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Annals of Surgical Oncology 9:148-155 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Systemic Irinotecan and Regional Floxuridine After Hepatic Cytoreduction in 185 Patients With Unresectable Colorectal Cancer Metastases

David A. Litvak, MD, Thomas F. Wood, MD, George J. Tsioulias, MD, DMSc, Mathew Chung, MD, Sant P. Chawla, MD, Leland J. Foshag, MD, Donald L. Morton, MD, Kenneth P. Ramming, MD and Anton J. Bilchik, MD, PhD

From the Division of Surgical Oncology (DAL, TFW, GJT, MC, LJF, DLM, AJB), John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, California; and Century City Hospital (SPC, LJF, KPR, AJB), Los Angeles, California.

Correspondence: Address correspondence and reprint requests to: Anton J. Bilchik, MD, PhD, 2200 Santa Monica Blvd., Santa Monica, CA 90404; Fax: 310-449-5261; E-mail: bilchika{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: This study evaluated our 7-year experience treating unresectable colorectal cancer (CRC) hepatic metastases refractory to systemic 5-fluorouracil.

Methods: A total of 185 patients with unresectable 5-fluorouracil-resistant CRC hepatic metastases underwent surgical cytoreduction. Postoperatively patients received either hepatic arterial floxuridine (FUDR) and systemic irinotecan as part of a phase II trial or no further treatment.

Results: Of the 185 patients undergoing surgical cytoreduction, 71 patients received adjuvant irinotecan/FUDR. There were no appreciable differences in synchronous or metachronous lesions or the median number or size of lesions between treatment groups. At a median follow-up of 20 months, there were fewer recurrences in patients treated with postoperative irinotecan/FUDR compared with untreated patients for both hepatic and extrahepatic recurrences. Progression-free and overall survival were longer for patients who received irinotecan/FUDR compared with patients who did not receive adjuvant therapy. The 2-year survival rate was significantly better for patients receiving adjuvant therapy compared with patients receiving no additional treatment. Predictors of improved survival included a preoperative carcinoembryonic antigen level <100 ng/dl, >30% postoperative reduction in carcinoembryonic antigen level, and adjuvant therapy.

Conclusions: Combined therapy with irinotecan/FUDR may improve the results of surgical cytoreduction for unresectable CRC hepatic metastases.

Key Words: Cytoreductive surgery • Cryosurgical ablation • Irinotecan • Floxuridine • Metastatic colorectal cancer • Regional chemotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
More than 130,000 new cases of colorectal cancer (CRC) are diagnosed annually, and >56,000 deaths are attributed to CRC each year.1 This represents 10% of cancer-related deaths in the United States and is second only to lung cancer.1 At the time of diagnosis, 20% to 25% of patients with CRC present with synchronous hepatic metastasis; an additional 20% to 25% of patients may develop metachronous liver metastasis.2–4 Complete surgical resection of liver metastasis offers the only chance for cure2–4 and produces 5-year survival rates of 25% to 40% associated with a median survival of 25 to 40 months.2–5 Unfortunately, however, only 20% of patients will have completely resectable liver disease. The majority of patients will not undergo surgical resection either because of the presence of hepatic dysfunction or because the number or location of hepatic lesions precludes safe or complete extirpation. Untreated colorectal hepatic metastases are associated with a 5-year survival of <1%.6,7 In addition, as many as two thirds of patients who do undergo resection will experience disease recurrence.8 Collectively, these findings have been the impetus for developing ablative techniques for destroying unresectable liver tumors and for developing chemotherapeutic regimens, such as regional therapy through hepatic artery infusion.

Cytoreductive surgery combines ablative modalities, such as cryosurgical ablation (CSA) or radiofrequency ablation (RFA), with standard resection (when possible) to completely treat all tumor burden in patients with otherwise nonoperable hepatic metastases. CSA is a technique that incorporates freezing malignant tissues with liquid nitrogen and has been applied safely to the destruction of liver tumors in patients with unresectable CRC metastasis.5,9 With this therapeutic modality, tumors can be precisely defined and completely eradicated under ultrasound guidance while normal tissue is spared. A median survival of up to 26 to 30 months has been reported for patients treated with CSA alone or in combination with hepatic resection.9,10 Moreover, in selected cases, the results of CSA may approach those of surgical resection for metastatic CRC.5,9,11,12 Nevertheless, as with hepatic resection, the majority of patients experience disease recurrence after CSA.

