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10.1245/ASO.2006.03.094
Annals of Surgical Oncology 13:58-65 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Treatment with 5-Fluorouracil/Folinic Acid, Oxaliplatin, and Irinotecan Enables Surgical Resection of Metastases in Patients With Initially Unresectable Metastatic Colorectal Cancer

Gianluca Masi, MD1, Samanta Cupini, MD1, Lorenzo Marcucci, MD1, Elisa Cerri, MD1, Fotios Loupakis, MD1, Giacomo Allegrini, MD1, Isa Maura Brunetti, MD2, Elisabetta Pfanner, MD2, Maurizio Viti, MD3, Orlando Goletti, MD4, Franco Filipponi, MD5 and Alfredo Falcone, MD1,6

1 Department of Oncology, Division of Medical Oncology, Presidio Ospedaliero, Viale Alfieri 36, 57124 Livorno, Italy
2 Department of Oncology, Division of Medical Oncology, Ospedale Santa Chiara, Via Roma 67, 56126 Pisa, Italy
3 Department of Oncology, Division of Surgery, Presidio Ospedaliero, Viale Alfieri 36, 57124 Livorno, Italy
4 Department of Oncology, Division of Surgery, Ospedale Lotti, Via Roma 180, 56025 Pontedera, Italy
5 Division of Liver Transplantation, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy
6 Cattedra di Oncologia Medica, University of Pisa, Via Roma 55, 56126 Pisa, Italy

Correspondence: Address correspondence and reprint requests to: Gianluca Masi, MD; E-mail: gl.masi{at}tin.it.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The prognosis of unresectable metastatic colorectal cancer might be improved if a radical surgical resection of metastases could be performed after a response to chemotherapy.

Methods: We treated 74 patients with unresectable metastatic colorectal cancer (not selected for a neoadjuvant approach) with irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin (FOLFOXIRI and simplified FOLFOXIRI). Because of the high activity of these regimens (response rate, 72%), a secondary curative operation could be performed in 19 patients (26%).

Results: Four patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients, surgical removal of extrahepatic disease was also performed. In seven patients, surgical resection was combined with intraoperative radiofrequency ablation. The median overall survival of the 19 patients who underwent operation is 36.8 months, and the 4-year survival rate is 37%. The median overall survival of the 34 patients who were responsive to chemotherapy, but who did not undergo operation, is 22.2 months (P = .0114).

Conclusions: The FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.

Key Words: 5-Fluorouracil • Colorectal cancer • Irinotecan • Liver metastases • Oxaliplatin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer is the second leading cause of cancer-related death in Western countries.1 At the time of diagnosis, approximately a quarter of patients will have metastatic disease, and ultimately half will develop metastatic disease.2 The prognosis of meta-static colorectal cancer is poor, but there are considerable differences between patients with unresectable disease and those with resectable disease. In fact, the median survival of unresectable metastatic colorectal cancer does not exceed 21 months, with a 5-year survival of <3%.3 However, long-term survival has been achieved in patients who could undergo primary surgical resection of metastases. In particular, in patients with disease confined to the liver, surgical resection of hepatic metastases is a potentially curative therapy, with a 5-year survival rate of 20% to 40%.4–6 More recent data also show that in patients with limited pulmonary disease, surgical resection of lung metastases results in a 5-year survival rate of 20% to 40%.7–11 Unfortunately, surgical resection is possible in <10% of patients with hepatic or lung metastases, and the recurrence rate after resection is high.

