Annals of Oncology Advance Access originally published online on September 6, 2007
Annals of Oncology 2007 18(11):1810-1816; doi:10.1093/annonc/mdm347
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© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer
1 Medical Oncology Unit 2, Fondazione IRCCS ‘Istituto Nazionale Tumori’, Milan, Italy
* Correspondence to: Dr E. Bajetta, Medical Oncology Unit 2, Fondazione IRCCS ‘Istituto Nazionale Tumori’, Via G. Venezian 1, 20133 Milano, Italy. Tel: +39 02 23902500; Fax: +39 02 23902149; E-mail: emilio.bajetta{at}istitutotumori.mi.it
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Abstract |
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Background: A phase I/II study was performed to determine the safety and activity of a capecitabine plus oxaliplatin and irinotecan (COI) regimen using capecitabine concurrently with oxaliplatin and irinotecan in previously untreated patients with metastatic colorectal cancer.
Patients and methods: Patients received irinotecan on day 1, oxaliplatin (85 mg/m2) on day 2 and capecitabine (1000 mg/m2 orally twice daily) on days 2–6 of a biweekly schedule. Three dose levels ranging from 150 to 180 mg/m2 were explored for irinotecan in sequential cohorts of three to six patients. Once the recommended dose was determined, a total of 28 eligible patients were planned at this dose level.
Results: Thirty-eight patients received a median of six cycles. The recommended phase II dose of irinotecan was 180 mg/m2. Toxicity was manageable: the most common severe toxicities were diarrhoea (24%) and nausea (16%). Of 27 assessable patients treated at the recommended dose, 17 achieved a partial response (overall response rate (ORR) 63%; 95% confidece interval (CI), 44 to 78%), with eight patients undergoing liver metastasectomy. Estimated progression-free survival and overall median survival were 8.5 and 23.5 months, respectively.
Conclusions: Biweekly COI is feasible and active. Tolerability and ease of administration make the regimen well suited for downsizing hepatic colorectal metastases before curative surgery.
Key words: colorectal cancer, capecitabine, irinotecan, oxaliplatin, triplet regimen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Over the last decade several different combinations of the newer cytotoxic agents, like irinotecan and oxaliplatin, with fluorouracil (5FU) and leucovorin (LV), significantly increased both tumour response and prolonged survival of patients with unresectable advanced colorectal cancer, with a response rate of 40–50% and a median survival of up to 20 months [1]. Since there is no consensus on which doublet is to be preferred in front-line, upfront three-drug combinations may represent an appropriate next step for clinical evaluation in an attempt to improve overall outcome through the exploitation of all three active drugs in all of patients who are fit to receive systemic chemotherapy. Phase II trials combining irinotecan and oxaliplatin concurrently with 5FU infusion (FOLFOXIRI regimen) showed promising activity in the first-line setting, achieving response rates of 58–69%, median time to progression of 10–11 months and median overall survival of 22–26 months [2, 3]. However, the inconvenience of FOLFOXIRI regimen is the necessity of continuous infusion of 5FU, which requires the placement of indwelling central venous catheters and portable infusion pumps.
Capecitabine is an oral fluoropyrimidine pro-drug that achieves tumour-selective generation of 5FU through exploitation of the higher activity of the thymidine phosphorylase enzyme in tumours, compared with healthy tissue [4]. Large-scale, phase III trials have shown that first-line treatment of metastatic colorectal cancer with capecitabine produced a significantly superior response rate and at least equivalent overall survival compared with bolus 5FU/LV [5, 6]. In addition, capecitabine demonstrated a superior safety profile with significantly less neutropenia, alopecia, diarrhoea and stomatitis, but increased palmar-plantar erythrodysaesthesia (PPE) [7]. Therefore, combination of capecitabine either with irinotecan or oxaliplatin instead of 5FU is an interesting alternative to increase the practicability of the treatment regimen [8–11].
