Clinical Characteristics of Patients with Advanced ALK-Translocated Non-small Cell Lung Cancers and Long-Term Responses to Crizotinib (CRIZOLONG GFPC 05-19 Study).

BACKGROUND: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib. OBJECTIVE: This study aimed to describe the clinical characteristics of these long-term responders. PATIENTS AND METHODS: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint. RESULTS: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively. CONCLUSIONS: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.

Three-Year Overall Survival of Patients With Advanced Non-Small-Cell Lung Cancers With ≥50% PD-L1 Expression Treated With First-Line Pembrolizumab Monotherapy in a Real-World Setting (ESCKEYP GFPC Study).

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non-small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non-small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab-chemotherapy combination). Information was collected from patients' medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59-72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1-positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1-45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9-9.2) and 22 (8.5-25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide "real-world" cohort reproduced those obtained in clinical trials.

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.

First-line single-agent pembrolizumab for PD-L1-positive (tumor proportion score ≥ 50%) advanced non-small cell lung cancer in the real world: impact in brain metastasis: a national French multicentric cohort (ESCKEYP GFPC study).

BACKGROUND: Few real-world data are available in patients with advanced metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy, particularly in those with brain metastases at treatment initiation. METHODS: This was a national, retrospective, multicenter study that consecutively included all patients with PD-L1-positive (tumor proportion score ≥ 50%) advanced NSCLC who initiated first-line treatment with pembrolizumab as a single agent between May 2017 (date of availability of pembrolizumab in this indication in France) to November 22, 2019 (approval of the pembrolizumab-chemotherapy combination). Data were collected from medical records with local response assessment. RESULTS: The cohort included 845 patients and 176 (20.8%) had brain metastases at diagnosis. There were no significant differences in outcomes for patients with and without brain metastases: 9.2 (95% CI 5.6-15) and 8 (95% CI 6.7-9.2, p = 0.3) months for median progression-free survival (PFS) and, 29.5 (95% CI 17.2-NA) and 22 (95% CI 17.8-27.1, p = 0.3) months for median overall survival (OS), respectively. Overall response rates were 47% and 45% in patients with and without cerebral metastases. In multivariate analysis, performance status 2-4 vs. 0-1 and neutrophil-to-lymphocyte ratio ≥ 4 vs. < 4 were the main independent negative factors for OS; brain metastasis was not an independent factor for OS. CONCLUSION: In this large multicenter cohort, nearly 20% of patients initiating pembrolizumab therapy for advanced NSCLC had cerebral metastases. There was no significant difference in response rates, PFS and OS between patients with and without brain metastases.

Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

BACKGROUND: Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. PATIENTS AND METHODS: In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging (

Phase III randomized study of carboplatin pemetrexed with or without bevacizumab with initial versus "at progression" cerebral radiotherapy in advanced non squamous non-small cell lung cancer with asymptomatic brain metastasis.

BACKGROUND: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM. METHODS: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin-pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537]. RESULTS: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p < 0.001); there were no significant differences between BR and ChT arms for median PFS: 4.7, 95% confidence interval (CI):3.4-7.5 versus 4.8, 95% CI: 2.4-6.5 months, for median OS: 8.5, 95% CI:.6-11.1 versus 8.3, 95% CI:4.5-11.5 months, cerebral and extra-cerebral ORR (27% versus 13%, p = 0.064, and 30% versus 41%, p = 0.245, respectively). The ChT arm had more grade 3/4 neutropenia than the BR arm (13% versus 6%, p = 0.045); others toxicities were comparable. CONCLUSION: The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR.

Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns of relapse and predictors of failure.

