Know Your Treatment Options for Colorectal Cancer Liver & Abdominal Metastases

Surgery followed by chemotherapy can improve outcomes for patients with colon cancer and operable liver metastases

by Dr. C.H. Weaver M.D. updated 10/2019

Nearly 140,000 Americans are expected to be diagnosed with colorectal (CRC) cancer this year, and more than 50% will have their cancer spread to their liver. (1,2) Many individuals with CRC involving the liver erroneously conclude that they have no treatment options other than systemic therapy. There are however several therapeutic options for the treatment of liver metastases that significantly prolong survival, and others being developed in clinical trials.

For patients with liver metastases that can be surgically removed, surgery offers a potentially curative treatment approach however radiofrequency ablation (RFA), chemoembolization (TACE), and radioactive microspheres are appropriate options in certain situations.

The type of liver directed therapy used is determined by the size of the cancer, the number of metastases, the location of the cancer within the liver, and the ability of the patient to undergo the treatment. Patients need to understand that many advanced treatment options are only available at cancer centers specializing in the treatment of CRC and patients should consider getting an opinion at one of these centers.

Surgery

  • Many liver metastases can be effectively treated with surgery, but not all cancer clinics have the expertise to offer surgery as a treatment option. One analyses has demonstrated that surgery for liver metastases that can be resected has produced long-term overall survival of nearly 50% at five years and nearly 30% at 10 years. (3)
  • Additional clinical trials have demonstrated that the addition of chemotherapy following surgery for liver metastases further improves treatment outcomes. (4)
  • In some patients with inoperable liver metastases, an initial round of chemotherapy or neoadjuvant radiation therapy can be used to shrink the liver metastases enough so that surgery becomes possible. (5)
  • Using minimally invasive techniques such as ablation, embolization, or radioembolization allows the delivery of radiation therapy or chemotherapy directly to the liver tumor(s).

What Does the Research Show About Surgery?

For patients with liver metastases that can be surgically removed, surgery offers a potentially curative treatment approach. Research has explored patient survival after surgery for liver metastases and has also evaluated the effects of giving chemotherapy in addition to surgery. Up to 30% of patients survive beyond 10 years when metastases can be surgically removed.(6)

To describe long-term survival after surgery for liver metastases, researchers in Canada evaluated the outcomes of 423 surgeries that were conducted between 1991 and 2002. (6)

  • Cancer-free survival at one, five, and 10 years was 64%, 27%, and 22%, respectively.
  • Overall survival at one, five, and 10 years was 93%, 47%, and 28%, respectively.
  • Factors contributing to a worse overall survival included the presence of cancer on the margins of tissue removed by surgery, large sites of cancer within the liver, several sites of cancer within the liver, and patient age of greater than 60 years.

The researchers concluded that long-term overall survival of nearly 50% at five years and nearly 30% at 10 years can safely be achieved with the use of surgery to remove liver metastases among patients with colorectal cancer. (3) These results have been confirmed by other leading cancer treatment teams. (3.1)

In addition to surgery there are other ways to treat cancer involving the liver. Learn about Radiofrequency Ablation

Does Chemotherapy After Surgical Removal Provide Additional Benefit?

To evaluate the addition of chemotherapy following surgery for liver metastases, researchers in France conducted a study among 173 colorectal cancer patients with liver metastases. (7) Approximately half the patients were treated with liver surgery only and half were treated with liver surgery plus chemotherapy. The chemotherapy consisted of 5-fluorouracil plus folinic acid, which was the standard chemotherapy combination when the trial began. However, recent improvements have been made in chemotherapy for colorectal cancer.

  • Five-year cancer-free survival was 33.5% among patients treated with surgery and chemotherapy and 26.7% among patients treated with surgery alone.

The researchers concluded that the addition of systemic chemotherapy to surgery improves cancer-free survival among patients with colorectal cancer and liver metastases.

Does Chemotherapy Before Surgical Removal Provide Additional Benefit?

