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Predictive role of skin rash in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib: a systematic review and meta-analysis.

ABSTRACT: Purpose:The survival benefit from gemcitabine plus erlotinib was on average marginal for advanced pancreatic cancer (APC) patients. Skin rash developed shortly after starting treatment seemed to be associated with better efficacy and might be used to assist clinical decision-making, but the results across studies were inconsistent. Thus, we conducted a systematic review and meta-analysis. Methods:PubMed, Embase, Cochrane Central Register of Controlled Trials, three Chinese databases, and the abstracts of important conferences were searched for eligible studies. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and objective response. The random-effects model was used to pool results across studies if heterogeneity was substantial. Otherwise, the fixed-effect model was used. Results:A total of 16 studies with 1,776 patients were included. Patients who developed skin rash during treatment had longer OS (8.9 vs 4.9 months, HR=0.57, 95% CI 0.50-0.64) and longer PFS (4.5 vs 2.4 months, HR=0.53, 95% CI 0.40-0.68) than those who did not. A dose- response relationship was also observed for both OS (HR=0.64 for grade-1 rash vs no rash and HR=0.46 for ?grade-2 rash vs no rash) and PFS (HR=0.72 for grade-1 rash vs no rash and HR=0.43 for ?grade-2 rash vs no rash). Conclusion:Skin rash was associated with better OS and PFS in APC patients treated with gemcitabine plus erlotinib. It might be used as a marker for efficacy to guide clinical decision-making toward a more precise and personalized treatment.

SUBMITTER: Zeng M

PROVIDER: S-EPMC6188168 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Predictive role of skin rash in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib: a systematic review and meta-analysis.

Zeng Minyan M Feng Qi Q Lu Ming M Zhou Jun J Yang Zuyao Z Tang Jinling J

OncoTargets and therapy 20181008

<h4>Purpose</h4>The survival benefit from gemcitabine plus erlotinib was on average marginal for advanced pancreatic cancer (APC) patients. Skin rash developed shortly after starting treatment seemed to be associated with better efficacy and might be used to assist clinical decision-making, but the results across studies were inconsistent. Thus, we conducted a systematic review and meta-analysis.<h4>Methods</h4>PubMed, Embase, Cochrane Central Register of Controlled Trials, three Chinese databas ...[more]

PMID: 30349297

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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:BACKGROUND:Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. METHODS:This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years). RESULTS:Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. CONCLUSIONS:Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.

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:PurposeTH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer.Patients and methodsPatients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety.ResultsTwo hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation.ConclusionPFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Dataset Information

Predictive role of skin rash in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib: a systematic review and meta-analysis.

Publications

Predictive role of skin rash in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib: a systematic review and meta-analysis.

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