Predictors of Survival After Radiofrequency Thermal Ablation of Colorectal Cancer Metastases to the Liver: A Prospective Study
http://www.100md.com
《临床肿瘤学》
the Department of General Surgery, and Hematology & Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH
ABSTRACT
PATIENTS AND METHODS: One hundred thirty-five patients with colorectal liver metastases who were not candidates for resection underwent laparoscopic RFA.
RESULTS: The median Kaplan-Meier survival for all patients was 28.9 months after RFA treatment. Patients with a carcinoembryonic antigen (CEA) less than 200 ng/mL had improved survival compared with those with a CEA more than 200 (34 v 16 months; P = .01). Patients with the dominant lesion less than 3 cm in diameter had a median survival of 38 v 34 months for lesions 3 to 5 cm, and 21 months for lesions greater than 5 cm (P = .03). Survival approached significance for patients with one to three tumors versus more than three tumors (29 v 22 months; P = .09). The presence of extrahepatic disease did not affect survival. Only the largest liver tumor size more than 5 cm was found to be a significant predictor of mortality by Cox proportional hazards model, with a 2.5-fold increased risk of death versus the largest liver tumor size less than 3 cm (P = .05).
CONCLUSION: This study determines which patients do best after RFA. Historical survival with chemotherapy alone is 11 to 14 months, suggesting RFA has a positive impact on overall survival. Limited amounts of extrahepatic disease do not appear to affect survival adversely. RFA is a useful adjunct to chemotherapy in those patients with liver-predominant disease.
INTRODUCTION
The management of these patients with liver metastases from colorectal cancer is a therapeutic challenge for surgeons and oncologists. Although surgical resection is the gold standard for treatment, only 10% to 20% of the patients are candidates for resection because of extensive disease or medical comorbidities. The remaining patients would traditionally make a decision with their oncologist to either undergo systemic chemotherapy or do nothing. However, in the recent years, a number of regional treatment methods have emerged to be an option for these patients, including chemoembolization, intrahepatic arterial infusion pumps, cryotherapy, and radiofrequency thermal ablation (RFA).4,5
RFA is a recently developed method of locally destroying primary and secondary liver tumors. The basic principle of RFA includes generation of high-frequency alternating current (approximately 400 MHz) that causes ionic agitation that is converted to heat, which induces cellular death as a result of coagulation necrosis. The procedure was initially performed percutaneously and via open surgery.6 Our group has had an interest in laparoscopic applications of this technology. We previously reported the safety and efficacy in a phase II trial.7
Recent studies have suggested a survival benefit for patients with colorectal liver metastases undergoing RFA compared with historical controls undergoing chemotherapy alone.8 Nevertheless, there are little data on predictors of survival. The aim of this study was to determine factors that might predict survival at the time of RFA in patients with colorectal liver metastases.
PATIENTS AND METHODS
The specific selection criteria for RFA included unresectable liver disease; predominant liver disease (however, with minor additional extrahepatic disease); enlarging liver lesions, worsening of symptoms, and/or failure to respond to other treatment modalities; fewer than eight liver metastases on preoperative computed tomography (CT) scan (nevertheless, some of the patients have additional liver lesions detected at the time of RFA due to the increased sensitivity of laparoscopic ultrasound, and these patients were not excluded from treatment); less than 20% of total liver volume replaced with tumor, based on the review of the CT scan by the radiologist and the surgeon; and normal biliary ductal diameters.
Within the same time period, 44 patients underwent liver resection for colorectal metastasis at the General Surgery Department of the Cleveland Clinic Foundation.
Statistical Analysis
To determine parameters at the time of the RFA that might predict survival, a number of variables were analyzed, including age, sex, the type of primary tumor (colon v rectal), nodal status of primary tumor, the type of liver metastases (synchronous v metachronous), the location of liver metastases (unilobar v bilobar), the number of liver metastases, the size of the largest liver metastases, preoperative chemotherapy, extrahepatic disease, and serum carcinoembryonic antigen (CEA) levels. Liver metastasis diagnosed at the same time as the original colorectal tumor was considered synchronous, and that diagnosed after the original colorectal tumor was considered metachronous. Survival time was measured in months after RFA. Cut points for continuous measures (age, number of lesions, tumor size, and CEA levels) were applied to convert these into ordinal-scale predictors to correspond with clinical categories used in the published literature or to create subgroups with more evenly distributed numbers of patients. Because all predictors were coded as either ordinal data or categoric data (eg, sex), univariate Kaplan-Meier survival analyses were applied. Posthoc comparisons between groups were performed using the log-rank test. Any predictors that were significant at P ≤ .15 in the Kaplan-Meier univariate analyses were candidates for entry into a multivariate Cox proportional hazards model. Data were analyzed using Statview 5.0.1 (SAS Institute Inc, Cary, NC) on a Macintosh personal computer (OS 9.2.1). Analyses were performed separately for disease-free or progression-free survival and overall survival. The patients who had extrahepatic disease at the time of RFA treatment were excluded from the analyses for disease-free or progression-free survival. Follow-up ranged between 1 and 52 months depending on how far out the patients were from the RFA procedure at the time of this analysis.
