Liver Metastasis

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Management of potentially resectable colorectal cancer liver metastases
INTRODUCTION

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• 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.
• The available regional treatments for hepatic metastases from CRC include
• surgical resection,
• local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions,
• cryotherapy,
• radiofrequency ablation [RFA]),
• regional hepatic intraarterial chemotherapy or
• chemoembolization, and
• radiation therapy (RT).
• Although hepatic resection used to be reserved for patients with a maximum of three lesions in the same lobe if it was possible to achieve 1 cm margins and those without portal lymph node metastases, all of these "rules" have been challenged in the modern era

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BIOPSY CONFIRMATION

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The risk of tract seeding from percutaneous fine needle aspiration (FNA) biopsy appears small

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SURGICAL RESECTION

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• Resection offers the greatest likelihood of cure for patients with liver-isolated CRC.
• five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent
• surgical mortality rates are generally <5 percent
• Patient selection
• absolute unresectability as nontreatable extrahepatic disease,
• unfitness for surgery, or
• involvement of more than 70 percent of the liver or six segments
• resectable CRC liver metastases simply as tumors that can be resected completely, leaving an adequate liver remnant
• For resection to be considered,
o no radiographic evidence of involvement of the hepatic artery, major bile ducts, main portal vein, or celiac/paraaortic lymph nodes
o adequate predicted functional hepatic reserve postresection.
• Preoperative liver MRI and
• intraoperative ultrasound offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures.
• Number and location of metastases — One of the classic contraindications to hepatectomy is the presence of portal lymph node metastases, thought to indicate systemic disease that could not be successfully treated surgically.
• PET scans — Guidelines from the NCCN recommend a staging PET scan for patients with potentially surgically curable metastatic colorectal cancer.
• Selecting patients for diagnostic laparoscopy — We use diagnostic laparoscopy in patients with a suspicion of small volume carcinomatosis on radiographic imaging studies (ie, CT, MRI, or PET) and for selected other cases at high risk (eg, a metachronous presentation with several liver metastases that do not respond to chemotherapy).

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NEOADJUVANT CHEMOTHERAPY

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• Conversion therapy for initially unresectable metastases — induction chemotherapy in patients with isolated but initially unresectable CRC liver metastases
• 12 and 33 percent of such patients have a sufficient objective response to permit a subsequent complete (R0) resection
• Five-year survival rates average 30 to 35 percent,
• complete pathologic response rate after neoadjuvant chemotherapy is only 4 to 9 percent
Choice of regimen
Guidelines from the NCCN suggest any of the following regimens are appropriate [22]:
• FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
• FOLFOX or CAPOX or FOLFIRI plus cetuximab or panitumumab (wild-type K-ras only)
• FOLFOXIRI (in the setting of synchronous metastatic disease)
• For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months, FOLFIRI with or without bevacizumab, or FOLFIRI with cetuximab or panitumumab (for wild-type K-ras only) is recommended.
• Guidelines from the NCCN further recommend that patients be reevaluated for conversion to resectable disease every two months [22].
Preoperative hepatic intraarterial (HIA) chemotherapy - when neoadjuvant therapy is required, systemic rather than regional therapy is indicated.
Initially resectable disease —
• whether there is a net benefit for upfront chemotherapy as compared to resection followed by adjuvant chemotherapy for patients with potentially resectable CRC liver metastases remains uncertain.
• Although we generally prefer immediate resection followed by chemotherapy for patients with potentially resectable disease, neoadjuvant chemotherapy is an acceptable approach, especially for borderline resectable disease [22].
• 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.
• Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following regimens:
• FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
• FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only)

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LOCAL OPTIONS FOR INCOMPLETELY RESECTED METASTATIC DISEASE

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Radiofrequency ablation (RFA) or cryosurgery is sometimes applied following macroscopically incomplete resection of CRC liver metastases or if there are incidentally found small lesions that are surgically inaccessible.

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TIMING OF HEPATECTOMY IN PATIENTS PRESENTING WITH METASTASES —

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delaying hepatic surgery by three to six months would permit the biological behavior of the metastatic disease to become evident, thus improving the selection of patients for whom hepatic metastasectomy might be curative.
Delayed resection does not seem to increase the risk of patients becoming unresectable due to growth of the initial metastases, although if patients are untreated during this interval, it can increase the volume of resected liver, a significant predictor of postoperative complications.

