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Intensive Systemic Chemotherapy Combined With Surgery for Metastatic Colorectal Cancer: Results of a Phase II Study

From the Oncologie Médicale, Chirurgie Générale et Digestive, Hôpital St-Antoine; Oncologie Médicale, Hôpital Tenon; Service de Chirurgie Viscérale, Institut Mutualiste Montsouris, Paris; and Oncologie Médicale, CHRU de Lille, Lille, France

Address reprint requests to J. Taïeb, MD, Service d'hépatogastroentérologie, Groupe Hospitalier Pitié Salpétrière, 47-83 Bd de l'hôpital, 75013 Paris, France; e-mail: jtaieb{at}club-internet.fr

	ABSTRACT

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PURPOSE: To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer.

PATIENTS AND METHODS: Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m², oxaliplatin 130 mg/m² in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m² in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m², irinotecan 180 mg/m² in a 90-minute infusion, bolus FU 400 mg/m², and FU 2,400 mg/m² as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery).

RESULTS: All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively.

CONCLUSION: The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.

	INTRODUCTION

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More than 300,000 new cases of colorectal cancer occur each year in Europe and the United States.^1,2 More than 50% of patients with colorectal cancer develop metastasis, and 15% to 25% of patients have liver metastases at diagnosis.^3,4 Surgery is currently the only curative treatment for metastases from colorectal cancer,^5,6 but only 10% to 25% of patients are suitable for resection. Even after curative surgery, 5-year survival rates are only 25% to 50% in the most recent reports.^7-9 There is no standard therapeutic approach after resection of metastases, and new strategies are needed to improve patient outcome. Adjuvant chemotherapy is a logical treatment for suspected micrometastases. Many previous studies have focused on intra-arterial chemotherapy, with or without systemic chemotherapy.^10-12 This approach showed a 2-year survival benefit in only one randomized trial, in which intra-arterial and systemic chemotherapy was combined.¹⁰ Intra-arterial chemotherapy requires highly trained surgical and medical oncologists, limiting its use in many centers.

Recent schedules combining fluorouracil (FU) and oxaliplatin or irinotecan have considerably improved the results of systemic chemotherapy in the palliative treatment of patients with metastatic colorectal cancer, in terms of the response rate, progression-free survival,^13-17 and overall survival.^14,15,17 The use of new schedules, such as oxaliplatin, leucovorin (LV), and FU (FOLFOX), and irinotecan, LV, and FU (FOLFIRI), in addition to surgery, is thus a promising approach for resectable metastatic colorectal cancer. We tested a new approach: the metastatic irinotecan plus oxaliplatin (MIROX) strategy, which is based on sequential FOLFOX/FOLFIRI before and/or after surgical resection. The rationale is to limit oxaliplatin-induced neuropathy by administering only six cycles of FOLFOX, and to bypass tumor cell resistance by administering both oxaliplatin and irinotecan over a short period. Here we report the feasibility and initial results of this original strategy.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were eligible for this study if they had pathologically proven colorectal carcinoma with fully resectable metastasis at the time of enrollment, as assessed by a multidisciplinary team including experienced medical and surgical oncologists and radiologists. Patients were eligible regardless of the metastatic site, provided R0 resection was considered possible. Other inclusion criteria were WHO performance status 0 to 2, age 18 to 80 years, no previous malignancies, and adequate marrow function (neutrophils > 1.5 x 10⁹/L, hematocrit > 30%, and platelets > 100 x 10⁹/L) and liver function (bilirubin < 1.5x the upper limit of normal). Patients having previously received FU-LV adjuvant chemotherapy for a stage III primary tumor were eligible if this treatment had ended more than 1 year before enrollment onto this study. Written informed consent was required. The MIROX strategy was approved by our Institutional Ethics Review Board. Between September 1999 and October 2001, all patients with resectable metastatic colorectal cancer referred to our institution for treatment were prospectively considered for this study.

Pretreatment evaluation included a physical examination, thoracic and abdominopelvic computed tomography (CT), and carcinoembryonic antigen (CEA) assay. Because of limited positron emission tomography scan availability in France at the beginning of the study, this procedure was encouraged but not required.

