Stereotactic ablative radiotherapy and systemic treatments for extracerebral oligometastases, oligorecurrence, oligopersistence and oligoprogression from lung cancer.

BACKGROUND: Stereotactic irradiation (SBRT) is a standard of care for inoperable stage I lung cancer and brain oligometastases from lung cancer but is controversial for extracranial oligometastases. We assessed outcomes of lung cancer patients with extracranial metastases in oligometastatic, oligorecurrent, oligopersistent and oligoprogressive settings ("oligometastatic spectrum") under strategies using SBRT +/- systemic treatments. METHODS: A retrospective multicentric study of consecutive lung cancer adult patients with 1-5 extracranial metastases treated with SBRT was conducted. RESULTS: Of 91 patients (99 metastases, median age 63, 64.8% adenocarcinomas, 19.8% molecular alterations), 11% had oligometastases, 49.5% oligorecurrence, 19.8% oligopersistence and 19.8% oligoprogression. Of 36% of patients under systemic treatments at initiation of SBRT, systemic treatment interruption was performed in 58% of them. With median follow up of 15.3 months, crude local control at irradiated metastases was 91%, while median distant progression-free survival (dPFS) and overall survival were 6.3 and 28.4 months (2-year survival 54%). Initial nodal stage and oligometastatic spectrum were prognostic factors for dPFS; age, initial primary stage and oligometastatic spectrum were prognostic factors for survival on multivariate analysis. Patients with oncogene-addicted tumors more frequently had oligoprogressive disease. Repeat ablative irradiations were preformed in 80% of patients who had oligorelapses. Worst acute toxicities consisted of 5.5% and one late toxic death occurred. CONCLUSION: The oligometastatic spectrum is a strong prognosticator in patients undergoing SBRT for extracranial metastases. Median survival was over two years but dPFS was about 6 months. Continuation of systemic therapy in oligoprogressive patients should be investigated.

Feasibility of Stereotactic Body Radiation Therapy on Unresectable Stage III NSCLC with Peripheral Primary Tumor: A Prospective Study (GFPC 01-14).

Concomitant radiochemotherapy (RTCT) is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). However, in patients with a peripheral primary tumor, the irradiated volume may include a large portion of normal lung and RT-CT is not possible. This multicenter phase II trial in unresectable stage III NSCLC with peripheral primary tumor evaluated the feasibility of stereotactic body radiation therapy (SBRT) in peripheral tumor after concomitant radio-chemotherapy (RT-CT). Nineteen patients were included and analyzed (median age, 60.9 years; male, 78%; adenocarcinoma, 74%; median size of peripheral primary tumor, 19 mm). At 6 months, the disease control rate was 79% (15/19). SBRT toxicity was generally mild with one (5%) patient having grade 3 lung toxicity. Recruitment for this study was stopped prior to completion, firstly due to the approval of adjuvant durvalumab after RT-CT, which was not anticipated in the design, and secondly due to the small number of stage III NSCLC patients with a peripheral tumor that was accessible to SBRT. Nevertheless, the combination of RT-CT and SBRT appeared to be feasible and safe.

[Decision making factors of the management of ductal carcinoma in situ of the breast with microinvasion]. / Facteurs décisionnels de la prise en charge des carcinomes canalaires in situ du sein avec micro-invasion.

INTRODUCTION: Microinvasive in situ ductal carcinomas of the breast are rare and of good prognosis. They are grouped with early stage invasive carcinomas in the TNM 2017 classification. This study assessed practitioners' treatment decisions and their justifications in comparison to the literature. MATERIALS AND METHODS: Three clinical cases were evaluated by anonymous forms regarding sentinel node decisions, tumour bed boost irradiation and hormone therapy. RESULTS: Sentinel lymph node was performed by 93.1%, 100% and 44.4% of the practitioners respectively. Radiation boost was a treatment option chosen by 62.1% and 61.1% of practitioners in both clinical cases. Hormone therapy was advocated for 65.5%, 94.7% and 50.0% patients depending on the clinical case. CONCLUSION: The therapeutic attitude proposed in microinvasive breast carcinomas was heterogeneous in this study, reflecting the absence of specific recommendations. In view of the existing literature, it is not currently possible to propose recommendations for these three therapeutic options. Prospective cohorts and meta-analyses of the microinvasive subgroup could provide answers.

