HIPEC for Adrenocortical Cancer

Overseen By Vilma L Rosario

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Columbia University

Must be taking: Mitotane

Disqualifiers: Heart failure, COPD, Brain metastases, Cirrhosis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Objectives: - To determine intraperitoneal (IP) progression free survival after optimal debulking and heated intraperitoneal chemotherapy (HIPEC) with cisplatin in patients with IP spread of adrenocortical cancer. - Determine morbidity of this procedure in this patient population. - Determine the impact of surgery and HIPEC on quality of life (QOL) and hormone excess. - Examine patterns of recurrence (local versus systemic). - Determine overall survival after optimal debulking and HIPEC in patients with IP spread of adrenocortical cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that mitotane may be continued. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment HIPEC for Adrenocortical Cancer?

Cisplatin, a component of the HIPEC treatment, has shown good results in previous studies for adrenal cancer, and cytoreduction with intraperitoneal chemotherapy has improved survival in other advanced cancers. ^{1 2 3 4 5}

Is HIPEC with Cisplatin safe for humans?

Cisplatin, used in various treatments, has been associated with side effects like nausea, vomiting, and kidney issues. However, these effects often subside after stopping the treatment. It's important to discuss potential risks with your doctor. ^{5 6 7 8 9}

How is the HIPEC treatment for adrenocortical cancer different from other treatments?

HIPEC (hyperthermic intraperitoneal chemotherapy) with cisplatin is unique because it involves directly applying heated chemotherapy into the abdominal cavity after surgery to remove as much of the cancer as possible. This method is different from standard chemotherapy, which is usually given through the bloodstream, and it allows for higher concentrations of the drug to target cancer cells in the abdomen. ^{10 11 12 13 14}

Research Team

Michael Kluger, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for adults with Adrenocortical Carcinoma (ACC) where the majority of cancer is in the peritoneal cavity and can be surgically removed or treated with radiofrequency ablation. Participants must have a life expectancy over three months, practice birth control, and have adequate organ function. Excluded are those with severe heart, lung conditions, active infections, significant neuropathy, brain metastases or pregnant/breastfeeding women.

Inclusion Criteria

Able to understand and sign the Informed Consent Document

My white blood cell count is healthy without needing medication.

Your platelet count is higher than 75,000 per cubic millimeter.

Exclusion Criteria

I have severe lung disease with very low lung function test results.

I have moderate to severe nerve pain or damage.

I do not have major illnesses like heart disease, severe infections, or blood clotting disorders.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Cytoreductive surgery to remove visible tumors and involved organs

1 week

1 visit (in-patient surgery)

Heated Intraperitoneal Chemotherapy (HIPEC)

Administration of heated cisplatin chemotherapy following surgery

1 week

1 visit (in-patient)

Follow-up

Participants are monitored for safety, effectiveness, and quality of life after treatment

Up to 5 years

Treatment Details

Interventions

• Cisplatin
• Cytoreductive surgery

Trial Overview The study tests if surgery followed by Heated Intraperitoneal Chemotherapy (HIPEC) using cisplatin improves survival without cancer spreading inside the abdomen. It also examines side effects, quality of life changes post-treatment and whether cancer comes back locally or spreads elsewhere.

Participant Groups

Group I: Surgery with HIPEC Experimental Treatment 3 Interventions

Cytoreductive surgery followed by HIPEC with cisplatin and sodium thiosulfate

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?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Findings from Research

Complete surgical resection is the preferred treatment for adrenocortical carcinoma, a rare cancer with a poor prognosis, while mitotane is used when surgery is not possible or for metastatic cases.

The Dutch Adrenal Network facilitates collaboration among specialists to improve treatment standards for advanced adrenocortical carcinoma, including a randomized trial to establish a standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adrenocortical carcinoma. van Ditzhuijsen, CI., van de Weijer, R., Haak, HR.[2013]

Mitotane combined with chemotherapy (etoposide, doxorubicin, and cisplatin) is currently the only proven effective treatment for advanced adrenocortical carcinoma, highlighting its importance in managing this rare cancer.

There is a need for better prognostic and predictive factors to identify which patients will benefit most from these therapies, as existing molecular targeted therapies have not shown efficacy in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update. Ferrari, L., Claps, M., Grisanti, S., et al.[2019]

The EDP-M chemotherapy regimen (etoposide, doxorubicin, cisplatin, and mitotane) is the standard treatment for advanced adrenocortical carcinoma, but it can be very toxic, making supportive care essential to manage side effects and maintain treatment intensity.

Effective management strategies include using adrenal steroidogenesis inhibitors to control Cushing syndrome before starting EDP-M, administering Granulocyte-Colony Stimulating Factors to prevent neutropenia, and considering continuous cisplatin infusion for patients with poor performance status or mild renal impairment to reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen. Turla, A., Laganà, M., Grisanti, S., et al.[2022]

In a phase II clinical trial involving 63 patients, 11 were eligible for treatment, and 9 underwent cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC), demonstrating that this approach can be safely performed with no perioperative mortality and manageable complications.

The treatment resulted in an intraperitoneal progression-free survival of 19 months, but disease recurrence was common, indicating that while HIPEC may offer some benefit, further treatment options should still be considered for recurrent adrenocortical carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma. Hughes, MS., Lo, WM., Beresnev, T., et al.[2022]

In a phase II trial involving 42 patients with metastatic or residual adrenocortical carcinoma, the combination of cisplatin (CDDP) and mitotane (o,p'DDD) showed an objective response rate of 30%, with a median response duration of 7.9 months.

