Surgery for Pancreatic Cancer with Liver Metastases

(PDAC-LIV Trial)

Overseen By Alexandre Brind'Amour, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Laval University

Must be taking: FOLFIRINOX

Disqualifiers: Advanced disease, >3 liver metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective, pilot study from a single center. Patients will be evaluated and operated on by one of five surgeons with a subspeciality in hepato-biliary and pancreatic surgery. After thorough, standard of care assessment for both pancreatic primary and liver metastases resectability with blood tumor markers (CEA, CA 19-9 and CA-125), triphasic CT-scan and liver magnetic resonance imaging (MRI), patients with resectable pancreatic ductal adenocarcinoma primary and three or less resectable liver metastases will be prospectively included in the study. PET-scan may be added to the investigation depending on CT-scan or MRI results to prove metastatic disease or rule out extrahepatic metastases. Patients will receive a total of 12 cycles of perioperative FOLFIRINOX (FFX), with first reassessment with triphasic CT-scan to monitor tumor response after the first six cycles. Every patient will receive at least 6 cycles of FFX before surgery. The remaining six cycles will be received either preoperatively or postoperatively, depending on patient tolerance and tumor response at reassessment. Patients with liver metastases only visible on MRI will also have liver MRI at reassessment, which is also standard of care. Patients with evidence of tumor response on both imaging using RECIST V.1.1 criteria (stable disease or partial response), and blood tumor markers (≥ 80% decrease and/or normalization of all tumor markers) will then undergo pancreatic resection, either distal pancreatectomy or pancreatoduodenectomy depending on tumor side, with liver metastases excision. Each case will be followed with blood tumor markers and CT-scan every three months for two years, and every four months afterwards or until recurrence, which is standard of care for patients with metastatic PDAC. For patients without evidence of tumor response on imaging, or \< 80% decrease of all tumor markers, the standard palliative systemic treatment will be continued.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the trial involves chemotherapy with FOLFIRINOX, it's important to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the treatment for pancreatic cancer with liver metastases?

Research shows that FOLFIRINOX significantly increases survival in patients with advanced pancreatic cancer, and modifications to this regimen improve safety and tolerability. FOLFOXIRI, similar to FOLFIRINOX, has shown effectiveness in colorectal cancer, suggesting potential benefits in pancreatic cancer treatment. ^{1 2 3 4 5}

Is the treatment involving FOLFIRINOX and related regimens generally safe for humans?

FOLFIRINOX, a treatment for advanced pancreatic cancer, often causes significant side effects, leading to dose reductions. Modified versions of FOLFIRINOX have been developed to improve safety, but high rates of severe side effects still limit its use. ^{2 6 7 8 9}

How is the FOLFIRINOX treatment unique for pancreatic cancer with liver metastases?

FOLFIRINOX is unique because it combines multiple chemotherapy drugs (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) and is used before surgery to shrink tumors, making them easier to remove. This approach has shown promising results in extending survival for patients with pancreatic cancer that has spread to the liver. ^{2 10 11 12 13}

Research Team

Alexandre Brind'Amour, MD, MSc

Principal Investigator

CHU de Québec

Eligibility Criteria

This trial is for patients with pancreatic cancer that has spread to the liver, who have not more than three liver metastases and are deemed operable. They must show a response to FOLFIRINOX chemotherapy as evidenced by imaging and blood tumor markers.

Inclusion Criteria

I had a liver surgery or don't need it due to successful chemotherapy.

I haven't developed new cancer spread after my initial chemo.

I am fit for surgery to remove part of my pancreas.

Exclusion Criteria

My cancer has spread beyond my liver.

I have more than 3 liver metastases.

I cannot receive FFX due to health reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Neoadjuvant Treatment

Participants receive 12 cycles of perioperative FOLFIRINOX, with reassessment after the first 6 cycles

Approximately 24 weeks

Regular visits for treatment and reassessment

Surgery

Pancreatic resection and liver metastases excision for patients with tumor response

1 week

1 visit (in-person)

Follow-up

Participants are monitored with blood tumor markers and CT-scan every three months for two years, and every four months afterwards or until recurrence

3 years

Regular visits every 3-4 months

Treatment Details

Interventions

• FOLFIRINOX
• Pancreatic resection and non-anatomic liver resections

Trial Overview The study tests if surgery to remove both the pancreatic tumor and up to three liver metastases after or during cycles of FOLFIRINOX chemotherapy can be beneficial. Patients will undergo detailed scans and receive up to 12 cycles of chemo before and/or after surgery.

