[Postoperative radiotherapy in non-small cell lung cancer stage IIIA - N2: Focus and perspectives]. / La radiothérapie postopératoire dans les cancers non à petites cellules de stade IIIA ­ N2 : mise au point et perspectives.

Patients with resectable stage IIIA - N2 lung cancer represent a very heterogeneous population with variable risks of postoperative recurrence depending on the type of N2 involvement (unisite N2, multisite N2, bulky N2, extra-capsular rupture, incomplete resection…). This heterogeneity associated with the difficulty of carrying out prospective randomized studies with sufficient power in stages IIIA - 2, results in the absence of clear and consensual recommendations (except for stages IIIA - N2 resectable R0, since LungART and PORT-C studies). The objective of this article is to make an update on the place of postoperative radiotherapy in the management of stages IIIA - N2 following the publication of two recent randomized trials (PORT-C and LungART) but also compare them fort a better understanding of the current issues raised by these first published results. Indeed, these two trials do not find any benefit in terms of progression free survival and overall survival of postoperative radiotherapy but exploratory analyzes from these two studies seem to show a potential benefit of postoperative in some pN2 populations at high risk of locoregional recurrence (N2 multisite, N2 bulky…). In addition, the advent of immunotherapy (atezolizumab or pembrolizumab) and targeted therapies (osimertinib) in the adjuvant situation are redebating the place of a possible indication for postoperative radiotherapy in stage IIIA - 2.

Budget Impact Analysis of Fixed Dose Versus Weight-Based Dosing Regimen of Nivolumab and Pembrolizumab in the Treatment of Non-Small Cell Lung Cancer.

In 2018, dosing regimens of the two most prescribed immune check point inhibitors (ICI), nivolumab (Opdivo®) and pembrolizumab (Keytruda®), in the treatment of lung cancer were changed from weight-based dosing to fixed dosing. The aim of this study was to compare the economic impact of this change in our university hospital group and then across Ile-de-France, the most inhabited French region. A budget impact analysis (BIA) has been performed on the French public health insurance data. The duration of treatment and the weight of the patients were calculated using data from the patients treated at our health facility and from clinical studies. The cost of treatment was calculated at the local level of our health facility and then for Ile-de-France. Our model demonstrates an additional cost of €550,115 in our hospital and €9,704,778 in Ile-de-France for a fixed dose prescription in 2018. In 2019, the BIA concluded an additional cost, according to the respective low and high assumptions, of €556,969 and €756,544 locally and € 10,201,027 to €14,486,141 for Ile-de-France for an equivalent efficacy between the two different drug dosing regimens of nivolumab and pembrolizumab. The adoption of the fixed dose regimen would lead, according to the least expensive hypothesis, to an additional cost of 26% for the ICI. These results encourage reflection on the strict adoption of this dosage modification. The option of maintaining the free choice between a prescription adapted to weight or in a fixed dose seems a relevant option and should be considered.

Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

[Nomadism of patients treated by radiotherapy in Île-de-France: Does our health system have as much money to waste?] / Nomadisme des patients traités par radiothérapie en Île-de-France : notre système de santé a-t-il autant d'argent à gaspiller ?

PURPOSE: Human, material, and financial resources being limited, the organization of the care system must allow an efficient allocation of resources. The management of cancers leads to specific and repetitive care for which the reimbursement of transport costs represents a high cost. We carried out an analysis of the additional transport costs, linked to the care of patients in Île-de-France, in a center other than the radiotherapy center closest to their home. MATERIALS AND METHODS: Using data from the Île-de-France Regional Health Agency, we have created a model evaluating the additional cost linked to transport generated by the care of a radiotherapy patient far from his home. In order to take into account the uncertainties linked to the hypotheses made in the development of the model, we carried out deterministic and probabilistic sensitivity analyzes. RESULTS: In the base case, the additional annual cost related to transport was 841,176 euros in Île-de-France. The probabilistic sensitivity analysis reports a total annual additional cost of 2,817,481 euros. CONCLUSION: Our results are similar to a report from the General Inspectorate of Social Affairs published in July 2011, which then pointed to an additional cost of between 4 and 6 million euros annually. The long-term care of cancer patients from their homes contributes to a deterioration in the quality of life linked to travel times, a delay in the care of potential treatment complications, and the spread of infectious diseases, such as COVID-19, and bacteria resistant to antibiotics.

Targeting DNA repair in combination with radiotherapy in pancreatic cancer: A systematic review of preclinical studies.