Extrahepatic Disease
Forty patients (30%) had extrahepatic disease at the time of RFA. These extrahepatic sites included aortocaval or periportal enlarged lymph nodes in 17 patients, lungs in 13 patients, peritoneum in five patients, diaphragm in three patients, and the abdominal wall in two patients. Peritoneal, diaphragmatic, and abdominal wall implants were not evident on preoperative CT scans and in most patients comprised up to several nodules less than 1 cm. Lung lesions varied from a single nodule to multiple nodules bilaterally.
Surgical Technique
Details of our laparoscopic RFA technique have been described in previous reports.7,9 In most cases, patients are monitored overnight and discharged home the morning after surgery. Within 1 week before surgery, triphasic CT scans of the liver (noncontrast, arterial, and portal-venous) were performed. Preoperative laboratory tests included a CBC, electrolytes, liver function tests, coagulation studies, and serum CEA levels. Follow-up studies included liver CT scan and laboratory studies repeated at 1 week and every 3 months postoperatively (Fig 1).
RESULTS
The median progression-free survival was 6 months for the patients who did not have extrahepatic disease at the time of RFA (Fig 7). In these patients, the initial recurrence was detected as a new liver metastasis in 53%, local recurrence (at the site of ablation) in 46%, lung metastasis in 23%, extrahepatic abdominal lesion in 17%, and brain metastasis in 1% of the patients. Univariate analysis identified only CEA level as a significant predictor of recurrence after RFA: the patients with a CEA less than 200 ng/mL had a significantly longer progression-free survival than those with a CEA more than 200 ng/mL (6 v 3 months, respectively; P = .01). Risk of disease progression by Cox proportional hazards model was 1.9 for CEA more than 200 ng/mL, 1.7 for the size of the largest liver lesion more than 5 cm, and 1.3 for the size of the largest liver lesion 3 to 5 cm (Table 4). However, none of these factors was statistically significant (P > .05). There was no effect of the other parameters in progression-free survival.
DISCUSSION
In this study, by analyzing multiple parameters related to the patient demographics, original colorectal primary tumor, and liver metastases, we determined parameters that identify the patients who do best after RFA of colorectal liver metastases. These are prognostic criteria at the time of the RFA treatment and include number and size of liver metastases, serum CEA level by univariate analysis, and tumor size by multivariate analysis. Thirty-three percent of the patients had minor extrahepatic disease, and it is of note that minor extrahepatic disease at the time of RFA did not effect survival.
Fong et al10 studied prognostic factors in 1,001 patients undergoing resection of colorectal liver metastases. They identified seven independent predictors of poor prognosis: positive margin, extrahepatic disease, node-positive primary, disease-free interval from primary to metastases less than 12 months, number of hepatic tumors more than one, largest hepatic tumor more than 5 cm, and CEA level more than 200 ng/mL. They derived a preoperative scoring system by assigning one point for each criterion and concluded that patients with up to two criteria could have a favorable outcome. They recommended experimental adjuvant trials for patients with three or more criteria.
In another study, Scheele et al11 examined indicators of prognosis after hepatic resection for colorectal secondaries. They found the following factors to be associated with less favorable crude survival: presence and extent of mesenteric lymph node involvement, grade 3 or 4 primary tumor, synchronous diagnosis of metastases, satellite metastases, limited resection margins, and nonanatomic procedures. In this group, 26 of 207 patients (13%) had extrahepatic disease with no difference in disease-free or overall survival.
