Post-Hepatectomy Chemotherapy for Liver Cancer

Overseen By Timothy Newhook

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Preoperative chemotherapy

Disqualifiers: Other malignancies, Pregnancy, others

Stay on Your Current Meds You can continue your current medications while participating

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: Unknown

Duration: 6 months

120 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine if the detection of ctDNA after surgical resection of CLM can stratify patients into high and low-risk cohorts for early disease recurrence in order to inform post-operative adjuvant therapy.

Will I have to stop taking my current medications?

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

What evidence supports the effectiveness of the drug combination used in the Post-Hepatectomy Chemotherapy for Liver Cancer trial?

Research shows that chemotherapy using 5-fluorouracil (5-FU) and other drugs like oxaliplatin and irinotecan can improve survival after surgery for liver metastases from colorectal cancer. These drugs are part of the treatment being studied, suggesting potential benefits for liver cancer patients. ^{1 2 3 4 5}

Is the chemotherapy treatment safe for humans?

The chemotherapy treatments involving drugs like 5-FU, capecitabine, oxaliplatin, and others have been studied for safety in various conditions. While they can have side effects, studies show they are generally considered safe with manageable toxicities when used under medical supervision. ^{6 7 8 9 10}

How does the post-hepatectomy chemotherapy treatment differ from other treatments for liver cancer?

This treatment is unique because it involves adjuvant chemotherapy, specifically using a regimen like mFOLFOX6, after liver surgery to potentially improve outcomes for liver metastases from colorectal cancer. Unlike standard treatments, it targets the liver directly through intra-arterial infusion, aiming to prevent cancer recurrence in the remaining liver tissue. ^{3 4 11 12 13}

Research Team

Timothy Newhook, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults over 18 with colorectal liver metastases (CLM) who have had or will have their primary cancer removed and plan to undergo surgery with the intent to cure. They must have completed at least 4 cycles of specific preoperative chemotherapy between July 2021 and December 2023. Pregnant women, patients with other active cancers needing treatment, those unable to receive post-surgery chemo, or unwilling/unable to provide blood samples for ctDNA testing are excluded.

Inclusion Criteria

I am over 18, have cancer in my liver from another place, and will have surgery to remove it after chemotherapy.

I have completed at least 4 rounds of chemotherapy before surgery.

Exclusion Criteria

I do not have any other cancers needing treatment.

I cannot have or am not planning to have chemotherapy after surgery.

I am currently pregnant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Participants undergo liver resection of colorectal liver metastases with curative intent

1 week

Treatment

Participants receive risk-stratified postoperative chemotherapy based on ctDNA status

6 months

Follow-up

Participants are monitored for recurrence-free survival and overall survival, with ctDNA measurements and adverse event assessments

1 year

Treatment Details

Interventions

• 5-FLUOROURACIL
• Bevacizumab
• Capecitabine
• Irinotecan
• Leucovorin
• Oxaliplatin

Trial Overview The study tests if circulating tumor DNA (ctDNA) can predict early disease recurrence after surgical removal of CLM. It aims to see whether detecting ctDNA helps classify patients into high or low risk for cancer coming back, which could guide further therapy after surgery. Drugs involved include Oxaliplatin, Leucovorin, Fluorouracil (5-FU), Irinotecan, Capecitabine, and Bevacizumab.

Participant Groups

Group I: ctDNA (Low Risk) Experimental Treatment 2 Interventions

Will receive less intense chemotherapy, such as capecitabine or 5-fluorouracil.

Group II: ctDNA (High Risk) Experimental Treatment 6 Interventions

Will receive more intense chemotherapy. This may include resuming the chemotherapy you received before surgery (for example, FOLFOX \[5-fluorouracil, leucovorin and oxaliplatin\] or FOLFIRI \[5-fluorouracil, leucovorin and irinotecan\] with or without bevacizumab)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Hepatic resection is currently the only treatment with curative potential for colorectal liver metastasis, but many patients experience recurrences, often in the remnant liver.

Combining surgery with adjuvant chemotherapy may improve survival rates, but further clinical trials are needed to determine the optimal treatment protocols and drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy and hepatectomy for liver metastasis from colorectal cancer]. Ohkubo, T., Takayama, T.[2009]

Adjuvant systemic chemotherapy, particularly with fluorouracil, has been shown to reduce recurrence rates and improve survival in patients with Dukes C colon cancer, highlighting its efficacy in managing metastatic growth in the liver.