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THERAPY AFTER RESECTION OF LIVER METASTASES

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Systemic chemotherapy
NCCN recommendations —
• total of six months of perioperative therapy with an active systemic chemotherapy regimen for patients who have undergone resection of hepatic metastases from colorectal cancer
• FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
• FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only)
Regional therapy —
Hepatic intraarterial chemotherapy alone —A later German trial was closed prematurely when interim analysis suggested a worse outcome from HIA
HIA plus systemic therapy — hepatic arterial infusion with or without systemic 5-FU and leucovorin is a reasonable approach after liver resection at institutions with experience in both the surgical and medical aspects of this therapy.
HIA plus other local approaches — use of HIA chemotherapy in that setting should be considered investigational.
Portal vein infusion — the role for this approach appears to be limited.
Systemic radioimmunotherapy

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SURVEILLANCE AFTER METASTASECTOMY

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Comparison of updated 2005 colorectal cancer surveillance guidelines from the American Society of Clinical Oncology (ASCO) and from the National Comprehensive Cancer Network (NCCN)
American Society of Clinical Oncology (ASCO) National Comprehensive Cancer Network (NCCN)
History and physical examination
Every three to six months for the first three years; every six months during years 4 and 5, then annually thereafter. Every three to six months for the first two years; then every six months for a total of five years.
Carcinoembryonic antigen
Serum CEA testing should be performed every three months for at least three years in patients with stage II or III colon or rectal cancer if they would otherwise be candidates for surgery or systemic therapy. Since adjuvant 5-FU-based therapy can falsely elevate the serum CEA, waiting until adjuvant therapy is finished to initiate surveillance is advised. Every three to six months for the first two years, then every six months for a total of five years for T2 or higher stage disease, if patient is a potential candidate for resection of isolated metastases.
Liver function tests
Not recommended Not recommended
Complete blood cell count
Not recommended Not recommended
Fecal occult blood test
The data are sufficient to recommend against periodic FOBTs in surveillance for colorectal cancer recurrence*. Not recommended
Chest x-ray
Not recommended Not recommended
Computed tomography
Patients with colon or rectal cancer at higher risk of recurrence (stage III or stage II with multiple poor risk features) should undergo annual CT of the chest and abdomen for three years if they would otherwise be eligible for curative intent surgery. Annual CT of the chest, abdomen, and pelvis for three years for patients at high risk of recurrence (lymphatic or venous invasion, or poorly differentiated tumors).
Annual pelvic CT for three years should be considered for rectal cancer surveillance, particularly if the patient has not been treated with pelvic radiation therapy. For resected stage IV disease: CT every three to six months for two years then every six to 12 months for a total of five years.
Colonoscopy
All patients with colon or rectal cancer should have a full colonoscopy in the preoperative or perioperative setting to document a cancer-free and polyp-free colon. Patients who present with an obstructing cancer should undergo full colonoscopy within six months of surgery. Repeat colonoscopy is recommended at three years, and if normal, every five years thereafter. For patients with high-risk genetic syndromes, the panel recommended that the screening guidelines of the American Gastroenterology Association be followed•. Colonoscopy in one year. If year one study shows advanced adenoma (villous polyp, any polyp >1 cm, or high-grade dysplasia), repeat in one year. If negative for polyps or not advanced adenoma, repeat in three years then every five years. If no preoperative colonoscopy due to obstructing lesion, colonoscopy in three to six months.
Flexible proctosigmoidoscopy, rectal cancer
For patients who have not received pelvic radiation therapy, direct imaging of the rectum with flexible proctosigmoidoscopy is recommended every six months for five years. Proctosigmoidoscopy every six months for five years if status post low anterior resection for rectal cancer.
Consensus-based guidelines from the NCCN recommend the following surveillance strategy for patients with stage IV disease who are rendered surgically NED (no evidence of disease):
• CEA every three months for two years, then every six months for three to five years
• CT of the chest/abdomen and pelvis every three to six months for two years, then every 6 to 12 months up to a total of five years
• Colonoscopy in one year; if no advanced adenoma repeat in three years, then every five years; if advanced adenoma is found, repeat in one year

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REPEAT RESECTION FOR RECURRENT METASTASES

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Although randomized trials have not been conducted to prove benefit, repeat hepatic resection may be considered in selected patients who recur in the liver with no evidence of extrahepatic disease, and a good performance status. In several reported series, perioperative mortality rates were less than 5 percent, and relapse-free survival rates ranged from 20 to 43 percent at two to five years (table 9) [16,42,158-170].
Patients with a relapse-free interval of longer than one year appear to have a more favorable outcome from reresection [157,162]. Other factors associated with a poor outcome include synchronous resection for the first liver metastases, and the presence of multiple lesions at second hepatectomy [163,164,168].