In some patients with inoperable liver metastases, an initial round of chemotherapy will shrink the liver metastases enough so that surgery becomes possible. Pre-surgery therapy is referred to as neoadjuvant chemotherapy. (8)

A study conducted in Italy involved 150 patients, and 116 had surgery without the need for neoadjuvant chemotherapy, and 34 had initially inoperable liver metastases but became candidates for surgery after neoadjuvant chemotherapy.

  • Three-year overall survival was similar in the two groups.
  • Three-year survival without cancer recurrence was lower in patients with initially inoperable liver metastases. Twenty-one percent of these patients survived for three years without cancer recurrence, compared to fifty percent of the patients who were able to undergo surgery without neoadjuvant chemotherapy.

This study suggests that among patients with initially inoperable liver metastases, those who are able to undergo surgery after neoadjuvant chemotherapy have a high rate of cancer recurrence. Nevertheless, the researchers note that the combination of neoadjuvant chemotherapy and surgery appears to result in better survival than chemotherapy alone for these patients.

Taken together, these studies indicate that some colorectal cancer patients are able to achieve prolonged cancer-free survival after surgery for liver metastases. The combination of surgery and chemotherapy (for those patients who are candidates for both treatments) may result in better survival than either treatment alone.

Can Surgery be Used to Treat a Second Cancer Recurrence in the Liver?

Researchers from France conducted a study to evaluate data including 40 patients with colorectal cancer who underwent two surgeries for liver metastasis from colorectal cancer. The researchers evaluated both short- and long-term results and identified factors that might help determine which subgroups of patients may experience better outcomes with a second surgery.

  • The postoperative mortality rate was 2.5%, which was not significantly different between patients who underwent a second surgery and those who only underwent one surgery.
  • Overall survival at three years was 55%.
  • Overall survival at five years was 31%.
  • Cancer-free survival at three year was 49%.
  • Cancer-free survival at five years was 27%.
  • The presence of cancer outside of the liver was associated with decreased survival.
  • If the duration of time between first and second hepatectomies was less than one year, survival was significantly decreased.

The researchers concluded: “A second liver resection because of recurrent liver metastases from colorectal cancer is safe and provides a survival benefit similar to that with single hepatectomy. Our analysis suggests that the benefit of treatment is limited in patients who undergo a second hepatectomy within 1 year of the first operation…. Repeat liver resection because of recurrent colorectal liver metastases can provide survival benefit with a low rate of complications.” (9)

Laparoscopy Can Guide Treatment of Colorectal Cancer Spread to Liver

Minimally invasive surgery to explore the extent of disease prior to more extensive surgery resulted in a change of treatment plans for roughly half of colorectal cancer patients with liver metastases, according to a study published in the Archives of Surgery.

Laparoscopy offers a minimally invasive surgical approach to exploring the extent of metastases and confirming (or changing) treatment plans prior to conducting more extensive surgery. Using laparoscopy, physicians can view the inside of the body by inserting a tool through a small incision in the abdomen.

To evaluate how treatment plans for liver metastases changed based on findings from laparoscopy, researchers in Oregon evaluated 136 colorectal cancer patients who, based on findings from CT or PET scans, appeared to have treatable metastases confined to the liver. By laparoscopy, 34 of these patients (25%) were found to have untreatable disease. Most of these patients had either very extensive liver metastases or metastases involving other sites in addition to the liver. In all, 48% of laparoscopies resulted in a change of treatment plans. For some patients, this involved a simple change, such as reducing or increasing radiofrequency ablation, while the type of treatment changed entirely for others.

The researchers conclude that use of staging laparoscopy in colorectal cancer patients influences treatment decisions for many patients who appear to have isolated liver metastases. Furthermore, for some patients (such as those who are found by laparoscopy to have untreatable disease), unnecessary and more extensive surgery can be avoided. (10)

The role of RFA, TACE, Surgery in the management of metastases to the liver

The liver is a common place for several types of cancer to spread, once the disease has become advanced. The spread of cancer to the liver is referred to as liver metastasis. Cancers originating in the pelvis or abdomen tend to have the higher rates of liver metastasis.