Based on these results, capecitabine combined with oxaliplatin and irinotecan (COI regimen) appears to be a logical step in the development of innovative chemotherapy combinations for improving current therapeutic results. The COI regimen was administered every other week and was designed to maximize the dose of irinotecan and sequence-dependent synergistic interactions among three drugs, while giving capecitabine and oxaliplatin at fixed clinically-relevant doses. Oxaliplatin was administered at a recommended dose of 85 mg/m2 in combination with irinotecan using a 3-weekly schedule [12]. We decided to escalate the dose of irinotecan according to the results of a phase I study evaluating dose escalation of irinotecan in combination with the recommended dose of oxaliplatin given every other week. This study showed that two different irinotecan doses, 175 and 150 mg/m2, were recommended in patients with a performance status score of 0–1 or 2, respectively [13]. Finally, capecitabine as the third element of the combination was used at a dose of 1000 mg/m2 twice daily on days 2 to 6. This is the recommended dose of capecitabine in combination with irinotecan or oxaliplatin according to a 3-weekly schedule [8–11].
Here we present a non-randomized, open-label, dose-finding phase I/II trial of COI in previously untreated patients with advanced colorectal cancer conducted at the National Cancer Institute in Milan. Once the recommended dose of irinotecan was established in a limited phase I assessment, we designed a phase II trial for better assessment of activity and tolerability of triplet combination in named patient population.
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patients and methods |
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study design and eligibility
The study consisted of phase I, open-label, dose-finding part and a phase II part. The primary objective was to determine the maximum-tolerated dose (MTD) of irinotecan when administered concurrently with oxaliplatin and capecitabine in close sequence in a 6-day schedule biweekly. Once the recommended dose of irinotecan was determined, patient accrual continued in a two-stage phase II, non-randomized, single-arm study with the primary objective to assess the response rate. Secondary objectives included progression-free survival (PFS), overall survival and further evaluation of tolerability profile of the recommended combination dosing and schedule.
Eligible patients had histologically confirmed metastatic colorectal cancer not amenable to curative surgery, age between 18 and 75 years, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. In addition, they had adequate organ function, as indicated by absolute neutrophil count 
1.5 x 109/l, a platelet count 100 x 109/l, serum creatinine 
1.3 mg/dl, serum bilirubin 1.25 times the upper limit of normal (UNL) and serum transaminases 3.0 times UNL (5.0 times UNL if liver metastases were present). Patients who had received prior adjuvant 5FU chemotherapy were eligible if they had remained free of disease for at least 6 months after the completion of adjuvant therapy. Exclusion criteria included active second malignancy (except for non-melanoma skin cancer or in situ cervical cancer), documented brain metastases, uncontrolled intercurrent illness, inflammatory bowel disease or malabsorption. Patients with clinically significant cardiac disease were also excluded.
The study was conducted in accordance with the standards of good clinical practice and in agreement with the Declaration of Helsinki, and was approved by the local institutional review board. Each patient provided written informed consent before registration.
Pre-treatment baseline evaluation included a complete medical history and physical examination, full blood count and chemistry including carcinoembrionic antigen, and a CT scan of the chest, abdomen, and pelvis.
treatment and dose escalation
The starting dose of irinotecan for dose escalation was selected to ensure both patient's safety and anti-tumour activity: the planned dose levels of irinotecan were 150, 160 and 180 mg/m2 given every 2 weeks. Treatment consisted of irinotecan infused over 90 min on day 1 followed by oxaliplatin 85 mg/m2 in a 3-h infusion on day 2 and capecitabine 1000 mg/m2/day orally twice daily from days 2 to 6 of a biweekly schedule. At least three patients were included sequentially in each dose level, and no intra-patient dose-escalation was allowed. Dose-escalation was permitted if no dose-limiting toxicity (DLT) was encountered by the end of the first or second cycle at the same dose level. If one out of three patients experienced a DLT, three additional patients were enrolled at the same dose level. MTD was defined as being reached if more than two out of three or four out of six patients experienced a DLT. The recommended dose for phase II study was the dose level just below the MTD. Once this dose level was established, additional patients were enrolled (maximum of six) to confirm the safety profile of the combination. However, if the MTD was not reached at the planned dose levels, the recommended dose was defined as 180 mg/m2 of irinotecan, which represented the recommended dose of irinotecan when combined with oxaliplatin at 85 mg/m2 using a biweekly schedule [13]. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0. A DLT was defined as any grade 4 haematological toxicity and/or grade 3 or 4 non-haematological toxicity.
