Perioperative therapy to control hepatic micrometastases in pancreatic ductal adenocarcinoma: an appraisal of the TOSPAC-02 study

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis across all disease stages and is projected to become the second leading cause of cancer-related deaths by 2030 (1). Although a modest improvement in survival has been observed with enhanced surgical care and the introduction of modern chemotherapy regimens, even patients who present with localized disease typically succumb to distant metastases within 2–5 years (2-10). This has been attributed to the early microscopic spread of cancer to the liver, lungs, and peritoneum. In the absence of novel therapies that significantly improve systemic control, efforts to reduce recurrence rates have focused on the use of neoadjuvant therapy (NAT) and organ-directed therapies such as portal vein infusion (PVI) (7,10). The rationale for early post-operative liver-directed chemotherapy is theoretically and empirically sound. The liver is the most common site of recurrence, and hepatic metastases are associated with particularly worse outcomes (6,8,9,11,12). Furthermore, recurrence-free survival (RFS) has been validated as a surrogate for overall survival (OS) for PDAC in the adjuvant setting (13). Therefore, interventions that prevent or delay hepatic recurrence may improve OS in patients who have undergone curative resection.

To this end, the recently published TOSPAC-2 trial investigated the use of 5-fluorouracil (5-FU)-based PVI and adjuvant S-1, a combination of tegafur, gimeracil, and oteracil, in a cohort of Japanese patients with resected PDAC (14). TOSPAC-02 builds on previous work by the group, which initially described a 2-week post-operative course of 5-FU-based PVI (PI2W) (14,15). A more intense regimen of 5-FU and heparin PVI plus systemic mitomycin C and cisplatin for 4 weeks (PI4W) was subsequently developed and tested (14). Although a study demonstrated that patients selected for PI4W went on to experience improved outcomes, these results were subject to confounding by indication and selection bias due to their observational, retrospective nature (15). Subsequently, the group initiated prospective studies and published the TOSPAC-01 trial, which established the feasibility of the PI4W strategy followed by administration of the adjuvant chemotherapy regimen of choice at the time, which was Gemcitabine monotherapy (16). TOSPAC-02 was a phase 2, single-arm trial that prospectively enrolled 64 patients with resected PDAC. Of this group, 50 patients ultimately received a portal vein catheter for PI4W followed by adjuvant S-1 (which is the current standard of care in Japan) (14,17,18). PI4W was completed by 47 patients and adjuvant S-1 was initiated in 44 patients, of whom 30 completed it. In the end, there were 29 patients (58% of the eligible cohort) who completed the full PI4W and S-1 regimen (14). The authors report that these data were comparable to previously published completion rates of adjuvant S-1, ranging from 60–70% (17,19,20). The rate of clinically significant toxicity was also considered to be in-line with prior expectations. The investigators thus demonstrate the successful technical implementation of this strategy and provide data on treatment adherence, safety, and survival. They conclude that comparative efficacy trials (CETs) may now be considered to investigate the possibility of a survival benefit associated with this approach.

In this context, the survival data reported for this cohort are promising, with median RFS and OS of 18.9 and 63.9 months respectively, as well as a long-term survival (LTS; >5-year OS) rate of 51.2%. However, the authors correctly emphasize that the role of PI4W has yet to be established and that major questions must be clarified by future CETs. Although the stated aim of the study was to evaluate the efficacy of the combined regimen versus adjuvant S-1 alone, TOSPAC-02 cannot demonstrate this in the absence of a control arm. While encouraging, the survival data observed in the study cohort should be interpreted with caution due to the highly selected patient population, small sample size, and relatively high proportion of censored patients noted after the 36-month timepoint (reducing the precision and reliability of survival data after this point). These factors may have contributed to the relatively high OS estimate, and these results cannot be benchmarked definitively against historical data from older studies (21,22). For example, adjuvant Gemcitabine in resected PDAC was associated with a median OS of 14.3 months in PREOPANC, 25.5 months in JASPAC-01, 22.8 months in CONKO-01, and 35.0 months in the trial by the Canadian Cancer Trials and Unicancer-GI–PRODIGE Groups (17,23-25). These variations demonstrate the limitations of cross trial comparisons of OS, RFS, and recurrence patterns due to differences in patient selection and post-protocol/recurrence therapies (26). Although the authors correctly highlight that their cohort achieved a similar or even improved OS and RFS versus the S-1 arm of JASPAC-01 despite having a higher prevalence of poor prognostic factors, such as elevated carbohydrate antigen 19-9 (CA19-9) and nodal metastases, clinicopathologic factors are not sufficiently reliable indicators of disease biology in PDAC (2,3,14,17). Thus, encouraging single-arm outcomes cannot be taken as evidence for the efficacy of PI4W + S-1 versus S-1 alone.

