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Annals of Surgical Oncology 10:348-354 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Feasibility of Adjuvant Hepatic Arterial Infusion of Chemotherapy After Radiofrequency Ablation With or Without Resection in Patients With Hepatic Metastases From Colorectal Cancer

Courtney L. Scaife, MD, Steven A. Curley, MD, Francesco Izzo, MD, Paolo Marra, MD, Paolo Delrio, MD, Bruno Daniele, MD, Franco Cremona, MD, Jeffrey E. Gershenwald, MD, Judy L. Chase, PharmD, Richard D. Lozano, RPh, Yehuda Z. Patt, MD, Bruno D. Fornage, MD, Jean Nicolas Vauthey, MD, Misty L. Woodall, ADN, Karen B. Gonzalez, PA and Lee M. Ellis, MD

From the Departments of Surgical Oncology (CLS, SAC, JEG, JNV, MLW, KBG, LME), Gastrointestinal Medical Oncology (YZP), and Diagnostic Radiology (BDF) and the Division of Pharmacy (JLC, RDL), The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and the Department of Surgery (FI, PM, PD, BD, FC), the G. Pascale National Tumor Institute, Naples, Italy.

Correspondence: Address correspondence and reprint requests to: Lee M. Ellis, MD, Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 444, Houston, TX 77030-4009; Fax: 713-792-4689; E-mail: lellis{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The safety of combined hepatic artery infusion chemotherapy (HAI) and radiofrequency ablation (RFA) for liver metastases has not been assessed. We conducted a study to determine the feasibility of using HAI after RFA for colorectal cancer (CRC) liver metastases.

Methods: Between 1996 and 2001, patients with hepatic metastases from CRC were enrolled onto a prospective study of RFA plus HAI consisting of continuous-infusion floxuridine and bolus fluorouracil. Surgical complications, treatment-related toxicities, and patient outcomes were recorded.

Results: Fifty patients were treated with RFA and HAI with or without resection. A median of two lesions per patient, with a median greatest diameter of 2.0 cm, were treated with RFA. Postoperative complications, including 1 death, occurred in 11 of 50 patients. Toxicity from HAI was relatively mild. At 20 months’ median follow-up, 32% of patients remained disease free. Ten percent of patients had recurrences at the site of RFA, 30% developed new liver metastases, and 48% developed extrahepatic disease.

Conclusions: RFA of CRC liver metastases followed by HAI is feasible and is associated with acceptable complication and toxicity rates. The high rate of disease recurrence in our patients indicates that novel combinations of regional and systemic therapies are needed to improve patient outcomes.

Key Words: Radiofrequency ablation • Hepatic artery infusion • Colorectal cancer • Hepatic metastases


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The liver is the most common site of distant metastasis in patients with colorectal carcinoma. Autopsy studies have shown that 83% of patients with metastatic colorectal adenocarcinoma have metastases to the liver.1 Surgical resection of hepatic metastases in patients with liver-only disease may provide a long-term survival benefit compared with nonsurgical therapies.2,3 However, fewer than 10% of patients with hepatic metastases from colorectal cancer are eligible for resection with curative intent.4–6 For colorectal cancer metastases to the liver that are deemed unresectable, radiofrequency ablation (RFA) is increasingly the treatment of choice.7

Despite aggressive surgical approaches to hepatic metastasis, locoregional recurrence is common. After RFA, several studies have reported a 5% to 30% recurrence rate at the site of thermal ablation.4,8–10 In addition, another 20% to 55% of patients develop new hepatic metastases distinct from the thermally ablated lesions.4,11–13