Over the last 10 years, improvements in chemotherapy for unresectable metastatic colorectal cancer have resulted in significant benefits in terms of both antitumor activity and efficacy. Fluorouracil (5-FU)–based regimens have been extensively used in the past and have produced an objective response rate of 10% to 25% and a median survival of approximately 1 year.3 Once the new active drugs irinotecan and oxaliplatin were introduced and combined with 5-FU in the first-line treatment of metastatic disease, the objective response rate increased to 40% to 50%, and the median survival increased to 17 to 21 months.12 In addition, the availability of highly active chemotherapy regimens has allowed considerable downsizing of metastatic disease and, in subgroups of patients with initially unresectable metastatic colorectal cancer, performance of radical operations on residual metastases. In particular, Giacchetti et al.13 retrospectively studied the outcome of 151 patients with unresectable liver metastases from colorectal cancer treated with a chronomodulated combination of 5-FU, leucovorin (LV), and oxaliplatin. The high activity of this regimen allowed a complete surgical resection of hepatic metastases in 58 (38%) patients. The 5-year survival estimate of these 58 patients with completely resected disease was 50%. Analogous results have been reported by Adam et al.,14 who used a similar combination of 5-FU, LV, and oxaliplatin in 701 patients with unresectable colorectal metastases. Ninety-five patients (13.5%) underwent a potentially curative resection of metastases after chemotherapy and reached a 5-year survival rate of 34%. Overall, these data show that the survival of patients with initially unresectable metastatic colorectal cancer who can undergo curative surgery after a response to chemotherapy is similar to the survival of patients with resectable disease who initially undergo operation. Moreover, there is evidence that by increasing the activity of the first-line therapy, it is possible to obtain an increase of post-chemotherapy curative surgery.15

We have, therefore, attempted to develop a new and potentially more active and effective chemotherapy regimen in the treatment of metastatic colorectal cancer by combining 5-FU/LV with both irinotecan and oxaliplatin. We conducted a phase I/II study with a twice monthly combination of irinotecan, oxaliplatin, and infusional 5-FU modulated by LV (FOLFOXIRI)16 and a successive phase II study with a simplified schedule of FOLFOXIRI17 in 42 and 32 metastatic colorectal cancer patients, respectively, with initially unresectable metastases. These studies demonstrated that such combinations are feasible and have manageable toxicities. Of interest, these regimens produced an increased response rate of 72% and a promising median overall survival of 26 to 28 months, as previously reported. Surgical resection of metastases was not a prospective part of these two studies, but, by using a multidisciplinary approach, it was routinely reconsidered in all patients after response to chemotherapy. Therefore, we conducted this analysis to evaluate the outcome of patients with initially unresectable metastatic colorectal cancer who were treated with a combination of irinotecan, oxaliplatin, and 5-FU/LV followed by a potentially curative resection of metastases.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
The main eligibility criteria in both phase II studies considered in this retrospective analysis included a histologically confirmed diagnosis of colorectal adenocarcinoma; age 18 to 75 years; Eastern Cooperative Oncology Group performance status ≤2; measurable disease; adequate bone marrow, liver, renal, and cardiac function; and unresectable metastatic disease. In particular, reasons for initial unresectability in patients with only liver metastases were the size, number, and unfavorable location of metastases that did not allow a complete resection of disease leaving at least 25% of normal liver parenchyma. In patients with extrahepatic metastases, reasons for unresectability were the presence of unresectable liver metastases or the presence of resectable liver metastases coupled with metastatic lymph nodes of the liver hilum or with diffuse extrahepatic disease. Of note, resectability of metastases was assessed by the same team of surgeons and medical oncologists before and after chemotherapy.

Exclusion criteria included previous chemotherapy that included irinotecan or oxaliplatin, symptomatic cardiac disease, myocardial infarction in the last 24 months, uncontrolled arrhythmia, active infections, inflammatory bowel disease, and total colectomy. The studies were conducted in accordance with the Helsinki declaration and Good Clinical Practice guidelines. Written informed consent was required from all patients.

Assessments
Pretreatment evaluation included a history and physical examination; performance status assessment; complete blood cell count with differential and platelet counts; complete blood profile; carcinoembryonic antigen evaluation; urine analysis; electrocardiogram, chest radiograph, or computed tomography (CT) scan; abdominal CT scan and sonogram; and any other appropriate diagnostic procedures to evaluate metastatic sites. Disease un-resectability at the study outset was established for all patients with a multidisciplinary assessment performed by a team that included surgeons and medical oncologists from the institutions involved in these studies. During treatment, a physical examination was performed every 2 weeks, a complete blood cell count was performed every week, and blood profile and urine analysis were performed every 2 weeks. Toxicities were monitored weekly and were scored according to the National Cancer Institute Common Toxicity Criteria, version 2. Sites of metastatic disease were evaluated at the onset of chemotherapy and after every 8 weeks (four cycles). For the evaluation of liver, lung, or abdominal metastases, an abdominal CT scan or magnetic resonance imaging scan was required, and, in case of response, disease resectability was reevaluated by the same team of surgeons and medical oncologists.