[Cardiac complications of breast radiation therapy]. / Complications cardiaques de la radiothérapie mammaire.

Adjuvant radiation therapy in breast cancer is a standard of care, either post-lumpectomy or in case of lymph node involvement. Internal mammary chain (IMC) is more and more included in the clinical target volume, because it increases overall survival. This increase must be weighed against cardiac complications in left breast cancer. Intensity modulated radiation therapy (IMRT) is used in this indication in order to better cover target volumes, but tends to increase irradiated healthy volumes, including the heart. The average cardiac dose is higher with IMRT, while it is also predictive of cardiovascular events in patients treated in 3D. This article aims to make an inventory of the IMC irradiations, as well as a review of the mechanisms of radiation-induced cardiac toxicity and ways to diagnose it early. Cooperation between medical oncologists, radiotherapy oncologists and cardiologists is needed to better support patients.

Safety of combined PD-1 pathway inhibition and radiation therapy for non-small-cell lung cancer: A multicentric retrospective study from the GFPC.

INTRODUCTION: Randomized prospective studies on patients with metastatic non-small-cell lung cancers (NSCLCs) showed that anti-programmed death-1 (PD-1) agents notably improved 2-year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing. METHODS: We retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes. RESULTS: Among 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra- or extracranial irradiation courses, any-grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune-related AE (IRAE). Respective 1- and 2-year OS rates were 48.8% and 29.1%, while 1- and 2-year progression-free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS. CONCLUSION: Radiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities.

[Radiation therapy in inflammatory breast cancer]. / Radiothérapie des cancers du sein inflammatoires.

BACKGROUND: Inflammatory breast cancer accounts for 1-5% of all breast cancers. It is associated with a poor prognosis, because of an increased risk to develop metastases in comparison with all breast malignancies. The treatment is multimodal. We have evaluated the role of radiotherapy: indications, techniques and impact for local control and overall survival. METHOD: The series of the literature with more than 40 patients irradiated for inflammatory breast cancer published since 1995 were analyzed. RESULTS: Chemotherapy was always delivered first. Adjuvant radiotherapy was associated with local control and overall survival at 10 years of 63-92% and 51-64 respectively. Without surgery, local control was 65% and overal survival 38% at 10years. Results of concomitant radiochemotherapy were reported: the studies were heterogenous. Modalities of radiotherapy were detailed with respect to dose and fractionation, target-volumes and technical considerations (including bolus). CONCLUSION: The multimodal strategy comprises systematically radiotherapy with an evaluation of tumor response to maximise resecability.

Proton therapy for locally advanced breast cancer: A systematic review of the literature.

BACKGROUND: Radiation therapy plays a major role in the management of adjuvant breast cancer with nodal involvement, with an iatrogenic increase of cardio-vascular risk. Photon therapy, even with intensity modulation, has the downsides of high mean heart dose and heterogeneous target coverage, particularly in the case of internal mammary irradiation. This systematic review of the literature aims to evaluate proton therapy in locally advanced breast cancer. MATERIAL AND METHODS: PubMed was searched for original full-text articles with the following search terms: «Proton Therapy¼ and «Breast Cancer¼. On-going trials were collected using the words "Breast Cancer" and "Protons". RESULTS: 13 articles met the criteria: 6 with passive proton therapy (Double Scattering), 5 with Pencil Beam Scanning (PBS) and 2 with a combination of both. Proton therapy offered a better target coverage than photons, even compared with intensity modulation radiation therapy (including static or rotational IMRT or tomotherapy). With proton therapy, volumes receiving 95% of the dose were around 98%, with low volumes receiving 105% of the dose. Proton therapy often decreased mean heart dose by a factor of 2 or 3, i.e. 1 Gy with proton therapy versus 3 Gy with conventional 3D, and 6 Gy for IMRT. Lungs were better spared with proton therapy than with photon therapy. Cutaneous toxicity observed with double scattering is improved with PBS. CONCLUSION: Proton therapy reduces mean heart dose in breast cancer irradiation, probably reducing late cardio-vascular toxicity. Large clinical studies will likely confirm a clinical benefit of proton therapy.

