GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

AIM: Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. METHOD: GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. RESULTS: Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. CONCLUSION: If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR 4): Long-term Results From a Multicenter, Randomized, Open-Label, Phase II Trial.

BACKGROUND: Systematic preoperative radiochemotherapy and total mesorectal excision are the standard of care for locally advanced rectal carcinoma. Some patients can be over- or undertreated. OBJECTIVE: This study aimed to investigate the long-term oncological, functional, and late morbidity outcomes after tailored radiochemotherapy and induction high-dose chemotherapy. DESIGN: This is a prospective, phase II, multicenter, open-label study at 16 tertiary centers in France. SETTINGS: Patients were operated on by surgeons from the French GRECCAR group. PATIENTS: Two hundred six patients were randomly assigned to treatment: good responders after chemotherapy (≥75% tumor volume reduction) to immediate surgery (arm A) or standard radiochemotherapy (capecitabine 50) plus surgery (arm B) and poor responders to capecitabine 50 (arm C) or intensive radiochemotherapy (capecitabine 60; 60 Gy irradiation; arm D) before surgery. INTERVENTIONS: Treatment was tailored according to MRI response to induction chemotherapy. RESULTS: After induction treatment, 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders; they were included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: R0 resection rates (90% CI) in the 4 arms were 100% (74-100), 100% (85-100), 83% (72-91), and 88% (77-95). At 5 years, overall survival rates were 90% (47.3-98.5), 93.3% (61.3-99.0), 84.3% (71.0-91.8), and 86.1% (71.6-93.5); disease-free survival rates were 80% (40.9-94.6), 89.5% (64.1-97.3), 72.9% (58.5-82.9), and 72.8% (57.7-83.2); local recurrence rates were 0%, 0%, 2.1% (0.3-13.9), and 9.3% (3.6-23.0); and metastasis rates were 20% (5.4-59.1), 10.5% (2.7-35.9), 18% (31.8-94.6), and 18.8% (10.2-33.0). Late morbidity and quality-of-life evaluations showed no significant difference between arms. LIMITATIONS: Limitations were due to the small number of patients randomly assigned in the good responder arms, especially arm A without radiotherapy. CONCLUSION: Tailoring preoperative radiochemotherapy based on induction treatment response appears to be promising. Future prospective trials should confirm this strategy. See Video Abstract at http://links.lww.com/DCR/B761 . REGISTRATION: URL: https://www.clinicaltrials.gov ; Identifier: NCT01333709. ESTRATEGIA HECHA A MEDIDA PARA EL TRATAMIENTO DEL CARCINOMA DE RECTO LOCALMENTE AVANZADO GRECCAR RESULTADOS A LARGO PLAZO DE UN ESTUDIO ALEATRIO MULTICNTRICO Y ABIERTO DE FASE II: ANTECEDENTES:La radio-quimioterapia pré-operatoria sistemáticas y la excisión total del mesorrecto son el estándar en el tratamiento del carcinoma de recto localmente avanzado. En éste sentido, algunos pacientes podrían recibir un sobre o un infra-tratamiento.OBJETIVO:Evaluar los resultados oncológicos, funcionales y de morbilidad a largo plazo después de radio-quimioterapia personalizada y quimioterapia de inducción a dosis elevadas.DISEÑO:Estudio aleatório multicéntrico y abierto de Fase II° realizado en 16 centros terciarios en Francia.AJUSTE:Aquellos pacientes operados por cirujanos del grupo GRECCAR francés.PACIENTES:206 pacientes fueron asignados aleatoriamente al tratamiento: los buenos respondedores después de quimioterapia (reducción del volumen tumoral ≥75%) a la cirugía inmediata (brazo A) o a la radio-quimioterapia estándar (Cap 50) asociada a la cirugía (brazo B); los malos respondedores a Cap 50 (brazo C) o a la radio-quimioterapia intensiva (Cap 60 (irradiación de 60 Gy) (brazo D) previas a la cirugía.INTERVENCIONES:Tratamiento adaptado según la respuesta de la RM a la TC de inducción.RESULTADOS:Después del tratamiento de inducción, 194 pacientes fueron clasificados como buenos (n = 30, 15%) o malos (n = 164, 85%) respondedores, y se incluyeron en los brazos A y B (16 y 14 pacientes) o C y D (113 y 51 pacientes). Se alcanzó el objetivo principal: las tasas de resección R0 [intervalo de confianza del 90%] en los cuatro brazos respectivamente, fueron del 100% [74-100], 100% [85-100], 83% [72-91] y 88% [77-95]. A los 5 años, las tasas fueron: de sobrevida global 90% [47,3-98,5], 93,3% [61,3-99,0], 84,3% [71,0-91,8], 86,1% [71,6-93,5]; de sobrevida libre a la enfermedad 80% [40,9-94,6], 89,5% [64,1-97,3], 72,9% [58,5-82,9], 72,8% [57,7-83,2]; de recidiva local 0, 0, 2,1% [0,3-13,9], 9,3% [3,6-23,0]; de metástasis 20% [5,4-59,1], 10,5% [2,7-35,9], 18% [31,8-94,6], 18,8% [10,2-33,0]. La evaluación tardía de la morbilidad y la calidad de vida no mostraron diferencias significativas entre los brazos.LIMITACIONES:Debido al pequeño número de pacientes asignados al azar en los brazos de buenos respondedores, especialmente en el brazo A de aquellos sin radioterapia.CONCLUSIÓN:Parecería muy prometedor el adaptar la radio-quimioterapia pré-operatoria basada en la respuesta al tratamiento de inducción. Estudios prospectivos en el futuro podrán confirmar la presente estrategia. Consulte Video Resumen en http://links.lww.com/DCR/B761 . (Traducción-Dr. Xavier Delgadillo )IDENTIFICADOR DE CLINICALTRIALS.GOV:NCT01333709. Groupe de REcherche Chirurgicale sur le CAncer du Rectum.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance.

