Best Combination Treatments for Stage 4 Pancreatic Cancer (2025)

Pancreatic cancer is among the most aggressive and difficult cancers to treat, particularly in its later stages. The prognosis remains poor, making the development of improved therapies critical. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), a subtype often diagnosed late, which complicates effective treatment. Notably, over 90% of PDAC cases harbor activating mutations in the KRAS gene, a key driver of tumor development and progression.

Pancreatic Cancer Awareness

Pancreatic cancer has a high mortality rate and frequently shows resistance to conventional therapies. Standard treatment options include surgical resection, chemotherapy, and radiation therapy; however, survival rates remain low. Recently, alternative strategies, such as repurposing existing drugs originally developed for non-cancer conditions, have gained attention.

The best conventional combination treatments for stage 4 pancreatic cancer currently involve multi-drug chemotherapy regimens that have demonstrated improved survival compared to older standards. 

Key effective chemotherapy combinations include:

• : A four-drug regimen consisting of liposomal irinotecan, 5-fluorouracil/leucovorin, and oxaliplatin. This combination demonstrated longer overall survival (11.1 months) compared to the two-drug regimen nab-paclitaxel plus gemcitabine (9.2 months) in a large Phase 3 clinical trial for metastatic pancreatic ductal adenocarcinoma1.

• : A combination of 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin. This regimen is a standard of care for metastatic pancreatic cancer and has been shown to extend survival compared to gemcitabine alone236.

• Gemcitabine plus a taxane (e.g., nab-paclitaxel): This combination also improves overall survival compared to gemcitabine alone, though fluoropyrimidine-based combinations like FOLFIRINOX or NALIRIFOX may offer further benefits23.

Additional considerations:

• Targeted therapies and immunotherapy may be options for patients with specific genetic mutations (e.g., BRCA1/2, PALB2) or biomarkers. Trials combining PARP inhibitors with immunotherapy agents like nivolumab or pembrolizumab plus olaparib have shown promising results in select patients5.

• Palliative care and symptom management are important components of treatment to improve quality of life in stage 4 disease37.

Clinical trials are strongly recommended to access emerging therapies and combinations beyond standard chemotherapy (7) e.g. potential role of Fenbendazole and Ivermectin (see below) in Stage 4 Pancreatic Cancer.

NALIRIFOX vs. FOLFIRINOX for Stage 4 Pancreatic Cancer

Efficacy

Recent studies and real-world analyses have compared the effectiveness of NALIRIFOX and FOLFIRINOX as first-line treatments for metastatic (stage 4) pancreatic cancer:

• NALIRIFOX has shown a numerically higher median overall survival (OS) of 11.1 months (95% CI, 10.0–12.1) in some studies.

• FOLFIRINOX has a median OS ranging from 9.1 to 11.7 months (95% CI, 7.8–10.9), depending on the study and patient population.

• Both regimens offer similar efficacy overall, with no statistically significant difference in OS or progression-free survival in pooled analyses.

• Some data suggest NALIRIFOX may have a higher overall response rate, though this is not always statistically significant.

Safety and Side Effects

• NALIRIFOX tends to cause more severe diarrhea but fewer severe hematological (blood-related) side effects, such as low platelet counts.

• FOLFIRINOX is associated with more hematological toxicity but less severe diarrhea.

Summary of Regimens

• NALIRIFOX

  • Median Overall Survival: 11.1 months

  • Key Side Effects: More diarrhea, less hematologic toxicity

  • Notes: May have a higher response rate

• FOLFIRINOX

  • Median Overall Survival: 9.1–11.7 months

  • Key Side Effects: More hematologic toxicity, less diarrhea

  • Notes: Well-established standard

Clinical Considerations

• Both NALIRIFOX and FOLFIRINOX are considered preferred options for patients with stage 4 pancreatic cancer who are fit enough for aggressive chemotherapy.