Hepatic arterial infusion (HAI) of chemotherapeutic agents has also been used to treat unresectable liver metastases, albeit with palliative intent. Hepatic metastases derive most of their blood supply from the hepatic artery, whereas the normal liver tissue is perfused primarily by the portal vein. With HAI, significantly greater concentrations of chemotherapeutic agents can be delivered directly to the tumor while relatively smaller doses are delivered to the normal liver tissue.14,15 Improved tumor response rates have been reported with HAI versus systemic chemotherapy.16 However, an overall survival advantage with HAI therapy over systemic therapy has been difficult to demonstrate. The combination of HAI with systemic chemotherapy has been used in the adjuvant setting after surgical resection of colorectal cancer liver metastases, with a suggestion that this approach increases the overall survival rate.17,18

Adjuvant regional chemotherapy after RFA is a potential means of decreasing the recurrence rate and increasing the overall survival rate associated with RFA alone. However, the safety of regional intra-arterial chemotherapy after RFA of liver metastases has not been assessed. We conducted a prospective study to determine the feasibility, safety, and outcome of adjuvant HAI chemotherapy after RFA alone or combined with resection of dominant lesions for colorectal cancer liver metastases.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between 1996 and 2001, patients with hepatic metastases from colorectal cancer were enrolled onto a prospective study of RFA (with or without resection) plus adjuvant HAI chemotherapy. The study was approved by the institutional review boards at the University of Texas M. D. Anderson Cancer Center, Houston, TX, and the G. Pascale National Tumor Institute, Naples, Italy; written, informed consent was obtained from all participants. Patients with seven or fewer metastatic lesions that could not be resected but that were amenable to RFA alone or RFA of smaller tumors combined with resection of large lesions were eligible for this study. Patients were excluded if they had a history of liver irradiation, had a Zubrod performance status >2, had received chemotherapy or radiotherapy within 10 days before entry onto the study, had extrahepatic disease found on exploration, had gross ascites, had cirrhosis, or had active gastric or duodenal ulcers.

All patients underwent a baseline evaluation that included a history and physical examination, serum tests of liver function, computed tomography or magnetic resonance imaging of the abdomen and pelvis, and chest radiography. All patients underwent intraoperative evaluation for extrahepatic disease and intraoperative hepatic ultrasonography to determine the extent of hepatic disease. RFA was performed during an open surgical procedure with the patient under general anesthesia. Patients were treated with an RF 2000 (100 W maximum power) or 3000 (200 W maximum power) generator system (Radio Therapeutics Corp., Mountain View, CA). The RF generator is used with a LeVeen (Radio Therapeutics Corp.) multiple array needle electrode placed directly into the tumor. The LeVeen needle electrode was deployed in situ under ultrasound guidance. The ablation was initiated at 50 to 80 W and increased in 10-W increments until the "roll-off" phenomenon (power output decreases precipitously as tissue impedance increases) was observed. Patients who had bilobar disease or multiple lesions not amenable to complete surgical resection underwent resection in addition to RFA. In these cases, the more involved lobe or larger lesions were resected, and the lesions in the contralateral lobe or the remaining smaller lesions were treated with RFA.

After RFA, with or without resection, an HAI pump catheter was placed in the gastroduodenal artery as previously described.16 Catheter placement and liver perfusion were confirmed during surgery by injection into the pump sideport with 5 mL of fluorescein while perfusion was visualized with a Wood’s lamp. Before patient discharge from the hospital, a radionuclide study was performed to reconfirm catheter placement and total liver perfusion. Patients were to receive six monthly cycles of adjuvant HAI chemotherapy, which consisted of continuous-infusion floxuridine (.1 mg/kg days 1–7) and bolus fluorouracil (12.5 mg/kg days 15, 22, and 29). Chemotherapy was initiated within 35 days after RFA and HAI pump placement.

Patients were followed up every 3 months with computed tomography or magnetic resonance imaging of the abdomen, chest radiography, serum liver function tests, complete blood counts, and measurements of carcinoembryonic antigen level. Surgical complications and treatment-related toxicities were scored and recorded in a prospective database at each follow-up visit. Recurrence of disease at the site of RFA treatment, new hepatic lesions, and new distant metastatic disease were also recorded.