While the treatment demonstrated efficacy, it also resulted in moderate to severe toxicity, primarily affecting gastrointestinal, renal, and neurological systems, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. Bukowski, RM., Wolfe, M., Levine, HS., et al.[2017]

In a Phase I study involving 40 patients with urologic and gynecologic cancers, cis-diamminedichloroplatinum(II) (CIS-DDP) was found to have manageable side effects, primarily nausea, vomiting, and anorexia, which resolved quickly after stopping the treatment.

The study indicated low levels of hematopoietic and renal toxicities, with no reported cases of hearing disturbances or tinnitus, suggesting a favorable safety profile for CIS-DDP at doses of 50 mg/m2 for single administration and 20 mg/m2/day for five consecutive days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase I study of a new antineoplastic agent, cis-diamminedichloroplatinum (II)]. [2013]

In a Phase II study involving 77 patients with urologic malignancies, cis-diaminedichloroplatinum(II) (CIS-DDP) demonstrated significant efficacy, with overall response rates of 73.3% for testicular tumors and 50.0% for bladder tumors, indicating its potential as an effective treatment option.

However, the treatment was associated with considerable adverse effects, including gastrointestinal issues in 78.5% of patients, as well as myelosuppression and renal dysfunction, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase II study on cis-diamminedichloroplatinum (II) by a collaborative study]. [2013]

In a study of 762 patients undergoing cisplatin chemotherapy, 21.7% experienced nephrotoxicity, with significant risk factors including high-dose cisplatin, cardiac disease, and hypertension.

Magnesium supplementation and diuretic use were found to reduce the risk of cisplatin nephrotoxicity, suggesting they could be effective preventive measures for at-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk Factors for Cisplatin-Induced Nephrotoxicity: A Multicenter Retrospective Study. Miyoshi, T., Uoi, M., Omura, F., et al.[2021]

In a pilot study involving 12 adult male Wistar rats, cisplatin (CP) administration primarily caused noticeable kidney toxicity within one week, indicating that the kidneys are the first organ affected by this chemotherapy drug.

Minimal testicular damage was observed, while no liver abnormalities were detected, suggesting that kidney monitoring should be prioritized during cisplatin treatment in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: Which one is the first observation as side effect of Cisplatin-induced toxicity in animal model? Nematbakhsh, M., Ashrafi, F., Pezeshki, Z., et al.[2021]

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 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]

In a study of 104 patients with peritoneal carcinomatosis, acute kidney injury (AKI) occurred in 17.3% of patients, with the highest incidence in those receiving hyperthermic intraperitoneal chemotherapy (HIPEC) at 31.2%.

The findings suggest that while HIPEC is a promising treatment for malignancies, it poses a significant risk to kidney function compared to intravenous cisplatin and surgery, indicating a need for strategies to minimize kidney damage during HIPEC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitonal chemotherapy is an independent risk factor for development of acute kidney injury. Dagel, T., Misirlioglu, S., Tanju, S., et al.[2019]

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) demonstrated a low perioperative mortality rate of 2% and a morbidity rate of 11%, indicating that this treatment is relatively safe for patients with peritoneal surface malignancies.

The study reported that 75% of patients had hospital stays of less than 2 weeks, suggesting effective pre-operative and post-operative management, although the evaluation of long-term efficacy in terms of survival is limited due to a short follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and management of toxicity of cytoreductive surgery/hyperthermic intraperitoneal chemotherapy: the initial experience of a single centre study. Lemstrova, R., Flasarova, D., Spisarova, M., et al.[2021]

For patients with newly diagnosed stage III ovarian or fallopian tube cancer who have stable disease after chemotherapy, hyperthermic intraperitoneal chemotherapy (HIPEC) should be considered during interval cytoreductive surgery, as it may improve treatment outcomes.

However, there is insufficient evidence to support the use of HIPEC in various other contexts, including primary cytoreductive surgery for advanced ovarian cancer and recurrent ovarian cancer, indicating that more research is needed before HIPEC can be recommended as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a clinical practice guideline. Auer, RC., Sivajohanathan, D., Biagi, J., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Adrenocortical carcinoma. [2013]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update. [2019]

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

Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen. [2022]

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

A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma. [2022]

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

Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. [2017]

6. Japan pubmed.ncbi.nlm.nih.gov

[Phase I study of a new antineoplastic agent, cis-diamminedichloroplatinum (II)]. [2013]

7. Japan pubmed.ncbi.nlm.nih.gov

[Phase II study on cis-diamminedichloroplatinum (II) by a collaborative study]. [2013]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Risk Factors for Cisplatin-Induced Nephrotoxicity: A Multicenter Retrospective Study. [2021]

9. Iran pubmed.ncbi.nlm.nih.gov

A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: Which one is the first observation as side effect of Cisplatin-induced toxicity in animal model? [2021]

10. 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]

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

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

12. Cyprus pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitonal chemotherapy is an independent risk factor for development of acute kidney injury. [2019]

13. Czech Republic pubmed.ncbi.nlm.nih.gov

Evaluation and management of toxicity of cytoreductive surgery/hyperthermic intraperitoneal chemotherapy: the initial experience of a single centre study. [2021]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a clinical practice guideline. [2021]