BACKGROUND: The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. METHODS: Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. RESULTS: Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8+ TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039). CONCLUSION: Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.

IDH mutation and 1p19q codeletion distinguish two radiological patterns of diffuse low-grade gliomas.

Diffuse low-grade gliomas (DLGG) prognosis is variable, depending on several factors, including the isocitrate dehydrogenase (IDH) mutation and the 1p19q codeletion. A few studies suggested associations between these parameters and tumor radiological characteristics including topography. Our aim was analyzing the correlations between the IDH and 1p19q statuses and the tumor intracerebral distribution (at the lobar and voxel levels), volume, and borders. We conducted a retrospective, monocentric study on a consecutive series of 198 DLGG patients. The IDH and 1p19q statuses were recorded. The pre-treatment magnetic resonance FLAIR imagings were reviewed for determination of lobar topography, tumor volume, and characterisation of tumor borders (sharp or indistinct). We conducted a voxel-based lesion-symptom mapping analysis to investigate the correlations between the IDH and 1p19q statuses and topography at the voxel level. The IDH mutation and 1p19q statuses were correlated with the tumor topography defined using lobar anatomy (p < 0.001 and p = 0.004, respectively). Frontal tumors were more frequently IDH-mutant (87.1 vs. 57.4%) and 1p19q codeleted (45.2 vs. 17.0%) than temporo-insular lesions. At the voxel level, these associations were not found. Tumors with sharp borders were more frequently IDH-mutant (p = 0.001) while tumors with indistinct borders were more frequently IDH wild-type and 1p19q non-codeleted (p < 0.001). Larger tumors at diagnosis (possibly linked to a slower growth rate) were more frequently IDH-mutant (p < 0.001). IDH wild-type, 1p19q non-codeleted temporo-insular tumors are distinct from IDH-mutant, 1p19q codeleted frontal tumors. Further studies are needed to determine whether the therapeutic strategy should be adapted to each pattern.

Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial.

BACKGROUND: Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally advanced rectal carcinoma, but some patients could be over- or undertreated. OBJECTIVE: This study aimed to assess the feasibility of radiochemotherapy tailored based on the tumor response to induction chemotherapy (FOLFIRINOX) to obtain a minimum R0 resection rate of 90% in the 4 arms of the study. DESIGN: This study is a multicenter randomized trial (NCT01333709). SETTING: This study was conducted at 16 French cancer specialty centers. PATIENTS: Two hundred six patients with locally advanced rectal carcinoma were enrolled between 2011 and 2014. INTERVENTIONS: Good responders (≥75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 50: 50 Gy irradiation and 1600 mg/m oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60, 60 Gy irradiation, arm D) before surgery. OUTCOME MEASURES: The primary end point was a R0 resection rate (circumferential resection margin >1 mm). STATISTICAL CONSIDERATIONS: The experimental strategies were to be considered effective if at least 28 successes (R0 resection) among 31 patients in each arm of stratum I and 34 successes among 40 patients in each arm of stratum II were reported (Simon 2-stage design). RESULTS: After induction treatment (good compliance), 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders who were included in arms A and B (16 and 14 patients) and arms C and D (113 and 51 patients). The trial was prematurely stopped because of low accrual in arms A and B and recruitment completion in arms C and D. Data from 133 randomly assigned patients were analyzed: 11, 19, 52, and 51 patients in arms A, B, C, and D. Good responders had smaller tumors than poor responders (23 cm vs 45 cm; p < 0.001). The surgical procedure was similar among groups. The R0 resection rates [90% CI] were 100% [70-100], 100% [85-100], 83% [72-91], and 88% [77-95]. Among the first 40 patients, 34 successes were reported in arms C and D (85% R0 resection rate). The circumferential resection margin ≤1 rates were 0%, 0%, 12%, and 5% in arms A, B, C, and D. The rate of transformation from positive to negative circumferential resection margin was 93%. LIMITATIONS: There was low accrual in arms A and B. CONCLUSION: Tailoring preoperative radiochemotherapy based on the induction treatment response appears safe for poor responders and promising for good responders. Long-term clinical results are needed to confirm its efficacy. See Video Abstract at http://links.lww.com/DCR/A359.

