HIPEC for Peritoneal Cancer

Overseen By Stephanie Canady, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticancer therapy

Disqualifiers: Extra-abdominal metastases, Major surgery, others

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

Compensation: Varies

Number of Visits: 3

Duration: 7-21 days hospitalization post-surgery

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Cytoreductive surgery (CRS) removes tumors in the abdomen. HIPEC is heated chemotherapy that washes the abdomen. CRS and HIPEC may help people with peritoneal carcinomatosis. These are tumors that have spread to the lining of the abdomen from other cancers. Researchers think they can improve results of CRS and HIPEC by choosing the chemotherapy drugs used in HIPEC. Objective: To see if HIPEC after CRS can be improved, by testing different chemotherapy drugs, using a model called the SMART (Sample Microenvironment of Resected Metastatic Tumor) System. Eligibility: Adults ages 18 and older who have peritoneal carcinomatosis that cannot be fully removed safely with surgery. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Computed tomography (CAT) scan Other imaging scans, as needed Electrocardiogram (EKG) Tumor biopsy, if needed Laparoscopy. Small cuts will be made in the abdomen. A tube with a light and a camera will be used to see their organs. Some screening tests will be repeated in the study. Participants will enroll in NIH protocol #13C0176. This allows their tumor samples to be used in future research. Participants will have CRS. As many of their visible tumors will be removed as possible. They will also have HIPEC. Two thin tubes will be put in their abdomen. They will get chemotherapy through one tube. It will be drained out through the other tube. They will be in the hospital for 7-21 days after surgery. Participants will give tumor, blood, and fluid samples for research. They will complete surveys about their health and quality of life. Participants will have follow-up visits over 5 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have received intraperitoneal chemotherapy or other anti-cancer therapy within the last 4 weeks, you may not be eligible to participate.

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

Research indicates that hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies, such as those from ovarian cancer, by applying drugs like cisplatin and oxaliplatin. These studies suggest that HIPEC can be a treatment option for certain cancers, although optimal drug dosages and treatment durations are still being studied. ^{1 2 3 4 5}

Is HIPEC generally safe for humans?

HIPEC can be safe, but it may cause side effects like acute kidney injury, especially when using cisplatin. A study showed that a combination of mitomycin C, 5-fluorouracil, and oxaliplatin was safe in a Phase I trial for patients at high risk of colorectal peritoneal metastasis. ^{3 5 6 7 8}

What makes HIPEC treatment for peritoneal cancer unique?

HIPEC (Heated Intraperitoneal Chemotherapy) is unique because it involves directly applying heated chemotherapy drugs like cisplatin and doxorubicin into the abdominal cavity after surgery, which may enhance drug effectiveness and target cancer cells more directly compared to traditional chemotherapy. ^{3 4 5 9 10}

Research Team

Andrew M Blakely, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with peritoneal carcinomatosis from ovarian, colorectal, appendiceal, or mesothelioma cancers that can't be fully removed by surgery. They must have good physical function and organ health, not received certain treatments recently, agree to use contraception and co-enroll in a tissue collection study.

Inclusion Criteria

Ability and willingness to co-enroll on the tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors.

Because therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 180 days after last study treatment; should a woman suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

My cancer, originating from the appendix, colon, ovary, or peritoneum, has spread within the abdomen.

Exclusion Criteria

I am HIV-positive with an undetectable viral load and on antiretroviral therapy.

I haven't had cancer treatment in the last 4 weeks.

I am allergic to medications that contain platinum.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, imaging, and biopsy

Treatment

Participants undergo cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with randomization to one of two accepted HIPEC treatment regimens

7-21 days hospitalization post-surgery

Inpatient stay for surgery and recovery

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of tumor response and quality of life

5 years

Every 3 months for 2 years, then every 6 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• 5-Fluorouracil
• Cisplatin
• Doxorubicin
• Heated Intraperitonial Chemotherapy
• Mitomycin C
• Oxaliplatin
• Sodium Thiosulfate

Trial Overview The trial is testing the effectiveness of heated chemotherapy (HIPEC) after tumor-removing surgery (CRS). Different chemo drugs are used based on a model called SMART System to see if they improve outcomes for patients with tumors spread within the abdomen lining.

Participant Groups

Group I: 4/ HIPEC: Cisplatin, Mitomycin C Randomized treatment assignme Experimental Treatment 4 Interventions

HIPEC with intraperitoneal cisplatin and mitomycin C, in addition to IV sodium thiosulfate, randomly assigned

Group II: 3/ HIPEC: Cisplatin, Doxorubicin Randomized treatment assignme Experimental Treatment 4 Interventions

HIPEC with intraperitoneal cisplatin and doxorubicin, in addition to IV sodium thiosulfate, randomly assigned

Group III: 2/ HIPEC: Mitomycin C Randomized treatment assignment Experimental Treatment 2 Interventions

HIPEC with intraperitoneal mitomycin C, randomly assigned

Group IV: 1/ HIPEC: Oxaliplatin Randomized treatment assignment Experimental Treatment 3 Interventions

HIPEC with intraperitoneal oxaliplatin and IV 5-FU, randomly assigned

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Continuous hyperthermic peritoneal perfusion (CHPP) of carboplatin (CBDCA) was safely administered to patients with small-volume residual ovarian cancer, with no core temperatures exceeding 40 degrees Celsius during treatment.

