Prognostic Factor Analysis of Overall Survival in Gastric Cancer from Two Phase III Studies of Second-line Ramucirumab (REGARD and RAINBOW) Using Pooled Patient Data

Abstract

PurposeTo identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer.Materials and MethodsWe pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters.ResultsOf 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64–0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor.ConclusionsThe identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.

Phase II clinical trial of S‐1 plus nanoparticle albumin‐bound paclitaxel in untreated patients with metastatic gastric cancer

“…Based on the dose‐escalation of Nab‐PTX with divided doses in combination with standard S‐1, in the present study, we use the recommended dose for Nab‐PTX 120 mg/m 2 on d1 and d8, q3w, achieving an efficacy/toxicity balance. A previous study showed the peritoneal metastases are an independent prognostic factor of poor survival in AGC patients . In this one‐arm trial where all patients received the same regimen, we found patients with peritoneal metastases had no significantly different efficacy or prognosis than other patients, which may indicate S‐1 plus Nab‐PTX had similar efficacy in patients with peritoneal metastases or without.…”

“…A previous study showed the peritoneal metastases are an independent prognostic factor of poor survival in AGC patients. 28 In this one-arm trial where all patients received the same regimen, we found patients with peritoneal metastases had no significantly different efficacy or prognosis than other patients, which may indicate S-1 plus Nab-PTX had similar efficacy in patients with peritoneal metastases or without. Because the sample sizes of the subgroups in our study were small, further study is required to confirm this good observation for patients with peritoneal metastases.…”

Elevation of Neutrophil-to-Lymphocyte Ratio before First-Line Chemotherapy Predicts a Poor Prognosis for Second-Line Chemotherapy in Gastric Cancer

“…As for the relationship between prognosis and histologic type, survival time was considerably shorter in patients with a diffuse histologic type according to the Lauren classification, although the difference was not statistically significant in our study. Since previous studies enrolling more than 1,000 cases showed that poor tumor differentiation was associated with a poor prognosis, the result of our study may be attributed to the relatively small number of cases enrolled [18, 24]. …”

“…A Russian group reported that PS 2, Hb < 10 g/dL, and TTP in first-line chemotherapy < 5 months were associated with a poor prognosis [22]. Recently, Fuchs et al [24], in their prognostic factor analysis based on two phase III trials of second-line ramucirumab (REGARD and RAINBOW) using pooled data, reported twelve negative prognostic factors: peritoneal metastasis, PS1, the presence of a primary tumor, TTP < 6 months after prior therapy, poor/unknown tumor differentiation, a low level of Alb, sodium, and lymphocytes, and a high level of neutrophils, aspartate aminotransferase, ALP, and lactate dehydrogenase.…”

“…Further, there is little evidence regarding the predictive marker(s) for second-line chemotherapy [6, 21-24]. The purpose of this study was to evaluate the prognostic value of NLR for second-line chemotherapy in patients with AGC.…”