Pain in desmoid-type fibromatosis: Prevalence, determinants and prognosis value.

The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P = .18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P = .013) and tumor site (P < .001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 [1.27-7.29]). Pain at baseline was significantly associated with poor quality of life (P < .001), depression (P = .02), lower performance status (P = .03) and functional impairment (P = .001); we also observed a nonsignificant association with anxiety (P = .10). In the univariate analysis, baseline pain was associated with poor EFS; the 3-year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 [1.23-2.68], P = .003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Advantages of everolimus therapeutic drug monitoring in oncology when drug-drug interaction is suspected: A case report.

INTRODUCTION: Drug interactions involving everolimus are fairly well known because of its common use, primarily as an immunosuppressant. Several recommendations regarding therapeutic drug monitoring are also available for the use of everolimus-based immunosuppression regimens. However, everolimus use in oncology differs substantially, particularly because of the high doses involved. Therapeutic drug monitoring, although sometimes necessary, is not recommended as a routine in oncology. Thus, it was deemed inapplicable due to the lack of clear recommendations. CASE REPORT: Here, we present a case where a patient was prescribed everolimus for renal cell carcinoma. The patient benefitted from a pharmaceutical consultation prior to treatment initiation, and a drug interaction with verapamil was suspected.Management and outcome: Therapeutic drug monitoring of everolimus was proposed. Based on the everolimus values reported in the literature, trough plasma concentration in the patient was greatly increased. The patient was then diagnosed with grade 4 oral mucositis, thereby requiring temporary suspension of everolimus treatment. Management of adverse effects was performed through multiple medicated mouthwashes. DISCUSSION: Therapeutic drug monitoring for everolimus is important for potential drug interactions or the occurrence of severe adverse events. In such cases, dose adjustments should be managed according to everolimus plasma concentrations. Clear oncological recommendations regarding plasma everolimus thresholds are required for a successful follow-up of the patient's condition and to ensure adequate response to treatment.

Once weekly paclitaxel associated with a fixed dose of oral metronomic cyclophosphamide: a dose-finding phase 1 trial.

BACKGROUND: The primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel (wP) administered in combination with oral metronomic cyclophosphamide (OMC). METHODS: Patients ≥ 18 years of age with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50 mg twice a day). A 3 + 3 design was used for dose escalation of wP (40 to 75 mg/m2) followed by an expansion cohort at RP2D. Dose-limiting toxicity (DLT) was defined over the first 28-day cycle as grade ≥ 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) or any toxicity leading to a dose reduction. RESULTS: In total, 28 pts. (18 in dose-escalation phase and 10 in expansion cohort) were included, and 16/18 pts. enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts. (hematological toxicity) at doses of 40, 60, 70 and 75 mg/m2 of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 patients in the expansion phase had a hematological DLT. At RP2D (n = 14), the maximal grade of drug-related adverse event was Gr1 in three patients, Gr2 in six patients, Gr3 in one patient and Gr4 in one patient (no AE in three patients). At RP2D, a partial response was observed in one patient with lung adenocarcinoma. CONCLUSION: The combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation. TRIAL REGISTRATION: TRN: NCT01374620 ; date of registration: 16 June 2011.

[Should we take into account the informational stress of the medical oncologist?] / Doit-on prendre en compte le stress informationnel de l'oncologue médical ?

Information overload, informational stress and its deleterious consequences constitute a subject of growing interest in the way of work. This is quite well documented among anesthesiologists. Studies have also been carried out on cancer patients or on the general public in terms of cancer prevention. After having defined the concepts and the consequences, we hypothesize the presence of informational stress among medical oncologists. We illustrate this hypothesis regarding adjuvant treatment of breast cancer. Specific studies (qualitative and quantitative ones) would be particularly interesting in oncology.

PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti-PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. SIGNIFICANCE: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti-PD-1 efficacy in mismatch repair-proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 1397.

[Withholding or withdrawing life-sustaining treatments in acute oncology situations: History and regulatory aspects in France]. / La « Limitation et/ou arrêt des thérapeutiques ¼ (LAT) en oncologie face à une situation aigüe : historique et aspects réglementaires en France.

The management of oncology patients, especially hospitalized patients, can lead to almost daily discussions regarding therapeutic limitations. Here, we review the history and propose a summary of the texts framing the notion of "withholding and withdrawing life-sustaining treatment" in oncology practice in France. This decision is regulated by the Claeys-Léonetti Law of February 2, 2016 recommending a collegial discussion and its documentation in the medical record. The decision to withhold or withdraw life-sustaining treatments is the subject of discussion between the patient, his physicians and his family and may take place at any time during his management. The work of intensive-care physicians provides many useful recommendations for acute oncology situations, however articles specific for oncology practice are scarce; this is a topic that oncologists must take up.

