Neoadjuvant FOLFIRINOX vs. Surgery in Resectable Pancreatic Head Cancer: NORPACT-1 Trial Insights

Abstract

Background: The standard treatment for resectable pancreatic ductal adenocarcinoma (PDAC) typically involves upfront surgery followed by adjuvant chemotherapy. The NORPACT-1 trial evaluates whether neoadjuvant chemotherapy with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) offers a survival advantage over the standard approach of upfront surgery.

Methods: NORPACT-1 was a multicenter, randomized phase 2 trial conducted across 12 hospitals in Denmark, Finland, Norway, and Sweden. Patients with resectable pancreatic head tumors suspected to be PDAC were randomly assigned to receive either neoadjuvant FOLFIRINOX followed by surgery and adjuvant chemotherapy or upfront surgery followed by adjuvant chemotherapy. The primary endpoint was overall survival (OS) at 18 months. Secondary endpoints included median OS, resection rates, and safety profiles.

Findings: Out of 140 patients enrolled, 77 were assigned to the neoadjuvant FOLFIRINOX group and 63 to the upfront surgery group. The 18-month OS was 60% in the neoadjuvant FOLFIRINOX group versus 73% in the upfront surgery group (p=0.032). Median OS was 25.1 months in the neoadjuvant group versus 38.5 months in the upfront surgery group (HR 1.52, p=0.050). Adverse events were similar between groups, with a higher incidence of grade 3 or worse adverse events in the neoadjuvant FOLFIRINOX group.

Interpretation: The NORPACT-1 trial did not demonstrate a significant survival benefit for neoadjuvant FOLFIRINOX compared with upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. The findings suggest that while neoadjuvant therapy is feasible, further studies with biomarker-driven approaches are needed to refine treatment strategies.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies to treat, with a high mortality rate and limited survival benefits despite advances in surgical techniques and chemotherapy. The standard management of resectable PDAC typically involves upfront surgical resection followed by adjuvant chemotherapy. However, this approach does not uniformly lead to optimal outcomes, prompting exploration of alternative treatment strategies.

Neoadjuvant chemotherapy, administered before surgical resection, has emerged as a potential strategy to enhance treatment efficacy. The rationale behind neoadjuvant therapy includes the opportunity to address micrometastatic disease earlier, potentially making the tumor more amenable to surgery and improving overall survival rates. The FOLFIRINOX regimen, which combines fluorouracil, leucovorin, irinotecan, and oxaliplatin, has been shown to improve overall survival compared to other chemotherapy regimens in the adjuvant setting. This has led to interest in evaluating its efficacy as a neoadjuvant treatment for resectable PDAC.

The NORPACT-1 trial sought to compare the outcomes of neoadjuvant FOLFIRINOX followed by surgery with the traditional approach of upfront surgery followed by adjuvant chemotherapy. This multicenter, randomized phase 2 trial was designed to assess whether neoadjuvant FOLFIRINOX could offer a survival advantage over upfront surgery, taking into account factors such as overall survival, resection rates, and safety profiles.

Literature Review

Current Standards in Pancreatic Cancer Treatment

The standard treatment for resectable PDAC typically involves surgical resection followed by adjuvant chemotherapy. The role of surgery is central to treatment, as it offers the best chance for long-term survival. However, even with resection, the prognosis remains poor due to the high likelihood of recurrence and metastasis. Adjuvant chemotherapy, often with regimens like gemcitabine or gemcitabine-based combinations, aims to address residual disease and improve survival outcomes.

Neoadjuvant Chemotherapy: Rationale and Evidence

Neoadjuvant chemotherapy has gained attention as a strategy to improve outcomes in resectable PDAC. The concept involves administering chemotherapy before surgical resection to reduce tumor size, address micrometastatic disease, and potentially increase the likelihood of complete surgical resection. This approach also allows for the evaluation of tumor responsiveness to chemotherapy, which can be valuable for planning subsequent treatment.

Several studies have evaluated the efficacy of neoadjuvant chemotherapy in PDAC. A pivotal study by Conroy et al. demonstrated that the FOLFIRINOX regimen, when used as first-line treatment in metastatic pancreatic cancer, significantly improved overall survival compared to gemcitabine-based regimens. This success in the metastatic setting prompted investigations into its role as a neoadjuvant therapy.