Statistical analysis of the data was completed by using a Fisher’s exact test calculated with InStat 2.03 software (GraphPad software, San Diego, CA). A P value of <.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
Fifty patients underwent intraoperative RFA of 112 hepatic lesions along with placement of an HAI chemotherapy pump (Table 1). The median age of the patients was 55 years (range, 31–74 years). Seventeen patients were women, and 33 were men. A median of two lesions per patient (range, one to seven) were treated with RFA. The median greatest diameter of the RFA-treated lesions was 2.0 cm (range, .5–8.5 cm). Thirty-one patients also underwent hepatic resection (7 nonanatomical and 24 anatomical resections) to remove additional hepatic metastases.


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  		TABLE 1. Characteristics of patients undergoing intraoperative radiofrequency ablation (RFA) and adjuvant hepatic arterial infusion chemotherapy for colorectal cancer liver metastases (n = 50)
 
Complications and Toxicity
There was one perioperative death (2%) in this series; the patient died of adult respiratory distress syndrome and multisystem organ failure. Postoperative complications occurred in nine other patients (18%): perihepatic abscesses occurred in three patients (6%), and pneumonia, atrial fibrillation, partial small-bowel obstruction, recurrent cholangitis, biloma, and bleeding occurred in one patient (2%) each.

Adverse events associated with the pump and catheter occurred in 8 (16%) of 49 assessable patients. One catheter became dislodged from the artery before chemotherapy was initiated. Two pump-site wound infections occurred, requiring only local wound care. Two pump-site seromas and one hematoma developed. Two catheters thrombosed; one of these was successfully opened with urokinase, and chemotherapy was completed.

HAI therapy had notable toxic effects in 17 (35%) of the 48 patients assessable for toxicity. Toxicities included pain and flulike symptoms (seven patients; 15%), gastritis/duodenitis (three patients; 6%), mucositis (three patients; 6%), significantly increased transaminases (two patients; 4%), and hand-foot syndrome (two patients; 4%). Four of the 17 patients with chemotherapy-related toxicity were able to complete the six cycles of chemotherapy despite their symptoms.

Thirty-one (62%) of the patients in this study completed the full prescribed course of chemotherapy. Two patients (4%) did not begin chemotherapy: one patient who died perioperatively and one patient who developed recurrent cholangitis after surgery. Of the 17 patients (34%) who began but did not complete the planned course of chemotherapy, 8 received all 6 scheduled cycles but at a decreased dose of floxuridine as a result of a trend toward increasing transaminase values. Nine of the 17 patients received the planned dosage of chemotherapy per cycle but discontinued treatment after the fourth or fifth cycle as a result of toxicities.

Table 2 compares the patients who had RFA and HAI with the patients who underwent RFA plus hepatic resection and HAI. The postoperative complication rate was higher in the patients who underwent resection, RFA, and placement of the HAI pump when compared with RFA and HAI pump placement (P = .04). The rates of chemotherapy-related toxicity, complications with the HAI pump and catheter, and failure to complete the planned course of chemotherapy did not differ between patients who were treated with RFA plus resection and HAI compared with those who underwent RFA and HAI only. The comparative complication rates between the two institutions are listed in Table 3.


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  		TABLE 2. Complications and toxicity rates of radiofrequency ablation (RFA) with adjuvant hepatic arterial infusion chemotherapy (HAI) versus RFA, adjuvant HAI, and surgical resection
 

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  		TABLE 3. Treatment outcomes and complication rates between the two study institutions
 
Outcomes
The median follow-up from the date of surgery for all patients was 20 months (range, 1–67 months). The median follow-up for patients who died of colorectal cancer was 14 months, and the median follow-up of survivors was 24 months. At the time of last follow-up, 16 (32%) of 50 patients remained free of disease, 17 (34%) were alive with disease, and 17 (34%) were dead of disease, including the patient who died perioperatively.

