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| 2. |
- Hammel, Pascal, et al.
(författare)
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Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib : The LAP07 Randomized Clinical Trial
- 2016
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 315:17, s. 1844-1853
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Tidskriftsartikel (refereegranskat)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 of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.DESIGN, SETTING, AND PARTICIPANTS InLAP07, an international, open-label, phase3randomized trial, 449 patientswere enrolled between 2008and 2011. Follow-up ended in February 2013.INTERVENTIONS In the first randomization, 223 patients received 1000mg/m(2) weekly of gemcitabine alone and 219 patients received 1000mg/m(2) of gemcitabine plus 100mg/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 outcomewas overall survival from the date of the first randomization. Secondary outcomeswere 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.
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| 3. |
- Jones, Robert P., et al.
(författare)
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Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma : A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial
- 2019
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Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 154:11, s. 1038-1048
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Tidskriftsartikel (refereegranskat)abstract
- Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P=.03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P=.04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P=.27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P=.85 and P=.35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P=.03).Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434. This secondary analysis of a randomized clinical trial investigates patterns of recurrence after adjuvant chemotherapy in pancreatic cancer and the association with survival.
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| 5. |
- Vernerey, Dewi, et al.
(författare)
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Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP)
- 2016
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 115:3, s. 281-289
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Tidskriftsartikel (refereegranskat)abstract
- Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial. Better discrimination for overall survival (OS) at diagnosis is needed. We address this issue by developing and validating a prognostic nomogram and a score for OS in LAPC (PROLAP).Methods: Analyses were derived from 442 LAPC patients enrolled in the LAP07 trial. The prognostic ability of 30 baseline parameters was evaluated using univariate and multivariate Cox regression analyses. Performance assessment and internal validation of the final model were done with Harrell's C-index, calibration plot and bootstrap sample procedures. On the basis of the final model, a prognostic nomogram and a score were developed, and externally validated in 106 consecutive LAPC patients treated in Besanc, on Hospital, France.Results: Age, pain, tumour size, albumin and CA 19-9 were independent prognostic factors for OS. The final model had good calibration, acceptable discrimination (C-index = 0.60) and robust internal validity. The PROLAP score has the potential to delineate three different prognosis groups with median OS of 15.4, 11.7 and 8.5 months (log-rank P<0.0001). The score ability to discriminate OS was externally confirmed in 63 (59%) patients with complete clinical data derived from a data set of 106 consecutive LAPC patients; median OS of 18.3, 14.1 and 7.6 months for the three groups (log-rank P<0.0001).Conclusions: The PROLAP nomogram and score can accurately predict OS before initiation of induction chemotherapy in LAPC-untreated patients. They may help to optimise clinical trials design and might offer the opportunity to define risk-adapted strategies for LAPC management in the future.
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- Bonnetain, Franck, et al.
(författare)
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Guidelines for time-to-event end-point definitions in trials for pancreatic cancer : Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials)
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:17, s. 2983-2993
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Forskningsöversikt (refereegranskat)abstract
- Background: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. Methods: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). Results: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. Conclusion: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.
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| 7. |
- Giraud, Paul, et al.
(författare)
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Investigation of Relation of Radiation Therapy Quality With Toxicity and Survival in LAP07 Phase 3 Trial for Locally Advanced Pancreatic Carcinoma
- 2021
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 110:4, s. 993-1002
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The LAP07 multicenter randomized study assessed whether chemoradiation therapy increases overall survival versus continuation chemotherapy in patients whose locally advanced pancreatic cancer was controlled after 4 months of induction chemotherapy. This analysis investigated whether failure to adhere to radiation therapy (RT) guidelines influenced survival and toxicity. Methods and Materials: This is a planned analysis of secondary objectives in the framework of a randomized international phase 3 trial. The protocol included detailed written RT guidelines. All participating institutions undertook an initial benchmark case to check adherence to protocol guidelines. Centers with major deviation were not allowed to include patients until they achieved a significant improvement and rigorously followed the guidelines. On-trial RT quality assurance consisted of a central review of treatment plan with dose-volume histograms for each patient. Adherence to guidelines was graded as per protocol (PP), minor deviation (MiD), or major deviation (MaD). Results: Fifty-seven benchmark cases were evaluated, 26% were classified as PP, 60% were MiD, and 14% were MaD. Among the 442 included patients, 133 patients were randomized in the chemoradiation therapy arm, and 117 patients were assessable for RT quality analysis. RT quality was graded as PP in 38.5% of patients, MiD in 43.6% of patients, and MaD in 17.9% of patients. The most frequent protocol violations were dose distribution heterogeneities. Median overall survival was 17 months with PP and MiD versus 13.4 months with MaD (hazard ratio [HR], 1.63; 95% confidence interval [CI], 0.99-2.71; P = .055). There was no difference in terms of progression-free survival (HR, 1.09; 95% CI, 0.66-1.8; P = .72). Patients with MaD had more nausea than patients treated PP or with MiD (P = .0045). Conclusions: MaD was associated with a trend for worst survival. There was no difference in terms of progression-free survival. Because of the low rate of major deviations, their effects on the LAP07 trial results may be negligeable. (C) 2021 Elsevier Inc. All rights reserved.
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| 8. |
- Neoptolemos, John P., et al.
(författare)
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Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4) : a multicentre, open-label, randomised, phase 3 trial
- 2017
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10073, s. 1011-1024
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Tidskriftsartikel (refereegranskat)abstract
- Background: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.Methods: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1: 1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.Findings: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI 23.5-31.5) compared with 25.5 months (22.7-27.9) in the gemcitabine group (hazard ratio 0.82 [95% CI 0.68-0.98], p=0.032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
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| 9. |
- Schernberg, Antoine, et al.
(författare)
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Predictive Value of Neutrophils Count for Local Tumor Control After Chemoradiotherapy in Patients With Locally Advanced Pancreatic Carcinoma
- 2021
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 110:4, s. 1022-1031
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Baseline neutrophil count may predict overall survival (OS) in patients with locally advanced pancreatic cancer (LAPC). Methods and Materials: The international multicenter randomized LAP07 phase 3 trial has enrolled 442 patients with LAPC. We analyzed the prognostic value of both baseline neutrophilia (neutrophil count >7 g/L) and elevated or increasing neutrophil count as (1) neutrophilia or (2) increased absolute neutrophil count after induction chemotherapy versus baseline for OS, progression-free survival, and local control (LC). A Cox proportional hazard model was used to assess elevated or increasing neutrophil count status by randomly assigned treatment interactions for each endpoint. Results: Among the 442 patients, 47 patients (11%) with baseline neutrophilia had worse OS (median 8.9 vs 13.3 months; P = .01). After induction chemotherapy, among the 235 patients whose blood counts were available, 90 patients (38%) had elevated or increasing neutrophil count associated with poorer OS in univariate (median 14.4 vs 17.9 months; P = .001) and multivariate analysis (P = .004). Elevated or increasing neutrophil count was also predictive of a decreased benefit of chemoradiation therapy on LC. In 126 patients without elevated or increasing neutrophil count, 1-year LC was 80% in the chemoradiation arm versus 54% in the chemotherapy arm (P < .001; interaction test P = .015). Conclusions: In this study, baseline neutrophilia and increased absolute neutrophil count were associated with worse OS in this large series of patients with LAPC. In addition, the counts were an independent prognosis factor and a strong predictive LC biomarker for chemoradiation therapy benefit. An assessment of neutrophils counts can help to improve the selection of patients who might benefit from chemoradiation therapy after induction chemotherapy. (C) 2021 Elsevier Inc. All rights reserved.
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