HIPEC for Gallbladder Cancer

Overseen By Brian Boone, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: West Virginia University

Must not be taking: Investigational agents

Disqualifiers: Metastatic disease, Hepatitis B/C, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: During procedure

10 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are receiving any other investigational agents or have had prior systemic therapy for gallbladder adenocarcinoma, you would not be eligible to participate.

What data supports the effectiveness of the treatment HIPEC for gallbladder cancer?

Research shows that HIPEC, which involves heating chemotherapy drugs, can make cancer cells more sensitive to treatment by interfering with their ability to repair DNA damage. This approach has shown a significant survival benefit in treating abdominal cancers, including ovarian cancer, suggesting potential effectiveness for gallbladder cancer as well. ^{1 2 3 4 5}

Is HIPEC generally safe for humans?

HIPEC, used for various cancers, can cause side effects mainly due to the chemotherapy drugs involved, but strategies exist to manage these effects. Studies suggest it is safe for patients, though healthcare workers need protection from exposure to the drugs during treatment. ^{6 7 8 9 10}

How is HIPEC treatment different for gallbladder cancer?

HIPEC is unique because it involves directly applying heated chemotherapy into the abdominal cavity during surgery, which may enhance the drug's effectiveness against cancer cells compared to traditional systemic chemotherapy that circulates throughout the body. ^{3 5 7 11 12}

What is the purpose of this trial?

Gallbladder adenocarcinoma is a devastating disease associated with a poor prognosis. Gallbladder and other biliary cancers will be responsible for an estimated 11,980 new cases, and 4,090 deaths in the US during 2020. The 5-year survival for all patients with gallbladder cancer is 18%, however this plummets to 2% for patients with metastatic disease. Patients with gallbladder cancer frequently develop peritoneal recurrence, particularly after intra-operative bile spillage during cholecystectomy for incidentally discovered gallbladder malignancy. Once developed, peritoneal metastases are difficult to treat and result in significant morbidity and mortality. As a result, novel approaches that target peritoneal metastases are needed for this disease. Prophylactic use of heated intraperitoneal chemotherapy (HIPEC) has been explored or is under active investigation for numerous gastrointestinal malignancies, including colon, gastric, and appendiceal cancers. HIPEC has efficacy in gallbladder cancer patients with macroscopic peritoneal disease undergoing cytoreductive surgery (CRS)/HIPEC and has been associated with a survival advantage in a multi-institutional retrospective case series. Incidentally discovered gallbladder cancer is treated with central hepatectomy and portal lymphadenectomy, therefore a prophylactic HIPEC can be easily incorporated into the second operation performed as part of the standard of care. In this early phase clinical trial, the investigators will explore the safety and feasibility of prophylactic HIPEC for gallbladder cancer in patients at high-risk of peritoneal recurrence. The primary endpoint is to assess feasibility of the prophylactic heated intraperitoneal chemotherapy (HIPEC) approach in gallbladder cancer. The primary endpoints include occurrence of intra-operative complications, technical challenges, 90-day postoperative morbidity and mortality, length of stay and readmission, which will be documented and compared with historical controls after follow-up.

Research Team

Brian Boone, MD

Principal Investigator

WVU Cancer Institute

Eligibility Criteria

This trial is for patients with high-risk gallbladder adenocarcinoma who've had bile spillage during surgery or have advanced tumors. They must have certain blood cell counts, normal organ function, no prior systemic therapy for this cancer, and not be pregnant or breastfeeding. Patients should be physically able to undergo additional surgery and agree to the study's terms.

Inclusion Criteria

ALT (SGPT) ≤ 2.5 X institutional upper limit of normal

My organ and bone marrow functions are normal.

Total bilirubin within normal institutional limits

Exclusion Criteria

You are currently taking any other experimental medications.

I have a blockage in my bile ducts thought to be caused by cancer, possibly needing a stent.

My cancer has spread to other parts of my body.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo prophylactic Heated Intra-peritoneal Chemotherapy (HIPEC) with mitomycin C

During procedure

1 visit (in-person)

Postoperative Monitoring

Participants are monitored for intraoperative complications, postoperative morbidity and mortality, length of stay, and readmission

90 days

Follow-up

Participants are monitored for peritoneal metastases and disease-free survival

Up to 5 years

Treatment Details

Interventions

• HIPEC

Trial Overview The trial tests the safety of HIPEC (heated chemotherapy delivered directly into the abdomen) as a preventive treatment against peritoneal recurrence in gallbladder cancer after surgery. It measures complications, recovery time, and any postoperative issues compared to past data.