Hepatic Intrarterial Chemotherapy (HIAC) for colorectal metastases results in objective responses in over 50% of patients and appears to positively impact survival, while surgical resection remains the most effective treatment option with a 30% five-year survival rate for colorectal cancer metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Liver metastasis: therapeutic strategy]. Gennari, L., Doci, R., Bignami, P.[2006]

In a study of 72 patients who underwent curative resection of synchronous colorectal liver metastases, those receiving postoperative chemotherapy with FOLFIRI/IFL or FOLFOX regimens had significantly better relapse-free survival (RFS) compared to those treated with 5-FU/LV, with median RFS of 20.8 months and 18.8 months respectively versus 14.4 months for 5-FU/LV.

Overall survival (OS) was also improved in patients receiving FOLFIRI/IFL and FOLFOX, with both groups showing OS greater than 60 months, compared to 38.5 months for the 5-FU/LV group, indicating that modern chemotherapy regimens are more effective after liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of postoperative oxaliplatin- or irinotecan-based chemotherapy after curative resection of synchronous liver metastases from colorectal cancer. Hsu, HC., Chou, WC., Shen, WC., et al.[2018]

In a randomized trial involving 300 patients with liver-only metastatic colorectal cancer, adjuvant chemotherapy with mFOLFOX6 after hepatectomy significantly improved disease-free survival (DFS) compared to surgery alone, with a 5-year DFS of 49.8% versus 38.7%.

Despite the improvement in DFS, overall survival (OS) was better in the hepatectomy alone group (83.1%) compared to the chemotherapy group (71.2%), indicating that while chemotherapy may help prevent cancer recurrence, it does not necessarily extend overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. Kanemitsu, Y., Shimizu, Y., Mizusawa, J., et al.[2022]

The 5-year risk of cancer progression after complete removal of liver metastases is high, ranging from 50% to 75%, indicating a significant need for effective treatment strategies.

While adjuvant chemotherapy with the LV5FU2 regimen for 6 months is considered a reasonable option for patients not in clinical trials, preoperative chemotherapy is generally not recommended unless there are uncertainties about resectability or other negative factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy with curative intent before (neoadjuvant) or after (adjuvant) surgery for colorectal cancer liver metastases]. Rougier, P., Guimbaud, R., Mitry, E., et al.[2007]

In a phase III trial involving 480 patients with metastatic colorectal cancer, maintenance treatment with single-agent bevacizumab showed no significant difference in progression-free survival (PFS) or overall survival (OS) compared to bevacizumab combined with capecitabine and oxaliplatin (XELOX).

The study indicates that while the noninferiority of bevacizumab alone cannot be confirmed, it is a viable maintenance option after initial XELOX plus bevacizumab treatment, with manageable safety profiles including common side effects like diarrhea and neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Díaz-Rubio, E., Gómez-España, A., Massutí, B., et al.[2022]

In a study with Sprague-Dawley rats, glycine supplementation significantly reduced liver injury caused by neoadjuvant chemotherapy, as indicated by lower transaminase levels and reduced microvesicular steatosis after treatment.

The protective effects of glycine are likely due to improved liver microcirculation and reduced activation of Kupffer cells, which are important for liver health, suggesting a potential therapeutic role for glycine in managing chemotherapy-related liver toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary glycine protects from chemotherapy-induced hepatotoxicity. Mikalauskas, S., Mikalauskiene, L., Bruns, H., et al.[2018]

The FOLFIRINOX regimen, while more toxic than gemcitabine, is considered safe and manageable for treating pancreatic cancer, as evidenced by its use in a case involving steatohepatitis that mimicked liver metastasis.

This case highlights the importance of recognizing atypical adverse events in patients undergoing FOLFIRINOX treatment, which can significantly impact treatment management and decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steatohepatitis due to FOLFIRINOX regimen in adjuvant pancreas cancer treatment mimicking liver metastasis. Bozkurt Duman, B., Çil, T.[2020]

In a phase III trial involving 1,886 patients with stage III colon cancer, the combination of capecitabine and oxaliplatin (XELOX) demonstrated a manageable safety profile, with treatment-related adverse events occurring at similar rates to the standard treatment of fluorouracil/leucovorin (FU/LV).