Although certain chemotherapy regimens by themselves have produced modest benefits in the treatment of patients with metastatic CRC, overall the results from systemic chemotherapy have been disappointing.13–17 The administration of systemic 5-fluorouracil (5-FU) has been the mainstay of treatment of these patients, but it has produced response rates of only 10% to 20% in clinical trials.18 Researchers have recognized the need for either novel therapeutic agents or delivery systems that better target metastatic CRC cells. Hepatic artery infusion with the fluoropyrimidine floxuridine (FUDR) offers the advantage of selectively treating predominantly arterial-fed hepatic tumors at 100- to 400-fold higher concentrations than systemic 5-FU with minimal toxicity because of almost complete extraction of the drug by the liver.19–22 FUDR produces response rates of 40% to 60% and seems to improve patient outcome, compared with standard systemic chemotherapy alone.19–23 In addition, the topoisomerase I inhibitor irinotecan (Camptosar; Pharmacia & Upjohn Co, Kalamazoo, MI) has been shown to be effective against both untreated and refractory metastatic CRC.24,25 In the studies by Rougier et al.26 and Saltz et al.27 involving patients with advanced CRC, median survival was significantly greater in the group treated with irinotecan in addition to 5-FU or 5-FU/leucovorin (LV), compared with 5-FU or 5-FU/LV alone. Largely on the basis of these and other studies, irinotecan, in combination with 5-FU and LV, is now used as standard first-line therapy for metastatic CRC. Nevertheless, the effects of combined therapy with FUDR and irinotecan in addition to either hepatic resection or cytoreductive surgery for metastatic CRC are still unknown and under investigation. This study evaluated the role of cytoreductive surgery alone and in combination with both regional FUDR and systemic irinotecan in the treatment of patients with unresectable CRC hepatic metastases refractory to 5-FU.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A total of 185 patients with unresectable hepatic metastases that had progressed (defined by changes noted on computed tomography scan, by increased or increasing carcinoembryonic antigen [CEA] levels, or both) while being treated with 5-FU underwent cytoreductive surgery between July 1992 and August 1999 at the John Wayne Cancer Institute and Century City Cancer Center. Two hundred twelve procedures were performed (with 25 patients undergoing 2 procedures and 1 patient undergoing 3 procedures). All patients had a histological diagnosis of adenocarcinoma of the colon or rectum. Curative resection was the primary treatment regimen, but when hepatic metastases were thought to be incompletely resectable because of patient liver dysfunction, the location or number of hepatic lesions, or both, cytoreductive surgery consisting of CSA with or without hepatic resection was considered. Patients with <50% liver involvement, a good performance status, and absence of extrahepatic disease were considered candidates for cytoreduction. Patients undergoing cytoreduction had complete treatment of all identifiable sites of disease.

Patients were treated with cytoreductive surgery alone in an early period between 1992 and 1996. In a late period between July 1996 and August 1999, patients were entered onto a phase II trial after cytoreduction. Informed consent was obtained for this trial under the approved guidelines of the participating institutional review boards. This trial evaluated irinotecan at a maximal dose of 125 mg/m2 every week and hepatic artery infusion consisting of FUDR (.18–.2 mg/kg), dexamethasone (10 mg), and in some cases LV (10 mg/m2). Treatment with FUDR was planned for six cycles, starting 2 weeks after cytoreduction. Treatment with irinotecan also was planned for six cycles 4 weeks after surgery. The dose of either irinotecan or FUDR was then adjusted according to patient tolerance. A postoperative computed tomography scan was obtained at 1 week, at 1 month, and then at 3-month intervals. CEA levels were obtained preoperatively, at 1 month, and then every 3 months.

Technique of CSA
During laparotomy, the liver was completely mobilized, and intraoperative ultrasound was performed with the 7.5-MHz linear array transducer (Aloka Ultrasound, Wallingford, CT) to better delineate the extent and location of disease. Liver resection was performed in the standard fashion in addition to CSA when feasible. Up to five insulated CSA probes (3 and 8 mm) were placed into the tumors under ultrasound guidance (CMS Accuprobe System; Cryo Medical Sciences, Rockville, MD). Liquid nitrogen was then circulated at -196°C, and each lesion was frozen for 15 minutes or until a 1-cm margin circumferentially was achieved with the ablation. The freezing process was monitored with real-time ultrasound. Although there were subtle advances in both the ultrasound and CSA technology during the study period, there were no major changes in technique.

