Efficacy and Safety of Combined Brain Stereotactic Radiotherapy and Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with Brain Metastases.

BACKGROUND: To analyze the outcomes of patients with brain metastases (BM) from non-small cell lung cancer (NSCLC) treated with immunotherapy (IT) and stereotactic radiotherapy (SRT) and to study the impact of the sequence between the two modalities. METHODS: The authors reviewed the records of 51 patients with 84 BM from NSCLC treated at Institut Curie with IT and SRT. BM were categorized into three groups: 'SRT before IT', 'concurrent SRT and IT', and 'SRT after IT.' Regional progression-free interval (R-PFI) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: After a median follow-up from SRT of 22.5 months (2.7-47.3), the 1-year and 2-year OS were 69.7% (95%CI [58.0-83.8]) and 44.0% [30.6-63.2], respectively. Concerning distant intracranial control, the 1-year and 2-year R-PFI were 40.1% [30.1-53.3] and 35.2% [25.1-49.4], respectively. Moreover, one-year R-PFI in 'SRT before IT', 'concurrent SRT and IT', and 'SRT after IT' groups were 24.1%, 49.6%, and 34.2%, respectively (p = 0.094). The type of therapeutic sequence did not appear to impact the risk of brain necrosis. CONCLUSIONS: The concurrent administration of SRT and IT appeared to offer the best locoregional control, without increasing the risk of toxicity, compared to patients treated with SRT before or after IT.

Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer: results of a randomised, triple blind, multicentre phase III trial.

BACKGROUND: Low-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm2. METHODS: This phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed. RESULTS: Among 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT. CONCLUSIONS: This study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01772706 . TITLE: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite). Study Start Date: October 2008. Primary Completion Date: October 2016. Responsible Party: Institut de Cancérologie de l'Ouest - Paul Papin. Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l'Ouest - Paul Papin. FUNDING: French Ministry of Health, French national funding scheme (PHRC 2008).

Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial.

PURPOSE: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. PATIENTS AND METHODS: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. RESULTS: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). CONCLUSION: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

Improved Outcome by Adding Concurrent Chemotherapy to Cetuximab and Radiotherapy for Locally Advanced Head and Neck Carcinomas: Results of the GORTEC 2007-01 Phase III Randomized Trial.

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.

Long-term Results of a Multicenter Randomized Phase III Trial of Induction Chemotherapy With Cisplatin, 5-fluorouracil, ± Docetaxel for Larynx Preservation.

BACKGROUND: The purpose of GORTEC 2000-01 was to compare the long-term efficacy and safety of induction chemotherapy with cisplatin (P) and 5-fluorouracil (F) with or without docetaxel (T) for larynx preservation. METHODS: Operable patients with untreated stage III or IV larynx or hypopharynx invasive squamous cell carcinoma who required total laryngectomy were randomly assigned to three cycles of induction chemotherapy with either TPF or PF, followed by radiation therapy for responders. The primary endpoint was three-year larynx preservation rate. Secondary endpoints included larynx dysfunction-free survival (LDFFS), overall survival (OS), disease-free survival (DFS), loco-regional control rate (LCR), cause of death, and later toxicity rates. Survival and other data were analyzed by Kaplan-Meier methods. All statistical tests were two-sided. RESULTS: Two hundred thirteen patients were treated with median follow-up of 105 months. The five- and 10-year larynx preservation rates were 74.0% (95% CI = 0.64 to 0.82) vs 58.1% (95% CI = 0.47 to 0.68) and 70.3% (95% CI = 0.58 to 0.8) vs 46.5% (95% CI = 0.31 to 0.63, P = .01) in the TPF vs PF arm, respectively. The five- and 10-year LDFFS rates were 67.2% (95% CI = 0.57 to 0.76) vs 46.5% (95% CI = 0.36 to 0.57) and 63.7% (95% CI = 0.52 to 0.74) vs 37.2% (95% CI = 0.24 to 0.52, P = .001), respectively. OS, DFS, and LCR were not statistically improved in the TPF vs the PF arm. Statistically fewer grade 3-4 late toxicities of the larynx occurred with the TPF regimen compared with the PF arm (9.3% vs 17.1%, G-test, P = .038). CONCLUSION: Long-term follow-up confirms that induction chemotherapy with TPF increased larynx preservation and larynx dysfunction-free survival. In this larynx preservation approach using induction chemotherapy, TPF should be recommended, followed by radiation therapy.

External irradiation models for intracranial 9L glioma studies.