The study found that peak concentrations of platinum in the perfusate were significantly higher than in plasma, indicating a regional advantage for drug delivery, although dose-limiting hematologic toxicity was observed at higher doses (1200 mg/m2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer. Steller, MA., Egorin, MJ., Trimble, EL., et al.[2014]

In a study of 80 patients undergoing hyperthermic intraperitoneal chemotherapy (HIPC), those treated with oxaliplatin (OX) experienced significant electrolyte disturbances, including lower sodium levels and higher rates of hyponatremia compared to those treated with mitomycin C (MMC).

Despite these electrolyte issues, the overall complication rates and 30-day mortality were similar between the OX and MMC groups, indicating that while OX may cause predictable disturbances, it does not lead to worse outcomes if monitored and managed properly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C. Rueth, NM., Murray, SE., Huddleston, SJ., et al.[2018]

In a study involving 13 women with epithelial ovarian cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatin and paclitaxel resulted in high drug concentrations in the peritoneal tissue while maintaining low levels in the bloodstream, indicating a favorable pharmacokinetic profile.

The treatment was associated with some surgical complications, with four patients experiencing grade 3-4 complications, but overall, HIPEC was deemed feasible and showed potential for effective localized treatment after cytoreductive surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer. Ansaloni, L., Coccolini, F., Morosi, L., et al.[2018]

In a study involving nine patients, only 10-15% of the expected oxaliplatin (OX) was detected in peritoneal perfusates during hyperthermic intraperitoneal chemotherapy (HIPEC), indicating significant drug transformation and loss during treatment.

The cytotoxicity of the perfusates remained largely unchanged during HIPEC, suggesting that ex vivo bioactivity assays could be valuable for assessing the effectiveness of OX and its derivatives, potentially guiding future HIPEC protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. Löffler, MW., Schuster, H., Zeck, A., et al.[2018]

In a study of 63 patients undergoing cisplatin (CDDP)-containing hyperthermic intraperitoneal chemotherapy (HIPEC), 66.1% experienced acute kidney injury (AKI), with the extent of parietal peritonectomy being a significant predictor of this complication.

Preclinical rat models showed that bilateral anterior parietal peritonectomy increased systemic absorption of CDDP by 1.6 to 2-fold, suggesting that careful consideration of CDDP dosage and concentration is crucial to minimize systemic toxicity and AKI risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury. Liesenfeld, LF., Quiring, E., Al-Saeedi, M., et al.[2023]

The combination of mitomycin C, 5-fluorouracil, and oxaliplatin (MMC-5FU-OHP) demonstrated significant tumor-suppressive effects against colorectal cancer cells in vitro, especially under hyperthermic conditions, indicating its potential efficacy for HIPEC.

In a Phase I clinical study involving nine patients, HIPEC with MMC-5FU-OHP was found to be safe, with no dose-limiting toxicity observed, and the recommended dose of oxaliplatin was established at 130 mg/m².

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study. Shimizu, T., Sonoda, H., Murata, S., et al.[2018]

In a study of 53 patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and doxorubicin, only 3.7% developed acute kidney injury (AKI), indicating a relatively low incidence of nephrotoxicity associated with this treatment.

However, there was a significant increase in hypomagnesemia, with levels dropping to 24.5% by day 7 and 30.1% by day 30 post-HIPEC, suggesting that monitoring magnesium levels is crucial after cisplatin administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery. Hakeam, HA., Breakiet, M., Azzam, A., et al.[2022]

Oxaliplatin degrades less in non-chloride carrier fluids compared to chloride-containing fluids, but the degradation rate remains low (10-15%) within 30 minutes, indicating that non-chloride solutions may help preserve the drug's effectiveness.

In both in vitro and in vivo studies, normal saline and Dianeal solutions showed higher absorption rates of oxaliplatin and acceptable degradation rates, suggesting they are more advantageous for use in oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) compared to 5% dextrose solution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo. Park, EJ., Ahn, J., Abuzar, SM., et al.[2022]

In a study of 145 patients with colorectal or appendiceal cancer, intraperitoneal doxorubicin showed significantly higher exposure to peritoneal surfaces (78 times greater) compared to plasma, indicating effective localized delivery of the drug.

Surgical factors, such as the extent of visceral resection and the size of the peritoneal space, significantly influenced doxorubicin clearance, suggesting that these factors should be considered when designing chemotherapy regimens for optimal efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis. Sugarbaker, PH., Van der Speeten, K., Anthony Stuart, O., et al.[2013]

In a multicenter phase-I study involving 30 patients with initially unresectable ovarian cancer, the recommended dose of cisplatin for hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant chemotherapy was determined to be 70 mg/m², as higher doses led to significant dose-limiting toxicities (DLTs).

The study found that at the highest dose of 80 mg/m², there were serious adverse events including renal failure and hemorrhage, highlighting the importance of careful dose selection to minimize toxicity while maximizing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer. Gouy, S., Ferron, G., Glehen, O., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer. [2014]

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

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C. [2018]

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

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer. [2018]

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

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. [2018]

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

Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury. [2023]

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

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study. [2018]

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

The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery. [2022]

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

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis. [2013]

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

Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer. [2022]