Dataset Information

Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial.

ABSTRACT:

Background

There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC.

Methods

A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed.

Results

Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6).

Conclusions

For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

SUBMITTER: Wei AC

PROVIDER: S-EPMC6868305 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial.

Wei Alice C AC Ou Fang-Shu FS Shi Qian Q Carrero Xiomara X O'Reilly Eileen M EM Meyerhardt Jeffrey J Wolff Robert A RA Kindler Hedy L HL Evans Douglas B DB Deshpande Vikram V Misdraji Joseph J Tamm Eric E Sahani Dushyant D Moore Malcolm M Newman Elliot E Merchant Nipun N Berlin Jordan J Goff Laura W LW Pisters Peter P Posner Mitchell C MC

Annals of surgical oncology 20190815 13

<h4>Background</h4>There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC.<h4>Methods</h4>A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were el ...[more]

PMID: 31418130

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Project description:LESSONS LEARNED:Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND:Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS:Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS:A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION:Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Project description:BACKGROUND:Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. METHODS:Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3?+?3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. RESULTS:MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P?=?0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P?=?0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P?=?0.64, 0.87). Grade 3-4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B). CONCLUSIONS:MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome. TRIAL REGISTRATION:This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008.

Project description:BackgroundThis study aims to comprehensively summarize the currently available evidences on the efficacy and safety of gemcitabine plus erlotinib for treating advanced pancreatic cancer.Methodology/principal findingsPubMed, EMBASE, The Cochrane Library and abstracts of recent major conferences were systematically searched to identify relevant publications. Studies that were conducted in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib (with or without comparison with gemcitabine alone) and reporting objective response rate, disease control rate, progression-free survival, time-to-progression, overall survival, 1-year survival rate and/or adverse events were included. Data on objective response rate, disease control rate, 1-year survival rate and adverse events rate, respectively, were combined mainly by using Meta-Analyst software with a random-effects model. Data on progression-free survival, time-to-progression and overall survival were summarized descriptively. Sixteen studies containing 1,308 advanced pancreatic cancer patients treated with gemcitabine plus erlotinib were included. The reported median progression-free survival (or time-to-progression), median overall survival, 1-year survival rates, objective response rates and disease control rates were 2-9.6 months, 5-12.5 months, 20%-51%, 0%-28.6% and 25.0%-83.3%, respectively. The weighted 1-year survival rate, objective response rate and disease control rate based on studies reporting robust results were 27.9%, 9.1% and 57.0%, respectively. According to the studies with relevant data, the incidences of total and severe adverse events were 96.3% and 62.9%, respectively. The most frequently reported adverse events were leucopenia, rash, diarrhea, vomitting, neutropenia, thrombocytopenia, anaemia, stomatitis, drug-induced liver injury, fatigue and fever. Compared with gemcitabine alone, the progression-free survival and overall survival with gemcitabine plus erlotinib were significantly longer, but there were also more deaths and interstitial lung disease-like syndrome related to this treatment.Conclusions/significanceGemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with mild but clinically meaningful additive efficacy compared with gemcitabine alone. Its safety profile is generally acceptable, although careful management is needed for some specific adverse events.

Project description:BackgroundThe outcomes of minimally invasive pancreaticoduodenectomy have not been adequately compared with those of open pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma. We performed a meta-analysis to compare the perioperative and oncological outcomes of these two pancreaticoduodenectomy procedures specifically in patients with pancreatic ductal adenocarcinoma.MethodsBefore this study was initiated, a specific protocol was designed and has been registered in PROSEPRO (ID: CRD42020149438). Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, PubMed, EMBASE, Web of Science, Cochrane Central Register, and ClinicalTrials.gov databases were systematically searched for studies published between January 1994 and October 2019. Overall survival, disease-free survival, and time to commencing adjuvant chemotherapy were the primary endpoint measurements, whereas perioperative and short-term outcomes were the secondary endpoints.ResultsThe final analysis included 9 retrospective cohorts comprising 11,242 patients (1377 who underwent minimally invasive pancreaticoduodenectomy and 9865 who underwent open pancreaticoduodenectomy). There were no significant differences in the patients' overall survival, operative time, postoperative complications, 30-day mortality, rate of vein resection, number of harvested lymph nodes, or rate of positive lymph nodes between the two approaches. However, disease-free survival, time to starting adjuvant chemotherapy, length of hospital stay, and rate of negative margins in patients who underwent minimally invasive pancreaticoduodenectomy showed improvements relative to those in patients who underwent open surgery.ConclusionsMinimally invasive pancreaticoduodenectomy provides similar or even improved perioperative, short-term, and long-term oncological outcomes when compared with open pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma.

Project description:BACKGROUND AND AIMS: Pancreaticoduodenectomy (PD) is a major operative intervention performed most commonly for malignancy in the head of pancreas. The aim of this study was to evaluate the utilization of blood transfusion for PD and to determine whether this had prognostic significance in a subset of patients with pancreatic ductal adenocarcinoma (PDAC). MATERIAL AND METHODS: Data on blood transfusion requirement were retrospectively collected for patients undergoing PD from 1998 to 2005. Standard prognostic factors and survival data were also collected in patients with PDAC. RESULTS: One-hundred-and-seventy patients underwent PD. Seventy-six patients (45%) received transfusion. The median (interquartile range) number of units of red cell concentrate (RCC) transfused perioperatively (intraoperatively and within 24 h of surgery) was 1.5 (0.5-2.5). The median preoperative haemoglobin (Hb) was 126 g/dl. The median number of units of RCC transfused perioperatively in patients with Hb <126 g/dl was 2 (1-3); for those with Hb > or = 126 g/dl the median was 0 (0-1); p=0.003. Forty-nine patients who were resected for PDAC were subjected to survival analysis. Univariate and multivariate analyses showed that only posterior resection margin invasion was associated with an adverse outcome (margin positive 198 [143-470] days vs margin negative 398 [303-859] days; p=0.02). Perioperative RCC transfusion requirement was not a significant predictor of survival (transfusion 408 [214-769] days vs no transfusion 331 [217-391] days; p=0.18). Furthermore, RCC transfusion within 30 days of operation was not a significant predictor of poor survival (transfusion 331 [201-459] days vs no transfusion 317 [196-769] days; p=0.43). CONCLUSIONS: PD can be performed with a moderately low requirement for RCC transfusion; however, low preoperative haemoglobin is a predictor for the requirement of RCC transfusion. Administration of RCC transfusion does not appear to be a significant adverse prognostic factor in patients with resected PDAC.

Project description:BackgroundDespite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.Methods/designThis is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m(2)) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.DiscussionThe NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.Trial registrationclinicalTrials.gov NCT01314027.

Dataset Information

Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial.

Background

Methods

Results

Conclusions

Publications

Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial.

Similar Datasets

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