We conducted this retrospective study to evaluate clinical efficacy and safety of irinotecan plus raltitrexed as salvage therapy in a group of 38 ESCC patients who had progressed after the failure of multiple systemic therapies. Our data showed an encouraging ORR of 23.68% and DCR of 78.94%, as well as less than 15% incidence of grade 3/4 toxicities. Median PFS was 105 days and the median OS was 221 days. These results indicate that this combination might be an option for refractory ESCC patients.
In preclinical study, it had been demonstrated a significant schedule-dependent synergism between irinotecan and raltitrexed in vitro. Aschele et al[18] found that greatest synergism was observed when SN–38 (an active metabolite of irinotecan) was administered 24 hours before raltitrexed by comparing ED50 (the dose required for 50% inhibition of cell growth) in different intervals (1h, 4h, and 24h), while smaller enhancement or nearly additive interactions was found when the two drug were switched or used simultaneously. Thereafter, several clinical studies employed 24h or 1h earlier schedule to treat different cancer[9, 16, 19]. In the present study, we administered irinotecan and raltitrexed in a suggested 24h earlier schedule to observe its clinical efficacy and safety in the treatment of ESCC.
Currently, no standard second or third-line chemotherapy has been well established in the treatment of ESCC. Although there are a few reports on raltitrexed combination chemotherapy in patients with advanced gastro-esophageal adenocarcinoma[20, 21], the clinical experience of raltitrexed in patients with ESCC is still unavailable. Recently, Ding et al reported that raltitrexed could decrease cell viability and proliferation, cause apoptosis and enhance the radiosensitivity of ESCC cells[22]. In patients with advanced colorectal cancer, raltitrexed has produced comparable efficacy as first line treatment when compared to 5-FU-based regimen[9] and still showed activity when combined with irinotecan as second line chemotherapy[16]. Since 5-FU plus irinotecan was an effective combination as a second line chemotherapy in ESCC[6], and raltitrexed was considered as a potential substitute for 5-FU, we investigated the clinical efficacy and safety of irinotecan plus raltitrexed and its potential utility as second or later-line therapy in ESCC patients.
Our data showed that the ORR was 23.68% and the DCR was 78.94%, which were slightly higher than results in colorectal cancer and pancreas cancer (ORR: 16%–16.7%, DCR: 56.7%–58%)[16, 19]. The survival results (median PFS and median OS) were similar to recently reported results from a prospective randomized, multicenter, open-labeled phase3 ESWN 01 trial[23]. Together with the previous reports, our results, showed that irinotecan plus raltitrexed could be a possible alternative regimen for previously treated ESCC patients.
Unlike our present study, only patients with no prior exposure to irinotecan or 5-FU were enrolled in the retrospective study conducted by Wang X et al[6] and the prospective ESWN 01 trial[23]. The reason might be partly because of similar action and thus similar resistance mechanisms associated with 5-FU and raltitrexed. In our present study, we found that patients without prior 5-FU exposure are sensitive to irinotecan plus raltitrexed chemotherapy with an ORR of 35.00%, which was numerically higher than the ORR in patients with prior 5-FU exposure. However, 5-FU inhibits TS through its metabolite 5-fluoro-deoxyuridine monophosphate, while raltitrexed directly and specifically inhibits TS without requiring any modulating agent[24]. Therefore, incomplete cross-resistance between 5-FU and raltitrexed has been confirmed in both preclinical research[25] and clinical studies[16]. In 5-fluorouracil refractory advanced colorectal cancer, irinotecan plus raltitrexed had a moderate improvement in response rate when compared indirectly with data from trial of second-line CPT–11 monotherapy[16, 26]. Our present study shown that patients with prior 5-FU exposure are still sensitive to irinotecan plus raltitrexed chemotherapy with an ORR of 11.11%. This matter of cross-resistance between 5-FU and raltitrexed in irinotecan treatment is an interesting question to further study. In general, irinotecan plus raltitrexed was effective in heavily treated (previous two-line or more chemotherapy or chemoradiotherapy) patients. However, the results provided are from a limited number of cases. To provide more evidence, a large-scale study is needed in the future.
In this study, we had lower toxicity compared with other reports[9, 16, 19, 27]. Hematological and gastrointestinal toxicities were the main toxicities. Grade 3/4 leukopenia occurred in 5 (13.15%) patients. According to previous reports, most studies used 300–350 mg/m2 irinotecan in the treatment of colorectal cancer[28, 29]. A lower dose of irinotecan (200mg/m2) combined with raltitrexed was administered to treat patients with advanced pancreatic adenocarcinoma from a randomized multicenter phase II study[19]. However, there was no study to determine the maximum tolerated dose of this combination in esophageal cancer. In a multicenter phase II study, 130 mg/m2 irinotecan combined with cisplatin were used to treat metastatic, unresectable esophageal cancer[30]. A slightly higher dose of 160 mg/m2 irinotecan combined with S–1 were used to treat Chinese esophageal cancer patients from a prospective randomized, multicenter, open-labeled phase 3 trial[23]. In our study, the median dose of irinotecan was 178 mg/m2 (118–217 mg/m2). Compared with the ESWN 01trial, both survival results and incidences of grade 3–4 leukopenia/neutropenia in the present study were similar. This indicates that irinotecan plus raltitrexed is a safe choice in previously treated recurrent/metastatic ESCC. However, the number of patients included in our study is small. And prospective clinical studies of irinotecan plus raltitrexed in patients with refractory ESCC are needed to determine the maximum tolerated dose and clinical efficacy of this combination.