Local (RFA site) hepatic tumor recurrence was observed in 5 (10%) of 50 patients but in only 5 (4%) of the 112 RFA-treated lesions (Fig. 1). New liver metastases developed in 15 patients (30%), and extrahepatic metastatic disease developed in 24 patients (48%). Surgical resection in addition to RFA did not significantly affect recurrence rates (Table 4). Thirty-five of the 50 patients included in this study underwent RFA of a lesion located within 5 mm of a major hepatic artery, hepatic vein, portal vein branch, or the inferior vena cava. Four of the five local tumor recurrences occurred in tumors adjacent to major vascular structures. The comparative patient outcomes between the two institutions are listed in Table 3.



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  		FIG. 1. Tumor recurrence after radiofrequency ablation with or without resection plus hepatic arterial infusion chemotherapy. Median follow-up, 20 months.

 

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  		TABLE 4. Tumor recurrence rates and patient outcomes after radiofrequency ablation (RFA) with adjuvant hepatic arterial infusion chemotherapy (HAI) versus RFA, adjuvant HAI, and surgical resectiona
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The 5-year survival rate of patients undergoing surgical therapy for colorectal cancer hepatic metastases is limited, despite multiple advances in this field. After hepatic resection for colorectal cancer metastases, the 5-year survival rate remains only 25% to 38%.19–21 Unfortunately, only approximately 10% of patients have surgically resectable hepatic metastases. For this reason, modern treatment modalities, including adjuvant chemotherapy and ablative therapy, have been used in an attempt to improve survival in patients with liver metastases. Systemic chemotherapy has had minimal effect on patients with metastatic colorectal cancer.22–25 The limited success with systemic chemotherapy has led to alternative strategies, including the use of regional chemotherapy, such as HAI chemotherapy. Early studies of regional chemotherapy indicated a modest survival advantage compared with systemic chemotherapy.26,27 Trials were also initiated that combined regional chemotherapy with surgical resection to prevent local disease recurrence, because up to 60% of patients with resected or ablated hepatic metastases experience hepatic tumor recurrences.28 Kemeny et al.18 investigated the use of HAI with systemic chemotherapy after hepatic metastasectomy. Patients were randomized to receive 5 days of systemic fluorouracil (325 mg/m2) and leucovorin (200 mg/m2) or the same systemic chemotherapy alternating with floxuridine (.25 mg/kg/day for 14 days) by HAI. The overall 2-year survival rate was 86% in the HAI group versus 72% in the control arm (P = .03). In another recently reported study, Kemeny et al.29 compared adjuvant systemic and HAI chemotherapy (regional floxuridine at .1 mg/kg/day) for 14 days followed by continuous systemic intravenous infusion of fluorouracil (200 mg/m2) versus no adjuvant therapy after surgical resection of hepatic metastases. In that study, no significant difference was shown in median survival (49 months for the control arm vs. 63 months for assessable treated patients; P = .6) or the 4-year survival rate (52% vs. 61% for the controls and treated patients, respectively; P = .6). However, the hepatic tumor recurrence rate was significantly decreased in the chemotherapy arm (34% vs. 57%; P = .04). These trials provide some evidence of the efficacy of regional chemotherapy after resection of colorectal cancer hepatic metastases.

This study was conducted to determine the feasibility, safety, and outcome of adjuvant HAI chemotherapy after RFA with or without resection for colorectal cancer liver metastases. Treatment feasibility can be assessed by determining the percentage of patients who were able to complete all of the planned therapy without toxicity or complications that required dose reduction or cessation of treatment. In this study, all of the patients underwent RFA with or without surgical resection plus HAI pump placement, and the rate of chemotherapy complications was low. Remarkably, 62% of the patients completed the entire prescribed course of chemotherapy. Because this series was planned as a feasibility study, a conservative adjuvant therapy regimen was intentionally used. Therefore, the ability to compare our findings with those in other regional therapy trials is limited; nevertheless, the chemotherapy regimen in this series was very well tolerated compared with others reported in the literature (Table 5).