All patients received serotonin receptor antagonists plus corticosteroids before the irinotecan and oxaliplatin infusions, and atropine sulphate 0.25 mg s.c. as prophylaxis against irinotecan-induced acute cholinergic-like syndrome. Loperamide and oral rehydration were prescribed in the event of delayed diarrhoea. No prophylactic treatment with granulocyte colony stimulating factors was recommended.
toxicity and tumour response evaluation
Blood cell counts were performed weekly and biochemistry at the beginning of each cycle. Treatment was interrupted in presence of grade 2 or higher events (with the exception of alopecia (grade 2), nausea or vomiting, and anemia) and was not resumed until the adverse event resolved or improved to grade 1 or less. If treatment had to be delayed for longer than 2 weeks, or any drug discontinued permanently, all affected patients were withdrawn from the study. In the event of DLTs, treatment was continued, after resolution, at doses of all cytotoxic agents reduced by 25% for the subsequent cycles, except for grade 3 or 4 diarrhoea when only irinotecan and capecitabine doses were reduced by 25%. Capecitabine dose was reduced by 25% in case of grade 3 or 4 stomatitis and/or PPE. For neurological toxicity lasting longer than 7 days, the dose of oxaliplatin only was reduced by 25 or 50% in patients with grade 2 and grade 3 peripheral neuropathy, respectively. Oxaliplatin was to be discontinued if grade 2 peripheral neuropathy or other severe neurotoxicity persisted between courses of treatment. If a further delay for toxicity occurred despite previous dose reduction, a 50% reduction of the original dose of drugs was made if clinically indicated.
Patients were evaluated for response according to the response evaluation criteria in solid tumours (RECIST) after 8 weeks (four cycles) unless clinically otherwise indicated [14]. Confirmatory scans were to be obtained 4 weeks following initial documentation of objective response. Treatment at any dose level could be continued for at least six cycles unless tumour progression, unacceptable toxicity, or patient refusal occurred. In case of patients with stable disease after six cycles, further treatment was at the discretion of the investigator.
statistical considerations
Descriptive statistical methodology was used to design and analyse the dose-escalation portion of the study. For the phase II part, conducted as an expansion of the recommended dose level, a minimax two-stage sequential design was utilized to permit early study termination [15]. Assuming a 10% type 1 error rate and 80% power, a sample size of 28 eligible patients was calculated. The trial had to be stopped if 6 or fewer responses were observed over the first 16 enrolled patients. Otherwise, 12 additional patients had to be accrued and treatment considered as disappointing at this dose and schedule if 14 or fewer responses were observed on the whole population. Efficacy analysis was performed on the intention-to-treat (ITT) population, which comprised all patients who received at least two cycles of study treatment. Results were reported with 95% confidence intervals (CI). PFS was defined as the interval between the first treatment and the first documentation of disease progression or death. Overall survival was measured from the time of starting treatment to death or last contact with the patient. Survival was estimated by the Kaplan–Meier method.
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patients characteristics
Between September 2003 and June 2005, a total of 38 consecutive patients were enrolled in three sequential dose-cohorts. The baseline patients characteristics are summarized in Table 1. The median age was 60 years. Most patients (53%) had synchronous metastases at primary diagnosis, and one third (34%) of study participants had received adjuvant 5FU/LV.