Off-Label Use of Crizotinib as a Neoadjuvant Treatment for a Young Patient When Conventional Chemotherapy Gave No Benefits in Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND The treatment of locally advanced non-small cell lung cancer involves a combination of chemotherapy, surgery, and radiotherapy. Each case is discussed and the best strategy is chosen individually, following international guidelines. CASE REPORT A 37-year-old man was diagnosed with locally advanced broncho-pulmonary adenocarcinoma (stage IIIA). The disease was stable after 2 cycles of cisplatin plus Navelbine used as neoadjuvant therapy. FISH analysis revealed an ALK rearrangement. The patient then received unlicensed crizotinib as second-line neoadjuvant treatment, which led to an almost complete radiological and metabolic response. A left upper lobectomy was performed, followed by post-operative chemotherapy and radiotherapy. At 18 months post-surgery, the patient is still disease-free according to the last CT scan. CONCLUSIONS Targeted therapy was an alternative solution when chemotherapy was not helping. Randomized studies are needed to define its precise role in the neoadjuvant scheme.

Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies for which surgery represents the mainstay of the treatment. Current practice for postoperative radiotherapy (PORT) is highly variable, and there is a lack of prospective, high level evidence. Réseau Tumeurs Thymiques et Cancer (RYTHMIC) is the nationwide network for TETs in France. Established in 2012, it prospectively collects data on all TET patients, for whom management is discussed at a national multidisciplinary tumor board (MTB). We assessed whether PORT decisions at the MTB were in accordance with RYTHMIC guidelines and ultimately implemented in patients. METHODS: All consecutive patients for whom PORT was discussed at the MTB from 2012 to 2015 were identified from the RYTHMIC prospective database, and a complete review of their medical records was performed. RESULTS: A total of 274 patients, including 243 with thymoma (89%) and 31 with thymic carcinoma (11%), were analyzed. The decision of the MTB was in accordance with guidelines in 221 patients (92%) of the 241 with stage I or III TET. An MTB decision to deliver PORT was made for 117 patients (43%). PORT was ultimately initiated in 101 patients. The most frequent reason for not delivering PORT was excessive (>3 months) delay after surgery. Dose-volume constraints defined by the International Thymic Malignancy Interest Group were followed in all but four patients. CONCLUSION: Our data provide a unique insight into the decision-making process for PORT in TETs, highlighting the need for systematic discussion at an expert MTB, while stressing the value of current available guidelines.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Squamous cell carcinoma of the esophagus: multimodal therapy in locally advanced disease.

The aim of this prospective study is to report our experience in the multimodal management of locally advanced esophageal squamous cell carcinoma (LAESC; stage III cTNM), focusing on the results of chemoradiotherapy followed by surgery. These findings were compared to the results of a standard group of patients with locally advanced esophageal carcinoma (LAEC; stage III pTNM) treated in our center with surgery alone. Sixty-one patients with LAESC underwent preoperative chemoradiotherapy (5-fluorouracil + cisplatin) with concomitant 45 Gray radiotherapy in a 5-week course. Transthoracic esophagectomy was performed 4 to 5 weeks after the end of the neoadjuvant therapy. Thirty-eight patients underwent surgery, and 37 of them had resections (resectability: 97% in the multimodal group; 84% in the standard surgical series; p = 0.07). The R0 (complete) resection rate was 78% compared to 56% in the standard surgical group (p <0.03). Eleven patients had no residual tumor in the resected specimen (pathologic complete response: pCR: 30%). The operative mortality rate was 19% compared with 8.8% in the standard series. The overall median survival of the resected patients was 21 months, with a 5-year survival rate of 11% (14% in the surgical group; NS). The 3-year and 5-year survival rates were 34% for the pCR group and respectively 5% and 0% for the group with pathologic incomplete response (pIR; p <0.05). The median survival was 28 months for the pCR patients and 19 months for the pIR group. In this non-randomized trial, preoperative chemoradiotherapy in LAESC seems to increase the resectability and R0 resection rates, to allow a higher pCR rate and a longer survival only in the pCR group, at the expense of an inadequate increase in operative mortality. This multimodal treatment cannot be proposed as a standard procedure unless less toxic regimens are developed, increasing the benefits with better local and distant failure control and decreasing operative mortality.