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Management of potentially resectable colorectal cancer liver metastases
SUMMARY AND RECOMMENDATIONS —

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• The only potentially curative option for patients with liver-isolated metastatic colorectal cancer is surgical resection.
• surgical exploration should only be ruled out in the following situations:
• Extensive unresectable extrahepatic disease as detected by CT and/or PET scans
• Radiographic evidence of involvement of the hepatic artery, major bile ducts, or main portal vein
• Extensive liver involvement (>70 percent, more than six segments (figure 1), or involvement of all three hepatic veins)
• Inadequate postresection functional hepatic reserve
• We suggest not using a clinical risk score to select patients for diagnostic laparoscopy (Grade 2C).
• We perform an initial diagnostic laparoscopy only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging
• We suggest immediate surgical resection for medically fit patients with four or fewer isolated hepatic metastases (Grade 2B).
• For patients with a good performance status who have more than four metastases (unless all are localized to a single lobe), radiographic suspicion for portal node involvement, or bilobar disease (ie, tumor involving any segments of the left and right hemi-liver), we suggest initial systemic chemotherapy followed by surgical reevaluation
• if preoperative chemotherapy is selected, the number of courses should be minimized.
• Radiographic response assessment should be performed at six week intervals, and surgery undertaken as soon as the metastases are clearly resectable.
• Chemotherapie reasonable choices:
• FOLFOX with or without bevacizumab (table 5 and table 6),
• FOLFOXIRI, or FOLFIRI plus cetuximab (for patients whose tumors lack K-ras mutations)
• We prefer a bevacizumab plus oxaliplatin or irinotecan-based combination regimen, or FOLFOXIRI.
• Guidelines from the NCCN suggest two to three months of therapy with any of the following regimens [22]:
• FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
• FOLFOX or FOLFIRI plus cetuximab or panitumumab (wild-type K-ras only)
• FOLFOXIRI (only for synchronous initially unresectable liver metastases)
• For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months, FOLFIRI with or without bevacizumab, or FOLFIRI with cetuximab or panitumumab (for wild-type K-ras only) is recommended (see 'Choice of regimen' above)
• Following complete resection of liver metastases,
• relative benefit and indications for HIA chemotherapy in patients with hepatic metastases from CRC remains uncertain.
• Although this approach is followed in some institutions, we suggest that it not be used (Grade 2C)
• we suggest a six month course of systemic chemotherapy containing oxaliplatin (Grade 2C).
• We recommend against the use of an irinotecan-based regimen in this setting
• Guidelines from the NCCN suggest a shorter course of postoperative therapy or observation alone for patients who have received neoadjuvant chemotherapy,

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Nonsurgical local treatment strategies for colorectal cancer liver metastases

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• For patients who could be considered surgical candidates if their metastases were smaller, we suggest initial systemic chemotherapy followed by reevaluation for surgery
• For patients with a limited number or metastases who are felt to be unable to tolerate surgery, we suggest regional tumor ablation rather than initial systemic chemotherapy (Grade 2C).
• If the decision is made to perform tumor ablation, we
• recommend radiofrequency ablation (RFA) as the procedure of choice (Grade 1B).
• The best results with RFA are in patients with three or fewer lesions, 5 cm or less in diameter, that are not located near major vascular structures.
• The regional administration of chemotherapy for intrahepatic metastases is based upon sound pharmacological principles and appears to increase the activity of 5-FU-based chemotherapy.
• the relative benefit of hepatic intraarterial chemotherapy for patients with hepatic metastases from CRC remains unclear, particularly when compared to the efficacy of newer systemic chemotherapy regimens.
• Although this approach is followed in some institutions, we suggest that it not be used (Grade 2C).
• The place of radioembolization in the therapeutic armamentarium, particularly its utility in patients treated with modern combination chemotherapy, is unclear, and we suggest that it not be used (Grade 2B).