Clinical Trials and Findings

The efficacy of neoadjuvant FOLFIRINOX has been explored in various trials. For instance, the PRODIGE 24 trial, which assessed neoadjuvant FOLFIRINOX followed by surgery, reported promising results with improved resection rates and survival outcomes compared to historical controls. Similarly, the PREOPANC trial, which investigated neoadjuvant chemotherapy including FOLFIRINOX, showed potential benefits in terms of resection rates and progression-free survival.

However, results from trials such as the NEOPANC study and others have highlighted variability in outcomes, including differences in overall survival and treatment-related adverse events. These studies underscore the need for further investigation to determine the optimal use of neoadjuvant therapy in PDAC.

Comparison with Upfront Surgery

Comparing neoadjuvant therapy to upfront surgery involves evaluating several critical factors, including overall survival, resection rates, and treatment-related adverse events. While neoadjuvant therapy may offer advantages in terms of early treatment of micrometastatic disease and improved surgical outcomes, it also presents challenges such as potential delays in surgery and increased risk of treatment-related toxicities.

Studies comparing neoadjuvant and adjuvant approaches have yielded mixed results. Some research indicates that neoadjuvant therapy can lead to improved outcomes, while others suggest that upfront surgery remains a viable option with comparable survival benefits. These findings highlight the complexity of treatment decision-making and the need for personalized approaches based on patient characteristics and disease factors.

Recent Advances and Future Directions

Recent advances in molecular biology and genomics have paved the way for personalized treatment strategies in pancreatic cancer. The identification of biomarkers associated with response to neoadjuvant therapy and the development of targeted therapies offer new avenues for improving outcomes. Future trials will need to incorporate biomarker-driven approaches to optimize treatment sequencing and enhance the effectiveness of neoadjuvant and adjuvant therapies.

The NORPACT-1 trial contributes valuable insights into the ongoing debate regarding the role of neoadjuvant chemotherapy in resectable PDAC. By comparing neoadjuvant FOLFIRINOX with upfront surgery, this study provides a critical assessment of treatment strategies and underscores the need for continued research to refine and optimize pancreatic cancer management.

Methodology

Study Design and Setting

The NORPACT-1 trial is a multicenter, randomized, phase 2 clinical trial designed to evaluate and compare the efficacy and safety of neoadjuvant FOLFIRINOX versus upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC). The study was conducted across 12 hospitals in Denmark, Finland, Norway, and Sweden, providing a diverse and representative sample of the patient population in the Nordic region. The trial aimed to assess whether neoadjuvant chemotherapy could improve overall survival and clinical outcomes compared to the conventional strategy of performing upfront surgery.

Participants

The study enrolled adult patients aged 18 years or older with a WHO performance status of 0 or 1, indicating they were fully active or able to carry out all pre-disease activities. Participants were required to have a radiologically confirmed resectable pancreatic head tumor suspected to be pancreatic adenocarcinoma. Key exclusion criteria included a history of prior chemotherapy or radiation therapy, significant comorbid conditions that could affect treatment or survival, and the presence of other malignancies that might interfere with the study objectives.

Randomization and Treatment Protocol

Randomization was performed using a computerized algorithm to ensure unbiased allocation of participants to treatment groups. The randomization process used a concealed block size of two to six to maintain balance between treatment groups across different centers. The study design included a randomization ratio of 3:2 before October 2018 and 1:1 thereafter, reflecting a modification in the trial’s protocol.

Patients were randomly assigned to either the neoadjuvant FOLFIRINOX group or the upfront surgery group.

• Neoadjuvant FOLFIRINOX Group: Participants received four cycles of neoadjuvant FOLFIRINOX chemotherapy. The regimen comprised oxaliplatin (85 mg/m²), irinotecan (180 mg/m²), leucovorin (400 mg/m²), and fluorouracil (400 mg/m² bolus followed by 2400 mg/m² over 46 hours) on day 1 of each 14-day cycle. After completing the neoadjuvant chemotherapy, patients underwent surgical resection of the tumor, followed by adjuvant chemotherapy.