Patients receiving XELOX experienced less diarrhea and alopecia but had higher rates of neurosensory toxicity and hand-foot syndrome compared to those on FU/LV, indicating that while XELOX is generally well-tolerated, it may have specific side effects that need monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. Schmoll, HJ., Cartwright, T., Tabernero, J., et al.[2022]

The modified FOLFIRINOX (mFOLFIRINOX) regimen showed a tolerable safety profile with lower hematological toxicity compared to the full-dose FOLFIRINOX, while still maintaining comparable efficacy in treating advanced pancreatic ductal adenocarcinoma (PDAC).

In a study of 18 patients, 80% achieved at least stable disease, with a median overall survival of 9.3 months and progression-free survival of 7.2 months, indicating that mFOLFIRINOX can be an effective treatment option for fit patients with advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. Ghorani, E., Wong, HH., Hewitt, C., et al.[2023]

In a study involving 23 patients who underwent liver surgery for metastatic colorectal cancer, those who received postoperative adjuvant locoregional chemotherapy showed significantly better disease-free rates at 1, 2, and 3 years compared to those who did not receive the treatment (100%, 80%, and 40% vs. 61.4%, 54.6%, and 28.1%).

The survival rates were also higher in the chemotherapy group, with 100% survival at 1 and 2 years and 60% at 3 years, compared to 73.7%, 63.3%, and 63.3% in the non-chemotherapy group, indicating that this treatment is effective in preventing cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prevention of postoperative recurrence after hepatic resection for metastatic colorectal cancer by adjuvant locoregional chemotherapy]. Endo, Y., Tani, T., Kawaguchi, A., et al.[2013]

In a study involving 36 male Wistar rats, chemotherapy with 5-fluorouracil (5-FU) after major liver surgery significantly increased plasma levels of the drug and its associated toxicity, indicating impaired drug clearance during liver regeneration.

The combination of hepatectomy and chemotherapy resulted in a lower liver regeneration rate and reduced intestinal health, as shown by decreased liver dihydropyrimidine dehydrogenase levels and ileal villous height, highlighting the risks of administering chemotherapy during liver recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model. Tada, K., Iwashita, Y., Shiraiwa, K., et al.[2022]

In a study of 16 patients receiving a combination of intra-arterial and oral chemotherapy for colorectal metastases, the intrahepatic recurrence rate was 31% after a median follow-up of 21 months, indicating a potential benefit in preventing liver recurrence post-surgery.

Patients with a single hepatic metastasis showed no recurrence, while those with multiple deposits had a higher recurrence rate of 45%, suggesting that the number of metastases significantly influences treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant hepatic intra-arterial chemotherapy after potentially curative hepatectomy for liver metastases from colorectal cancer: a pilot study. Moriya, Y., Sugihara, K., Hojo, K., et al.[2021]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Chemotherapy and hepatectomy for liver metastasis from colorectal cancer]. [2009]

2. Italy pubmed.ncbi.nlm.nih.gov

[Liver metastasis: therapeutic strategy]. [2006]

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

Efficacy of postoperative oxaliplatin- or irinotecan-based chemotherapy after curative resection of synchronous liver metastases from colorectal cancer. [2018]

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

Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

[Chemotherapy with curative intent before (neoadjuvant) or after (adjuvant) surgery for colorectal cancer liver metastases]. [2007]

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

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. [2022]

7. Austria pubmed.ncbi.nlm.nih.gov

Dietary glycine protects from chemotherapy-induced hepatotoxicity. [2018]

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

Steatohepatitis due to FOLFIRINOX regimen in adjuvant pancreas cancer treatment mimicking liver metastasis. [2020]

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

Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. [2023]

11. Japan pubmed.ncbi.nlm.nih.gov

[Prevention of postoperative recurrence after hepatic resection for metastatic colorectal cancer by adjuvant locoregional chemotherapy]. [2013]

12. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Adjuvant hepatic intra-arterial chemotherapy after potentially curative hepatectomy for liver metastases from colorectal cancer: a pilot study. [2021]