Technique of Pump Insertion
The hepatic artery infusion pump was inserted in a standard fashion, with the infusion catheter (Arrow, Inc., Walpole, MA) being inserted into the gastroduodenal artery with its tip at the junction of the hepatic artery. Hepatic perfusion was confirmed intraoperatively with 10 ml of fluorescein and an ultraviolet Wood’s light and then reconfirmed postoperatively with a nuclear medicine study.

Statistical Analysis
Overall survival and progression-free survival were estimated from the time of surgery to first recurrence of disease or death, respectively, by the Kaplan-Meier method. Comparisons were made between survival curves by using log-rank and Wilcoxon tests. We assessed the effect of prognostic factors (univariate analysis) on survival by using a Cox proportional hazards model. Analysis of the combined effects of prognostic factors (multivariate analysis) was not performed because of the moderate size of the treatment groups. Statistical significance was defined as P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Eighty-eight percent of patients treated in this study had been treated previously with 5-FU-based chemotherapy for a median of 6 months, and this treatment had failed. These patients received 5-FU and LV as part of either the Mayo Clinic regimen28 (425 and 20 mg/m2, respectively, daily for 5 days every 4 weeks) or the Roswell Park regimen29 (600 and 500 mg/m2, respectively, weekly for 6 weeks followed by a 2-week rest). Although patients described in this study were from distinctly different periods (1992–1996 and 1996–1999), the patient characteristics were comparable in each treatment group (Table 1). There were 114 patients who were treated with cytoreductive surgery alone and 71 patients who received irinotecan and FUDR in addition to cytoreduction. The median number (3–4) and size (4 cm) of lesions treated were comparable for each group. Thirty percent of patients had synchronous hepatic metastases and 70% of patients had metachronous metastases in each group. Forty-four patients (24%) had unilobar lesions, and 141 patients (76%) had bilobar lesions. The median preoperative CEA level was 159 ng/dl (range, .2–4000 ng/dl). Sixty-seven patients (36%) underwent concurrent liver resections. Approximately 80% of patients completed at least three cycles of FUDR treatment. Total dose reductions in FUDR of >50% were necessary in approximately 40% of patients. Thirty percent of patients treated with irinotecan required dose reductions because of toxicity. These rates of dose reductions in FUDR and irinotecan were similar to those reported previously.18,27


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  		TABLE 1. Baseline patient characteristics
 
Operative complications and adverse effects from adjuvant treatment were minor overall. The median length of operation was 3.5 or 4 hours for those also undergoing placement of a hepatic artery infusion pump (range, 3–8 hours). The median stay in the intensive care unit was 1.5 days (range, 1–14 days), and the median hospitalization was 7 days (range, 5 days to 1 month). Postoperatively the most common complication was a sympathetic pleural effusion, which occurred in 70% of patients. Only 6% of patients, however, required chest tube placement or thoracentesis. Eight percent of patients were taken back to the operating room in the first 48 hours for bleeding, and 4% of patients developed a bile leak requiring either endoscopic stenting or percutaneous drainage. The perioperative mortality was 2%. Of all patients, 1% developed renal failure, 1% developed multisystem organ failure, and 5% developed respiratory failure requiring prolonged intubation. Approximately 30% of patients experienced an increase in serum alkaline phosphatase levels, and 60% of patients had increased transaminase levels. Sixty percent of patients required a dose reduction in FUDR, and 30% did not complete the full 6-month course of FUDR. Neutropenia and diarrhea were common adverse effects of irinotecan, requiring dose reductions in approximately 30% of patients.

At a median follow-up of 20 months, 123 patients (66%) had recurrence (Table 2). Forty-three patients (23%) had liver recurrences only, 60 patients (32%) had liver and extrahepatic recurrences, and 20 patients (11%) had extrahepatic recurrences only. Overall, 103 patients (56%) had liver recurrence: 21 (11%) at the previous CSA site and 82 (44%) away from the previous CSA site. The median time to progression was 10 months in the cytoreduction-alone group and 19 months in the group that received adjuvant irinotecan and FUDR (P < .001). There also were significantly more recurrences in the cytoreduction-alone group (78%) compared with the irinotecan/FUDR group (48%; P < .05). The incidence of liver recurrence in patients receiving FUDR and irinotecan was 37%, significantly less than in patients receiving no adjuvant therapy (68%; P < .01). The proportion of patients developing extrahepatic recurrences also was significantly less in the group receiving adjuvant therapy (31%) compared with the group receiving no further treatment postoperatively (51%; P < .05).