Treatment of liver metastases with chemotherapy rarely produces a durable complete remission leading researcher to develop liver directed therapies to be used alone or in combination with systemic treatment. (1) Several therapeutic options exist for the treatment of liver metastases.

  • Surgery to remove the metastasis
  • Chemoembolization
  • Radiofrequency ablation
  • Radiation beads

Surgery and radiofrequency ablation are among the most commonly used types of treatment for liver metastases

About Radiofrequency Ablation

Radiofrequency ablation entails the use of an electric current that is passed into a target area (tumors of the liver) through a needle probe. Heat is generated by the electric current at the site of the tumor, which ultimately destroys cancer cells. The procedure works as follows: conventional imaging methods, such as ultrasound, a computerized tomography (CT) scan, or magnetic resonance imaging (MRI) are utilized to guide the physician in the placement of the needle probe into the cancer. An electrical current is then generated and passed through the probe directly into the cancer cells. These cancer cells are heated by the electrical current to the point of irreversible ablation (destruction). Angio-CT involves the injection of a dye into the main artery of the liver prior to a CT scan (angio-CT). The dye enhances the contrast on CT scans, allowing physicians to visualize the small masses of cancer cells.

RFA may also be performed during surgery. The high-energy waves heat the cancer cells such that they later become coagulated and are destroyed. RFA is a useful addition to systemic chemotherapy or precision cancer medicines in patients with colorectal cancer and liver metastases.

RFA as Effective as Surgery?

Researchers from France conducted a clinical trial to compare the rates of local recurrences following intra-operative RFA or surgery in the treatment of liver metastasis. This trial included 88 patients who were treated with intent to cure with either RFA or surgery to remove their liver metastases. Patients with large metastases, or small metastases that were located on the periphery of the liver were treated with surgery, and patients with small metastases that were located in the central area of the liver were treated with RFA. There was an average of approximately 5 liver metastases that were treated per patient. The average follow-up was nearly 28 months. Local recurrences occurred in 5.7% of patients treated with RFA, 7.1% of patients with small metastases located on the periphery of the liver and treated with surgery, and 12.5% of patients with large metastases who were treated with surgery.

Surgical Removal of Single Site of Cancer Spread to Liver Improves Survival Compared to RFA in Colorectal Cancer

The surgical removal of a single site of cancer that has spread to the liver improves survival compared to RFA among patients with advanced colorectal cancer.

Researchers from the M.D. Anderson Cancer Center analyzed data from patients with colorectal cancer who had only one site of liver metastasis with no cancer spread elsewhere in the body. Patients were either treated with surgery (hepatic resection) to entirely remove the cancer and surrounding tissue or with RFA. This study included 180 patients; 50 of whom underwent hepatic resection and 30 of whom underwent RFA.

  • At five years, recurrences near or at the site of the liver metastasis occurred in just 5% of patients treated with surgery, compared with 37% of patients treated with RFA.
  • Survival at five years was 71% for those who underwent surgery, compared with only 27% for those who underwent RFA.

The researchers concluded that it appears that hepatic resection for patients with colorectal cancer whose cancer has only spread to a single site in the liver appears to significantly improve survival when compared to treatment with RFA.

RFA Most Effective with Smaller Metastases

In a report of 135 individuals with liver metastases who underwent laparoscopic RFA patients who had a blood marker known as CEA that measured less than 200 ng/ml had a greater survival advantage than those patients whose CEA was greater than 200ng/ml and the size of the liver lesions was also correlated with survival. Patients with smaller lesions (less than 3cm) had an average survival of 38 months; patients with medium lesions (3-5 cm) had an average survival of 34 months; and patients with large lesions (greater than 5 cm) had an average survival of 21 months. Multiple lesions also affected the overall survival. The presence of 1-3 tumors resulted in a survival period of 29 months, compared to 22 months for patients who had more than 3 tumors.