It is not possible to compare hepatic resection series with RFA series like ours that include patients who have failed all conventional treatment options, such as resection in some and systemic chemotherapy in most, in which ablation is performed with a palliative intent, in contrast to the curative intent in liver resection. Conversely, the prognostic criteria in our study parallel those of the liver resection studies. A common finding in the resection series and our study is that the amount of liver tumor burden, as suggested by the number and size of liver metastases and serum CEA level, determine survival. The patients in our study had a predominance of liver disease and because most of the patients with liver metastasis die from progression of hepatic disease, these prognostic factors are not surprising. We also speculate that this is why limited amount of extrahepatic disease was not found to affect survival in our study. Although another explanation could be that pre-RFA chemotherapy resulted in stabilization of extrahepatic disease, thereby nullifying its effect on survival, a major indication for referral to our RFA program was a failure or lack of continued response to chemotherapy. Given that more advanced disease is treated with RFA in a palliative intent, specific features of the primary tumor may be more important in liver resection for prognosis because they determine tumor aggressivity.
Seifert and Morris12 investigated the prognostic factors in 116 patients with colorectal liver metastases undergoing cryotherapy and found that low serum level of CEA (< 5 ng/mL), small (≤ 3 cm) diameter of ablated metastases, absence of untreated extrahepatic disease at laparotomy, absence of nodal involvement at primary resection, complete cryotreatment, synchronous development of liver metastases, and good or moderate differentiation of the primary tumor were independently associated with a favorable outcome. In this group, 11 of 116 patients (10%) had extrahepatic disease. Six patients had their extrahepatic disease resected at the time of the cryotherapy, whereas five patients did not have resection. There was a survival difference between the patients with no extrahepatic disease and those who did not have resection of their extrahepatic disease (P = .0024). There was no difference in survival, conversely, between patients without extrahepatic disease and those who had resection of their extrahepatic disease at the time of cryoablation. The patients treated in our study had more advanced disease, as evidenced by 30% having extrahepatic disease compared with 10% in this study.12 Although the findings regarding the prognostic value of the extent of liver disease are similar to those of our study, the significances detected for the presence of untreated extrahepatic disease and primary tumor characteristics suggest that these factors might have more prognostic implications in less advanced disease compared with more advanced stage when the disease has been systemically established. The amount of liver tumor burden then creates the difference in survival when these patients are treated with locoregional methods.
Although 30% of the patients had extrahepatic disease at the time of RFA in our study, it was possible to calculate the median progression-free survival in the remaining patients, which was 6 months. These results show that because all of the patients have extensive disease at the time of their referral, it is not unusual to discover recurrent disease shortly after RFA, but extrahepatic disease at the time of RFA should not be used as an exclusion criterion. Although disease-free survival has been a useful parameter to follow in traditional surgical series in which excision is done with a curative intent, we do not expect it to be as useful in our group of patients with a high incidence of known extrahepatic disease at the time of RFA, or who are likely to develop extrahepatic disease in follow-up. The purpose of RFA in these patients is to decrease the risk of death from progression of liver disease, as we found that progression of liver disease contributed to the cause of death in 70% of the patients who died in follow-up.
The other treatment modalities for patients with unresectable colorectal liver metastases include percutaneous alcohol injection chemoembolization and hepatic artery infusion (HAI). Percutaneous alcohol injection, although an option for small hepatocellular carcinoma, has been found to be ineffective for treating colorectal liver metastases.13 Chemoembolization enables minimal survival advantage compared with chemotherapy; a high rate of complications is related to the therapy. Studies involving patients with colorectal liver metastases have reported tumor response between 29% to 63%, with a median survival ranging between 8.6 to 14 months.14,15 HAI has allowed for higher response rates and downstaging of unresectable liver disease in patients with colorectal liver metastases. Randomized trials evaluating the treatment of unresectable disease with HAI therapy have demonstrated higher response rates (31% to 50%) than those seen with systemic chemotherapy (8% to 20%) but no survival benefit. HAI is also commonly associated with locoregional toxicity.16,17
Overall, the results of this prospective study are encouraging and suggest a survival advantage when compared with chemotherapy alone. Limited amounts of extrahepatic disease do not appear to affect survival adversely. Although our sample size might be insufficient for making decisive conclusions on the nonsignificance of the potential risk factors, we believe that RFA is a useful adjunct to chemotherapy in this group of patients.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Presented as a poster at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Kavolius J, Fong Y, Blumgart LH: Surgical resection of metastatic liver tumors. Surg Oncol Clin N Am 5:337-352, 1996
