Author Tilda Barliya PhD
Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem. The liver is the dominant metastatic site for patients with CRC, and although two-thirds of affected patients have extrahepatic spread, some have disease that is isolated to the liver. For patients with isolated liver metastases, regional treatment approaches may be considered as an alternative to systemic chemotherapy (1).
Metastases from CRC most commonly develop within 2 years of resection of the primary tumor and are usually asymptomatic; rarely, patients may complain of vague upper abdominal pain. Hepatic metastases associated with CRC may occur regardless of the initial stage of the primary tumor although nodepositive primary lesions are more likely to precede hepatic metastasis (2).
The available regional treatments for hepatic metastases from CRC include (1):
- Surgical resection
- Local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions
- Radiofrequency ablation [RFA])
- Regional hepatic intraarterial chemotherapy or chemoembolization
- Radiation therapy (RT)
**Among these treatments, only surgery is associated with a survival plateau.
Screening for Hepatic metastasis (3):
- A biopsy may be indicated to confirm the diagnosis, depending upon the clinical picture. However, fine needle aspiration cytology has not been advocated as a screening test, because of its high risk of complications. It has been shown that the incidence of needle tract metastases is 0.4%-5.1% after fine needle aspiration and use of the procedure in abdominal tumors is fatal in 0.006%-0.031% of cases. Most deaths are due to hemorrhage of liver tumors (3).
- Laparoscopy has not been advocated as a screening test for colorectal liver metastases due to its invasiveness.
- Imaging modalities, such as contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography CT (PET-CT), may establish the diagnosis of liver metastasis of colorectal cancer. However, it is more difficult to make the clinical diagnosis of early liver metastases of colorectal cancer due to the absence of typical symptoms or signs.
- Serological examination including tumor and biochemical markers for liver function evaluation is routinely performed, though its accuracy is not high. In that aspect, carcinoembryonic antigen (CEA) levels is elevated in 63% of patients, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is increased in about 30% of patients with liver metastases of colorectal cancer.
Surgical Resection (1)
Resection offers the greatest likelihood of cure for patients with liver-isolated CRC. In surgical case series, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent and surgical mortality rates are generally <5 percent (1). It’s worth noted that subgroups with advanced age, comorbid disease, and synchronous hepatic and colon resection may have higher procedure-related mortality and worse long-term outcomes.
The five-year survival rate was only 25 percent, Even so, five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 percent, only about one-fifth of whom have a sustained disease remission. More so, approximately one-third of five-year survivors suffer a cancer-related death, while those who survive 10 years appear to be cured (4).
Because of its clear survival impact, surgical resection is the treatment of choice when feasible. Unfortunately, no more than 20 percent of patients with isolated hepatic metastases are amenable to potentially curative resection. Most are not surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.
Patient candidates for resection – The criteria for resectability differ among individual liver surgeons regarding borderline cases, from center to center and from country to country. One consensus statement defined absolute unresectability as nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (1,2). Patients are evaluaed using preoperative liver MRI and intraoperative ultrasound which offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures.
Modern multidisciplinary consensus for resectable CRC liver metastases:
- Tumors that can be resected completely (leaving an adequate liver remnant)
- No involvement of the hepatic artery, major bile ducts, main portal vein, orceliac/paraaortic lymph nodes
- Adequate predicted functional hepatic reserve postresection
Criteria for unresectable liver metastases (5):
- Pateitns with more than three lesions, those
- Patients with bilobar distribution (ie, tumor involving any segments of the left and right hemi-liver),
- Patients in whom it was not possible to achieve 1 cm margins,
- Patients with portal lymph node or other extrahepatic metastases, and
- Patients with liver metastases from cancers other than colorectal tumors
Some of these exclusion criteria have been challenged.
- Better and safer surgical techniques are now more suitable for patients with multiple, even bilobar tumors.
- A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases
- Achieving wide margins doesn’t increase the 5-year survival. **** Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate.
- Presence of portal lymph node metastases – still been challenged and results are controversy.
- A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases. The presence of portal node metastases is not inevitably associated with distant metastases. Outcome was more favorable if nodal involvement was limited to the porta as compared to along the common hepatic artery.
- The presence of other sites of limited extrahepatic metastases (particularly lung) should not be considered a contraindication to resection as long as the disease is amenable to complete extirpation. However, outcomes in this group are not as favorable, particularly when there are >6 liver metastases.
Diagnostic Laparoscopy
In modern treatment paradigms, laparoscopy is infrequently performed, particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor. Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease.
A growing number of authors report that staging laparoscopy (including laparoscopic US) performed under general anesthesia just prior to planned resection will identify 16 to 64 percent of patients with unresectable disease.
This approach is particularly useful in identifying small peritoneal metastases, additional hepatic metastases, and unsuspected cirrhosis. Laparoscopy in this setting is less likely to identify lymph node metastases, vascular compromise, and extensive biliary involvement that might render a patient unresectable (2,6).
Neoadjuvant chemotherapy
The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection. It may be considered as a means of “downsizing” liver metastases prior to resection to lessen the complexity of hepatic metastasectomy or for initially unresectable metastatic disease (1). Chemotherapy, has many side effects including liver toxicity such as: steatosis (chemotherapy-associated steatohepatitis, CASH), vascular injury, and nodular regenerative hyperplasia in the livers.