Participant Groups

Group I: Intervention Experimental Treatment 1 Intervention

Patients will undergo surgery for primary pancreatic cancer and liver metastases.

FOLFIRINOX is already approved in European Union, United States for the following indications:

Approved in European Union as FOLFIRINOX for:

• Advanced pancreatic cancer

Approved in United States as FOLFIRINOX for:

• Metastatic pancreatic cancer

Who Is Running the Clinical Trial?

Laval University

Lead Sponsor

Trials

439

Recruited

178,000+

Findings from Research

Modified-FOLFIRINOX (mFOLFIRINOX) significantly improves safety and tolerability for Chinese patients with locally advanced pancreatic cancer (LAPC), with a response rate of 37.1% and common severe side effects including neutropenia and anemia.

Patients with LAPC who received neoadjuvant therapy with mFOLFIRINOX and subsequently underwent surgery had a median overall survival of 27.7 months, which is significantly better than the 8.9 months seen in patients who had upfront surgery without prior chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population. Li, X., Guo, C., Li, Q., et al.[2023]

In a study of 289 patients with advanced pancreatic ductal adenocarcinoma, the FOLFOXIRI chemotherapy regimen showed similar overall survival (11.1 months) compared to the standard FOLFIRINOX regimen (11.6 months), indicating no significant therapeutic advantage for FOLFOXIRI.

FOLFOXIRI was associated with a higher incidence of grade 3/4 digestive adverse events (28.7% vs. 19.5% for FOLFIRINOX), suggesting that while it is feasible, it may lead to more severe side effects without improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study. Vienot, A., Chevalier, H., Bolognini, C., et al.[2020]

In a study of 102 patients with locally advanced and metastatic pancreatic cancer, FOLFIRINOX treatment showed promising efficacy, with median overall survival of 13.1 months for metastatic patients and 23 months for locally advanced patients when using modified doses.

Despite the efficacy of dose-modified FOLFIRINOX, safety concerns were highlighted, as 43% of patients experienced severe hematologic adverse events, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience. Chllamma, MK., Cook, N., Dhani, NC., et al.[2022]

In a pilot study of 14 patients with resectable pancreatic cancer, treatment with 4 cycles of neoadjuvant FOLFIRINOX resulted in varying degrees of tumor regression, with 28.6% of patients showing significant tumor destruction (Evans grade III).

The study highlights the heterogeneity of pancreatic cancer responses to FOLFIRINOX, indicating that while some patients benefit significantly, others do not, suggesting the need for further research on optimal treatment duration and standardized grading for better comparison.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathologic Response to Primary Systemic Therapy With FOLFIRINOX in Patients With Resectable Pancreatic Cancer. Polish, A., Joseph, NE., Marsh, RW.[2020]

In a study of 69 chemotherapy-naïve patients with metastatic pancreatic cancer, the modified FOLFIRINOX regimen resulted in a median overall survival of 11.2 months and a response rate of 37.7%, indicating its efficacy in this patient population.

The modified regimen demonstrated a better safety profile compared to previous studies, with a 47.8% incidence of grade 3 or higher neutropenia and fewer serious adverse events, suggesting it can be administered without prophylactic pegfilgrastim.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. Ozaka, M., Ishii, H., Sato, T., et al.[2019]

In a study of 243 patients with advanced pancreatic adenocarcinoma treated with FOLFIRINOX, the relative dose intensity (RDI) of the treatment agents did not significantly correlate with disease control or objective response, suggesting that dose reductions may not compromise treatment effectiveness.

The median cumulative multi-drug RDI was 80%, and including RDI in predictive models did not enhance the ability to forecast disease control, indicating that oncologists can safely adjust doses without fearing a loss of therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX relative dose intensity and disease control in advanced pancreatic adenocarcinoma. Vary, A., Lebellec, L., Di Fiore, F., et al.[2022]

In a multicenter phase II study involving 31 patients with locally advanced pancreatic cancer (LAPC) and 44 with metastatic pancreatic cancer (MPC), modified FOLFIRINOX showed comparable efficacy to full-dose FOLFIRINOX in MPC, with a response rate of 35.1% and a median overall survival of 10.2 months.