Chemotherapy
The treatment planned in the first study (42 patients) consisted of irinotecan 125 mg/m2 in the initial three patients and then 175 mg/m2, followed by oxaliplatin 100 mg/m2, I-LV 200 mg/m2, and 5-FU 3800 mg/m2 administered as a 48-hour chronomodulated continuous infusion (FOLFOXIRI), as previously reported. The treatment planned in the later study (32 patients) consisted of irinotecan 165 mg/m2 followed by oxaliplatin 85 mg/m2, I-LV 200 mg/m2, and 5-FU 3200 mg/m2 administered as a 48-hour flat continuous infusion (simplified FOLFOXIRI). Treatment schedules are outlined in Fig. 1Go. Both regimens were repeated every 2 weeks. Treatment was administered twice monthly until evidence of progression, unacceptable toxicity, or patient refusal or for a maximum of 12 cycles.


Figure 1
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  		FIG. 1. Treatment schedules. CPT-11, irinotecan; LOHP, oxaliplatin; I-LV, leucovorin; 5-FU, 5-fluorouracil; IV, intravenous. The FOLFOXIRI regimen consisted of CPT-11 175 mg/m2 in 250 mL of NaCl .9% over 1 hour immediately followed by LOHP 100 mg/m2 in 250 mL of dextrose 5% and I-LV 200 mg/m2 in 250 mL of dextrose 5% infused concomitantly over 2 hours via a Y-connector, immediately followed by 5-FU 3800 mg/m2 infused as a 48-hour chronomodulated infusion. The simplified FOLFOXIRI regimen consisted of CPT-11 165 mg/m2 in 250 mL of NaCl .9% over 1 hour immediately followed by LOHP 85 mg/m2 in 250 mL of dextrose 5% and I-LV 200 mg/m2 in 250 mL of dextrose 5% infused concomitantly over 2 hours via a Y-connector, immediately followed by 5-FU 3200 mg/m2 infused as a 48-hour continuous infusion.

 
Surgery
Surgical resection of metastases was reconsidered during chemotherapy and was attempted when technically feasible and potentially curative. In patients with liver disease, a complete exploration of the abdomen, including intraoperative ultrasonography, was recommended. Different surgical techniques were used to enable resection of metastases. Radiofrequency ablation was also considered, only in association with surgery, to treat few (three or fewer) or small (≤3 cm) but otherwise unresectable liver metastases. Postoperative chemotherapy was not planned but was allowed at the discretion of the investigator. After surgery, follow-up was performed every 2 months with physical examination, complete blood profile, carcinoembryonic antigen evaluation, and CT scan of the chest and abdomen.

Survival Analysis
Progression-free survival was calculated as the period from the start of chemotherapy to the first observation of disease progression or death from any cause. The overall survival time was calculated as the period from the start of chemotherapy until death from any cause or until the date of the last follow-up. Both progression-free and overall survival times were estimated by the Kaplan-Meier method. Survival curves were compared with the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Between May 1999 and October 2002, 74 patients were enrolled onto these 2 studies (Table 1Go). Overall, 53 (72%) patients achieved an objective response to chemotherapy (World Health Organization criteria). In 23 of these 53 patients, surgical tumor removal was not reconsidered because of the extent of disease, and the remaining 30 patients were reevaluated by a multidisciplinary team for surgical resection of metastases. Among these 30 patients, 11 were unable to undergo operation with a curative intent because this was judged not feasible after a clinical and instrumental reevaluation (5 patients) or after an exploratory laparotomy (4 patients), whereas in 2 patients, an operation was performed, but it was not radical (R1). Finally, 19 patients (26% of the initial 74 patients) could undergo operation with curative intent that consisted of a radical surgical resection of all metastatic sites (R0; 12 patients) or an R0 resection of metastases combined with intraoperative radiofrequency ablation of small residual hepatic nodules (7 patients). Characteristics of these 19 patients, listed in Table 2Go, were as follows: median age, 66 years (range, 45–73 years); Eastern Cooperative Oncology Group performance status ≥1 in 6 patients (32%); and median number of metastases, 3 (range, 1–10). Twelve patients (63%) had synchronous metastases, whereas seven patients had metachronous metastases, with a median disease-free interval of 12 months (range, 7–33 months). The main reasons for initial unresectability in these 19 patients were the presence of unresectable liver disease (15 patients); the location (6 patients), number (6 patients), or size (3 patients) of liver metastases; the presence of liver disease coupled with metastatic lymph nodes of the liver hilum (3 patients); or the presence of diffuse lung metastases (1 patient). Disease resectability was assessed by the same team of surgeons and medical oncologists before and after chemotherapy.