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  		TABLE 2. Patterns of recurrence
 
The median survival of all patients was 38 months from diagnosis of liver metastases and 26 months from cytoreduction. Patients who underwent cytoreduction alone had a median survival of 20 months compared with 30.6 months for those patients who also received irinotecan and FUDR (P < .007; Fig. 1). The actuarial 2-year survival rate for patients receiving adjuvant therapy was 75%, compared with 35% for patients receiving no additional treatment (P < .01). This survival benefit was evident regardless of the presence of unilobar or bilobar lesions, synchronous or metachronous metastases, or the size and number of lesions (Table 3). The survival of patients who underwent repeat CSA was 53 months from diagnosis of liver metastases and 42 months from the date of the first CSA. By univariate analysis, preoperative CEA levels (Fig. 2) and postoperative reduction in CEA (Table 4) were correlated with improved survival. The median survival was 31.7 months for patients who had a >60% reduction in CEA versus 9.8 months in those patients who had a <30% reduction in CEA.



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  		FIG. 1. Overall survival after cytoreductive surgery was significantly improved by the postoperative administration of irinotecan and floxuridine (FUDR; P = .007).

 

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  		TABLE 3. Analysis of factors affecting survivala
 


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  		FIG. 2. Preoperative carcinoembryonic antigen (CEA) level (<100 ng/dl) was a significant prognostic factor of improved survival after cytoreductive surgery (P < .05).

 

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  		TABLE 4. Post–cytoreductive surgery decrease in CEA levels
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the United States, CRC is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths.1 Hepatic metastases occur in more than 50,000 patients per year, making the liver the most common site of metastases.30 Surgical resection remains the only potentially curative option, but only 20% of patients are candidates for complete surgical resection. Cytoreductive surgery, combining ablative techniques with resection, may offer patients with unresectable metastatic CRC a viable alternative to chemotherapy alone. By using tumor ablation, such as CSA in this study, multiple lesions can be accurately destroyed under ultrasound guidance while the normal liver parenchyma is preserved. Nevertheless, as with hepatic resection for CRC, the majority of patients will have recurrence (predominantly in the liver). Even though patients described in this study were from different treatment periods, our results suggest that the addition of adjuvant systemic (irinotecan) and regional (FUDR) therapy may reduce the incidence of tumor recurrence and increase survival after cytoreductive surgery.

Results of several studies have demonstrated that ablative techniques, such as CSA and RFA, are safe, have no cumulative toxicity, and effectively destroy CRC metastases.5,9–12,31–34 Nevertheless, the role of ablation (with or without concomitant resection) in the treatment of patients with CRC metastases is still debatable. In this study, by using CSA in addition to resection, we noted a perioperative mortality rate of 2% and a majority of complications that were minor and resolved spontaneously, comparable to complication rates of hepatic resection alone.5,9–12,34 In addition, CSA was repeated in 25 patients with a median survival of 53 months from the date of diagnosis of liver metastases and 42 months from the date of the initial CSA. This suggests that recurrences after CSA can be re-ablated safely without increased operative risk and with, perhaps, a significant effect on overall survival. An alternative ablative technique, RFA, is replacing CSA as the ablative strategy of choice for CRC metastases.31–33 RFA seems to offer the advantage of fewer operative complications, shorter operative times, and faster patient recovery.31–33 However, RFA may be inferior to CSA in the treatment of larger tumors (>3 cm); this is reflected in higher recurrence rates after RFA compared with CSA.31,32 However, the development of more effective, larger RFA probes may improve the results of RFA for large tumors. The recurrence rates observed previously by our group31,32,35 and others5,9–12,33 after cytoreduction alone (with either CSA or RFA), and the survival advantage seen in patients receiving regional therapy, systemic therapy, or both after cytoreduction from this and our earlier study,35 underscore both the limitations of cytoreduction alone and the benefits of adjuvant chemotherapy in this setting. Currently, we do not favor the use of cytoreduction alone in the treatment of patients with unresectable CRC metastases.