Due to high number of patients with liver toxicity and morbidity, these instructions have been suggested:
- For low-risk (medically fit, four or fewer lesions), potentially resectable patients, initial surgery rather than neoadjuvant chemotherapy should be chosen, followed by postoperative chemotherapy.
- For patients who have higher risk, borderline resectable or unresectable disease, neoadjuvant chemotherapy is the preferred approach.
Neoadjuvant Chemotherapy Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following:
- FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
- FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) or
- FOLFOXIRI alone
Bevacizumab – Its addition to traditional chemotherapy results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab. However, these benefits have come at the cost of significant treatment-related toxicity. Such as: such as stroke and arterial thromboembolic events, bowel perforation and bleeding. Data regarding the need and timing of use of bevacizumab is somewhat conflicting.
Cetuximab (if K-ras wild type) and panitumumab (if K-ras wild type) are also suggested as part of the chemotherapy regimen in certain clinics are regional dependent.
Intraarterial (HIA) chemotherapy – The administration of chemotherapy into the hepatic artery. The benefit of this approach is remains unclear. A combined approach of HIA floxuridine plus systemic chemotherapy (oxaliplatin plus irinotecan) was explored in a single institution study of 49 patients with initially unresectable CRC liver metastases. Overall, 92 percent had either a complete or partial response rate to chemotherapy, and 23 (43 percent) were able to undergo a later resection, 19 with negative margins. The median overall survival from pump placement for the entire cohort was 40 months (1, 7). Another approach is HIA oxaliplatin combined with systemic 5-FU and leucovorin for patients with initially unresectable but isolated hepatic CRC metastasis.
It should be noted that this approach is not used by many clinicians outside of New York City. The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial.
Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis, administration into the portal vein has been explored as an alternative. hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply. Like HIA infusion, portal vein infusion (PVI) carries with it a significant regional exposure advantage.
The potential benefit of adjuvant PVI with FUDR after resection or ablation of isolated hepatic metastases was evaluated in two trials conducted at the City of Hope Medical Center (1, 8). The benefit of this approach was somewhat lower than has been reported with HIA FUDR and systemic 5-FU. Therefore, the use of this approach is limited.
Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy through the use of yttrium-labeled microspheres. Radiation therapy (RT) has traditionally had a limited role in the treatment of liver tumors, primarily because of the low whole-organ tolerance of the liver to radiation (9). When radiation is applied to the entire liver, RT doses of 30 to 33 Gy carry about a 5% risk of radiation-induced liver disease (RILD). The risk rises rapidly, such that by 40 Gy, the risk is approximately 50%. Considering that most solid tumors require RT doses higher than 60 Gy to provide a reasonable chance for local control, it is not surprising that wholeorgan liver RT provides only a modest palliative benefit rather than durable tumor control. Hepatic dysfunction after RT is a very frequent event.
Summary:
Liver metastasis are a very tough disease to battle and the outcome is not encouraging. Currently, surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer. For appropriately selected patients with four or fewer metastases, five-year relapse-free survival rates average 30 percent. Diagnostic laparoscopy is suggested only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging and for selected other cases at high risk for intraperitoneal metastatic disease. The optimal chemotherapy regimen is still not fully established but some suggestions have been made and the benefits of using HIA is still not clear.
Standardization of scoring, timing, surgical techniques , results from clinical trials and advanced research will offer better hope for these patients, who now, have a very bad prognosis and survival rates.
Reference:
1. Venook AP and Curley SA. Management of potentially resectable colorectal cancer liver metastases. UpToDate Jun 2013. http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases
2. Smith AJ., DeMatteo RP., Fong Y and Blumgart LH. Metastatic Liver Cancer. HEPATOBILIARY CANCER. http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/Hepatobiliary%20Cancer/DOCS/Ch4.pdf
3. Wu XZ., Ma F., and Wang XL. Serological diagnostic factors for liver metastasis in patients with colorectal cancer. World J Gastroenterol. 2010 August 28; 16(32): 4084–4088. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928464/
4. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575. http://www.ncbi.nlm.nih.gov/pubmed?term=17925551
5. Tanabe KK. Palliative liver resections. J Surg Oncol. 2002;80(2):69. http://onlinelibrary.wiley.com/doi/10.1002/jso.10108/abstract;jsessionid=F19964733A4A1A2708A0BA0E274CF586.d01t03
6. Ravikumar TS. Laparoscopic staging and intraoperative ultrasonography for liver tumor management. Surg Oncol Clin N Am 1996;5:271–282. http://www.ncbi.nlm.nih.gov/pubmed/9019351
7, Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, Jarnagin WR, Patel D, D’Angelica M. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646304/
8. Faynsod M, Wagman LD, Longmate J, Carroll M, Leong LA. Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.J Clin Oncol. 2005;23(22):4876. http://www.ncbi.nlm.nih.gov/pubmed?term=16009960
9. I. Frank Ciernik and Theodore S. Lawrence. Radiation Therapy for Liver Tumors. Book: Systemic and Regional Therapies. Chapter 7. http://www.jblearning.com/samples/0763718572/Chapter_07.pdf
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