• The choice between regimens should be individualized, taking into account the patient’s risk factors for gastrointestinal versus hematologic toxicity, other medical conditions, and personal preferences.

• No direct head-to-head randomized clinical trial has definitively established one regimen as superior; most data come from indirect comparisons and real-world studies.

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Potential Role of Fenbendazole and Ivermectin in Stage 4 Pancreatic Cancer

Given the limited success of conventional treatments, alternative therapies have attracted interest. Fenbendazole and ivermectin—antiparasitic drugs widely used in veterinary medicine—are being explored for their potential anti-cancer properties.

• Several peer-reviewed studies and case reports suggest these agents may exert multiple anti-cancer mechanisms.
• Using SEER 5-year survival statistics as a benchmark (median survival ~3–6 months post-diagnosis) vs multiple cases reporting survival beyond one year with fenbendazole and ivermectin treatment.

Fenbendazole and Ivermectin in the Treatment of Stage 4 Pancreatic Cancer: A Compilation of Case Reports

Patient Characteristics and Treatment Regimens

The cohort included 20 patients (age range 36–78 years; both sexes represented) with advanced PDAC (Pancreatic Ductal AdenoCarcinoma), many with liver, lung, or lymph node metastases. Several had failed multiple lines of chemotherapy prior to initiation of fenbendazole and ivermectin.

Fenbendazole doses ranged from 444 mg to 2000 mg daily; ivermectin doses ranged from 12 mg daily to 1.5 mg/kg/day. Some patients received adjunctive chemotherapy or radiation.

Tumor Marker and Imaging Responses

• CA19-9 reductions: Most patients experienced dramatic declines in CA19-9, with reductions ranging from 43% to >99%. For example, one 77-year-old patient’s CA19-9 dropped from 44,960 to 21 after fenbendazole and mebendazole therapy.
• Tumor shrinkage: Imaging showed significant tumor volume reductions, including a 99.7% shrinkage of a liver metastasis in one patient after 4 months of combined therapy.
• Remission: Several patients achieved no evidence of disease (NED) status or complete radiologic remission after treatment.
• Clinical improvement: Patients reported improved energy, weight gain, symptom relief, and extended survival beyond expected prognoses.

Summary of Case Reports

Abbreviations and Notes:

• PDAC: Pancreatic Ductal AdenoCarcinoma.
• CA19-9: Cancer antigen 19-9, a tumor marker for pancreatic cancer
• CEA: Carcinoembryonic antigen, another tumor marker
• NED: No evidence of disease
• CBD: Cannabidiol oil, used as adjunct in some cases
• FOLFIRINOX: Combination chemotherapy regimen (folinic acid, fluorouracil, irinotecan, oxaliplatin)
• Turbo Cancer: Term used to describe aggressive tumor growth post COVID-19 mRNA vaccination in some reports (hypothetical and unproven).

Summary

The compiled cases demonstrate consistent patterns of:

• Significant tumor marker reductions (CA19-9 and CEA)
• Radiological tumor shrinkage or complete response
• Clinical improvement in symptoms and quality of life
• Responses observed even in chemotherapy-resistant or advanced metastatic disease
• Use of fenbendazole and ivermectin as monotherapy or adjuncts to chemotherapy and radiation

Conclusion

Current best treatments for stage 4 pancreatic cancer involve aggressive multi-agent chemotherapy such as NALIRIFOX or FOLFIRINOX, with regimen choice tailored to patient tolerance and tumor genetics. Both regimens offer similar efficacy, with NALIRIFOX potentially providing a slight survival advantage but higher rates of diarrhea. FOLFIRINOX remains a well-established standard, particularly for patients at risk of gastrointestinal side effects.

Combining chemotherapy with targeted or immunotherapy agents is an evolving and promising approach. Meanwhile, emerging evidence also suggests that repurposed drugs like fenbendazole and ivermectin could offer additional therapeutic options, warranting further clinical investigation.