Patient characteristics are summarized in Table . From May 2003 to March 2010, a total of 154 patients received GTX. Ninety-four percent of the treated patients received treatment after 2006. At the time of GTX administration, 37 patients had radiographically confirmed locally advanced disease and 117 had confirmed evidence of metastatic disease. (Twenty of the 37 patients with locally advanced disease had a prior history of radiation therapy.) Records were obtained from three medical centers: Johns Hopkins Hospital, Memorial Sloan Kettering Comprehensive Cancer Center and US Oncology—Dallas (Table S1).
The median age of the patients reviewed was 62 years. The majority of patients was metastatic (77%) and had an ECOG performance status (ECOG PS) of 1 (66%). GTX was the first regimen attempted for 51% of cases reviewed, and the average number of cycles completed was 4. Twenty-one percent of patients had prior surgery with curative intent prior to initiating GTX therapy. None of the patients received GTX in the adjuvant setting.
Hematological and non-hematological toxicities were assessed in all treated patients (n = 154) and are shown in Table . No GTX-related deaths were noted. Hospitalization data were available on 50% of patients, of which 33% required at least one inpatient hospitalization while receiving GTX. Nine percent of patients experienced grade 3/4 non-hematological toxicity, and 41% experienced hematological toxicity. Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 12%, 34% and 13% of patients, respectively (Table ).
Frequency of toxicities, overall and by staging
Grade 3/4 toxicity from GTX was found to be independent of treatment location (Table S3), stage, grade, ECOG PS, prior surgery, ascites or hospitalization (Table S3). Any prior chemotherapy minimally correlated with grade 3/4 toxicity (adjusted odds ratio (OR) 2.01, 95% CI 0.97–4.16, P = 0.057).
Dose reductions and chemotherapy modifications were evaluated in half of the patients (77/154). Hematological complications (myelosuppression) resulted in dose reduction in 34% of the patients (26/77). Non-hematological toxicities that resulted in dose modifications occurred in 30% of the patients (23/77). The reasons that resulted in GTX dose modifications included one or more of the following: fatigue (n = 4) anasarca (n = 2), decreased performance status (n = 2), diarrhea/mucositis (n = 12), intractable nausea/vomiting (n = 3), hand and foot syndrome (n = 2) or multiple procedures required (n = 1).
One hundred and forty-six (95%) of the 154 cases were evaluable for response using RECIST criteria [16
]. Assessments were performed after every 2–3 cycles of GTX chemotherapy. Partial responses were seen in 11% (n
= 16) of patients. Stable disease was seen in 62% of cases (n
= 91) and progressive disease in 27% (n
= 39). No complete responses were observed. Response rates by extent of disease and line of therapy are summarized in Table .
Elevated ALT, any neutropenia and hospitalization correlated strongly with achieving a partial response (adjusted OR 3.57, 95% CI 0.92–13.8, P = 0.045, ALT elevation; adjusted OR 5.10, 95% CI 0.9–28.91, P = 0.041, any neutropenia; adjusted OR 5.37, 95% CI 1.09–26.51, P = 0.032, hospitalization). A borderline significant correlation with improved response was noted in metastatic patients who received GTX as their first-line therapy (adjusted OR 2.56, 95% CI 0.62–10.59, P = 0.055). Prior chemotherapy negatively correlated with response (adjusted OR 0.16, 95% CI 0.03–0.83, P = 0.012). These findings are summarized in Table .
Tumor marker analysis
Longitudinal CA19-9 values for the first two cycles of therapy were available for 86 cases. Patients that did not express CA19-9 were excluded from the analysis. Seventy-seven percent (n = 66) of patients demonstrated a measurable decline in CA19-9 after two cycles of therapy with GTX. When GTX was used as first-line therapy (n = 48), a decline CA19-9 was observed in 91% of cases (Fig. ). In the second line or greater (n = 38), the CA19-9 response was seen in 63% of cases.
Waterfall plot of the CA19-9 response in patients treated with first-line therapy with GTX
There was no correlation between CA19-9 response, objective radiographic response (Table ) or survival when measured as a continuous variable (Figure S1). Even when CA19-9 responses were separated into groups using cutoffs defined by percent decline in CA19-9 levels or by line of therapy, there was no correlation with overall survival (Tables , S4).
Estimates of OS (time from start of GTX therapy to death) for patients who received their first line of GTX
Chemotherapy naïve patients achieved a mOS of 11.6 months (n = 75) and a 1-year survival of 46% when treated with GTX. Patients who received first-line GTX with metastatic and locally advanced disease achieved a median survival of 11.3 and 25.0 months, respectively (Fig. ). In the first-line setting, only ECOG PS correlated with improved survival (adjusted HR 2.57, 95% CI 1.03–6.41, P = 0.043) as shown in Table .
Kaplan–Meier estimates of patients treated with GTX as first-line therapy with a locally advanced and b metastatic pancreatic cancer
When GTX was used as second line or greater (n = 79), the mOS was 5.7 months and 1-year survival was 32% (Table S4). In patients with locally advanced disease, the mOS was 16.2 and 5.7 months in metastatic patients. Prior surgery with curative intent (adjusted HR 529.1, 95% CI 3.52–79,433.25, P = 0.014) strongly correlated with improved survival. In the second line setting, experiencing any grade 3/4 toxicity was a negative factor for survival (adjusted HR 0.47, 95% CI 0.25–0.9, P = 0.022).
In the first and second lines of therapy with GTX, there was a marked improvement in survival in patients who demonstrated a RECIST-based partial response (Table , Table S4).