Our results showed that FOLFIRINOX was the most potentially beneficial regimen in advanced PC, but in terms of long-time benefits, there was no statistical difference compared with nab-paclitaxel + gemcitabine. Interestingly, Kang [17] and Papneja [23] et al. also reported that FOLFIRINOX had no significant benefit versus nab-paclitaxel + gemcitabine in patients with metastatic PC. Furthermore, FOLFIRINOX and nab-paclitaxel + gemcitabine had superior benefits to the other group with regards to survival of patients with advanced PC, consistent with other recent studies that reported similar findings [16, 19, 25].
From an OS perspective, the use of total FOLFIRINOX can benefit patients with metastatic PC, owing to a direct increase in the OS rate of disease control. However, results from our heterogeneity analysis were relatively large, necessitating further validation. In addition, results from subgroup analysis of the heterogeneity indicated that FOLFIRINOX exerted survival benefits irrespective of whether the control group comprised monotherapy or gemcitabine-based combination chemotherapy, consisted with Orlandi [22] and Terashima [27] et al. who found significantly higher survival benefits in the FOLFIRINOX relative to the control group. Similarly, results from a retrospective study on unresectable PC [28], also showed that FOLFIRINOX may have a survival benefit. Conversely, reported contrasting results [26]. We hypothesized that the conclusion of Tahara et al. might be attributed to the small sample size used in their study. Because the control group of this article contained different chemotherapy regimens, from the perspective of the first-line chemotherapy regimen of nab-paclitaxel + gemcitabine as the control group, our results proved that the regimen of FOLFIRINOX has potential survival benefits trend on patients with metastatic PC, consistent with previous studies [5, 24].
FOLFIRINOX had superior OS benefits relative to monotherapy, followed by FOLFIRINOX versus gemcitabine-based combination chemotherapy not included nab-paclitaxel + gemcitabine. In the monotherapy and combination chemotherapy regimen, gemcitabine accounted for the majority of the benefit. Therefore, we attributed this difference in efficacy to the mechanism of drug action. As a deoxycytidine analog of gemcitabine, its cytotoxic activity was based on several activities of DNA synthesis. Functionally, structural differences between the fluorine substituents on the 2'position of the furanose ring of gemcitabine gives gemcitabine the unique cellular pharmacological characteristics, metabolism, and mechanism action with other nucleoside analogs [31]. However, gemcitabine is highly resistant, which appears within a few weeks of chemotherapy [32]. The mechanism may be caused by an alteration of gemcitabine drug metabolism that causes incorporation of cytidine analogs into DNA [33], or it may be related to a reduction of gemcitabine-induced apoptosis [34, 35].
Results from our subgroup analysis of FOLFIRINOX versus nab-paclitaxel + gemcitabine, showed that the overall trend was biased towards the regimen of FOLFIRINOX, however, there was no statistical difference, which may be related to the small sample size. With the expansion of the sample size, the benefit trend of FOLFIRINOX may appear. For the combination chemotherapy of nab-paclitaxel + gemcitabine, its benefits were crucial in clinical treatment. Related studies have shown that the combination of nab-paclitaxel + gemcitabine can increase the drug concentration of gemcitabine in tumor cells, thereby causing cytotoxicity [36]. And this combination medication program was widely used in clinical practice. For the regimen of FOLFIRINOX, given the relatively large toxicity of FOLFIRINOX reported in previous studies and the higher physical requirements of this program [37], the population's clinical application is not extensive and needs careful consideration. Furthermore, PFS had no benefit, possibly due to the small sample size and insufficient follow-up time [21, 22]. This may also be attributed to the difference between indicators setting up in each article and the type of study (whether it is RCT). Despite FOLFIRINOX’s superior benefits compared to the control regimen, further research is needed to evaluate its clinical value.
In the FOLFIRINOX program, previous studies have shown that irinotecan exerts specific clinical activity in patients with advanced PC [38, 39]. Similarly, preclinical studies by Azrak [40], Mans [41], and Mullany [42] et al. have shown that a combination of irinotecan with calcium folinate and fluorouracil produces significant synergistic effect [43]. Interestingly, clinical trials by Ducreux [44] et al. revealed that oxaliplatin produces individual clinical activity against PC only when combined with fluorouracil. Furthermore, a synergistic effect is produced when combined with irinotecan in vitro [45]. Consequently, Ychou [8], Conroy [46] et al. explored the benefits of irinotecan, oxaliplatin, fluorouracil, and calcium leucovorin in patients with advanced PC and found that FOLFIRINOX had encouraging clinical benefits.
Researchers need to consider both the efficacy and toxicity before extensive clinical applications. Therefore, anticancer drugs' AEs are a vital consideration in clinical oncology [47]. AEs associated with FOLFIRINOX were mainly targeted the blood and gastrointestinal systems. We speculated that this might be positively correlated with the mechanism of action of the drug itself. Previous studies have shown that, as a third-generation platinum compound [48], bone marrow suppression is a joint AE of oxaliplatin, and can cause blood system toxicity such as thrombocytopenia. Other studies have shown that the blood system toxicity of oxaliplatin may also be related to the immune-dependent mechanism [49] and the induced spleen enlargement [50]. Regarding the gastrointestinal system, we speculated that AE occurrence might be related to the anatomical location of the tumor.
FOLFIRINOX toxicity is a problem that cannot be ignored. This is because it had clear benefits, but was also accompanied by relatively large toxicities. Consequently, mFOLFIRINOX has been employed as a potential agent for reducing toxicity and achieved significant curative effects. For instance, Kang [51], and Ghorani [52] et al. reported that mFOLFIRINOX generated comparable efficacies to FOLFIRINOX in patients with metastatic PC, and this was accompanied by weak toxicity. They suggested that if clinically necessary, 75% of the standard dose should be used for treatment, and can alleviate the toxicity without affecting the efficacy. Unfortunately, this study did not include more related clinical trials on mFOLFIRINOX. Therefore, more clinical trials are needed to evaluate ways of minimizing FOLFIRINOX toxicity to enhance its use in the clinical treatment of advanced PC.
Limitations:
Our analysis included several retrospective studies, which could have compromised accuracy of our results. In addition, the diverse treatment options in the control group may have generated potential heterogeneity, although we comprehensively and systematically compared efficacy of FOLFIRINOX as the experimental group in patients with advanced PC. Nevertheless, the different medication regimens used indicated that FOLFIRINOX had more apparent benefits affirming our conclusions. However, these conclusions need to be validated using a large number of clinical trials.