Participant Groups

Group I: HIPEC Experimental Treatment 1 Intervention

Prophylactic Heated Intra-peritoneal Chemotherapy (HIPEC) 30 mg of mitomycin C (MMC) over the first 60 minutes followed by 10 mg over an additional 30 minutes. Perfusate will be heated to obtain a tissue temperature of 42°.

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

Approved in United States as HIPEC for:

• Peritoneal metastases from ovarian, stomach, colorectal, and appendiceal cancers
• Gallbladder adenocarcinoma with high risk of peritoneal recurrence

Approved in European Union as HIPEC for:

• Peritoneal metastases from ovarian, stomach, colorectal, and appendiceal cancers
• Malignant peritoneal mesothelioma

Approved in Canada as HIPEC for:

• Peritoneal metastases from ovarian, stomach, colorectal, and appendiceal cancers

Who Is Running the Clinical Trial?

West Virginia University

Lead Sponsor

Trials

192

Recruited

64,700+

Findings from Research

Hyperthermic intraperitoneal chemotherapy (HIPEC) enhances the effectiveness of chemotherapy in heat-sensitive ovarian cancer cells by disrupting DNA damage repair mechanisms, as shown by the identification of 349 differentially expressed proteins in a study using mass spectrometry on the A2780 cell line.

The protein RBL1 was significantly upregulated in cells treated with both hyperthermia and chemotherapy, suggesting it may play a crucial role in the enhanced sensitivity of these cells to chemotherapeutic drugs, making it a potential target for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair. Ni, LP., Sun, HT., Wang, P., et al.[2022]

A systematic review and meta-analysis of six studies involving 674 patients indicated that hyperthermic intraperitoneal chemotherapy (HIPEC) can improve overall survival (OS) and disease-free survival (DFS) in patients with advanced epithelial ovarian cancer after neoadjuvant chemotherapy, particularly when using higher temperatures (≥42 °C) for shorter durations (≤60 min).

The addition of HIPEC did not lead to an increase in high-grade complications, suggesting it is a safe treatment option, especially when cisplatin is used as the chemotherapy agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Hyperthermic Intraperitoneal Chemotherapy Associated with Cytoreductive Surgery in the Treatment of Advanced Ovarian Cancer: Systematic Review and Meta-Analysis. Llueca, M., Ibañez, MV., Climent, MT., et al.[2023]

In a study using a rat model, hyperthermic intra-peritoneal perfusion of cisplatin did not enhance drug uptake in small abdominal tumors compared to normothermic perfusion or traditional bolus injection, suggesting that mild hyperthermia may not provide additional benefits in this context.

Both hyperthermic and normothermic perfusion achieved similar plasma drug levels, indicating that the method of drug delivery may be more important than the temperature used during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of cisplatin after intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC). Zeamari, S., Floot, B., van der Vange, N., et al.[2013]

In patients with advanced epithelial ovarian cancer who underwent interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT), the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) significantly improved both progression-free survival (PFS) by 4.68 months and overall survival (OS) by 11.81 months compared to surgery alone, based on a review of 14 studies involving 1813 women.

However, in primary debulking surgery (PDS) and recurrent ovarian cancer (ROC), HIPEC did not show significant benefits in PFS or OS, and there was a slight increase in the risk of severe post-operative complications with the combined approach, indicating that while HIPEC can be beneficial in certain contexts, its role in other settings remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): New Approaches and Controversies on the Treatment of Advanced Epithelial Ovarian Cancer-Systematic Review and Meta-Analysis. Della Corte, L., Conte, C., Palumbo, M., et al.[2023]

In a study evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer, combining hyperthermia with taxane chemotherapy did not enhance the cytotoxic effects on ovarian cancer cells, as the median lethal dose (LD50) remained consistent across different temperatures and exposure durations.

The findings suggest that, at the concentrations and durations tested, hyperthermia does not provide additional benefits in killing ovarian cancer cells when used with taxanes, indicating that further research may be needed to explore other combinations or methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cytotoxic effect of combined hyperthermia and taxane chemotherapy on ovarian cancer cells: results of an in vitro study. Muller, M., Chérel, M., Dupré, PF., et al.[2018]

Hyperthermic intraperitoneal chemotherapy (HIPEC) for gastrointestinal cancers can lead to a range of significant side effects, including digestive fistulas, neutropenia, and renal impairment, as identified in a review of 79 articles.