Further nuance in interpreting the survival data from TOSPAC-02 arises when considering the recurrence patterns observed in the study cohort. Despite the implementation of PI4W, the liver remained the most common site of recurrence (24%), including early recurrence (ER; 55.6%), and similar data were observed in TOSPAC-01 (26.4% and 57.1%). These rates are consistent with prior studies of patients not receiving PVI, in which the liver is the most common site of recurrence, accounting for ~20% of cases (though this figure has been reported in many studies and varies) (8,9,11,12,14,16,17,27). Notably, TOSPAC-2 does not report liver metastasis-free survival, an endpoint that would more directly assess the effect of the liver-directed PI4W component. The authors performed logistic regression and identified completion of both PI4W and adjuvant therapy as a strong negative predictor of ER in both TOSPAC-01 and TOSPAC-02. However, the effects of both PVI and systemic therapy are impounded together in this variable. PI4W, the investigational therapy with a liver-directed component, was completed by >90% of patients in both studies (14,16). On the other hand, systemic therapy was completed by considerably fewer patients in each cohort (~60%). Thus, the patients who did not complete PI4W + adjuvant therapy and had greater odds of ER primarily experienced suboptimal systemic therapy rather than incomplete liver-directed treatment. Since adjuvant chemotherapy has been shown to reduce extra-pancreatic (including hepatic) recurrence, (6,17,24,25), this result could reflect differences in total treatment density, the systemic component of therapy (mitomycin C, cisplatin, and S-1), or other confounding. Although the data in this study are promising, the absence of a control group that received systemic therapy but not PVI and the fact that the liver remained the commonest site of recurrence limit the strength of the conclusions that can be drawn.

The need for randomized evidence from a CET to support the clinical role of PI4W is further underscored by the authors’ discussion of the current standard of care in Japan, as established by JASPAC-01. That trial was designed as a non-inferiority study because S-1 is considered to be more tolerable than gemcitabine in the Japanese population (16,17). Since TOSPAC-01 had already demonstrated the technical feasibility of PI4W followed by adjuvant gemcitabine, it is reasonable to question whether a prospective single-arm study was necessary to establish feasibility with the less toxic S-1, rather than proceeding directly to a CET. The data on adjuvant S-1 dose delivery are also noteworthy. Although rates of gemcitabine completion, with or without dose reduction, in TOSPAC-01 were similar to those observed in JASPAC-01 (approximately 60%), S-1 completion in TOSPAC-02 was lower and required more aggressive dose reductions, despite S-1 being considered better tolerated (17). Consistent with this, the mean and median relative dose intensities (RDIs) of S-1 in TOSPAC-02 were 76% and 86% respectively, compared with 89% and 98% in JASPAC-01 (17). The authors rightfully acknowledge that maximizing delivery of systemic therapy with proven survival benefits is paramount in PDAC (1,6,7,10,28). In fact, much of the enthusiasm for the developing neoadjuvant paradigm in pancreatic cancer is driven by the premise that higher systemic treatment density can be achieved before, rather than after, pancreatectomy (5,10). Although the authors attribute the reduced RDI of S-1 to the older age of the study population and a conservative approach to toxicity management, it is important to note that 94% of the patients enrolled in TOSPAC-02 were required to tolerate PI4W in addition to surgery. This regimen includes the non-trivial toxicities of systemic mitomycin C and platinum-based chemotherapy in addition to PVI. It is therefore plausible that toxicity related to PI4W, the investigational intervention, limited patients’ ability to tolerate the total planned course of S-1 regimen, the therapy with proven efficacy. Ultimately, the balance between the potential benefits of PI4W, incorporating both liver-directed and systemic components, and the potential harms of reduced dose intensity of standard adjuvant chemotherapy can only be fairly assessed in a CET.

In summary, the TOSPAC-02 trial demonstrates the technical feasibility of integrating PI4W into evidence-based post-operative management for resected PDAC in Japan and confirms that PVI can be delivered safely without an unacceptable increase in treatment-related adverse events. Although the reported outcomes are encouraging, a randomized controlled trial is necessary to convincingly demonstrate that this PVI strategy can significantly delay or prevent hepatic recurrence and translate into a true survival benefit.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0024/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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