Does bevacizumab increase joint pain in patients with cancer? Results of the prospective observational BEVARTHRALGIA study.

PURPOSE: The occurrence of arthralgia and myalgia during treatment with bevacizumab (Bev) has been described but not spontaneously reported. We aimed to evaluate the frequency of arthralgia in patients treated with Bev and identify the risk factors. METHODS: In this observational prospective study, a self-administered questionnaire was distributed to patients at the initiation of Bev and at 3 and 6 months of treatment. Bev (5-15 mg/kg) was administered every 2 or 3 weeks, with or without chemotherapy. RESULTS: A total of 71 patients (42 with colorectal cancer, 22 with ovarian cancer, and 7 with lung cancer) were enrolled from January to November 2018. All patients completed the questionnaire at initiation, while only 56 (78.9%) and 36 (50.7%) patients completed the questionnaire at 3 and 6 months, respectively. The frequency of joint pain was 29.6% before Bev treatment and increased to 41.8% and 50% at 3 and 6 months, respectively, without reaching significance. The evolution of pain was significant according to the Common Terminology Criteria for Adverse Events grades (P = 0.032). No significant increase in the impact of pain on instrumental or elementary activities was observed over time. The frequency of arthralgia significantly increased at 3 months in patients with ovarian cancer versus those with colorectal cancer (odds ratio: 19.50; 95% confidence interval 4.53-83.98; P < 0.001). CONCLUSIONS: Bev­including regimens tend to be associated with a significant increase in the frequency of arthralgia in women treated for ovarian cancer. Physicians should be aware of this side effect. CLINICAL TRIAL NUMBER: NCT03455907, date of registration: March 7, 2018.

Creating scripted video-vignettes in an experimental study on two empathic processes in oncology: Reflections on our experience.

OBJECTIVE: The aims were to: (1) apply the guidelines to develop and test the validity of video-vignettes manipulating empathy and context in oncology; (2) compare lay people's and patients' assessments of validity; (3) reflecting on our experiment METHODS: Guidelines were followed: (1) deciding whether video-vignettes were appropriate; (2) developing a valid script; (3) designing valid manipulations; (4) converting the scripted consultations into videos. One hundred sixteen lay people and 46 cancer patients filled in the Video Engagement Scale, the CARE, and ad hoc questionnaires on realism and emotions. RESULTS: The video-vignettes are valid for experimental use. Differences appeared in the emotions participants reported. The empathic processes were successfully manipulated and perceived. Lay people's and patients' assessments were equivalent, except for video-vignettes in neutral consultations. Participants' comments on nonverbal behavior, camera perspective, scripts and empathy assessment were reported. CONCLUSION: Patients' assessments are impacted by their personal experiences. Researchers should control for this in analogue patient studies. PRACTICE IMPLICATIONS: Based on this experience, we reflect on: (1) adopting congruent nonverbal behavior throughout the video-vignettes; (2) alternating camera perspectives; (3) avoiding the sole use of written scripts; (4) using quantitative and qualitative analysis to validate scripts and video-vignettes.

Symptomatic acute hypotension associated with high-dose dacarbazine.

We observed several cases of hypotension associated with high-dose dacarbazine. We conducted a retrospective observational analysis of all patients treated with high-dose dacarbazine from January 2018 to August 2019 in Oscar Lambret Center, Lille, France. In our study, a total of 23 patients in outpatient care were analyzed, they underwent 57 treatment cycles. We observed 8 episodes of hypotension in 7 of the 23 consecutive treated patients (30.4%). We discuss herein several hypotheses explaining dacarbazine-induced hypotension. Dacarbazine high dose and administration methods seem to be the main causes of hypotension adverse events. Administration methods include administration duration, which should be above 2 hours, concomitant hydration with 500 ml 0.9% sodium chloride, and UV-resistant pump tube downstream the administration tree.

Hormonal therapies in uterine sarcomas, aggressive angiomyxoma, and desmoid-type fibromatosis.

