Stepped-wedge clinical trials in pancreatic cancer: a step backward in improving overall survival or a leap forward to enhance quality of care?

Pancreatic cancer represents a pressing problem worldwide. With a growing epidemiological burden, it is expected to become the second leading cause of cancer-related death in developed countries by 2030 (1). In the past two decades, significant advances in the management of pancreatic cancer have been achieved. Data from randomized clinical trials (RCTs) have shown a consistent benefit in overall survival with perioperative chemotherapy for patients with resectable disease (2) and multi-agent chemotherapy for patients with advanced disease (3). However, the results of these RCTs have translated into little survival improvement at the population level (4). Multiple studies have described poor outcomes outside clinical trials, especially in the metastatic setting, where overall survival is reported to be less than 3 months (5,6).

The failure to improve outcomes in this scenario might be related to inconsistent adoption of evidence-based recommendations by institutions delivering health care to patients with pancreatic cancer (7,8). Recent data suggest significant variability in compliance with multidisciplinary management in pancreatic cancer (8), with no to little improvement over time (9). Therefore, additional efforts to foster the widespread adoption of the current clinical recommendations at the point-of-care level could lead to better survival results at the population level.

After consulting pertinent stakeholders, one possible strategy is to implement such recommendations as new nationwide health policy interventions in the hope of increasing their adoption. Then studies can be designed and carried out to evaluate differences in outcomes before and after this policy is enforced. However, the simple comparison carries the risk of multiple biases, and new study methodologies can mitigate some of the drawbacks of non-randomized investigations performed at the population level (10). One approach increasingly used in this setting is the stepped-wedge cluster design.

In a stepped-wedge cluster randomized trial (SW-CRT), patient clusters are sequentially transitioned from control to intervention in a randomized fashion until all clusters are exposed to intervention (Figure 1A) (11). In opposition, in a conventional parallel cluster randomized trial (PCRT), intervention is delivered only to a fraction of the population (Figure 1B). Some SW-CRTs include a transition period in which the intervention is implemented. However, data on outcomes in this period are discarded since the new policy has not been fully implemented within each cluster (Figure 1C) (10). This study design is vulnerable to bias arising from changes in clinical practice over time that are not related to the intervention—called secular trends (11). For this reason, all SW-CRTs must be adjusted for differences in outcomes using mathematical models that deal with secular trends. Additional bias, including identification and recruitment bias, within-cluster contamination, and cluster imbalance can also occur. Therefore, proper justification for carrying out an SW-CRT should always be provided. This study design can be considered reasonable when: (I) someone wishes to carry out a randomized analysis that would be unfeasible otherwise; (II) someone wants to facilitate cluster recruitment; (III) someone wants to improve the logistical feasibility of the study; (IV) increased study power is needed (11).

Figure 1 Schematic representation of cluster randomized trials [adapted from reference (10)]. Stepped-wedge cluster design (A), parallel cluster design (B), and stepped-wedge cluster design with a transition period (C).

This year at JAMA Surgery, Mackay et al. published the results of a SW-CRT (PACAP-1 trial) that assessed the impact of multiple policy interventions in the 1-year survival of patients with pancreatic cancer treated in 17 cancer networks throughout the Netherlands, namely: (I) optimal use chemotherapy in the resectable (target: ≥70%), locally advanced (target ≥60%), and metastatic (target ≥40%) settings; (II) improved adherence to pancreatic enzyme replacement therapy (PERT) and dietician specialist referral; and (III) increased use of metal stents for biliary drainage (12).

With a 25-month total duration, this multicenter study by the Dutch Pancreatic Cancer Group (DPCG) included 5,887 patients between May 2018 and July 2020. It failed to demonstrate increased adoption of neoadjuvant or adjuvant chemotherapy, while the use of palliative chemotherapy in the metastatic setting slightly increased (23.9% vs. 29.6%). There was no significant difference in dietician specialist referral (59.3% vs. 62.9%); however, the authors identified increased use of PERT (34.7% vs. 45.0%) and metal stents (73.3% vs. 82.3%) after the intervention. Despite the improved adherence to some of the best practices, the study failed to show improvement in the study’s primary outcome, with 24% and 23% of patients alive one year after the diagnosis in the control and intervention arms, respectively. Also, subgroup analyses showed similar intervention effects across staging groups. Finally, 10% of the patients filled validated quality of life (QoL) questionnaires and there were no differences in terms of QoL between the two groups.