Chemoembolization and RFA is more effective than either treatment alone.

Transarterial chemoembolization (TACE) is designed to stop blood flow to the tumor. The lack of blood supply deprives the tumor of needed oxygen and nutrients, causing cell death. The blood flow is stopped by using small particles saturated with chemotherapy drugs that soak the tumor in chemotherapy for a prolonged period.

Researchers in China conducted a study in 291 patients diagnosed with liver cancer larger than 3 centimeters. Patients were randomly assigned to receive treatment with either TACE alone, RFA alone, or a combination of TACE and RFA. The goal of the study was to evaluate survival benefits as well as response rates to these various techniques.

  • After an average follow up of 28.5 months, the average survival times were 24 months among the patients who received TACE, 22 months for patients who received RFA, and 37 months among those who received TACE and RFA.
  • Further analysis revealed that treatment of multiple tumors within the liver with combination therapy produced better outcomes than treatment of single tumors with RFA or TACE alone.
  • Response rates that were sustained for six months were highest among patients treated with TACE and RFA (54%) compared with 35% for patients treated with TACE alone and 36% among patients treated with RFA alone.

Patients with larger liver tumors, a combination of TACE and RFA was successful in improving overall survival outcomes.

Patients with liver metastases should be seen at a cancer center that provides RFA, TACE or other liver directed therapies and speak with their physician about the risks and benefits of RFA or the participation in a clinical trial further evaluating RFA or other promising therapeutic approaches.

Microspheres:

SIR-Spheres® Y-90 microspheres have been added as a new treatment option in the latest National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology for colon cancer and rectal cancer. SIR-Spheres Y-90 resin microspheres are a medical device used in an interventional radiology procedure known as selective internal radiation therapy (SIRT), or radioembolization, which targets high doses of radiation directly to liver tumors.

The treatment consists of tens of millions of radioactive Y-90 coated resin particles, each no bigger in diameter than a human hair. SIR-Spheres Y-90 are injected into the hepatic artery, which is the main blood supply to the liver via a catheter inserted into the femoral artery through an incision in the groin. The Y-90 resin microspheres become lodged in the smaller blood vessels that surround cancer in the liver, where they deliver a high dose of radiation to the cancer, while sparing healthy liver tissue.

Ongoing research is being conducted in clinical trials to find new treatments for CRC. By learning about clinical trials, you can identify opportunities that advance the treatment of CRC and possibly benefit your personal prognosis.(14)

HIPEC:

HIPEC: Hyperthermic (or Heated) Intraperitoneal chemotherapy is a surgical procedure where surgeons pump a powerful dose of heated chemotherapy inside a patient’s abdomen. HIPEC Intraperitoneal (IP) delivers chemotherapy directly into the abdominal cavity, where there is the greatest number of cancer cells. The chemotherapy is administered through a large catheter that is placed into the abdomen during the surgery to remove the cancer. The 108-degree chemotherapy bath circulates throughout the peritoneal cavity, delivering highly concentrated doses of hot chemotherapy. After about 90 minutes of the infusion, the chemo is washed out and incisions are closed.

HIPEC is mainly used to treat metastases to the peritoneum and appears to be most effective if surgery or other therapy has already reduced the size of any remaining cancer deposits.

Radioembolization

Radioembolization is another strategy to optimize the delivery of radiation to liver metastases while sparing healthy tissue. This strategy utilizes radioactive microspheres (small spheres containing radioactive material). The small spheres are injected into vasculature of the liver, where they tend to get lodged in the vasculature responsible for providing blood and nourishment to the cancer cells. While lodged in place, the radioactive substance spontaneously emits radiation to the surrounding cancerous area while minimizing radiation exposure to the healthy portions of the liver. Results from a small study published in the Journal of Clinical Oncology indicated that radioembolization with concomitant chemotherapy (oxaliplatin, fluorouracil, and leucovorin) was active in colorectal cancer patients with inoperable liver metastases who had no prior treatment; median time to cancer progression within the liver in this study was over one year.