Surgery
During laparotomy, all patients underwent complete visual and manual abdominal exploration before resection of metastases. The extent of metastatic liver involvement was assessed by means of bimanual palpation and intraoperative ultrasonography to confirm the number and size of metastases, to determine their relationship with vascular and biliary structures, and to look for occult metastases. Anatomic and nonanatomic resections were used to achieve complete resection of all detected lesions, in a single procedure, including a margin of uninvolved parenchyma and with maximal preservation of uninvolved liver. Resectable extrahepatic intra-abdominal limited tumorous deposits (localized carcinomatosis) were resected as appropriate and pulmonary metastases were removed by wedge resection.

Treatment Schedule
The MIROX strategy consisted of six cycles of oxaliplatin 130 mg/m² given as a 2-hour infusion in 250 mL of 5% dextrose, concurrently with LV 400 mg/m² as a 2-hour infusion, then a 46-hour infusion of FU 2,400 mg/m² (the FOLFOX-7 regimen), followed by six cycles of irinotecan 180 mg/m² given as a 90-minute infusion, concurrently with LV 400 mg/m² as a 2-hour infusion, followed by bolus FU 400 mg/m² and a 46-hour infusion of FU 2,400 mg/m² (the FOLFIRI regimen), as previously described^18,19 (Fig 1). Treatment was repeated every 2 weeks if the neutrophil count was more than 1.5 x 10⁹/L and the platelet count more than 100 x 10⁹/L. Treatment was discontinued because of disease progression, repeated grade 3 to 4 toxicity, or patient refusal.

View larger version (19K): [in this window] [in a new window]   Fig 1. The metastatic irinotecan plus oxaliplatin (MIROX) strategy. (A) Adjuvant setting; (B) neoadjuvant setting. LV, leucovorin; FU, fluorouracil; FOLFOX-7, leucovorin 400 mg/m2, oxaliplatin 130 mg/m2 in a 120-minute infusion, and FU 2,400 mg/m2 in a 46-hour infusion, every 2 weeks; FOLFIRI, leucovorin 400 mg/m2, irinotecan 180 mg/m2 in a 90-minute infusion, bolus FU 400 mg/m2, and FU 2,400 mg/m2 as a 46-hour infusion, every 2 weeks.

Assessment of Response
The treatment response was evaluated in patients treated in the neoadjuvant setting after four cycles of FOLFOX-7 by CT. WHO criteria²⁰ were used to define responses and their duration: a complete response (CR) was defined as a complete disappearance of all assessable disease; a partial response was defined as a decrease of at least 50% in the sum of the products of the two largest perpendicular diameters of measurable lesions, lasting at least 4 weeks; stable disease was defined as a decrease in tumor size of less than 50% or an increase of less than 25%; and progressive disease was defined as a greater than 25% increase in the sum of the products of two perpendicular diameters of at least one tumor, or the appearance of a new lesion. Objective responses were confirmed by a second evaluation 4 weeks later.

Measurement of Efficacy
Patients were examined during and after therapy; patient history was recorded and a physical examination was performed. To diagnose recurrence, CT of the chest, abdomen, and pelvis, and plasma CEA assay were performed every 3 months after surgery. Recurrence was diagnosed if new lesions appeared on CT. Positron emission tomography scan or repeat CT was performed if the CEA value increased to more than 10 ng/mL.

Toxicity Evaluation and Dose Modifications
Toxicity was recorded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). Physical examination and a CBC were performed within 48 hours before each cycle. Patients were questioned specifically about nausea and vomiting, mucositis, diarrhea, malaise, appetite, and neurotoxicity. All patients who received at least one course of chemotherapy were evaluated for toxicity.

If grade 3 characteristic cumulative sensory peripheral neuropathy occurred, oxaliplatin was discontinued and LV plus FU alone were administered according to the above-described schedule. If non-neurologic grade 3 to 4 NCI-CTC toxicity occurred, the subsequent cycle was postponed until recovery, and the oxaliplatin dose was reduced to 100 mg/m² (FOLFOX-7 regimen) or the FU bolus was omitted (FOLFIRI regimen). If specific irinotecan-induced grade 3 to 4 toxicities occurred, the irinotecan dose was reduced to 140 mg/m²; if subsequent grade 3 to 4 toxicities occurred, irinotecan was then discontinued, and LV plus FU alone were administered according to the above-described schedule.

