Gemcitabine plus capecitabine (Gem–Cape) biweekly in chemorefractory metastatic colorectal cancer

There is a lack of evidence on the use of chemotherapy in multi-treated, refractory metastatic colorectal cancer (mCRC) patients; moreover, alternative treatments have yet to be standardized their true benefit fully evaluated.

The published data of the few phase III studies [1, 2] that have been performed in this setting showed unsatisfactory results for overall survival (OS) with a median of 5.8–6.4 months, highlighting the need for further research and looking toward new active agents or new chemotherapy combinations.

Gemcitabine is a pyrimidine analogue that has been turned into difluorodeoxycytidine triphosphate (dFdCTP) and inhibits deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by four mechanisms: (1) inhibiting DNA polymerases (α, β, and δ); (2) adhering directly to DNA, thus prohibiting chain elongation; (3) inhibiting ribonucleotide reductase, resulting in decreased levels of essential deoxyribonucleotides for DNA synthesis; (4) and finally, incorporating itself into RNA, producing alterations in its processing and mRNA translation [3, 4].

Capecitabine, another antimetabolite, is an inactive prodrug that undergoes a complex process to reach its active form. Capecitabine conversion to 5-fluorouracil (5-FU) is higher in tumor cells than in normal tissues because of the higher expression of thymidine phosphorylase [5]. The depletion of the reduced nucleotide pool could increase the incorporation of the 5-FU metabolite fluorouridine monophosphate (FUTP) into RNA and of FdUTP into DNA, resulting in damaged RNA and DNA synthesis and function [6] (Fig. 1).

This analysis evaluates the survival, efficacy, and toxicity profile of gemcitabine–capecitabine (Gem–Cape) and intends to identify possible predictive factors in patients with mCRC treated in a single university hospital.

The use of irinotecan, oxaliplatin, fluoropyrimidines, and the incorporation of biological agents such as bevacizumab, cetuximab, and panitumumab, has improved considerably ORR, PFS, and OS in patients with mCRC [2, 10‐12]. Nevertheless, despite all of these drugs, patients become refractory; their lack of any standardized treatment alternatives reflects the necessity to continue efforts to uncover new schedules or drugs that are not only beneficial in terms of their action, but also in terms of their tolerability and effects on the quality of life.

Currently, very few trials have clearly shown a survival advantage for any regimen or particular drug in chemorefractory patients with mCRC; instead, the main advance has been the incorporation of antitarget therapies, such as panitumumab and regorafenib, both of which have been evaluated in phase III studies [2, 12]. Regorafenib showed an ORR of 1 %, disease control in 41 %, PFS of 1.9 months, and OS of 6.4 months. In comparison with placebo, regorafenib produced a benefit of 1.4 months, but also grade 3 toxicity (hand–foot syndrome, fatigue, hypertension, diarrhea, and rash) in more than 5 %. With conventional chemotherapy, nevertheless, advances have been limited. Thus, Gem–Cape has emerged as an exploratory treatment due to the synergy of these antimetabolites [13].

In vitro studies in CRC have demonstrated the synergy of gemcitabine with 5-FU [14], and phase I and phase II trials have evaluated doses, efficacy, and toxicity of this combination in patients with refractory tumors, especially in those with pancreatic and colorectal cancers [15]. Thus, gemcitabine and fluoropyrimidines have been evaluated in at least eight phase I or phase II studies [13, 15‐21], showing an ORR of 30–38 % in naive patients but of 3.8–10.8 % in refractory cases after the failure of two or more chemotherapy lines during oxaliplatin and irinotecan regimens, with PFS of 2.7–4.2 months, and OS of between 8.9 and 11.3 months. Toxicity in these studies was manageable [22]. These data suggest that Gem–Cape is very attractive in patients with refractory mCRC, as demonstrated in some preclinical and phase I–II trials [13, 15‐21]. Still, questions as to appropriate dosages and schedules have not been fully resolved. In the present series, most patients used capecitabine in second line; maintenance of activity and synergy with other drugs, including gemcitabine, was sought in third and subsequent lines of treatment. In order to take advantage of this synergy and consolidated activity of fluoropyrimidines in mCRC, we used a combination of Gem–Cape after the disease had progressed to oxaliplatin- and irinotecan-based regimens.

No serious toxicity was detected, and all patients completed treatment, with 13 % requiring cycle delays and 6 % dose reductions. Our series appeared to exhibit less toxicity than Bitossi’s report in 2008, who used continuous infusion of 5-FU with 36.1 % discontinuation or dose reduction rate that increased to 69.4 % in cases of gemcitabine [13]. The same combination was chosen for pancreatic cancer, which was treated with gemcitabine on days 1, 8, and 15 and with capecitabine for 14 days every 3 weeks, yielding grades 3–4 neutropenia in 22 % of the patients [23]. In this series, using gemcitabine on day 1 and weekly capecitabine for every 2-week cycle, the rate of grades 3–4 neutropenia was 0 %. Therefore, Gem–Cape is more manageable and tolerable than a continuous infusion of 5-FU associated with gemcitabine weekly for 3 weeks.

Despite the lower-dose intensity, the ORR achieved was 6.72 %; disease control 44.53 %; PFS 2.87; and OS 6.53 months. It was probably influenced by second line and no monoclonal treatment in a subgroup of patients. These data are comparable to those reported in heavily pretreated mCRC [13, 17, 18]. The ORR and clinical benefit were relevant because they are seemed to be the best predictive factors for survival (OS and PFS) in multivariate analysis. Bitossi et al. [13] published an ORR of 10.8 % in 37 patients, Fillos et al. [17] reported 3.8 % in 26 patients, and Qiu 0 % in 12 patients [18]. In 2009, Merl et al. [22] published a review of refractory mCRC patients with a PFS of 2.7–4.2 months. Thus, based on the historical data, this regimen appears to provide a clinical advantage over combinations using a gemcitabine dose intensity of 1,000 mg/m² and capecitabine dose intensity of 2,000 mg/m², 7 days every 2 weeks; this combination has been shown to have a similar ORR to that of others reported schemes, as shown in Table 4.

These results support the conclusion that under specific circumstances, including response to previous treatment lines; less aggressive tumor behavior; ECOG PS ≤2; and good liver, kidney, and bone marrow function, a new chemotherapy regimen, such as the one used here, might be useful in heavily pretreated mCRC.

Furthermore, achieving clinical benefit or response had an impact on survival (OS and PFS) and was an independent predictive factor for these survival outcomes, as demonstrated by univariate and multivariate analyses. These results lead us to believe that the benefit obtained with this chemotherapy alternative remains stable. This series revealed a strong tendency toward higher survival rates and greater clinical benefit among patients who had not received biological agents in previous regimens, supporting the rebound effect paradigm or a subgroup with a worse prognosis. The first concept was demonstrated after the suspension of monoclonal antibodies use, as well as the favorable outcomes achieved when these treatments were administered and maintained [24].

The major limitations of this study included the unicentric origins of the data, many years of data collection, the retrospective nature of the analysis, and the lack of a control group. As shown in Fig. 3, despite the long period of time, patients are distributed among the 10 years and following clinical guidelines, the state of the K-ras gene is known in most since 2008.

In summary, Gem–Cape seems to be active, possessing manageable toxicity and the capacity to accommodate heavily pretreated patients with mCRC who may not be eligible to participate in clinical trials. Nevertheless, further studies will improve our understanding of better chemotherapeutic approaches for “real-life” clinical practice.