The current study—a large prospective, multicenter, randomized Phase III trial—was designed to evaluate the safety and efficacy of radioembolization combined with the chemotherapy agent fluorouracil in heavily pretreated colorectal cancer patients. All 44 patients in this study had metastatic colorectal cancer with inoperable metastases limited to the liver and had disease progression following standard chemotherapy including the agents fluorouracil, oxaliplatin, and irinotecan. Patients were randomized to receive either treatment with fluorouracil alone or radioembolization plus fluorouracil. At a median follow-up of 24.8 months, radioembolization plus fluorouracil significantly improved the median time to tumor progression and the time to liver progression. In addition, treatment with the radioembolization plus fluorouracil was well tolerated with only one patient experiencing significant toxicity compared with six patients in the fluorouracil arm.The researchers concluded that radioembolization combined with fluorouracil may benefit metastatic colorectal cancer patients with liver-limited disease who have progressed following prior chemotherapy.

References:

  1. American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019. Atlanta: American Cancer Society, 2017.
  2. Cho M, Gong J and Fakih M.The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Review of Anticancer Therapy, 2016; 16(2): 229–245.
  3. Wei A, Greig P, Grant D, et al. Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience. Annals of Surgical Oncology. 2006; 13:668-676.
  4. Tomlinson J, Jarnagin W, DeMatteo R, et al. Actual 10-Year survival after resection of colorectal liver metastases defines cure. Journal of Clinical Oncology. 2007;25: 4575-4580.
  5. Portier G, Elias D, Bouche O, et al. Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial. Journal of Clinical Oncology. 2006; 24: 4976-4982.
  6. Capussotti L, Muratore A, Mulas MM, Massucco P, Aglietta M. Neoadjuvant Chemotherapy and Resection for Initially Irresectable Colorectal Liver Metastases. British Journal of Surgery. 2006;93:1001-1006.
  7. van Hazel GA, Heinemann V, Sharma NK et al. SIRFLOX: Randomized Phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2016; 34: 1723–1731.
  8. Portier G, Elias D, Bouche O, et al. Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial. Journal of Clinical Oncology. 2006; 24: 4976-4982.
  9. Capussotti L, Muratore A, Mulas MM, Massucco P, Aglietta M. Neoadjuvant Chemotherapy and Resection for Initially Irresectable Colorectal Liver Metastases. British Journal of Surgery. 2006;93:1001-1006.
  10. Cunha A, Laurent C, Rault a, et al. A second liver resection due to recurrent colorectal liver metastases. Archives of Surgery. 2007;142:1144-1149.
  11. Thaler K, Kanneganti S, Khajanchee Y et al. The evolving role of staging laparoscopy in the treatment of colorectal hepatic metastasis. Archives of Surgery. 2005;140:727-734.
  12. Ahmad A, Chen S, Bilchik A, et al. Role of repeated hepatectomy in the multimodal treatment of hepatic colorectal metastases. Archives of Surgery. 2007;142:526-532.
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  14. Berber E, Pelley R, Siperstein A, et al. Predictors of Survival After Radiofrequency Thermal Ablation of Colorectal Cancer Metastases of the Liver: A Prospective Study. Journal of Clinical Oncology.2005; published online ahead of print January 31, 2005.
  15. Cheng, B., Jia, C., Liu C., et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3cm. Journal of the American Medical Association. 2008; 299(14): 1669-1677
  16. Mulcahy MF, Lewandowski RJ, Ibrahim SM et al. Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres. Cancer [early online publication]. March 6, 2009.
  17. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy. Journal of Clinical Oncology[early online publication]. June, 21 2010.

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