PURPOSE: Radiotherapy has been shown to be an effective for the treatment human glioma and consists of 30 fractions of 2 Gy each for 6-7 weeks in the tumor volume with margins. However. in preclinical studies, many different radiation schedules are used. The main purpose of this work was to review the relevant literature and to propose an external whole-brain irradiation (WBI) protocol for a rat 9L glioma model. MATERIALS AND METHODS: 9L cells were implanted in the striatum of twenty 344-Fisher rats to induce a brain tumor. On day 8, animals were randomized in two groups: an untreated group and an irradiated group with three fractions of 6 Gy at day 8, 11 and 14. Survival and toxicity were assessed. RESULTS: Irradiated rats had significantly a longer survival (p = 0.01). No deaths occurred due to the treatment. Toxicities of reduced weight and alopecia were increased during the radiation period but no serious morbidity or mortality was observed. Moreover, abnormalities disappeared the week following the end of the therapeutic schedule. CONCLUSIONS: Delivering 18 Gy in 3 fractions of 6 Gy every 3 days, with mild anaesthesia, is safe, easy to reproduce and allows for standardisation in preclinical studies of different treatment regimens glioma rat model.

Radiotherapy for glioblastoma in the elderly.

BACKGROUND: There is no community standard for the treatment of glioblastoma in patients 70 years of age or older. We conducted a randomized trial that compared radiotherapy and supportive care with supportive care alone in such patients. METHODS: Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were randomly assigned to receive supportive care only or supportive care plus radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy). The primary end point was overall survival; secondary end points were progression-free survival, tolerance of radiotherapy, health-related quality of life, and cognition. RESULTS: We randomly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone. The trial was discontinued at the first interim analysis, which showed that with a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone. A final analysis was carried out for the 81 patients with glioblastoma (median age, 73 years; range, 70 to 85). At a median follow-up of 21 weeks, the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, as compared with 16.9 weeks for the 42 patients who received supportive care alone. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29 to 0.76; P=0.002). There were no severe adverse events related to radiotherapy. The results of quality-of-life and cognitive evaluations over time did not differ significantly between the treatment groups. CONCLUSIONS: Radiotherapy results in a modest improvement in survival, without reducing the quality of life or cognition, in elderly patients with glioblastoma. (ClinicalTrials.gov number, NCT00430911 [ClinicalTrials.gov].).

Effects of syngeneic cellular vaccinations alone or in combination with GM-CSF on the weakly immunogenic F98 glioma model.

Cancer vaccines are one approach for the treatment of brain tumors. Most experimental studies are performed on so-called "immunogenic" brain tumor models such as the rat 9L glioma which does not reflect characteristics of human glioblastoma. In the present study, we tested syngeneic cellular vaccinations alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) on the weakly immunogenic F98 glioma model. Previous studies have shown the efficacy of this treatment on the 9L glioma model. Fisher rats received an intracerebral implantation of F98 cells. Three days later, two subcutaneous vaccinations with irradiated F98 cells were realized in presence or absence of GM-CSF. This scheme of vaccination induced a systemic cellular and humoral immune response capable of in vitro cytolytic activity against F98 cells. However, no significant differences in survival times were noted between vaccinated and untreated animals. Animals vaccinated with GM-CSF or without GM-CSF had respectively a survival time of 26 +/- 2.1 and 25 +/- 4.4 days following tumor challenge versus 26.5 +/- 2.4 days for untreated rats. Fourteen days after the intracerebral tumor implantation, the tumors of vaccinated animals showed a robust infiltration by T lymphocytes, NK cells, dendritic cells, granulocytes and CD11b/c+ myeloid cells. This infiltration was nearly absent in untreated animals except for CD11b/c+ myeloid cells. This study shows that, contrary to the 9L glioma model, the F98 glioma model is resistant to syngeneic cellular vaccinations although a strong peripheral and intratumoral immune response can be induced. These results suggest that the F98 glioma is an attractive model to understand the mechanisms of glioma immunotherapy resistance.

Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma.

BACKGROUND: The authors developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. The strategy was evaluated initially to provide localized and sustained delivery of the radiosensitizer 5-fluorouracil (5-FU) after patients underwent surgical resection of malignant glioma. In this study, the microspheres were implanted by stereotaxy into deeply situated and inoperable brain tumors. METHODS: Ten patients with newly diagnosed, inoperable, malignant gliomas were included in the study, and 1 dose of 5-FU was studied (132 mg). After histologic confirmation, a suspension of poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres was implanted by stereotaxy into the tumor in one or several trajectories with one to seven deposits per trajectory. External beam radiation (59.4 grays) was started before postoperative Day 7. Patients were followed by clinical examination, computed tomography scanning, magnetic resonance imaging, and 5-FU assays in blood and cerebrospinal fluid (CSF). RESULTS: The number of trajectories was adapted to the size and shape of the tumor. Microsphere implantation was tolerated well, except in four patients who received a single trajectory and experienced a transitory worsening of preexisting neurologic symptoms. There were no episodes of edema or hematologic complications. 5-FU was detected in CSF and blood in some patients at very low concentrations. The median overall survival was 40 weeks, with 2 patients who had longer survival (71 weeks and 89 weeks, respectively). CONCLUSIONS: In this study, the authors demonstrated that biodegradable microspheres could be implanted by stereotaxy and were efficient systems for drug delivery into brain tumors. This method may have future applications in the treatment of patients other malignancies.