Statistical Analysis
This was a phase II study of intensive systemic adjuvant chemotherapy after (or before and after) resection of metastases from colorectal cancer. The primary objective was to determine efficacy in terms of overall survival and recurrence. Results are expressed as means ± standard deviation or range, as appropriate. Follow-up started from the outset of chemotherapy. The censoring event for relapse was the date of diagnosis of disease progression. The censoring event for survival was the date of death. Survival curves were plotted with NCSS software (Number Cruncher Statistical Systems, Kaysville, UT), using the Kaplan-Meier method.

	RESULTS

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Between September 1999 and October 2001, 47 patients with resectable metastatic colorectal cancer were referred to our institution for treatment, and were prospectively enrolled onto the study. Patient characteristics are summarized in Table 1.

Surgery
R0 resection was possible in 45 patients, and R1 resection was possible in one patient. One patient was not resected because multiple liver metastases were found during surgery. The surgical procedures are listed in Table 2. Only one patient had two distinct metastatic sites (liver and lung), both of which were resected during a single procedure.

Toxicity
Toxicity data were available for all 47 patients treated with FOLFOX-7 and all 44 patients treated with FOLFIRI (Tables 3 and 4). A total of 273 cycles (97%) of FOLFOX-7 and 257 cycles (97%) of FOLFIRI were administered, for planned totals of 282 and 264 cycles, respectively. No treatment-related deaths occurred. Grade 3 to 4 toxicity occurred in 14 patients (30%) during the FOLFOX-7 regimen. Ten patients (21%) had grade 2 peripheral neuropathy, whereas none had grade 3 peripheral neuropathy. Hematologic toxicity was the most common severe adverse effect, followed by gastrointestinal disorders. Grade 3 to 4 neutropenia was observed in six patients (13%); there were no occurrences of febrile neutropenia. There were five occurrences (11%) of grade 3 thrombocytopenia, but none was associated with bleeding events. Grade 3 diarrhea, hand-foot syndrome, and nausea or vomiting occurred in five, one, and one patient, respectively. Dose reduction of oxaliplatin (100 mg/m²) and FU (2,000 mg/m²) was necessary in 12 and five patients, respectively; no further hematologic or gastrointestinal adverse effects occurred, and there was no increase in the severity of neuropathies. Five occurrences of grade 3 to 4 neutropenia were observed during the FOLFIRI regimen; there were no occurrences of febrile neutropenia. Other grade 3 toxicities comprised diarrhea in two patients, and hand-foot syndrome in one patient. Grade 2 alopecia occurred in eight patients (17%). An irinotecan dose reduction (150 mg/m²) was necessary in five patients, and the FU bolus was omitted in six patients; no additional severe hematologic or gastrointestinal toxicity occurred.

The median overall survival time has not been reached in the entire group of 47 patients. The median disease-free survival time is 21 months. The 2- and 3-year recurrence-free rates are 47% and 33%, respectively. The median time to recurrence was 17 months (3 to 28 months). The 2- and 3-year overall survival rates are 89% and 61%, respectively. In the subgroup of patients who experienced relapse, the 2-year overall survival rate is 77%.

	DISCUSSION

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Two years after resection of liver metastases from colorectal cancer, approximately 65% of patients are alive and 25% are free of detectable disease.^21-23 New approaches are needed to improve these outcomes. We evaluated a new strategy based on sequential systemic adjuvant chemotherapy, including the most effective drugs currently available, in patients with resectable metastatic colorectal cancer.