While the negative results of this trial seem disappointing at first glance, we believe multiple lessons can be learned from the results of this pioneering trial. While overall survival remains the ultimate outcome in oncology (13), future trials in this field can aim at different outcomes, including clinical and financial toxicity indexes. Furthermore, one should refrain from being over-optimistic about the effectiveness of policy interventions. A 10% improvement in 1-year overall survival seems very unlikely with baseline survival rates as low as 20–25%, especially in a study with a 25-month duration. This is especially true since not all suggested interventions have been undoubtedly associated with improvements in overall survival. While there is little discussion about the benefits of PERT, nutrition (and physical) rehabilitation, and metal stenting in the management of pancreatic cancer, there is no robust evidence these interventions are associated with improved overall survival. While retrospective data suggest PERT is associated with improved survival (14), prospective randomized trials suffer from small sample sizes, outcome heterogeneity, and controversial findings. Besides, not all patients with pancreatic cancer are expected to benefit from PERT (15). Similarly, while biliary adverse events during neoadjuvant chemotherapy have been associated with inferior survival (16), the superior patency and decreased risk of cholangitis associated with metal stents have not translated into improved post-operative complications or R0 resection rates (17). Last, the 1-year timeline might fail to detect differences in survival in specific subgroups. In the PREOPANC trial conducted by the DPCG, a clear benefit of neoadjuvant therapy could only be found after long-term results were published (18,19), suggesting further follow-up might be needed in some scenarios. Conversely, in the metastatic setting, the median survival reported in pivotal phase 3 studies using polychemotherapy for clinically selected patients has been systematically less than 12 months (3).

Another striking finding of the PACAP-1 trial is the dismal prognosis of patients with pancreatic cancer at the population level. The median overall survival for the whole study population was only 3.8 months. In this study, most patients presented with metastatic disease (58–60%), and a third of these patients did not have histological confirmation of malignancy before death. Moreover, 61% of the patients did not receive any type of anti-cancer therapy. The reasons for such a low treatment rate are still unclear, as most patients with known performance status were in good clinical conditions [65–70% of patients with Eastern Cooperative Oncology Group (ECOG) 0–1]—though the study presents a high percentage of missing data for this variable. Probably, patients who are not submitted to histological confirmation and treatment are the ones with more aggressive diseases or more decompensated comorbidities. For these patients, improved population awareness and screening techniques might help diagnose pancreatic cancer in a timely fashion. Increased awareness about the disease symptoms has been pointed out as one of the research priorities by patients with pancreatic cancer and their caregivers (20). Additionally, while screening for pancreatic cancer is only endorsed in a few groups of high-risk individuals (21,22), improvements in molecular diagnostics may provide means to improve compliance with treatment in the future.

Without further developments in the understanding and targeting of the different molecular mechanisms underpinning the development and progression of pancreatic cancer, we believe increased adherence to chemotherapy will very unlikely improve survival in a significant manner. Even with the emergence of multiple treatment approaches in the past decades, 5-year overall survival rates have improved modestly (5% to 13%) between the 1980s and the present (23,24). Additionally, increased compel to provide chemotherapy might also be associated with worse clinical outcomes. In the PAPAC-1 trial, there was a numerical increase in the number of patients undergoing chemotherapy in the last month of life, which is known to be a marker of poor-quality care (25). Therefore, efforts should be made to improve accrual onto pancreatic cancer clinical trials to improve our understanding of the disease biology and test innovative therapeutical strategies. Interestingly, in the PACAP-1 trial, the was no significant increase in the percentage of patients enrolled into the DPCG RTCs, possibly due to the rather limited study time span.

Despite all the pitfalls, the PACAP-1 is a pioneer study in pancreatic cancer, as the first study to test policy interventional using the SW-CRT as a framework. It showed it is possible to improve the quality of care for patients with pancreatic cancer beyond increased administration of chemotherapy or PERT, or use of metal stents. Despite the increased number of patients given chemotherapy in the last month of life and the metastatic setting, there was a numerical decrease in the number of grades 3/4 complications from chemotherapy. The reasons for this improvement in toxicity remain unclear, as measures such as a higher rate of granulocyte colony-stimulating factor (G-CSF) use can decrease hematological toxicity. However, it might very well be the case that educational measures embedded in the policy interventions decreased the risk of severe toxicity and this might not have been captured by QoL indexes due to the low proportion of patients filling these questionnaires.

We believe this study should not be considered a failure, but a successful example of the potential for policy interventions to improve the quality of care for patients with pancreatic cancer. While improvements in overall survival might involve developments in other aspects of pancreatic cancer care, other outcomes are still valid and improvements in such outcomes should continue to be pursued with the goal of improved quality of care. Future trials in this field should be able to capture detailed data on critical outcomes, including clinical and financial toxicity. The latter should be given utmost attention because of the financial burden of incoming targeted therapy in the management of KRAS-mutant pancreatic cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-472/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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