Pascal Hammel1, Florence Huguet2, Jean-Luc van Laethem3, David Goldstein4, Bengt Glimelius5, Pascal Artru6, Ivan Borbath7, Olivier Bouché8, Jenny Shannon9, Thierry André10, Laurent Mineur11, Benoist Chibaudel12, Franck Bonnetain13, Christophe Louvet14. 1. Department of Digestive Oncology, Beaujon Hospital (AP-HP), Clichy, France. 2. Department of Radiotherapy, Tenon Hospital (AP-HP), Paris, France. 3. Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. 4. Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia5Australasian Gastrointestinal Trials Group (AGITG), Camperdown, Australia6Prince of Wales Clinical School, University of New South Wales, Sydney, Australia. 5. Department of Radiology, Oncology, and Radiation Science, University of Uppsala, Uppsala, Sweden. 6. Department of Gastroenterology, Jean Mermoz Hospital, Lyon, France. 7. Department of Gastroenterology, Saint-Luc University Clinics, Brussels, Belgium. 8. Department of Gastroenterology, Robert Debré Hospital, Reims, France. 9. Australasian Gastrointestinal Trials Group (AGITG), Camperdown, Australia6Prince of Wales Clinical School, University of New South Wales, Sydney, Australia11Department of Medical Oncology, Nepean Hospital NSW, Sydney, Australia. 10. Department of Medical Oncology, Saint-Antoine Hospital (AP-HP), Paris, France. 11. Department of Radiotherapy and Medical Oncology, Sainte-Catherine Institute, Avignon, France. 12. Department of Medical Oncology, Franco-British Hospital Institute, Levallois-Perret, France15Oncology Multidisciplinary Research Group (GERCOR), Paris, France. 13. Department of Methodology and Quality of Life in Oncology, Hospital Minjoz, Besançon, France. 14. Department of Medical Oncology, Institute Mutualiste Montsouris, Paris, France.
Abstract
IMPORTANCE: In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown. OBJECTIVES: To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months ofgemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival. DESIGN, SETTING, AND PARTICIPANTS: In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013. INTERVENTIONS: In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects. RESULTS:A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea. CONCLUSIONS AND RELEVANCE: In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months ofinduction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00634725.
RCT Entities:
IMPORTANCE: In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown. OBJECTIVES: To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival. DESIGN, SETTING, AND PARTICIPANTS: In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013. INTERVENTIONS: In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects. RESULTS: A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea. CONCLUSIONS AND RELEVANCE: In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00634725.
Authors: Jayanth S Shankara Narayanan; Partha Ray; Tomoko Hayashi; Thomas C Whisenant; Diego Vicente; Dennis A Carson; Aaron M Miller; Stephen P Schoenberger; Rebekah R White Journal: Cancer Immunol Res Date: 2019-08-13 Impact factor: 11.151
Authors: E Bonnet; C Mastier; A Lardy-Cléaud; P Rochefort; M Sarabi; P Guibert; A Cattey-Javouhey; F Desseigne; C de La Fouchardière Journal: Curr Oncol Date: 2019-08-01 Impact factor: 3.677