Longitudinal assessment of quality of life, neurocognition, and psychopathology in patients with low-grade glioma on first-line temozolomide: A feasibility study.

Background: The treatment timing and choice after neurosurgical resection in patients with newly diagnosed diffuse low-grade glioma (DLGG) remain controversial. Indeed, the effect of such treatments must be balanced with the possible side effects. This study evaluated the feasibility of longitudinal exhaustive quality of life (QoL) and neuropsychological assessments in patients with DLGG receiving first-line temozolomide. Methods: QoL, neurocognition, and psychological disorders were assessed prospectively until disease progression, using testing, clinician-reported, and self-reported questionnaires. The primary endpoint was the participation and adherence to this complete assessment at Baseline (before temozolomide initiation), months 6 and 12 of treatment, and month 6 post-treatment. The QoL and neuropsychological changes over time also were described. Results: Twenty-six of the twenty-nine eligible patients were enrolled (participation rate: 89.7%, 95% CI: 72.6-97.8). The adherence rate was 95.7% (95% CI: 78.1-99.9; n = 23 because 3 patients progressed in the first 12 months of treatment). Up to month 6 post-treatment, QoL and fatigue remained stable (EORTC QLQC30 and BN20, MFI-20); some specific symptoms were transitory. Both subjective (FACT-Cog) and objective (Z-scores of neurocognitive tests) neurocognitive outcomes remained stable or tended to improve. The percentage of patients with severe depression (BDI-II), anxiety (STAI-Y), or anger (STAXI-II) was stable over time. Conclusions: This prospective study demonstrated the feasibility of an exhaustive and longitudinal evaluation of QoL, neurocognition, and psychological disorders, with high acceptability by patients with DLGG undergoing chemotherapy. First-line temozolomide seems to have limited short-term effects on QoL and neurocognition. These findings must be confirmed in the long term and in a larger cohort.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Time-Dependent ROC Curve Analysis for Assessing the Capability of Radiation-Induced CD8 T-Lymphocyte Apoptosis to Predict Late Toxicities after Adjuvant Radiotherapy of Breast Cancer Patients.

Late fibrosis can occur in breast cancer patients treated with curative-intent radiotherapy. Predicting this toxicity is of clinical interest in order to adapt the irradiation dose delivered. Radiation-induced CD8 T-lymphocyte apoptosis (RILA) had been proven to be associated with less grade ≥2 late radiation-induced toxicities in patients with miscellaneous cancers. Tobacco smoking status and adjuvant hormonotherapy were also identified as potential factors related to late-breast-fibrosis-free survival. This article evaluates the predictive performance of the RILA using a ROC curve analysis that takes into account the dynamic nature of fibrosis occurrence. This time-dependent ROC curve approach is also applied to evaluate the ability of the RILA combined with the other previously identified factors. Our analysis includes a Monte Carlo cross-validation procedure and the calculation of an expected cost of misclassification, which provides more importance to patients who have no risk of late fibrosis in order to be able to treat them with the maximal irradiation dose. Performance evaluation was assessed at 12, 24, 36 and 50 months. At 36 months, our results were comparable to those obtained in a previous study, thus underlying the predictive power of the RILA. Based on specificity and cost, RILA alone seemed to be the most performant, while its association with the other factors had better negative predictive value results.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER PRODIGE 23): Health-related quality of life longitudinal analysis.

