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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a blood test (ctDNA) can predict the risk of cancer recurrence after liver surgery for individuals with liver metastases from colorectal cancer. By identifying high or low risk, the trial will assess whether patients should receive more or less intense chemotherapy. The treatments being tested include various combinations of drugs such as 5-fluorouracil (a chemotherapy drug) and bevacizumab (an anti-cancer drug). Suitable candidates have undergone liver surgery to remove cancer after completing at least four cycles of chemotherapy before the surgery. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer care.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatments in this trial have safety evidence from past studies. The FOLFOX regimen, which includes 5-fluorouracil, leucovorin, and oxaliplatin, is generally well-tolerated. While side effects can occur, they are usually manageable. The FOLFIRI regimen, which includes irinotecan, 5-fluorouracil, and leucovorin, is also considered safe for many patients, with side effects typically controlled with proper care.

Bevacizumab, another treatment in this trial, is often used with other drugs. It has proven effective and safe, though some patients may experience side effects like high blood pressure. Capecitabine is considered a safe option, especially for those who cannot tolerate other treatments, and it is generally well-received with manageable side effects.

Finally, 5-fluorouracil alone has been used in many treatments and works well with other drugs, with side effects usually handled with care.

Overall, these treatments have a history of being well-tolerated, with side effects that are mostly manageable. This prior evidence suggests a reasonable safety profile for participants in this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for liver cancer because they offer personalized chemotherapy based on ctDNA risk levels. Unlike standard treatments, which often follow a one-size-fits-all approach, this trial uses ctDNA to tailor the intensity of chemotherapy. High-risk patients receive a combination of drugs, potentially including bevacizumab, which targets blood vessels feeding tumors, while low-risk patients are treated with milder options like capecitabine. This targeted approach aims to maximize effectiveness and minimize unnecessary side effects, making treatment more efficient and patient-friendly.

What evidence suggests that this trial's treatments could be effective for liver cancer?

In this trial, researchers will assign participants to different treatment arms based on their risk level. Studies have shown that treatments like FOLFOX and FOLFIRI are effective for patients with liver cancer that has spread from colorectal cancer. For instance, patients treated with FOLFOX have lived longer. Participants in the high-risk arm may receive more intense chemotherapy, such as FOLFOX or FOLFIRI, which combines irinotecan and 5-fluorouracil and has helped patients live longer and respond better to treatment. Bevacizumab, another treatment in this trial, has helped the liver heal and may delay cancer's return. Participants in the low-risk arm may receive less intense chemotherapy, such as capecitabine or 5-fluorouracil. Capecitabine, often used after surgery, has shown promise in reducing cancer recurrence with only mild side effects. Lastly, 5-fluorouracil, a common chemotherapy drug, has been effective in preventing cancer from returning after surgery. These treatments offer several ways to manage and treat liver cancer effectively. ^{1 2 6 7 8}

Who Is on the Research Team?

Timothy Newhook, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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