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dose-escalation findings
The number of patients entered in each dose level and the type of DLTs encountered are summarized in Table 2. At the initial dose level, severe diarrhoea affected one of six patients after the first cycle of treatment. Three patients entered into the second dose level, and no DLT was observed during the first two cycles. Dose-escalation proceeded to dose level 3 (irinotecan 180 mg/m2). At this dose two DLTs were experienced in the six patients treated: grade 3 diarrhoea and nausea (one patient) and grade 4 diarrhoea (one patient). The recommended dose was therefore established at the dose level 3. As specified per protocol, this dose level was further expanded to a total of 12 patients. The dose level 3 was feasible, with none of the six further patients experiencing a DLT after the first two cycles of treatment. The cohort receiving the recommended dose was further expanded to a total of 29 patients as planned in the phase II part of the study.
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safety assessment
Thirty-eight treated patients were assessable for safety. A total of 222 treatment cycles were administered, and the median number of cycles per patient was six (range: 1–10 cycles). Overall the regimen was well tolerated: the majority of treatment-related adverse events were mild to moderate in intensity except for delayed diarrhoea and emesis. Grade 2 peripheral neuropathy was observed in one patient who received a cumulative oxaliplatin dose of 680 mg/m2. The majority of patients (76%) completed six or more cycles of treatment, and early discontinuation due to dose-limiting gastrointestinal toxicity occurred in only two patients on the phase II part of the study. Both patients required hospitalization for diarrhoea with dehydration, and refused to continue study treatment. In addition, four responding patients discontinued after four cycles of treatment in order to undergo liver metastasectomy.
Details on the treatment-related worst toxicity are shown in Tables 3 and 4
. Nine (24%) patients experienced at least one episode of grade 3 to 4 diarrhoea, which occurred in 6% of all treatment cycles. No events of grade 4 nausea and vomiting occurred during the study.
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Most cycles (77%) were administered every 2 weeks as per protocol. Among delayed cycles, 23 (10% of cycles) were delayed for 3 to 7 days, and 29 (13%) were delayed for more than 7 days, mostly (52%) for non-treatment-related reasons (i.e. personal reasons, logistic reasons or pending imaging studies for response evaluation). Nine (24%) patients underwent a dose reduction (41 cycles) due to diarrhoea. All but one patient underwent one dose reduction.
Median dose intensities of capecitabine, oxaliplatin and irinotecan, calculated during the entire treatment period among the 29 patients treated at the irinotecan dose of 180 mg/m2, were 4180 mg/m2/week (84% of projected), 34 mg/m2/week (81% of projected) and 73 mg/m2/week (81% of projected), respectively.
efficacy assessment
At the dose level 1, three out of six patients achieved an objective tumour regression. Twenty-seven out of 29 patients treated at the recommended phase II dose were evaluable for response because two patients discontinued study treatment after only one cycle (Table 5). Among patients treated at the recommended dose, there were 17 partial responses for an overall response rate of 63% (95% CI, 44–78%). In addition, seven (26%) patients achieved disease stabilization that lasted for at least 4 months. Eight of the responding patients treated at the recommended dose underwent surgical resection for liver metastases after chemotherapy, and R0 resection could be performed in five patients.
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Time-related events were measured for all patients after the intent-to-treat analysis (Figure 1). After a median follow-up duration of 17 months as of November 2006, the median PFS was 8.5 months (95% CI, 6.5 to 11.5 months), with seven patients censored (six patients remained disease-free after liver resection, and one patient was lost to follow-up without evidence of progressive disease). At the time this analysis was performed, 18 (47%) patients were still alive; the median survival time was 23.5 months (range, 7.6 to 38.2+ months). Twenty-three patients with disease progression as of this writing had received second-line therapy, whereas eleven (48%) of them receiving a combination containing irinotecan plus cetuximab.
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discussion |
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To the best of our knowledge, this is the first full report that describes the activity and tolerability of irinotecan and oxaliplatin combination associated with capecitabine, rather than 5FU, as first-line therapy in metastatic colorectal cancer. It is interesting to note that irinotecan was given before oxaliplatin in the FOLFOXIRI regimen, and this sequence was also used to add capecitabine as the ternary element.