BACKGROUND: Results from the phase 3 PRODIGE 23 study showed that neoadjuvant chemotherapy (NAC) with mFOLFIRINOX and preoperative chemoradiotherapy improved disease-free survival compared with preoperative chemoradiotherapy in patients with locally advanced rectal cancer. We aimed to assess the health-related quality of life (HRQOL) outcomes from this study. PATIENTS AND METHODS: A total of 461 patients (231 versus 230 patients) from 35 French hospitals were randomly assigned to either NAC with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil 2400 mg/m2 over 46 h intravenously every 2 weeks for 6 cycles) followed by preoperative chemoradiotherapy or chemoradiotherapy only. HRQOL was assessed at baseline, during treatments and at 2-year follow-up using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. RESULTS: Compared to baseline, HRQOL scores during NAC were better for tumour symptoms but worse for global health status, functional domains, fatigue, nausea/vomiting and appetite loss. During follow-up, improved emotional functioning was observed, but deterioration of body image, increased urinary incontinence, and lower male sexual function were observed. Linear mixed model exhibited a treatment-by-time interaction effect for nausea/vomiting and insomnia symptoms showing a greater deterioration in the standard-of-care group. Only treatment arm and baseline physical functioning were independent significant favourable prognostic factors. CONCLUSION: NAC improved tumour-related symptoms and transitorily reduced most functional scores. Adding NAC before chemoradiotherapy and increased physical functioning at baseline were independent significant prognostic factors for longer disease-free survival.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

Importance: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. Objective: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. Design, Setting, and Participants: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. Interventions: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. Main Outcomes and Measures: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Results: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). Conclusion and Relevance: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT02404935.

The 2008 food price crisis negatively affected household food security and dietary diversity in urban Burkina Faso.

Although the 2008 food price crisis presumably plunged millions of households into poverty and food insecurity, the real impact of the crisis has rarely been documented using field data. Our objective was to assess the consequences of this crisis for household food insecurity and dietary diversity in urban Burkina Faso. Two cross-sectional surveys were conducted among randomly selected households in Ouagadougou in July 2007 (n = 3017) and July 2008 (n = 3002). At each round, food insecurity assessed by the Household Food Insecurity Access Scale (HFIAS), the Dietary Diversity Score of an index-member of the household (IDDS = number of food groups consumed in the last 24 h), and food expenditure were collected. Food prices of the 17 most frequently consumed food items were recorded throughout the study area. Food prices at local markets increased considerably between 2007 and 2008, especially those of fish (113%), cereals (53%), and vegetable oil (44%), increasing the household monthly food expenditure by 18%. Thirty-three percent of households were food secure in 2007 and 22% in 2008 (P = 0.02). Individuals consumed fewer fruits and vegetables, dairy products, and meat/poultry in 2008 than in 2007 (mean IDDS = 5.7 ± 1.7 food groups in 2007 vs. 5.2 ± 1.5 in 2008; P < 0.0001). Differences in IDDS and HFIAS between the 2 y were even more marked after adjustment for confounding factors and food expenditure. Food security and dietary diversity significantly decreased between 2007 and 2008, whereas food prices increased. Households increased their food expenditure, but this was not sufficient to compensate the effects of the crisis.

Magnetic Resonance-Guided Reirradiation for Local Recurrence within the Prostate or in the Prostate Bed: One-Year Clinical Results of a Prospective Registry Study.

Around 33% of patients treated by EBRT or brachytherapy will present a biochemical recurrence. SBRT is a new option for the treatment of patients with local-only recurrence. MRgRT seems to be interesting for the treatment of these recurrences. This article presents the one-year late tolerance and biochemical recurrence-free survival results of a prospective registry study. Patients with intraprostatic (or in the prostate bed) recurrence were treated with 5 to 9 fractions (median dose of 30 Gy in 5 fractions) with the MRIdian® system. PSA level and toxicities were evaluated before treatment and at three, six and 12 months after treatment. Thirty-seven patients with a median age of 74.5 years old were treated between 21 October 2019 and 7 December 2020. Acute tolerance was excellent with no grade >2 toxicities. Twelve months after treatment, we observed an increase of grade 1−2 dysuria (46% vs. 13% before treatment) and grade 1 polyuria (73% vs. 7%). The six, nine and 12-months biochemical-recurrence free survival were 97.3%, 86.5% and 65.0%. Fifteen patients (40%) presented a biochemical recurrence. Nine of these 15 patients (60%) had a persistent disease within the treated volume. In conclusion, MRgRT is safe and has promising survival results.

Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial.