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  		TABLE 1. Characteristics of all patients receiving FOLFOXIRIa
 

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  		TABLE 2. Characteristics of patients who underwent "curative surgery" after FOLFOXIRIa
 
Treatments
Among the 19 patients treated with a potentially curative operation, a total of 219 cycles of chemotherapy were administered, with a median of 12 cycles per patient (range, 9–15). The duration of chemotherapy ranged from 4.2 to 8.2 months (median, 5.7 months). A partial response was achieved in 17 patients, whereas 2 patients had reached a clinical complete response to chemotherapy and underwent operation at the first evidence of disease progression. The median time between the end of chemotherapy and operation was 2.5 months (range, .5–11.9 months). In particular, four patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients with liver metastases, surgical removal of residual extrahepatic disease was also performed (abdominal lymph nodes in three patients, lung in one patient, and peritoneum in 1 patient). In seven patients, surgical resection of metastases was combined with intraoperative radio-frequency ablation of small hepatic nodules that could not be resected (Fig. 3Go). There was no intra-operative or postoperative mortality within 2 months after surgery. Six patients received three to six cycles of postoperative hepatic arterial chemotherapy with floxuridine (three patients) or floxuridine and mitomycin C. Two of these patients died during the intrahepatic chemotherapy, one because of sepsis and gastrointestinal bleeding and one because of acute renal failure. After disease recurrence, 1 patient was treated with repeated hepatectomy followed by systemic chemotherapy (5-fluorouracil and irinotecan), 2 patients again underwent chemotherapy (FOLFOXIRI) followed by operation, and 13 patients received systemic chemotherapy with FOLFOXIRI (5 patients), 5-fluorouracil and irinotecan (7 patients), or 5-fluorouracil and oxaliplatin (1 patient), but no surgical re-resection could be performed.


Figure 3
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  		FIG. 3. Computed tomography of a 69-year-old man who presented with multiple bilateral hepatic metastases: baseline (A1 and A2), after 12 cycles of chemotherapy (B1 and B2), and after surgical resection (C1 and C2).

 
Disease Recurrence and Survival
At a median follow-up of 34.4 months, 16 of the 19 patients who underwent operation had relapsed or died, and the median progression-free survival was 18.4 months. For the two patients who achieved a clinical complete response to chemotherapy and underwent operation at the first occurrence of disease progression, the time to progression was calculated as the period from the start of chemotherapy to the first observation of disease progression after surgery.

Ten of the 19 patients who underwent operation have died: 8 because of progression of disease and 2 because of complications during postoperative intrahepatic chemotherapy. The median overall survival from the onset of chemotherapy for the 19 patients who underwent operation (group A) is 36.8 months, and the estimated actuarial 4-year survival rate is 37%. For comparison, the median overall survival of the 34 patients who were responsive to chemotherapy but did not undergo operation (group B) is 22.2 months (log-rank P value, group A vs. group B: .0114), whereas the median survival of the 21 patients who did not achieve an objective response to FOLFOXIRI or undergo operation (stable disease and progression; group C) is 14.6 months (log-rank P value, group A vs. group C: .0075). Survival curves are reported in Fig. 2Go.