The overall tolerability of COI was highly satisfactory, with haematologic events being rare. No grade 3 or 4 neutropenia was reported, and this toxicity profile compares favourably with that of FOLFOXIRI, which produced severe neutropenia in 45–86% of patients, with febrile neutropenia occurring in up to 14% of cases [2, 3]. The most common severe toxicities induced by COI were gastrointestinal disturbances including diarrhoea and emesis. Diarrhoea was the main toxicity, with 24% of the patients experiencing grade 3 or 4 events during treatment. Six of these patients resumed therapy after irinotecan and capecitabine doses were reduced by 25%, and no further severe diarrhoea occurred. Of note, there were no fatalities associated with treatment, and no prevention of delayed diarrhoea and/or delayed emesis was attempted throughout the study. Also, the short, intermittent administration schedule of capecitabine induced no cases of PPE. Only one patient complained of grade 2 sensory neuropathy, even if this finding was likely to be related to low cumulative doses of oxaliplatin.
The present study shows that the COI regimen can induce good disease response. Confirmed tumour-regression rate at the recommended dose was 63%, with further 26% of patients showing stable disease for at least 4 months. Response occurred a median of 2.1 months after the start of treatment; median PFS was 8.5 months, and median survival time was 23.5 months.
While the usual limitations of cross-study comparisons should be taken into account, these findings are comparable to studies investigating FOLFOXIRI, with reported overall response rates of 58–69% [2, 3]. More recently, in two trials comparing FOLFOXIRI with irinotecan plus the de Gramont regimen (FOLFIRI), triplet regimen achieved response rates of 43–60%, and median PFS of 8.4–9.8 months, but produced higher incidence of severe toxicities [16, 17]. It should be noted that the Greek study failed to demonstrate any superiority of the FOLFOXIRI combination compared with the FOLFIRI regimen [16]. These results highlight that the true clinical value of any new triplet needs to be demonstrated in a randomized setting.
The present findings are very promising, but limited by the small sample size of a phase II trial conducted at a single centre. The patient and tumour characteristics were representative of a typical first-line metastatic population, except for the possible selection bias of a better-prognosis cohort due to the inclusion of patients with only a good performance status. However, most of patients (53%) who entered the study had synchronous metastases, and this group of patients retains a distinctly worse prognosis [18].
Potential drawbacks of COI might be the total dose of capecitabine and the lengthy outpatient 2-day schedule for irinotecan and oxaliplatin administration. Experimental data indicate that inhibition of tumour growth depends on the total dose of capecitabine but not on its administration schedule [19]. Nevertheless the activity attained by COI compares favourably with response rates of 35% associated with the different schedules reported for combinations of irinotecan and oxaliplatin [12, 20]. Thus, it is unlikely that the delivered total dose of capecitabine can compromise the contribution of the drug to the regimen. Despite the inconvenience of a 2-day administration schedule for intravenous agents, preclinical evidence from human colon cancer cell lines suggested synergistic effects only when SN38, the active metabolite of irinotecan, was delivered 24–48 h before the oxaliplatin and 5FU/i.v. sequence [21]. However, from the analysis of the current study data and the results of the other studies discussed, it is clear that COI remains particularly attractive not only because of tolerability and ease of administration, but also because of efficacy. Eight patients with unresectable liver metastases underwent curative surgery of the residual disease after an initial response to chemotherapy. It is also worth noting that four of the responding patients were eligible for liver resection after only two months of treatment.
In conclusion, the results of this study show that COI is feasible and safe. This particular schedule of combining capecitabine concurrently with irinotecan and oxaliplatin is highly active, and may represent an option for selected patients with metastatic colorectal cancer. Only a few cycles of such intensive regimen may induce downsize of liver metastases to permit a curative surgery. The ease of administration and good safety profile also make the COI regimen particularly well suited for use as a platform for newer combinations with other biologic agents.
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The authors would like to thank the ITMO scientific service for data management and Dr Arpine Gevorgyan for her skilful assistance in preparing the manuscript.
Received for publication April 26, 2007. Revision received May 24, 2007. Accepted for publication May 29, 2007.
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References |
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