In unresectable metastatic colorectal cancer, the debate currently focuses on how best to combine the most active agents.²⁴ Many studies suggest that more active initial treatment, using irinotecan or oxaliplatin combined with FU-LV, is more effective in these patients.^13-17 The tritherapies combining FU-LV, oxaliplatin, and irinotecan has given interesting results in terms of survival and the response rate.^25,26 However, these schedules are highly toxic, with grade 3 to 4 neutropenia in 45% to 80% of patients (febrile neutropenia in 6% to 14% of patients), grade 3 to 4 diarrhea in 20% to 32% of patients, and grade 2 alopecia in 40% of patients.^25,26 Sequential regimens based on FU-LV plus oxaliplatin and FU-LV plus irinotecan, used in the palliative setting, seem to be far less toxic while offering similar efficacy.^16,27 In our study, the patients had limited disease or were tumor free at the time of chemotherapy, and this might partly explain the good toxicity profile relative to patients treated palliatively. However, tolerability was excellent, with no grade 3 to 4 toxicities in 70% of patients. Considering both therapeutic sequences, severe hematologic toxicities (ie, thrombocytopenia and neutropenia) occurred in 12 patients (25%), without any febrile neutropenia. No grade 3 neurotoxicity was observed after 3 months of FOLFOX-7 treatment, and grade 3 diarrhea occurred in only 6% of patients during FOLFIRI treatment. No treatment-related deaths occurred.

Two large studies have included experimental arms combining intra-arterial and intravenous (IV) chemotherapy, in comparison with IV therapy alone¹⁰ or surgery alone.¹¹ Our MIROX strategy compares well with these latter treatments. In the study by Kemeny et al,¹⁰ three deaths caused by toxicity (4%) occurred in the group receiving both IV and intra-arterial chemotherapy. Although the latter authors did not assess toxicity with NCI-CTC criteria, significantly more patients in the combined-treatment group than in the systemic treatment group had toxic diarrhea or required hospitalization for adverse effects. Moreover, complications related to the pump and catheter used for hepatic arterial infusion occurred in 22% of patients. In the second study by Kemeny et al,¹¹ no deaths caused by toxicity occurred, but grade 3 to 4 toxicities were observed in 32% of patients, including nine patients (20%) who had severe hepatic toxicity. Moreover, in these two studies, only two thirds of the patients received the planned number of hepatic arterial infusions because of toxicity or progression. Thus, although hepatic arterial infusion seems to reduce the risk of hepatic recurrence and showed a survival benefit in one randomized study (in combination with systemic chemotherapy), this procedure requires a high level of expertise and carries a risk of specific complications. The toxicity results of the European Organization for Research and Treatment of Cancer randomized controlled trial, comparing adjuvant FOLFOX to surgery alone in patients with resectable hepatic metastases from colorectal cancer, will not be available before the middle of 2005.

With 2-year overall and recurrence-free survival rates of 89% and 47%, respectively, and a response rate of 77% (including two confirmed CRs) in patients who received neoadjuvant FOLFOX-7, our results compare favorably with those of previous trials of chemotherapy in this setting (Fig 2). In the two above-mentioned studies,^10,11 and in a recent publication evaluating IV irinotecan combined with intra-arterial floxuridine in the same setting,²⁸ the results were similar to those obtained here with the MIROX strategy. In the only two trials comparing systemic chemotherapy with surgery alone, survival rates at 4 and 5 years were 10% better with FU-LV than with surgery alone, although the differences were not statistically significant.^29,30 The promising efficacy observed here cannot be attributed to patient selection.

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall and recurrence-free survival rates.

The MIROX strategy therefore appears to be well tolerated and offers good disease-free and overall survival. As such, it is an attractive alternative treatment for patients with resectable metastases of colorectal cancer. This strategy is currently being evaluated in a phase III trial, in comparison with a simplified LVFU2 regimen for 6 months, in patients with resectable metastatic colorectal cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Christophe Louvet, Aventis, Sanofi-Synthelabo; Aimery de Gramont, Baxter, Sanofi-Synthelabo. Honoraria: Pascal Artru, Bristol-Myers Squibb, Sanofi-Synthelabo; Thierry Andre, Aventis, Baxter, Sanofi-Synthelabo. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.

	NOTES

 
Both J.T. and P.A. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted May 13, 2004; accepted October 16, 2004.

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