Effective management strategies for these adverse events include forming a multidisciplinary team, considering alternative chemotherapy drugs, and utilizing careful preoperative assessments, which can help minimize the frequency and severity of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side-effects of hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal cancers. Hu, J., Wang, Z., Wang, X., et al.[2023]

In a study of 78 patients with stage III gallbladder cancer, hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) combined with radical surgery and capecitabine significantly improved median survival time to 19.2 months compared to 15.3 months for the control group receiving only surgery and capecitabine.

The HIPEC treatment did not increase surgery-related complications, indicating it is a safe option for enhancing survival in patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Hyperthermic Intraperitoneal Perfusion Chemotherapy Combined with Radical Surgery and Capecitabine on Stage III Gallbladder Cancer. Liu, S., Zhong, Z., Yi, W., et al.[2021]

Healthcare workers involved in hyperthermic intraperitoneal chemotherapy (HIPEC) are at risk of exposure to dangerous cytotoxic drugs, with evidence of environmental contamination in operating rooms and potential inhalation of harmful compounds.

There is a significant lack of standardized protective measures and biological monitoring for caregivers, highlighting the need for improved sampling methods and new biological indicators to effectively track and mitigate exposure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is hyperthermic intraperitoneal chemotherapy (HIPEC) safe for healthcare workers? Rodier, S., Saint-Lorant, G., Guilloit, JM., et al.[2018]

In a study of 1,200 patients with peritoneal carcinomatosis treated with hyperthermic intraperitoneal chemotherapy (HIPEC), the procedure demonstrated a high objective remission rate of 95.6% for malignant ascites, indicating its effectiveness in this patient population.

The safety profile of HIPEC was favorable, with low rates of serious complications (e.g., 0.6% hemorrhage and 0.5% anastomotic leakage), and most adverse events were transient, suggesting that HIPEC can be a safe treatment option for patients with peritoneal carcinomatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study. Ba, M., Cui, S., Long, H., et al.[2022]

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) is safe for high-risk patients with a peritoneal carcinomatosis index (PCI) of 0, showing no perioperative mortalities and a complication rate of 43% among 37 patients studied over a median follow-up of 5.2 years.

The treatment is associated with favorable long-term outcomes, with a 5-year recurrence-free survival (RFS) of 77% and overall survival (OS) of 100%, indicating its potential effectiveness in preventing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for patients at High-Risk of Peritoneal Metastases. Morris, MC., Dhar, VK., Stevenson, MA., et al.[2020]

A review of current literature indicates that hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery significantly improves overall survival in ovarian cancer patients, with no significant increase in severe complications compared to surgery alone.

There is emerging evidence supporting the efficacy of HIPEC in treating uterine sarcoma with peritoneal sarcomatosis, suggesting it could be a promising new treatment strategy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy (HIPEC) for gynecological cancer. Tsuyoshi, H., Inoue, D., Kurokawa, T., et al.[2021]

In a study involving 184 patients with advanced primary ovarian cancer, the use of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery resulted in lower consumption of non-opioid analgesics and reduced maximum pain intensity on the first postoperative day.

The findings suggest that HIPEC does not increase postoperative pain, indicating it can be safely integrated into treatment without exacerbating pain management challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of warm saline irrigation, hyperthermic intraperitoneal chemotherapy on postoperative pain in primary ovarian cancer from the KOV-HIPEC-01 randomized trial. Kim, JH., Park, KN., Park, EY., et al.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of Hyperthermic Intraperitoneal Chemotherapy Associated with Cytoreductive Surgery in the Treatment of Advanced Ovarian Cancer: Systematic Review and Meta-Analysis. [2023]

3. Greece pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of cisplatin after intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC). [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): New Approaches and Controversies on the Treatment of Advanced Epithelial Ovarian Cancer-Systematic Review and Meta-Analysis. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The cytotoxic effect of combined hyperthermia and taxane chemotherapy on ovarian cancer cells: results of an in vitro study. [2018]

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

Side-effects of hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal cancers. [2023]

7. Egypt pubmed.ncbi.nlm.nih.gov

Effect of Hyperthermic Intraperitoneal Perfusion Chemotherapy Combined with Radical Surgery and Capecitabine on Stage III Gallbladder Cancer. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Is hyperthermic intraperitoneal chemotherapy (HIPEC) safe for healthcare workers? [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for patients at High-Risk of Peritoneal Metastases. [2020]

11. Australia pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy (HIPEC) for gynecological cancer. [2021]

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

Impact of warm saline irrigation, hyperthermic intraperitoneal chemotherapy on postoperative pain in primary ovarian cancer from the KOV-HIPEC-01 randomized trial. [2023]