BACKGROUND AND PURPOSE: To assess the long-term outcomes of patients with squamous cell carcinoma of the anal canal (SCCAC) treated with Intensity-Modulated Radiation Therapy (IMRT). MATERIAL AND METHODS: From 2007 to 2015, 193 patients were treated by IMRT for SCCAC. Radiotherapy delivered 45 Gy in 1.8 Gy daily-fractions to the primary tumor and elective nodal areas, immediately followed by a boost of 14.4-20 Gy to the primary tumor and involved nodes. Concurrent chemotherapy with 5-FU-mitomycin (MMC) or cisplatin was added for locally advanced tumors. Survivals were estimated by Kaplan-Meier method. Locoregional (LR) relapses were precisely assessed. Prognostic factors were evaluated by uni- and multivariate analyses. Late toxicity was scored according to the Common Toxicity Criteria for Adverse Events v4.0. RESULTS: Median follow-up was 70 months (range, 1-131). Forty-nine men (25%) and 144 women (75%) were analyzed. Median age was 62 years. Tumor stages were I, II, III and IV in 7%, 24%, 63% and 6% of cases, respectively. Chemotherapy was delivered in 167 patients (87%), mainly MMC (80%). Five-year OS, DFS, CFS and LR control rates were 74%, 68%, 66% and 85%, respectively. Forty-one patients (21%) had a relapse: 22 were LR, mostly in-field (68%). Predictors for LR failure were exclusive radiotherapy, chemotherapy lacking MMC and treatment breaks >3 days. Overall late toxicity ≥grade 2 occurred in 43% of patients, with 24% grade 3 and one case of grade 4 (hematuria). CONCLUSION: CRT with IMRT assures excellent local control in locally advanced SCCAC with manageable long-term toxicity. Multicentric prospective trials are required to reinforce those results.

IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center.

PURPOSE: To assess outcomes of patients with carcinoma of the anal canal (CAC) treated with intensity-modulated radiation therapy (IMRT). METHOD AND MATERIALS: From August 2007 to January 2011, seventy-two patients suffering from CAC were treated with IMRT. Concurrent chemotherapy was added in case of locally advanced tumors. Radiation course consisted in delivering an initial plan to the PTV1 defined as the primary tumor and the risk area including pelvic and inguinal nodes. Forty-five Gy in daily 1.8 Gy-daily fractions were delivered five days a week. A second plan of 14.4-20 Gy to the primary tumor (PTV2) was administered in 1.8-2 Gy-daily fractions, 5 days a week. We present here the results of dosimetry, toxicities, and clinical outcome of the first 39 patients with a median follow-up of 24 months. RESULTS: Thirty-one women and eight men were included in the present analysis. Tumors were classified as stages I, II, III and IV in 2, 7, 27 and 2 patients, respectively. Median age was 59 years (range, 38-85). Radiotherapy alone (RT) or combined with chemotherapy (RCT) were delivered in 6 (15%) and 33 (85%) patients, respectively.Six patients (15%) required a treatment break ≥ 3 days, and median time for treatment break was 8 days (range, 3-14 days). Acute grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were seen in 10 and 5% of patients, respectively. Grade 4 toxicity was only hematologic and occurred in 12% patients receiving RCT. With a median follow-up of 24 months, no patient experienced any late grade 4 toxicity. The 2-year overall survival rate was 89%, the 2-year local relapse free survival was 77% and the 2-year colostomy-free survival rate was 85%. CONCLUSION: IMRT is well tolerated with acceptable treatment interruption allowing dose escalation.

Bilateral kidney preservation by volumetric-modulated arc therapy (RapidArc) compared to conventional radiation therapy (3D-CRT) in pancreatic and bile duct malignancies.