Figure 2
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  		FIG. 2. Survival of the 74 patients treated with FOLFOXIRI. Group A included 19 patients who were responsive to FOLFOXIRI and had undergone curative surgery (median survival, 36.8 months). Group B included 34 patients responsive to FOLFOXIRI but who had not undergone curative surgery (median survival, 22.2 months). Group C included 21 patients who were not responsive to FOLFOXIRI (stable disease and progression) and who had not undergone surgery (median survival, 14.6 months). Log-rank P value, group A versus group B: .0114. FOLFOXIRI, irinotecan, oxaliplatin, 5-fluorouracil, leucovorin.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Surgical resection of colorectal cancer metastases is the only treatment that achieves long-term survival. However, only a minority of patients are able to undergo a curative operation. Therefore, patients with unresectable metastatic colorectal cancer are candidates for systemic chemotherapy, but long-term survival is rarely observed with this option. However, recently, the availability of new active drugs has produced consistent improvements in terms of both antitumor activity and overall survival.18 In particular, regimens combining 5-FU with oxaliplatin or irinotecan are associated with increased response rates, and this has led to their use as neoadjuvant treatment of unresectable metastatic colorectal cancer.19 Several series show that survival of patients with radically resected disease after neoadjuvant chemotherapy is similar to that of patients whose disease was operable at diagnosis. Two retrospective analyses in patients with unresectable colorectal liver metastases indicated that neoadjuvant chemotherapy with chronomodulated 5-FU/LV and oxaliplatin allowed curative operation in 38% and 14% of patients, respectively.13,14 The 5-year survival rate of the patients who underwent operation was 50% and 35%, respectively. One of these analyses14 also reported the survival of patients with both hepatic and extrahepatic metastases radically resected after chemotherapy and showed an interesting 5-year survival of 36% in patients with solid-organ resectable disease; in contrast, the prognosis of patients with lymph nodal disease was still poor. More recently, Pozzo et al.20 achieved similar results in a prospective study that evaluated the combination of irinotecan and 5-FU/LV as neoadjuvant treatment in patients with unresectable colorectal metastases confined to the liver. The objective response rate was 48%, and a potentially curative liver resection after chemotherapy was performed in 32% of patients. At a median follow-up of 19 months, all patients were alive. A recent retrospective analysis reported the outcome of 31 patients with pulmonary metastases from colorectal cancer treated with surgery and perioperative chemotherapy.21 Eleven patients (35%) received pre-operative chemotherapy with a fluoropyrimidine in combination with oxaliplatin or mitomycin C. Pre-operative chemotherapy produced a high response rate (82%), and the 5-year survival rate after surgery was 26%.

We studied the combination of 5-FU with both irinotecan and oxaliplatin in an attempt to develop an extremely active and a potentially more effective first-line chemotherapeutic treatment of metastatic colorectal cancer. We conducted 2 consecutive studies in 74 metastatic colorectal cancer patients with unresectable disease and demonstrated that these regimens are feasible and highly active, with a response rate of 72%. Moreover, treatment toxicities, mainly diarrhea and neutropenia, were manageable, and, in particular, neither hepatic toxicity nor toxic deaths have occurred.16,17 Even though a secondary operation was not initially planned and patients were not selected for a neoadjuvant approach, a potentially curative operation of metastases could be performed in 19 patients after chemotherapy (26% of the initial 74 patients). This resectability rate is similar to that obtained by using combinations of 5-FU and oxaliplatin or of 5-FU and irinotecan, but this feature is scarcely comparable between studies because of the heterogeneity of recruited patients and because of the different definitions of unresectability. An interesting finding arising from our analysis was the survival of patients with curatively resected disease. In fact, we observed a 4-year survival rate of 37%, which is in line with that observed in other studies. However, these results were achieved in a particularly difficult setting—patients with metastatic colorectal cancer who were not selected for a neoadjuvant approach and in whom the initial treatment had mainly a palliative purpose because of the extent of metastatic disease. Of interest, among the 53 patients responsive to FOLFOXIRI, the median survival was significantly longer in the 19 patients who underwent a secondary operation on residual metastases (36.8 vs. 22.2 months). This result is probably related to the different baseline characteristics of the two group of patients; however, the magnitude of the difference might also suggest an effect of the surgical resection of metastases performed after a response to chemotherapy.

In conclusion, our results and those of several studies previously mentioned suggest a potential role of a radical surgical approach to residual metastases after chemotherapy in patients with initially unresectable disease. In particular, the FOLFOXIRI regimen seems particularly promising because of its increased activity, feasibility, and tolerability and its capacity to allow a secondary potentially curative operation in a quarter of patients with initially unresectable and diffuse metastatic colorectal cancer nonselected for a neoadjuvant strategy. A prospective evaluation of FOLFOXIRI as neoadjuvant treatment in metastatic colorectal cancer patients is therefore warranted.


   ACKNOWLEDGMENTS
 
The authors thank Michele Andreuccetti (Division of Oncology, Livorno) for data analysis and technical assistance. This study was partially supported by Fondazione A.R.C.O.

Received for publication March 25, 2005. Accepted for publication August 9, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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