• Upfront Surgery Group: Participants underwent surgical resection without prior chemotherapy. Following surgery, they received adjuvant chemotherapy. Initially, the adjuvant regimen consisted of gemcitabine plus capecitabine, administered as gemcitabine (1000 mg/m² over 30 minutes on days 1, 8, and 15 of each 28-day cycle) and capecitabine (830 mg/m² twice daily for three weeks with one week of rest per 28-day cycle). A protocol amendment later allowed the use of modified FOLFIRINOX as adjuvant therapy, which included oxaliplatin (85 mg/m²), irinotecan (150 mg/m²), leucovorin (400 mg/m²), and fluorouracil (2400 mg/m² over 46 hours), administered for eight cycles in the neoadjuvant group and 12 cycles in the upfront surgery group.

Endpoints and Analysis

The primary endpoint of the NORPACT-1 trial was overall survival (OS) at 18 months. Secondary endpoints included median OS, progression-free survival (PFS), resection rates, and safety outcomes. OS was defined as the time from randomization to death from any cause, while PFS was defined as the time from randomization to disease progression or death.

The study utilized both intention-to-treat (ITT) and per-protocol analyses. The ITT analysis included all patients who were randomly assigned to treatment groups, regardless of adherence to the treatment protocol. The per-protocol analysis focused on patients who adhered strictly to the assigned treatment regimen. Safety was assessed based on adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE).

Statistical Methods

Data analysis involved descriptive statistics to summarize patient characteristics, treatment adherence, and safety profiles. Kaplan-Meier survival curves were constructed to estimate OS and PFS, and differences between treatment groups were evaluated using the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Statistical significance was set at a p-value of less than 0.05.

Results

Patient Enrollment and Characteristics

A total of 140 patients were enrolled in the NORPACT-1 trial between February 8, 2017, and April 21, 2021. Of these, 77 patients were assigned to the neoadjuvant FOLFIRINOX group and 63 to the upfront surgery group. The baseline characteristics of patients were generally balanced between the two groups, including factors such as age, sex, performance status, and tumor stage.

Treatment Adherence and Resection Rates

In the neoadjuvant FOLFIRINOX group, 61 (79%) of 77 patients completed the planned four cycles of chemotherapy. The resection rate was comparable between groups, with 63 (82%) of 77 patients in the neoadjuvant FOLFIRINOX group and 56 (89%) of 63 patients in the upfront surgery group undergoing surgical resection (p=0.24). This indicates that both treatment strategies were feasible in terms of surgical resection, although a higher proportion of patients in the upfront surgery group underwent surgery.

Survival Outcomes

The 18-month overall survival rate was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group, compared to 73% (95% CI 62-84) in the upfront surgery group (p=0.032). Median overall survival was 25.1 months (95% CI 17.2-34.9) for the neoadjuvant FOLFIRINOX group and 38.5 months (95% CI 27.6-not reached) for the upfront surgery group, yielding a hazard ratio of 1.52 (95% CI 1.00-2.33; p=0.050) in the ITT analysis. The per-protocol analysis showed a median OS of 23.0 months (95% CI 16.2-34.9) for the neoadjuvant FOLFIRINOX group and 34.4 months (95% CI 19.4-not reached) for the upfront surgery group, with a hazard ratio of 1.46 (95% CI 0.99-2.17; p=0.058).

Safety and Adverse Events

Safety profiles for both treatment groups were generally similar. In the neoadjuvant FOLFIRINOX group, 42 (58%) of 73 patients experienced at least one grade 3 or worse adverse event, while 19 (40%) of 47 patients in the upfront surgery group experienced similar events. Neutropenia was the most common grade 3 or worse adverse event, affecting 22% of patients in the neoadjuvant FOLFIRINOX group and 11% in the upfront surgery group. Two deaths occurred in the neoadjuvant FOLFIRINOX group: one sudden death of unknown cause and one death related to COVID-19.

Adjuvant Chemotherapy

Adjuvant chemotherapy was administered to 51 (86%) of 59 patients with resected PDAC in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients in the upfront surgery group (p=0.56). Modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) in the upfront surgery group.

Discussion

The results of the NORPACT-1 trial offer important insights into the treatment of resectable pancreatic ductal adenocarcinoma. Despite the theoretical benefits of neoadjuvant therapy, including early treatment of potential micrometastatic disease and the possibility of shrinking the tumor before surgery, the trial did not show a significant survival advantage for neoadjuvant FOLFIRINOX compared to the traditional upfront surgical approach.