2. Blumgart LH, Fong Y: Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 32:333-421, 1995
3. Saltz L, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000
4. Cady B, Stone MD: The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 18:399-406, 1991
5. Siperstein A, Garland A, Engle K, et al: Local recurrence after laparoscopic radiofrequency thermal ablation of hepatic tumors. Ann Surg Oncol 7:106-113, 2000
6. Rossi S, Di Stasi M, Buscarini E, et al: Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol 167:759-768, 1996
7. Siperstein A, Garland A, Engle K, et al: Laparoscopic radiofrequency ablation of primary and metastatic liver tumors: Technical considerations. Surg Endosc 14:400-405, 2000
8. Siperstein A, Rogers SJ, Machi J, et al: Longterm follow-up of patients undergoing radiofrequency thermal ablation for primary and metastatic liver tumors: A multicenter trial. Presented at Am Coll Surg Clin Congress, San Francisco, CA, October 2002 (abstr)
9. Berber E, Flesher NL, Siperstein AE: Initial clinical evaluation of the RITA 5-centimeter radiofrequency thermal ablation catheter in the treatment of liver tumors. Cancer J Sci Am 6:S319-S329, 2000
10. Fong Y, Fortner J, Sun R, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999
11. Scheele J, Stangl R, Altendorf-Hofmann A, et al: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110:13-29, 1991
12. Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228:201-208, 1998
13. Amin Z, Bown SG, Lees WR: Local treatment of colorectal liver metastases: A comparison of interstitial laser photocoagulation (ILP) and percutaneous alcohol injection (PAI). Clin Radiol 48:166-171, 1993
14. Tellez C, Benson AB, Lyster MT, et al: Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer 82:1250-1259, 1998
15. Leichman CG, Jacobson JR, Modiano M, et al: Hepatic chemoembolization combined with systemic infusion of 5-fuorouracil and bolus leucovorin for patients with metastatic colorectal carcinoma: A Southwest Oncology Group pilot trial. Cancer 86:775-781, 1999
16. Elaraj DM, Alexander HR: Current role of hepatic artery infusion and isolated liver perfusion for the treatment of colorectal cancer liver metastases. Cancer J 10:128-138, 2004
17. Kerr DJ, McArdle CS, Ledermann J, et al: Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: A multicentre randomised trial. Lancet 361:368-373, 2003(Eren Berber, Robert Pelle)
ABSTRACT
PATIENTS AND METHODS: One hundred thirty-five patients with colorectal liver metastases who were not candidates for resection underwent laparoscopic RFA.
RESULTS: The median Kaplan-Meier survival for all patients was 28.9 months after RFA treatment. Patients with a carcinoembryonic antigen (CEA) less than 200 ng/mL had improved survival compared with those with a CEA more than 200 (34 v 16 months; P = .01). Patients with the dominant lesion less than 3 cm in diameter had a median survival of 38 v 34 months for lesions 3 to 5 cm, and 21 months for lesions greater than 5 cm (P = .03). Survival approached significance for patients with one to three tumors versus more than three tumors (29 v 22 months; P = .09). The presence of extrahepatic disease did not affect survival. Only the largest liver tumor size more than 5 cm was found to be a significant predictor of mortality by Cox proportional hazards model, with a 2.5-fold increased risk of death versus the largest liver tumor size less than 3 cm (P = .05).
CONCLUSION: This study determines which patients do best after RFA. Historical survival with chemotherapy alone is 11 to 14 months, suggesting RFA has a positive impact on overall survival. Limited amounts of extrahepatic disease do not appear to affect survival adversely. RFA is a useful adjunct to chemotherapy in those patients with liver-predominant disease.
INTRODUCTION
The management of these patients with liver metastases from colorectal cancer is a therapeutic challenge for surgeons and oncologists. Although surgical resection is the gold standard for treatment, only 10% to 20% of the patients are candidates for resection because of extensive disease or medical comorbidities. The remaining patients would traditionally make a decision with their oncologist to either undergo systemic chemotherapy or do nothing. However, in the recent years, a number of regional treatment methods have emerged to be an option for these patients, including chemoembolization, intrahepatic arterial infusion pumps, cryotherapy, and radiofrequency thermal ablation (RFA).4,5
RFA is a recently developed method of locally destroying primary and secondary liver tumors. The basic principle of RFA includes generation of high-frequency alternating current (approximately 400 MHz) that causes ionic agitation that is converted to heat, which induces cellular death as a result of coagulation necrosis. The procedure was initially performed percutaneously and via open surgery.6 Our group has had an interest in laparoscopic applications of this technology. We previously reported the safety and efficacy in a phase II trial.7
Recent studies have suggested a survival benefit for patients with colorectal liver metastases undergoing RFA compared with historical controls undergoing chemotherapy alone.8 Nevertheless, there are little data on predictors of survival. The aim of this study was to determine factors that might predict survival at the time of RFA in patients with colorectal liver metastases.