We review the role of hormonal therapy in the management of different conjunctive tumors. Progestin and aromatase inhibitors seem active in low-grade endometrial stromal sarcoma, but larger case-series are needed. There is no evidence to support the use of hormonal therapy as an adjuvant treatment for low-grade endometrial stromal sarcoma. We did not find relevant data on the use of hormonal therapy for other uterine sarcomas (e.g., high-grade endometrial sarcoma, undifferentiated uterine sarcoma, and adenosarcoma). Gonadotropin-releasing hormone agonist, anti-estrogens and aromatase inhibitor seem active in advanced aggressive angiomyxoma, but larger studies are warranted. The use of aromatase inhibitor in estrogen-receptor-positive uterine leiomyosarcoma requires further clinical investigation. There is no evidence supporting the use of hormonal therapy in desmoid-type fibromatosis. International collaboration efforts are warranted to better explore the role of hormonal therapies in management of estrogen-receptor-positive uterine leiomyosarcoma, low-grade endometrial stromal sarcoma, and aggressive angiomyxoma.

Spatial heterogeneity of KRAS mutations in colorectal cancers in northern France.

BACKGROUND: Somatic mutations in the KRAS gene are the most common oncogenic mutations found in human cancers. However, no clinical features have been linked to KRAS mutations in colorectal cancer [CRC]. PURPOSE: In this study, we attempted to identify the potential geographical population clusters of KRAS mutations in CRC patients in northern France. PATIENTS AND METHODS: All patients with CRC who were identified to have KRAS mutations between 2008 and 2014 at the Regional Molecular Biology Platform at Lille University Hospital were included. 2,486 patients underwent a KRAS status available, with 40.9% of CRC with KRAS mutations in northern France. We retrospectively collected demographic and geographic data from these patients. The proportions of KRAS mutation were smoothed to take into account the variability related to low frequencies and spatial autocorrelation. Geographical clusters were searched using spatial scan statistical models. RESULTS: A mutation at KRAS codon 12 or 13 was found in 1,018 patients [40.9%]. We report 5 clusters of over-incidence but only one elongated cluster that was statistically significant [Cluster 1; proportion of KRAS mutation among CRC: 0.4570; RR=1.29; P=0.0314]. We made an ecological study which did not highlight a significant association between KRAS mutations and the distance to the Closest Waste Incineration Plant, and between KRAS mutations and The French Ecological Deprivation Index but few socio-economic and environmental data were available. CONCLUSION: There was a spatial heterogeneity and a greater frequency of KRAS mutations in some areas close to major highways and big cities in northern France. These data demand deeper epidemiological investigations to identify environmental factors such as air pollution as key factors in the occurrence of KRAS mutations.

Brain Metastasis and Renal Cell Carcinoma: Prognostic Scores Assessment in the Era of Targeted Therapies.

AIM: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. PATIENTS AND METHODS: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. RESULTS: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. CONCLUSION: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score.

Impact of early palliative care on overall survival of patients with metastatic upper gastrointestinal cancers treated with first-line chemotherapy: a randomised phase III trial.

INTRODUCTION: Palliative care (PC) has usually been offered at the end-of-life stage, although the WHO recommends providing PC as early as possible in the course of the disease. A recent study has shown that early PC (EPC) provides a more meaningful effect on quality of life and, surprisingly, on overall survival (OS) than standard treatment for patients with metastatic lung cancer. Whether EPC benefits also apply to patients with metastatic upper gastrointestinal (GI) cancers is unknown. METHODS AND ANALYSIS: EPIC is a randomised phase III trial comparing EPC plus standard oncologic care versus standard oncologic care in patients with metastatic upper GI cancers. Its primary objective is to evaluate the efficacy of EPC in terms of OS. Its secondary objectives are to assess the effects of EPC on patient-reported outcomes (quality of life, depression and anxiety) and the effect of EPC on the number of patients receiving chemotherapy in their last 30 days of life. Assuming an exponential distribution of survival time, 381 deaths are required to ensure an 80% power for an absolute difference of 10% in 1 year OS rates (40% vs 50.3%, HR=0.75; log rank test two-sided alpha=5%), leading to a planned sample size of 480 patients enrolled over 3 years and a final analysis at 4 years. The main analysis will be performed on the intent-to-treat dataset. ETHICS AND DISSEMINATION: This study was approved by the 'Comité de Protection des Personnes Nord-Ouest I' (4 April 2016), complies with the Helsinki declaration and French laws and regulations and follows the International Conference on Harmonisation E6 (R1) Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: EudraCT: 2015-A01943-46; Pre-results. NCT02853474.

High expression levels of egfl7 correlate with low endothelial cell activation in peritumoral vessels of human breast cancer.