The observed median overall survival rates were slightly higher in the upfront surgery group compared to the neoadjuvant FOLFIRINOX group. This could suggest that the traditional approach of upfront surgery may offer a survival benefit, possibly due to the lack of delay in surgical intervention and the potential benefits of immediate tumor resection.

The safety profiles of both treatment strategies were comparable, indicating that neoadjuvant FOLFIRINOX is a feasible approach with manageable adverse events. However, the higher incidence of neutropenia in the neoadjuvant FOLFIRINOX group highlights the need for careful monitoring and management of side effects associated with this regimen.

Limitations

The study had several limitations that may impact the interpretation of the results. The trial was not blinded, which could introduce bias in the assessment of outcomes and treatment adherence. Additionally, the relatively small sample size and variability in adjuvant chemotherapy regimens limit the generalizability of the findings. The trial’s design also evolved over time, with changes in randomization ratios and adjuvant chemotherapy regimens, which may affect the results.

Future Prospects

Biomarker-Driven Approaches

Future research should focus on identifying biomarkers that can predict patient response to neoadjuvant therapy. By identifying patients who are most likely to benefit from neoadjuvant chemotherapy, clinicians can tailor treatment strategies and improve outcomes. Ongoing research into genetic and molecular markers may help refine treatment protocols and optimize patient selection.

Enhanced Neoadjuvant Regimens

Further studies are needed to explore and refine neoadjuvant chemotherapy regimens. Investigating novel drug combinations, alternative dosing schedules, and integration with other therapeutic modalities could improve treatment outcomes. For instance, the inclusion of targeted therapies or immunotherapy in the neoadjuvant setting may enhance efficacy and reduce resistance. Clinical trials evaluating these advanced regimens could provide valuable insights into optimizing neoadjuvant treatment for pancreatic ductal adenocarcinoma.

Combination Therapies

Exploring combination therapies that integrate neoadjuvant chemotherapy with other modalities, such as radiation therapy or immunotherapy, may offer additional benefits. Combining treatments could potentially address the limitations observed in the NORPACT-1 trial by enhancing the overall therapeutic effect. For example, combining neoadjuvant FOLFIRINOX with radiation therapy might improve local control and survival rates. Similarly, incorporating immunotherapy could help target residual tumor cells and improve immune response.

Long-Term Follow-Up and Data Collection

Extended follow-up of patients enrolled in the NORPACT-1 trial and future studies will be crucial for assessing long-term outcomes. Detailed data collection on survival, quality of life, and disease recurrence will provide a more comprehensive understanding of treatment efficacy and safety. Long-term follow-up can also help identify late-onset adverse effects and assess the durability of treatment responses, informing future treatment strategies and patient management.

Integration of Advanced Technologies

The integration of advanced technologies, such as artificial intelligence and machine learning, could enhance treatment planning and outcome prediction. These technologies can analyze large datasets to identify patterns and predict patient responses to different treatment regimens. By incorporating these advanced tools into clinical practice, personalized treatment approaches for pancreatic ductal adenocarcinoma can be developed, potentially improving patient outcomes.

Conclusion

The NORPACT-1 trial provides important insights into the treatment of resectable pancreatic ductal adenocarcinoma. Despite the theoretical benefits of neoadjuvant FOLFIRINOX, the trial did not demonstrate a significant improvement in overall survival compared to the traditional upfront surgery approach. While neoadjuvant therapy was feasible and well-tolerated, it did not offer a clear survival advantage in this study population.

Implications for Clinical Practice

The findings highlight the need for a balanced approach when considering treatment options for resectable pancreatic ductal adenocarcinoma. While neoadjuvant FOLFIRINOX is a viable option, it may not provide a definitive survival benefit over upfront surgery. Clinicians should carefully weigh the potential benefits and risks of neoadjuvant therapy in individual patients and consider factors such as tumor characteristics, patient health, and treatment goals.

Future Directions

Future research should focus on identifying biomarkers that can guide treatment decisions, refining neoadjuvant regimens, and exploring combination therapies. Long-term follow-up and the integration of advanced technologies will be essential for improving treatment strategies and patient outcomes. By addressing the limitations of current treatment approaches and incorporating innovative strategies, the management of pancreatic ductal adenocarcinoma can continue to evolve, with the goal of improving survival and quality of life for patients.

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