BACKGROUND: To compare volumetric-modulated arc therapy plans with conventional radiation therapy (3D-CRT) plans in pancreatic and bile duct cancers, especially for bilateral kidney preservation. METHODS: A dosimetric analysis was performed in 21 patients who had undergone radiotherapy for pancreatic or bile duct carcinoma at our institution. We compared 4-field 3D-CRT and 2 arcs RapidArc (RA) plans. The treatment plan was designed to deliver a dose of 50.4 Gy to the planning target volume (PTV) based on the gross disease in a 1.8 Gy daily fraction, 5 days a week. Planning objectives were 95% of the PTV receiving 95% of the prescribed dose and no more than 2% of the PTV receiving more than 107%. Dose-volume histograms (DVH) for the target volume and the organs at risk (right and left kidneys, bowel tract, liver and healthy tissue) were compared. Monitor units and delivery treatment time were also reported. RESULTS: All plans achieved objectives, with 95% of the PTV receiving ≥ 95% of the dose (D95% for 3D-CRT = 48.9 Gy and for RA = 48.6 Gy). RapidArc was shown to be superior to 3D-CRT in terms of organ at risk sparing except for contralateral kidney: for bowel tract, the mean dose was reduced by RA compared to 3D-CRT (16.7 vs 20.8 Gy, p = 0.0001). Similar result was observed for homolateral kidney (mean dose of 4.7 Gy for RA vs 12.6 Gy for 3D-CRT, p < 0.0001), but 3D-CRT significantly reduced controlateral kidney dose with a mean dose of 1.8 Gy vs 3.9 Gy, p < 0.0007. Compared to 3D-CRT, mean MUs for each fraction was significantly increased with RapidArc: 207 vs 589, (p < 0.0001) but the treatment time was not significantly different (2 and 2.66 minutes, p = ns). CONCLUSION: RapidArc allows significant dose reduction, in particular for homolateral kidney and bowel, while maintaining target coverage. This would have a promising impact on reducing toxicities.

Plan comparison of volumetric-modulated arc therapy (RapidArc) and conventional intensity-modulated radiation therapy (IMRT) in anal canal cancer.

BACKGROUND: To compare volumetric-modulated arc therapy (RapidArc) plans with conventional intensity-modulated radiation therapy (IMRT) plans in anal canal cancers. METHODS: Ten patients with anal canal carcinoma previously treated with IMRT in our institution were selected for this study. For each patient, three plans were generated with the planning CT scan: one using a fixed beam IMRT, and two plans using the RapidArc technique: a single (RA1) and a double (RA2) modulated arc therapy. The treatment plan was designed to deliver in one process with simultaneous integrated boost (SIB) a dose of 59.4 Gy to the planning target volume (PTV2) based on the gross disease in a 1.8 Gy-daily fraction, 5 days a week. At the same time, the subclinical disease (PTV1) was planned to receive 49.5 Gy in a 1.5 Gy-daily fraction. Plans were normalized to 99% of the PTV2 that received 95% of the prescribed dose. Planning objectives were 95% of the PTV1 will receive 95% of the prescribed dose and no more than 2% of the PTV will receive more than 107%. Dose-volume histograms (DVH) for the target volume and the organs at risk (bowel tract, bladder, iliac crests, femoral heads, genitalia/perineum, and healthy tissue) were compared for these different techniques. Monitor units (MU) and delivery treatment time were also reported. RESULTS: All plans achieved fulfilled objectives. Both IMRT and RA2 resulted in superior coverage of PTV than RA1 that was slightly inferior for conformity and homogeneity (p < 0.05).Conformity index (CI95%) for the PTV2 was 1.15 ± 0.15 (RA2), 1.28 ± 0.22 (IMRT), and 1.79 ± 0.5 (RA1). Homogeneity (D5% - D95%) for PTV2 was 3.21 ± 1.16 Gy (RA2), 2.98 ± 0.7 Gy (IMRT), and 4.3 ± 1.3 Gy (RA1). RapidArc showed to be superior to IMRT in terms of organ at risk sparing. For bowel tract, the mean dose was reduced of 4 Gy by RA2 compared to IMRT. Similar trends were observed for bladder, femoral heads, and genitalia. The DVH of iliac crests and healthy tissue resulted in comparable sparing for the low doses (V10 and V20). Compared to IMRT, mean MUs for each fraction was significantly reduced with RapidArc (p = 0.0002) and the treatment time was reduced by a 6-fold extent. CONCLUSION: For patients suffering from anal canal cancer, RapidArc with 2 arcs was able to deliver equivalent treatment plan to IMRT in terms of PTV coverage. It provided a better organ at risk sparing and significant reductions of MU and treatment time per fraction.