PATIENTS AND METHODS
The specific selection criteria for RFA included unresectable liver disease; predominant liver disease (however, with minor additional extrahepatic disease); enlarging liver lesions, worsening of symptoms, and/or failure to respond to other treatment modalities; fewer than eight liver metastases on preoperative computed tomography (CT) scan (nevertheless, some of the patients have additional liver lesions detected at the time of RFA due to the increased sensitivity of laparoscopic ultrasound, and these patients were not excluded from treatment); less than 20% of total liver volume replaced with tumor, based on the review of the CT scan by the radiologist and the surgeon; and normal biliary ductal diameters.
Within the same time period, 44 patients underwent liver resection for colorectal metastasis at the General Surgery Department of the Cleveland Clinic Foundation.
Statistical Analysis
To determine parameters at the time of the RFA that might predict survival, a number of variables were analyzed, including age, sex, the type of primary tumor (colon v rectal), nodal status of primary tumor, the type of liver metastases (synchronous v metachronous), the location of liver metastases (unilobar v bilobar), the number of liver metastases, the size of the largest liver metastases, preoperative chemotherapy, extrahepatic disease, and serum carcinoembryonic antigen (CEA) levels. Liver metastasis diagnosed at the same time as the original colorectal tumor was considered synchronous, and that diagnosed after the original colorectal tumor was considered metachronous. Survival time was measured in months after RFA. Cut points for continuous measures (age, number of lesions, tumor size, and CEA levels) were applied to convert these into ordinal-scale predictors to correspond with clinical categories used in the published literature or to create subgroups with more evenly distributed numbers of patients. Because all predictors were coded as either ordinal data or categoric data (eg, sex), univariate Kaplan-Meier survival analyses were applied. Posthoc comparisons between groups were performed using the log-rank test. Any predictors that were significant at P ≤ .15 in the Kaplan-Meier univariate analyses were candidates for entry into a multivariate Cox proportional hazards model. Data were analyzed using Statview 5.0.1 (SAS Institute Inc, Cary, NC) on a Macintosh personal computer (OS 9.2.1). Analyses were performed separately for disease-free or progression-free survival and overall survival. The patients who had extrahepatic disease at the time of RFA treatment were excluded from the analyses for disease-free or progression-free survival. Follow-up ranged between 1 and 52 months depending on how far out the patients were from the RFA procedure at the time of this analysis.
Extrahepatic Disease
Forty patients (30%) had extrahepatic disease at the time of RFA. These extrahepatic sites included aortocaval or periportal enlarged lymph nodes in 17 patients, lungs in 13 patients, peritoneum in five patients, diaphragm in three patients, and the abdominal wall in two patients. Peritoneal, diaphragmatic, and abdominal wall implants were not evident on preoperative CT scans and in most patients comprised up to several nodules less than 1 cm. Lung lesions varied from a single nodule to multiple nodules bilaterally.
Surgical Technique
Details of our laparoscopic RFA technique have been described in previous reports.7,9 In most cases, patients are monitored overnight and discharged home the morning after surgery. Within 1 week before surgery, triphasic CT scans of the liver (noncontrast, arterial, and portal-venous) were performed. Preoperative laboratory tests included a CBC, electrolytes, liver function tests, coagulation studies, and serum CEA levels. Follow-up studies included liver CT scan and laboratory studies repeated at 1 week and every 3 months postoperatively (Fig 1).
RESULTS
The median progression-free survival was 6 months for the patients who did not have extrahepatic disease at the time of RFA (Fig 7). In these patients, the initial recurrence was detected as a new liver metastasis in 53%, local recurrence (at the site of ablation) in 46%, lung metastasis in 23%, extrahepatic abdominal lesion in 17%, and brain metastasis in 1% of the patients. Univariate analysis identified only CEA level as a significant predictor of recurrence after RFA: the patients with a CEA less than 200 ng/mL had a significantly longer progression-free survival than those with a CEA more than 200 ng/mL (6 v 3 months, respectively; P = .01). Risk of disease progression by Cox proportional hazards model was 1.9 for CEA more than 200 ng/mL, 1.7 for the size of the largest liver lesion more than 5 cm, and 1.3 for the size of the largest liver lesion 3 to 5 cm (Table 4). However, none of these factors was statistically significant (P > .05). There was no effect of the other parameters in progression-free survival.