Regional hepatic arterial infusion with FUDR is effective against liver metastases both because of high first-pass liver extraction and because of the capability of FUDR to selectively target these predominantly arterial-fed tumors.18 Initial studies with FUDR suggested that the agent provided an improvement in local control but not in overall survival.19–21,36 However, these studies were criticized because of both patient cross-over to systemic therapy (because of significant regional therapy toxicity) and technical complications relating to placement of the hepatic pump that also may have adversely affected the results. More recent studies have demonstrated a lower complication rate and better tolerance to treatment.18,23,37–39 In six randomized trials that compared hepatic artery FUDR with systemic chemotherapy with 5-FU, response rates with FUDR ranged from 40% to 62%, compared with 10% to 20% for systemic chemotherapy.18–21,36,40 An analysis of these studies by Harmantas et al.37 demonstrated a statistically significant survival advantage of hepatic artery chemotherapy over systemic chemotherapy. Furthermore, recent evidence suggests that FUDR is useful in reducing tumor recurrence after hepatic resection by targeting microscopic tumors.18 In a prospective, randomized trial, Kemeny et al.18 demonstrated that overall survival was increased by 12.9 months and that local recurrence rates were decreased by 33% when patients were treated with regional FUDR after hepatic resection for CRC metastasis. In this study, 88% of patients had demonstrated resistance to 5-FU/LV. Despite treatment failure with systemic 5-FU, the patients in our study who received regional therapy with FUDR (in combination with systemic irinotecan) were characterized not only by reduced local recurrence rates, but also by significantly increased survival, compared with patients who received no postoperative therapy. Previous studies have shown up to a 30% to 52% response rate in patients receiving FUDR despite being resistant to systemic 5-FU,23,39 demonstrating the efficacy of this agent in previously treated patients.

The results from this and our previous study35 suggest that systemic irinotecan may be effective in decreasing the incidence of recurrent extrahepatic disease after cytoreductive surgery. In this study, 31% of patients treated with FUDR and irinotecan developed extrahepatic recurrences, significantly less than the 51% of patients treated with cytoreduction alone. Several clinical studies have demonstrated that metastatic CRC lesions often are resistant to fluoropyrimidines because of high thymidylate synthase gene expression.41,42 Irinotecan bypasses this type of drug resistance typical of CRC and is now generally accepted as first-line chemotherapy for metastatic CRC.26,27,43 There is, however, very little information concerning the use of irinotecan after hepatic metastasectomy, and this needs to be investigated.

A therapeutic dilemma often arises for clinicians when metastatic hepatic lesions are considered unresectable. Discerning factors that might predict which of such patients would benefit from surgical cytoreduction, as opposed to systemic or regional chemotherapy alone, has been difficult. A number of potential prognostic factors for predicting a better outcome from either curative liver resection or cytoreduction have been proposed and debated. One recent study10 of 195 patients treated with CSA suggested that size <3 cm correlated with a more favorable outcome. However, in the study by Weaver et al.9 of 136 patients, size was not prognostic of better outcome after CSA. In addition, although the number of metastatic lesions has been shown to be of prognostic value in some series of patients,2,3,6,8,44 it has not been shown to be of significance in other series.9,45 In an analysis of 1001 consecutive liver resections by Fong et al.,2 a disease-related composite score to better predict success after resection was proposed. The patient characteristics correlating with decreased survival after resection included the presence of synchronous liver metastases, more than one lesion, size of largest lesion >5 cm, CEA level >200 ng/dl, and a node-positive primary tumor.2,3,8 Other factors that were highly predictive of therapeutic failure were the presence of extrahepatic disease and the involvement of the resection margin by tumor.2,3,8 Similar to these results, the results from the study by Siefert and Morris10 also suggested that incomplete cryotreatment correlated with decreased survival. In our study, number and size of metastatic lesions were not prognostic factors. Both preoperative CEA level <100 ng/dl and postoperative reduction in CEA levels by at least 30% were shown to be important indicators of improved survival in our study; these also have been shown to correlate with survival in other studies.9,46,47 A small reduction in CEA level postoperatively probably represents inadequate treatment of liver lesions or occult disease that has not been addressed. Future studies may better define prognostic factors that would refine the algorithm for treating patients with unresectable CRC hepatic metastasis.

In conclusion, evidence seems to indicate that hepatic metastases may best be treated by a multimodality approach that includes adjuvant therapy in addition to cytoreductive surgery for unresectable lesions. Cytoreductive surgery, incorporating ablative techniques such as CSA, RFA, or both, clearly has been shown to effectively destroy liver metastases and may be best used complementary to liver resection. On the basis of the results of our study, the addition of hepatic artery infusion with FUDR and systemic chemotherapy with irinotecan to cytoreduction seems to improve both local and extrahepatic failure rates. This regimen may provide patients with unresectable CRC hepatic metastases with the best chance for long-term survival and is currently being examined in a prospective trial.


   Acknowledgments
 
Supported by funding from the Rogovin-Davidow Foundation, Los Angeles, CA, and the Rod Fasone Memorial Cancer Fund, Indianapolis, IN.


   Footnotes
 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 17, 2001. Accepted for publication October 2, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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