Bolus gemcitabine with capecitabine is an active doublet in a variety of solid tumors [2
]. Combining FDR gemcitabine and capecitabine has the potential advantage of producing higher, more efficacious intracellular concentrations of the active metabolite of gemcitabine, dFdCTP. Therefore, we conducted this dose escalation study to find a suitable regimen for phase II testing.
Treatment yielded an MTD of capecitabine 500 mg/m2 PO BID days 1-14 with FDR gemcitabine at 800 mg/m2 infused at 10 mg/m2/min days 1 and 8 on a 21-day cycle. DLTs included, at 400 mg/m2 of gemcitabine, grade 3 rash (one patient); at 600 mg/m2 of gemcitabine, grade 3 thrombocytopenia ≥ 7 days and grade 3 ANC ≥ 7 days in the same patient; at 800 mg/m2 of gemcitabine, grade 3 ANC ≥ 7 days; and, at 1000 mg/m2 of gemcitabine, grade 4 ANC ≥ 7 days and grade 4 thrombocytopenia ≥ 7 days in one patient and grade 4 ANC ≥ 7 days in another patient. This regimen was safe and well tolerated. Dose modification occurred in 15.4% (20/130) of cycles, including 16.7% (4/24) of cycles at dose level 3, the MTD. The predominant grade ≥ 3 toxicity (13/30 patients) and most common reason for dose reduction was myselosuppression, particularly neutropenia. However, neutropenic fever did not occur. Hand-foot syndrome was infrequent (i.e., two grade 1 and one grade 2 events).
The frequent occurrence of grade ≥ 3 neutropenia in our patients with the use of FDR gemcitabine was not surprising. FDR gemcitabine is expected to produce more neutropenia than bolus gemcitabine because prolonging the gemcitabine infusion produces higher intracellular concentrations of dFdCTP [1
]. Combining capecitabine with FDR gemcitabine is expected to potentiate neutropenia. Because of this, we utilized a dose of capecitabine that was siginificantly lower than that recommended in studies of bolus gemcitabine/capecitabine [6
Two other phase I evaluations of FDR gemcitabine with capecitabine have been reported. The first phase I trial was conducted by Rini et al. [14
]. The first dose level of the Rini study was FDR gemcitabine at 600 mg/m2
on days 1, 8 and 15 with capecitabine 830 mg/m2
PO BID days 1-21 on a 28-day cycle. The second dose level was FDR gemcitabine at 600 mg/m2
on days 1, 8 and 15 with capecitabine 415 mg/m2
PO BID days 1-21 on a 28-day cycle. Due to DLTs in the initial dose levels of this study, the MTD was exceeded and the study was stopped. These DLTs included hand-foot syndrome at the first dose level and persistent infection/neutropenia with fever at the second dose level. These toxicities may have occurred because of the use of three weekly doses of gemcitabine as well as 21, rather than 14, continuous days of capecitabine on a 28-day cycle.
Our results are similar to those of a phase I study by Santini et al. [17
]. These investigators reported an MTD of capecitabine at 650 mg/m2
PO BID days 1-14 with gemcitabine at 800 mg/m2
days 1 and 8 infused at 10 mg/m2
/min on a 21-day cycle. As in our patients, cytopenias accounted for the majority of grade ≥ 3 toxicities. In contrast to our study, hand-foot syndrome was more frequent (five grade 1 events and one grade 2 event vs. two grade 1 events and one grade 2 event) over the same number of cycles (i.e., 130 cycles). This may be attributable to the lower capecitabine dose used in our study (500 mg/m2
PO BID vs. 650 mg/m2
PO BID). Additionally, diarrhea, a toxicity more ascribable to capecitabine than gemcitabine, appears to have been less frequent and less severe in our patients. However, for unclear reasons, nausea/vomiting were more common in our patients. These comparisons are limited by small patient numbers. Ultimately, the difference in capecitabine dose between our MTD and that of Santini et al. is small. Both regimens were tolerated well. Therefore, both regimens appear appropriate for phase II evaluation.
Among 27 patients evaluable for response, we noted four with a PR and 12 with SD. The median duration of PR was 5.5 months. The median duration of SD was 4.1 months. Based on these preliminary efficacy results, our regimen may deserve further evaluation in advanced esophageal, biliary, renal cell, bladder, rectal, pancreatic and anal carcinomas. Advanced breast carcinoma may also be appropriate for phase II evaluation with our regimen given the activity of bolus gemcitabine with capecitabine in this setting [2
]. The preliminary results of two small ongoing phase II studies of FDR gemcitabine with capecitabine using the regimen recommended in the Santini phase I study [17
] have been reported thus far only in abstract form. First, in 21 chemotherapy-naïve patients with advanced biliary carcinoma, the response rate (RR) was 30% (including one patient with CR and five with PRs) and median overall survival (OS) was 15 months [16
]. Second, Santini et al. reported a RR of 24% (including one patient with a CR and four with PRs) and median OS of eight months in 25 chemotherapy-naïve patients with advanced pancreatic carcinoma [15
A limitation in the interpretation of our findings is that 57% (17/30) of patients had a PS of 1 and only two patients (6.7%) had a PS of 2. Additionally, 85% (17/20) of patients in the Santini phase I study had a PS of 0 and no patient had a PS of 2 [17
]. Therefore, these safety and tolerability results may not generalize well to patients with a PS > 1.
We conclude that capecitabine at 500 mg/m2 PO BID days 1-14 with FDR gemcitabine at 800 mg/m2 infused at 10 mg/m2/min days 1 and 8 on a 21-day cycle is a safe and tolerable regimen for patients with advanced solid malignancies. Advanced gastrointestinal and genitourinary carcinomas may be appropriate for further evaluation of this regimen.