DISCUSSION
In this study, by analyzing multiple parameters related to the patient demographics, original colorectal primary tumor, and liver metastases, we determined parameters that identify the patients who do best after RFA of colorectal liver metastases. These are prognostic criteria at the time of the RFA treatment and include number and size of liver metastases, serum CEA level by univariate analysis, and tumor size by multivariate analysis. Thirty-three percent of the patients had minor extrahepatic disease, and it is of note that minor extrahepatic disease at the time of RFA did not effect survival.
Fong et al10 studied prognostic factors in 1,001 patients undergoing resection of colorectal liver metastases. They identified seven independent predictors of poor prognosis: positive margin, extrahepatic disease, node-positive primary, disease-free interval from primary to metastases less than 12 months, number of hepatic tumors more than one, largest hepatic tumor more than 5 cm, and CEA level more than 200 ng/mL. They derived a preoperative scoring system by assigning one point for each criterion and concluded that patients with up to two criteria could have a favorable outcome. They recommended experimental adjuvant trials for patients with three or more criteria.
In another study, Scheele et al11 examined indicators of prognosis after hepatic resection for colorectal secondaries. They found the following factors to be associated with less favorable crude survival: presence and extent of mesenteric lymph node involvement, grade 3 or 4 primary tumor, synchronous diagnosis of metastases, satellite metastases, limited resection margins, and nonanatomic procedures. In this group, 26 of 207 patients (13%) had extrahepatic disease with no difference in disease-free or overall survival.
It is not possible to compare hepatic resection series with RFA series like ours that include patients who have failed all conventional treatment options, such as resection in some and systemic chemotherapy in most, in which ablation is performed with a palliative intent, in contrast to the curative intent in liver resection. Conversely, the prognostic criteria in our study parallel those of the liver resection studies. A common finding in the resection series and our study is that the amount of liver tumor burden, as suggested by the number and size of liver metastases and serum CEA level, determine survival. The patients in our study had a predominance of liver disease and because most of the patients with liver metastasis die from progression of hepatic disease, these prognostic factors are not surprising. We also speculate that this is why limited amount of extrahepatic disease was not found to affect survival in our study. Although another explanation could be that pre-RFA chemotherapy resulted in stabilization of extrahepatic disease, thereby nullifying its effect on survival, a major indication for referral to our RFA program was a failure or lack of continued response to chemotherapy. Given that more advanced disease is treated with RFA in a palliative intent, specific features of the primary tumor may be more important in liver resection for prognosis because they determine tumor aggressivity.
Seifert and Morris12 investigated the prognostic factors in 116 patients with colorectal liver metastases undergoing cryotherapy and found that low serum level of CEA (< 5 ng/mL), small (≤ 3 cm) diameter of ablated metastases, absence of untreated extrahepatic disease at laparotomy, absence of nodal involvement at primary resection, complete cryotreatment, synchronous development of liver metastases, and good or moderate differentiation of the primary tumor were independently associated with a favorable outcome. In this group, 11 of 116 patients (10%) had extrahepatic disease. Six patients had their extrahepatic disease resected at the time of the cryotherapy, whereas five patients did not have resection. There was a survival difference between the patients with no extrahepatic disease and those who did not have resection of their extrahepatic disease (P = .0024). There was no difference in survival, conversely, between patients without extrahepatic disease and those who had resection of their extrahepatic disease at the time of cryoablation. The patients treated in our study had more advanced disease, as evidenced by 30% having extrahepatic disease compared with 10% in this study.12 Although the findings regarding the prognostic value of the extent of liver disease are similar to those of our study, the significances detected for the presence of untreated extrahepatic disease and primary tumor characteristics suggest that these factors might have more prognostic implications in less advanced disease compared with more advanced stage when the disease has been systemically established. The amount of liver tumor burden then creates the difference in survival when these patients are treated with locoregional methods.
