were done (modifications of target volumes, doses or indications). CONCLUSIONS: Between 2012 and 2018, more than 1,000 pediatric irradiation cases were discussed in our web-based conference leading to 15% of change in radiation protocol. The rarity and the complexity of these situations need those meetings. They provide a place to improve the global knowledge and the quality of the treatments provided.

Cytokine release syndrome and tumor lysis syndrome in a multiple myeloma patient treated with palliative radiotherapy: A case report and review of the literature.

We present the case of a 53-year-old woman treated with analgesic radiotherapy for a multiple myeloma bone lesion of the forearm. After a first fraction of 5 Gray (Gy), she presented with an acute respiratory syndrome with fever a few hours after the treatment. The same symptoms occurred after the second fraction 3 days later. The patient recovered quickly thanks to intravenous hydration and suspension of the radiotherapy. Biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. This is the second time in the literature that cytokine release syndrome has been described following radiotherapy. First, we synthesize TLS and radiotherapy to determine how radiotherapy could be a trigger associated with other well-known factors. Furthermore, we discuss radiotherapy and cytokine release syndrome. SUMMARY: We present the case of a woman treated with analgesic radiotherapy for a multiple myeloma bone lesion. Following the first and the second treatment fraction, the patient presented with an acute respiratory syndrome with fever and biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. Furthermore, we discuss how radiotherapy could be a trigger of cytokine release syndrome and tumor lysis syndrome in association with chemotherapy drugs.

Standard 6-week chemoradiation for elderly patients with newly diagnosed glioblastoma.

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI 95%: 10-13 months). Median PFS was 9.5 months (CI 95%: 9-10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for "real-life" elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

The von Willebrand factor stamps plasmatic extracellular vesicles from glioblastoma patients.

Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.

Hypofractionated stereotactic body radiation therapy (SBRT) in pediatric patients: preliminary toxicity results of a national prospective multicenter study.

OBJECTIVES: While hypofractionated stereotactic body radiotherapy (SBRT) has been largely adopted in the adult setting, its use remains limited in pediatric patients. This is due, among other factors, to fear of potential toxicities of hypofractionated regimens at a young age. In this context, we report the preliminary acute (<3 months from SBRT) and middle-term (3-24 months) toxicity results of a national prospective study investigating SBRT in pediatric patients. METHODS: Between 2013 and 2019, 61 patients were included. The first 40 patients (median age: 12 y, range: 3-20) who completed a 2-year-follow-up were included in the present analysis. SBRT was used for treating lung, brain or (para)spinal lesions, either as first irradiation (35%) or in the reirradiation setting (65%). RESULTS: Acute and middle-term grade ≥2 toxicities occurred in 12.5 and 7.5% of the patients, respectively. No grade ≥4 toxicities occurred. Almost all toxicities occurred in the reirradiation setting. CONCLUSION: SBRT showed a favorable safety profile in young patients treated for lung, brain, and (para)spinal lesions. ADVANCES IN KNOWLEDGE: SBRT appeared to be safe in pediatric patients treated for multiple oncology indications. These results support further evaluation of SBRT, which may have a role to play in this patient population in the future.

[Influence of age on indications and modalities of radiation therapy: What to keep in mind for adolescents and young adults?] / Impact de l'âge et radiothérapie : points clés chez les AJA.

When using radiation therapy for adolescents and young adults (AYA), paediatricians, adults' oncologists and radiation oncologists need to keep in mind several particularities through the whole therapeutic process. They embrace the indication, target volumes, prescribed dose, treatment techniques and follow-up. Indeed, the young age and the cancer features that characterised this population influence the modalities of irradiation. This article highlights the key points of AYA care with radiation therapy.

Radiomics for radiation oncologists: are we ready to go?

Radiomics have emerged as an exciting field of research over the past few years, with very wide potential applications in personalised and precision medicine of the future. Radiomics-based approaches are still however limited in daily clinical practice in oncology. This review focus on how radiomics could be incorporated into the radiation therapy pipeline, and globally help the radiation oncologist, from the tumour diagnosis to follow-up after treatment. Radiomics could impact on all steps of the treatment pipeline, once the limitations in terms of robustness and reproducibility are overcome. Major ongoing efforts should be made to collect and share data in the most standardised manner possible.

Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models.