The study found that modified FOLFIRINOX significantly reduced adverse events such as neutropenia, vomiting, and fatigue, while demonstrating notable efficacy in LAPC with a median progression-free survival of 17.8 months and overall survival of 26.6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Stein, SM., James, ES., Deng, Y., et al.[2022]

In a study of 71 patients with advanced pancreatic cancer who progressed after initial treatment with modified FOLFIRINOX, second-line chemotherapy resulted in a 7.1% partial response rate and a 27.1% disease stabilization rate.

The median overall survival for these patients was 6.2 months, with CA19.9 levels above the normal limit indicating worse survival outcomes, suggesting that certain prognostic factors can help identify patients who may benefit more from salvage chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line therapy for advanced pancreatic cancer: evaluation of prognostic factors and review of current literature. Caparello, C., Vivaldi, C., Fornaro, L., et al.[2022]

In a study involving 65 Chinese patients with metastatic pancreatic cancer, the modified FOLFIRINOX regimen demonstrated a 32.3% objective response rate and a 73.8% disease control rate, indicating its efficacy as a first-line treatment.

The modified regimen was well-tolerated, with major grade 3 or 4 adverse events occurring in only a small percentage of patients (12.3% neutropenia and 6.2% diarrhea), and no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of modified FOLFIRINOX as first-line chemotherapy for Chinese patients with metastatic pancreatic cancer. Wang, ZQ., Zhang, F., Deng, T., et al.[2022]

A patient with metastatic pancreatic adenocarcinoma underwent neoadjuvant FOLFIRINOX chemotherapy followed by a combined surgical resection of the pancreas and liver.

Four years after diagnosis, the patient remains disease-free, suggesting that this aggressive treatment approach may be effective in managing advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Disease-free Survival Following Combination Multi-visceral and Metastatic Resection with Neoadjuvant FOLFIRINOX for Pancreatic Adenocarcinoma: A Case Report. Sodergren, M., Brammer, K., Cunningham, D., et al.[2020]

A patient with pancreatic ductal adenocarcinoma and a solitary liver metastasis showed a favorable response to nine cycles of FOLFIRINOX therapy, which is a combination chemotherapy regimen.

After surgery that included distal pancreatectomy and hepatectomy, the patient remained disease-free for 2 years post-operation and 28 months after the initial diagnosis, suggesting the potential effectiveness of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of metastatic pancreatic adenocarcinoma with prolonged survival after combination of neoadjuvant FOLFIRINOX therapy and synchronous distal pancreatectomy and hepatectomy. Neofytou, K., Giakoustidis, A., Smyth, EC., et al.[2015]

Neoadjuvant FOLFIRINOX treatment in patients with borderline resectable pancreatic cancer (BRPC) resulted in a median overall survival of 22.2 months and a high resection rate of 67.8%, indicating its potential effectiveness in this patient group.

The treatment was associated with manageable adverse events, with the most common being neutropenia, diarrhea, and fatigue, but no deaths were reported due to FOLFIRINOX, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. Janssen, QP., Buettner, S., Suker, M., et al.[2021]

A nomogram was developed to predict 6-month survival in patients with metastatic and locally advanced pancreatic cancer treated with FOLFIRINOX, based on four key prognostic factors: performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio.

The nomogram demonstrated good accuracy in predicting outcomes, with a C index of 0.762 in an independent validation cohort, helping to identify patient subsets with varying prognoses based on the number of poor prognostic features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan. Fornaro, L., Leone, F., Vienot, A., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population. [2023]

2. China pubmed.ncbi.nlm.nih.gov

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study. [2020]

3. England pubmed.ncbi.nlm.nih.gov

FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pathologic Response to Primary Systemic Therapy With FOLFIRINOX in Patients With Resectable Pancreatic Cancer. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. [2019]

6. England pubmed.ncbi.nlm.nih.gov

FOLFIRINOX relative dose intensity and disease control in advanced pancreatic adenocarcinoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Second-line therapy for advanced pancreatic cancer: evaluation of prognostic factors and review of current literature. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

The efficacy and safety of modified FOLFIRINOX as first-line chemotherapy for Chinese patients with metastatic pancreatic cancer. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Long-term Disease-free Survival Following Combination Multi-visceral and Metastatic Resection with Neoadjuvant FOLFIRINOX for Pancreatic Adenocarcinoma: A Case Report. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

A case of metastatic pancreatic adenocarcinoma with prolonged survival after combination of neoadjuvant FOLFIRINOX therapy and synchronous distal pancreatectomy and hepatectomy. [2015]

12. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan. [2020]