Although 30% of the patients had extrahepatic disease at the time of RFA in our study, it was possible to calculate the median progression-free survival in the remaining patients, which was 6 months. These results show that because all of the patients have extensive disease at the time of their referral, it is not unusual to discover recurrent disease shortly after RFA, but extrahepatic disease at the time of RFA should not be used as an exclusion criterion. Although disease-free survival has been a useful parameter to follow in traditional surgical series in which excision is done with a curative intent, we do not expect it to be as useful in our group of patients with a high incidence of known extrahepatic disease at the time of RFA, or who are likely to develop extrahepatic disease in follow-up. The purpose of RFA in these patients is to decrease the risk of death from progression of liver disease, as we found that progression of liver disease contributed to the cause of death in 70% of the patients who died in follow-up.
The other treatment modalities for patients with unresectable colorectal liver metastases include percutaneous alcohol injection chemoembolization and hepatic artery infusion (HAI). Percutaneous alcohol injection, although an option for small hepatocellular carcinoma, has been found to be ineffective for treating colorectal liver metastases.13 Chemoembolization enables minimal survival advantage compared with chemotherapy; a high rate of complications is related to the therapy. Studies involving patients with colorectal liver metastases have reported tumor response between 29% to 63%, with a median survival ranging between 8.6 to 14 months.14,15 HAI has allowed for higher response rates and downstaging of unresectable liver disease in patients with colorectal liver metastases. Randomized trials evaluating the treatment of unresectable disease with HAI therapy have demonstrated higher response rates (31% to 50%) than those seen with systemic chemotherapy (8% to 20%) but no survival benefit. HAI is also commonly associated with locoregional toxicity.16,17
Overall, the results of this prospective study are encouraging and suggest a survival advantage when compared with chemotherapy alone. Limited amounts of extrahepatic disease do not appear to affect survival adversely. Although our sample size might be insufficient for making decisive conclusions on the nonsignificance of the potential risk factors, we believe that RFA is a useful adjunct to chemotherapy in this group of patients.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Presented as a poster at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Kavolius J, Fong Y, Blumgart LH: Surgical resection of metastatic liver tumors. Surg Oncol Clin N Am 5:337-352, 1996
2. Blumgart LH, Fong Y: Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 32:333-421, 1995
3. Saltz L, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000
4. Cady B, Stone MD: The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 18:399-406, 1991
5. Siperstein A, Garland A, Engle K, et al: Local recurrence after laparoscopic radiofrequency thermal ablation of hepatic tumors. Ann Surg Oncol 7:106-113, 2000
6. Rossi S, Di Stasi M, Buscarini E, et al: Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol 167:759-768, 1996
7. Siperstein A, Garland A, Engle K, et al: Laparoscopic radiofrequency ablation of primary and metastatic liver tumors: Technical considerations. Surg Endosc 14:400-405, 2000
8. Siperstein A, Rogers SJ, Machi J, et al: Longterm follow-up of patients undergoing radiofrequency thermal ablation for primary and metastatic liver tumors: A multicenter trial. Presented at Am Coll Surg Clin Congress, San Francisco, CA, October 2002 (abstr)
9. Berber E, Flesher NL, Siperstein AE: Initial clinical evaluation of the RITA 5-centimeter radiofrequency thermal ablation catheter in the treatment of liver tumors. Cancer J Sci Am 6:S319-S329, 2000
10. Fong Y, Fortner J, Sun R, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999
11. Scheele J, Stangl R, Altendorf-Hofmann A, et al: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110:13-29, 1991
12. Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228:201-208, 1998
13. Amin Z, Bown SG, Lees WR: Local treatment of colorectal liver metastases: A comparison of interstitial laser photocoagulation (ILP) and percutaneous alcohol injection (PAI). Clin Radiol 48:166-171, 1993
14. Tellez C, Benson AB, Lyster MT, et al: Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer 82:1250-1259, 1998
15. Leichman CG, Jacobson JR, Modiano M, et al: Hepatic chemoembolization combined with systemic infusion of 5-fuorouracil and bolus leucovorin for patients with metastatic colorectal carcinoma: A Southwest Oncology Group pilot trial. Cancer 86:775-781, 1999
16. Elaraj DM, Alexander HR: Current role of hepatic artery infusion and isolated liver perfusion for the treatment of colorectal cancer liver metastases. Cancer J 10:128-138, 2004
17. Kerr DJ, McArdle CS, Ledermann J, et al: Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: A multicentre randomised trial. Lancet 361:368-373, 2003(Eren Berber, Robert Pelle)