Importance: Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available. Objective: To report 5-year outcomes and explore prognostic factors for overall survival. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021. Interventions: A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks. Main Outcomes and Measures: Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined. Results: Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months' follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5-43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor. Conclusions and Relevance: The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma. Trial Registration: EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.

Image-Guided Liver Stereotactic Body Radiotherapy Using VMAT and Real-Time Adaptive Tumor Gating: Evaluation of the Efficacy and Toxicity for Hepatocellular Carcinoma.

Liver SBRT is a therapeutic option for the treatment of HCC in patients not eligible for other local therapies. We retrospectively report the outcomes of a cohort of consecutive patients treated with SBRT for HCC at the Montpellier Cancer Institute. Between March 2013 and December 2018, 66 patients were treated with image-guided liver SBRT using VMAT and real-time adaptive tumor gating in our institute. The main endpoints considered in this study were local control, disease-free survival, overall survival, and toxicity. The median follow-up was 16.8 months. About 66.7% had prior liver treatment. Most patients received 50 Gy in five fractions of 10 Gy. No patient had local recurrence. Overall survival and disease-free survival were, respectively, 83.9% and 46.7% at one year. In multivariate analysis, the diameter of the lesions was a significant prognostic factor associated with disease-free survival (HR = 2.57 (1.19-5.53) p = 0.02). Regarding overall survival, the volume of PTV was associated with lower overall survival (HR = 2.84 (1.14-7.08) p = 0.025). No grade 3 toxicity was observed. One patient developed a grade 4 gastric ulcer, despite the dose constraints being respected. Image-guided liver SBRT with VMAT is an effective and safe treatment in patients with inoperable HCC, even in heavily pre-treated patients. Further prospective evaluation will help to clarify the role of SBRT in the management of HCC patients.

Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients.

Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) accumulation in the peripheral blood of gastric cancer (GC) patients. We observed that c-Met is expressed on circulating monocytes from GC patients. The elevated expression on monocytes is associated with clinical parameters linked to an aggressive disease phenotype and correlates with a worse prognosis. Monocyte-derived dendritic cells from GC patients differentiated in the presence of HGF adopt a regulatory phenotype with a lower expression of co-stimulatory molecules, impaired maturation capacities, and an increased ability to produce interleukin-10 and to induce Treg differentiation in vitro. In the MEGA-ACCORD20-PRODIGE17 trial, GC patients received an anti-HGF antibody treatment (rilotumumab), which had been described to have an anti-angiogenic activity by decreasing proliferation of endothelial cells and tube formation. Rilotumumab decreased circulating Treg in GC patients. Thus, we identified that HGF indirectly triggers Treg accumulation via c-Met-expressing monocytes in the peripheral blood of GC patients. Our study provides arguments for potential alternative use of HGF/c-Met targeted therapies based on their immunomodulatory properties which could lead to the development of new therapeutic associations in cancer patients, for example with immune checkpoint inhibitors.

Quality assurance program and early toxicities in the phase III BONBIS randomized trial evaluating the role of a localized radiation boost in ductal carcinoma in situ.

PURPOSE: To describe the quality assurance (QA) program and early toxicities in the phase III randomized trial BONBIS (NCT00907868) on the role of a localized radiation boost in ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: From November 2008 to July 2014, 2004 patients were randomized in arm A (only whole breast radiotherapy, WBRT) and arm B (WBRT + boost). The QA program involved 44 participant centers that performed the dummy run (DR). Compliance and uniformity of clinical target volume (CTV) delineations, and dose prescription and delivery according to the BONBIS trial radiotherapy guidelines were analyzed. Acute toxicities (during and up to 3 months after radiotherapy completion, NCI-CTCAE v3.0 classification) were evaluated in 1929 patients. RESULTS: The differences in whole breast CTV (CTV1) and planning target volume (PTV1) were ≤10%, and the differences in boost CTV (CTV2) and PTV (PTV2) were ≥20% compared with the reference DR values; 95% of the prescribed dose encompassed 98.7% and 100% of the median CTV1 and CTV2. Grade ≥2 breast erythema (38.3% vs. 22.4% of grade 2 and 5.4% vs. 2.1% of grade 3, p < 0.001), grade ≥2 dermatitis (2.8% vs. 0.7%, p < 0.001), and grade 2 hyperpigmentation (6.9% vs. 3.6%, p = 0.005) were more frequent in arm B than arm A. No acute lung or cardiac toxicity was observed. Smoking history, large breast size, and large breast CTV were strong predictive factors of grade ≥2 acute skin toxicities. CONCLUSIONS: The QA program showed deviations in breast and tumor bed delineation. The boost significantly increased acute skin toxicities.