Background. The tumor vasculature acts as an interface for the primary tumor. It regulates oxygenation, nutrient delivery, and treatment efficacy including radiotherapy. The response of the tumor vasculature to different radiation doses has been disparately reported. Whereas high single doses can induce endothelial cell death, improved vascular functionality has also been described in a various dose range, and few attempts have been made to reconcile these findings. Therefore, we aimed at comparing the effects of different radiation fractionation regimens on the tumor vascular microenvironment. METHODS: Lewis lung and prostate PC3 carcinoma-derived tumors were irradiated with regimens of 10 × 2 Gy, 6 × 4 Gy, 3 × 8 Gy or 2 × 12 Gy fractions. The tumor vasculature phenotype and function was evaluated by immunohistochemistry for endothelial cells (CD31), pericytes (desmin, α-SMA), hypoxia (pimonidazole) and perfusion (Hoechst 33342). RESULTS: Radiotherapy increased vascular coverage similarly in all fractionation regimens in both models. Vessel density appeared unaffected. In PC3 tumors, hypoxia was decreased and perfusion was enhanced in proportion with the dose per fraction. In LLC tumors, no functional changes were observed at t = 15 days, but increased perfusion was noticed earlier (t = 9-11 days). CONCLUSION: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters.

Update in pediatric nasopharyngeal undifferentiated carcinoma.

Many of the principles established in adults with undifferentiated nasopharyngeal carcinoma (NPC) apply to children, adolescents and young adults. However, NPC in young patients should be distinguished from the adult form by several points. This review focuses mainly on differences between adult and pediatric NPC. The role of biology and genetics in pediatric NPC is discussed. Systemic treatment modalities including type of chemotherapy induction, timing of treatment, role of immunotherapy as adjuvant treatment, or in relapsing/ metastatic diseases are reported. Radiation modalities (doses, techniques…) in children are also reviewed. Long-term effects including secondary cancers are finally be discussed in this young NPC population.

Tumor vasculature remodeling by radiation therapy increases doxorubicin distribution and efficacy.

The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10 × 2 Gy and 2 × 12 Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy.

Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial.

PURPOSE: To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT). PATIENTS AND METHODS: One hundred and fifty-four patients from the Gating 2006 prospective randomized trial were treated with conformal RT with or without respiratory motion management. For patients with a LRF as first event, treatment planning with simulation CT, pre-treatment 18FDG PET-CT and post-treatment images demonstrating recurrence were registered and analyzed. Measurable LRF was contoured (rGTV) and classified as in-field, marginal, or out-of-field. RESULTS: Median follow-up was 27.8 months. Forty-eight patients presented with LRF. One-year and 2-year locoregional disease-free survival rates were 77% (95% CI 70-83) and 72% (95% CI 64-79) respectively. 79% of the patients with LRF as first event relapsed within the RT field (55% isolated), 30% had marginal LRF component. Isolated out-of-field failure occurred in only 3% of all patients. The regions of highest FDG-uptake on pre-treatment PET-CT were located within the recurrence in 91% of patients with in-field LRF. CONCLUSION: In-field failure was the most common pattern of failure. Escalated dose RT with high-dose fractions guided by PET parameters warrants further investigation.

Can We Spare the Pancreas and Other Abdominal Organs at Risk? A Comparison of Conformal Radiotherapy, Helical Tomotherapy and Proton Beam Therapy in Pediatric Irradiation.

OBJECTIVES: Late abdominal irradiation toxicity during childhood included renal damage, hepatic toxicity and secondary diabetes mellitus. We compared the potential of conformal radiotherapy (CRT), helical tomotherapy (HT) and proton beam therapy (PBT) to spare the abdominal organs at risk (pancreas, kidneys and liver- OAR) in children undergoing abdominal irradiation. METHODS: We selected children with abdominal tumors who received more than 10 Gy to the abdomen. Treatment plans were calculated in order to keep the dose to abdominal OAR as low as possible while maintaining the same planned target volume (PTV) coverage. Dosimetric values were compared using the Wilcoxon signed-rank test. RESULTS: The dose distribution of 20 clinical cases with a median age of 8 years (range 1-14) were calculated with different doses to the PTV: 5 medulloblastomas (36 Gy), 3 left-sided and 2 right-sided nephroblastomas (14.4 Gy to the tumor + 10.8 Gy boost to para-aortic lymphnodes), 1 left-sided and 4 right-sided or midline neuroblastomas (21 Gy) and 5 Hodgkin lymphomas (19.8 Gy to the para-aortic lymphnodes and spleen). HT significantly reduced the mean dose to the whole pancreas (WP), the pancreatic tail (PT) and to the ipsilateral kidney compared to CRT. PBT reduced the mean dose to the WP and PT compared to both CRT and HT especially in midline and right-sided tumors. PBT decreased the mean dose to the ispilateral kidney but also to the contralateral kidney and the liver compared to CRT. Low dose to normal tissue was similar or increased with HT whereas integral dose and the volume of normal tissue receiving at least 5 and 10 Gy were reduced with PBT compared to CRT and HT. CONCLUSION: In children undergoing abdominal irradiation therapy, proton beam therapy reduces the dose to abdominal OAR while sparing normal tissue by limiting low dose irradiation.