BACKGROUND: Current research that combines radiation with targeted therapy may dramatically improve prognosis of pancreatic ductal adenocarcinoma (PDAC). We investigated preclinical outcomes of DNA repair inhibitor targeted therapy associated with radiotherapy. METHODS: We searched Pubmed database to identify publications assessing DNA damage targeted therapies in preclinical models of PDACin vitro and in vivo. Standard enhancement ratio, median survival and growth delay were extracted. RESULTS: We identified fourteen publications using DNA repair targeted therapies in preclinical models of PDAC. Ten publications comprising twenty-eight experiments evaluated radiosensitization with different DNA repair inhibitors in vitro and displayed cell killing by a factor of 1.35 ±â€¯0.047. Moreover, 86 % (24/28) of in vitro experiments showed radiosensitization with DNA damage response inhibitor. However, only 60 % (9/15) of the in vivo experiments presented radiosensitization effects. CONCLUSION: DNA repair targeted therapies use promising radiosensitizers for PDAC and could successfully be translated into clinical trials.

Brain metastasis formation and irradiation by stereotactic radiation therapy combined with immunotherapy: A systematic review.

INTRODUCTION: Brain metastasis (BM) is a complex process that implies immune cells and microglia. Stereotactic radiation therapy (SRT) and immunotherapy (IT) are established to increase the immune response; but their association has never been prospectively studied. MATERIALS AND METHODS: Two reviewers performed a systematic review in original papers published up to September 2019. We analysed OS, local (mLRF) and regional (mBRF) median disease-free survival in patients with BMs after SRT with and without IT. RESULTS: Upon 14 studies, eleven concerned melanoma, three concerned lung cancers. SRT-IT showed better OS, mLRF and mBRF than SRT. mBRF was better if SRT was performed with short delay from IT. No higher rates of radionecrosis and haemorrhage were found among groups. CONCLUSION: This review suggests SRT combined to IT in melanoma is safe and could provide better BRF, suggesting a lymphocytic immune reaction in brain. No improvement trend was found in lung cancer BM.

Cost-effectiveness analysis of stereotactic body radiotherapy and surgery for medically operable early stage non small cell lung cancer.

BACKGROUND: Projections estimate an increase of 50% of the incidence of lung cancer by 2030. Early-stage non-small cell lung cancer represented 19% of NSCLC cases diagnosed in the US between 2005 and 2011. There is rising evidence in favour of lung cancer screening, which will reduce the occurrence of later-stage lung cancers while raising the incidence of early-stage NSCLC. Current guidelines state that for early-stage NSCLC, surgical resection should be performed, and stereotactic body radiotherapy (SBRT) is an option for patients who are non-medically operable. In this study, we compared the cost-effectiveness of SBRT with lobectomy in medically operable patients. METHODS: We developed a Markov model based on the survival results of two randomized studies comparing SBRT and video assisted thoracoscopic surgery (VATS) lobectomy in early-stage NSCLC, to describe survival and treatment related complications of patients treated for early-stage NSCLC. This analysis was conducted from the French payer perspective on a lifetime perspective. Utility values, recurrence risks, and costs were adapted from the literature. Deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed to assess the influence of the assumptions made. RESULTS: The Markov model developed was consistent with survival data reported in the pool analysis of the randomized studies. SBRT and lobectomy total costs were 9,234.15€ and 10,726.98€, respectively, and the quality-adjusted life expectancies were 16.35 and 15.80 QALYs, respectively. The DSA, run on every assumption made, revealed that the incremental cost-effectiveness ratio was mainly sensitive to the decrement of utility caused by treatment related complications and initial cost of both surgery and SBRT. The PSA showed that SBRT had the highest probability of cost-effectiveness compared to lobectomy. CONCLUSIONS: This is the first medico-economic study evaluating SBRT and lobectomy in stage I NSCLC based on randomized studies, and our analyses suggest that SBRT is dominant over lobectomy in operable early-stage NSCLC treatment. Deterministic and probabilistic sensitivity analyses confirmed that this result was robust and that it was not modified by the assumptions made in the Markov model building.

A systematic review of palliative bone radiotherapy based on pain relief and retreatment rates.

Palliative radiotherapy has been shown to have effects on Quality of Life during painful bone metastasis. This review aimed to determine equivalence in pain relief (PR) and retreatment rate (RR) using both single and multi-fraction irradiations, based on evaluation of the trial's quality. We performed a systematic review since ICRU 50 Report (1993) to June 2017, then evaluated trials for reproducibility and good methodology criteria. We found five studies that were reproducible in both dose and volume prescription. One study used three-dimensional (3D) treatment planning. Equivalence between single and multi-fraction schedules was demonstrated for PR after 3 months, but a 2-3 time RR appeared after single-fraction schedules, notably in the first year after treatment (primarily during the first four months). Reserving long course therapy for well-preserved patients would allow for better long-term efficacy with lower RR, while altered patients would suffer less from single-fraction treatments. It appears that life expectancy might not be used as a criterion for this choice.

Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review.

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.