Tumor blood vessels participate in the immune response against cancer cells and we previously used pre-clinical models to demonstrate that egfl7 (VE-statin) promotes tumor cell evasion from the immune system by repressing endothelial cell activation, preventing immune cells from entering the tumor mass. In the present study, the expression levels of egfl7 and that of ICAM-1 as a marker of endothelium activation, were evaluated in peritumoral vessels of human breast cancer samples. Breast cancer samples (174 invasive and 30 in situ) from 204 patients treated in 2005 were immunostained for CD31, ICAM-1 and stained for egfl7 using in situ hybridization. The expression levels of ICAM-1 and egfl7 were assessed in peritumoral areas using semi-quantitative scales. There was a strong and significant inverse correlation between the expression of ICAM-1 and that of egfl7 in CD31+ blood vessels. When the ICAM-1 score increased, the egfl7 score reduced significantly (P=0.004), and vice-versa (Cuzick's test for trend across ordered groups). In order to determine which gene influenced the other gene between egfl7 and ICAM-1, the expression levels of either gene were modulated in endothelial cells. Egfl7 regulated ICAM-1 expression while ICAM-1 had no effects on egfl7 expression in the same conditions. Altogether, these results provide further results that egfl7 serves a regulatory role in endothelial cell activation in relation to immune infiltration and that it is a potential therapeutic target to consider for improving anticancer immunotherapies.

ERCC1 and CYP1B1 polymorphisms as predictors of response to neoadjuvant chemotherapy in estrogen positive breast tumors.

PURPOSE: Neoadjuvant chemotherapy (NCT) using anthracyclines and taxanes is a standard treatment for locally advanced breast cancer. Efficacy of NCT is however variable among patients and predictive markers are expected to guide the selection of patients who will benefit from NCT. A promising approach stand with polymorphisms located in genes encoding drug transporters, drug metabolizing enzymes and target genes which can affect drug efficacy. Our study investigated the potential of 37 polymorphisms to predict response to NCT in breast cancer. METHODS: 118 women with breast adenocarcinoma were treated with FEC100 and taxotere. Genotyping was performed on germline DNA using the BioMark platform (Fluidigm). Pathological complete response (pCR) according to Sataloff criteria was correlated to clinical characteristics and genotypes using univariate and multivariate analyses. RESULTS: 25 patients (21.2%) reached complete pathologic response. pCR rate is increased in SBRIII (p = 0.009), ER negative (p = 0.005) and triple negative (p = 0.006) tumors. pCR rate is significantly increased for patients carrying at least one variant allele for BRCA1, ERCC1 or SLCO1B3, and for patients homozygous for CYP1B1. The combination of ERCC1 and CYP1B1 polymorphisms is a potential predictor of NCT response in breast cancer (pCR rate reached 50 vs 21.2% for unselected patients), and particularly in ER + breast cancer subtype where pCR rate reached 41.2 vs 13.5% for unselected patients. CONCLUSIONS: This study is the first to report ERCC1, BRCA1 and SLCO1B3 as markers of response to NCT in breast cancer. ERCC1/CYP1B1 combination might be of particular interest to predict response to NCT in breast cancer and particularly to help NCT indication for ER+ breast tumors.

[Radiotherapy promises: focus on lung cancer]. / Les promesses de la radiothérapie. Focus sur les tumeurs pulmonaires.

Radiotherapy is a key cancer treatment, which greatly modified its practice in recent years thanks to medical imaging and technical improvements. The systematic use of computed tomography (CT) for treatment planning, the imaging fusion/co-registration between CT/magnetic resonance imaging (MRI) or CT/positron emission tomography (PET) improve target identification/selection and delineation. New irradiation techniques such as image-guided radiotherapy (IGRT), stereotactic radiotherapy or hadron therapy offer a more diverse therapeutic armamentarium to patients together with lower toxicity. Radiotherapy, as well as medical oncology, tends to offer a personalized treatment to patients thanks to the IGRT, which takes into account the inter- or intra-fraction anatomic variations. IGRT leads to adaptive radiotherapy (ART) with a new planification in the treatment course in order to decrease toxicity and improve tumor control. The use of systemic therapies with radiations needs to be studied in order to improve efficiency without increasing toxicities from these multimodal approaches. Finally, radiotherapy advances were impacted by radiotherapy accidents like Epinal. They led to an increased quality control with the intensification of identity control, the emergence of in vivo dosimetry or the experience feedback committee in radiotherapy. We will illustrate through the example of lung cancer.