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  		TABLE 5. Reported hepatic arterial infusion (HAI) chemotherapy complication and toxicity rates
 
The HAI device-related complication rate in our series was only 16%, which is comparable to or better than other studies’ reported 22% to 42% complication rates associated with implanted HAI devices after surgical resection (Table 5).18,29–31 We recently reviewed the complication rates in several published series of RFA and found that the mortality rate in the combined studies was .5%, the major complication rate was 2% (range, 0%–9%), and the minor complication rate was 6% (range, 0%–28%).32 Table 6 compares the reported complication rates of published RFA series with the data from our study of RFA and HAI chemotherapy. Although the postoperative complication rate in this study is higher than that for RFA alone, this is to be expected given that many of our patients also had major liver resection and all had surgical HAI pump placement. Published series of RFA include many patients treated with percutaneous ablation for small peripheral lesions. The complication rate after percutaneous RFA of liver tumors is low, commensurate with the minimally invasive nature of the approach.4,7 The principal disadvantages of percutaneous RFA are incomplete staging of the extent of liver disease, inadequate assessment for the presence of extrahepatic disease, and incomplete thermal destruction of the tumors, manifested as markedly higher local recurrence rates compared with intraoperative RFA.32 Although the postoperative complication rate in our series is higher than percutaneous RFA complication rates, it is equivalent to the reported 25% to 40% complication rates of major hepatic resections.33–35 Thus, the addition of RFA and HAI pump placement to resection does not seem to have increased the postoperative complication rate.


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  		TABLE 6. Complication rates and patient outcomes from published reports of RFA versus this series
 
Table 6 compares the disease recurrence patterns and patient outcomes in published RFA studies and the current RFA plus HAI chemotherapy study. Although the intent of regional chemotherapy after RFA is to reduce hepatic tumor recurrence rates, the rate of local recurrences in our series did not differ from the rates seen after RFA with no local adjuvant therapy. The failure to prevent recurrence of hepatic disease may be related to the regional chemotherapy regimen we used, although previous studies with this regimen in patients with unresectable colorectal cancer liver metastases showed response rates in excess of 60%.36 The patients enrolled in our trial had advanced, surgically unresectable, or bilobar disease, which also may have contributed to the higher local tumor recurrence rate. The failure to achieve local tumor control seems to correlate with failure to increase patient survival by using the combination of regional chemotherapy and tumor ablation. Disease-free and overall survival rates may be improved by using higher doses of floxuridine or different combinations of regional and systemic chemotherapeutic agents. Randomized studies of innovative drug and dosing regimens are necessary to identify the ideal regional and systemic chemotherapy for colorectal cancer liver metastases.

In conclusion, our study demonstrates that RFA of colorectal cancer liver metastases followed by adjuvant HAI therapy is feasible and is associated with acceptable complication and chemotherapy-related toxicity rates. However, the high rate of disease recurrence in the liver and at extrahepatic sites in our patients indicates that novel combinations of regional and systemic therapy are still needed if we are to improve patient outcomes.


   Acknowledgments
 
Misty L. Woodall, research nurse, is supported in part by Radio Therapeutics Corp. The authors thank Vicki Ellis from the Department of Surgical Oncology for database management and Melissa G. Burkett from the Department of Scientific Publications for editorial assistance.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
Presented at the 55th Annual Cancer Symposium of the Society of Surgical Oncology, Denver, Colorado, March 14–17, 2002.

This study demonstrates that radiofrequency ablation of liver metastases can be combined with adjuvant hepatic arterial infusion chemotherapy with no increase in the complication rate. However, tumor recurrence does not seem to be reduced by local adjuvant therapy after radiofrequency ablation.

Received for publication August 27, 2002. Accepted for publication December 20, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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