Phase I/II trial of irinotecan plus high-dose 5-fluorouracil (TTD regimen) as first-line chemotherapy in advanced colorectal cancer

E. Aranda1,*, A. Carrato2, A. Cervantes3, J. Sastre4, M. A. Gómez1, A. Abad5, B. Masutti6, F. Ribera7, E. Marcuello8, L. Pronk9, M. Balcells10 and E. Díaz-Rubio4

1 Hospital Universitario Reina Sofía, Córdoba; 2 Hospital General Universitario, Elche; 3 Hospital Clínico Universitario, Valencia; 4 Hospital Clínico San Carlos, Madrid; 5 Hospital Universitario Germans Trias i Pujol, Badalona; 6 Hospital General, Alicante; 7 Hospital Marqués de Valdecilla, Santander; 8 Hospital de la Santa Creu i Sant Pau, Barcelona; 9 Aventis Pharma, Madrid; 10 Prasfarma-Grupo Almirall Prodesfarma, Barcelona, Spain

Received 2 October 2003; revised 15 December 2003; accepted 22 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

We conducted a phase I/II study of weekly irinotecan [30 min intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m2 weekly 48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with advanced colorectal cancer (CRC).

Patients and methods:

The maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of gastrointestinal solid tumors (in phase I), and the antitumor activity and toxicity of the recommended phase I dose (in phase II) were determined.

Results:

Diarrhea was the DLT, and irinotecan 80 mg/m2 plus 5-FU 3 g/m2 was the recommended phase I dose. In phase II, the confirmed response rate was 44% [95% confidence interval (CI) 29% to 59%] and the median overall survival was 23.8 months. However, grade 3/4 diarrhea affected 59% of patients and led to withdrawal of three patients. A second cohort of patients studied using the same schedule but with a reduced 5-FU starting dose of 2.25 g/m2 showed improved tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2 months.

Conclusions:

We found weekly irinotecan 80 mg/m2 plus TTD regimen (5-FU 2.25 g/m2 given as 48-h i.v. infusion) to be a feasible and active combined chemotherapy for the first-line treatment of advanced colorectal cancer.

Key words: antitumoral, colorectal cancer, 5-FU, irinotecan, toxicity, TTD regimen


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
5-Fluorouracil (5-FU) is still the most extensively studied chemotherapy agent for the treatment of metastatic colorectal cancer (CRC) [1]. Several attempts have been conducted to increase the efficacy of 5-FU by changing the dose, schedule or route of administration. One of these regimens is the weekly continuous intravenous (i.v.) infusion of high-dose 5-FU (TTD regimen) developed by our study group as an effective and safe treatment for CRC. The use of a continuous i.v. infusion for 48 h on a weekly basis was based on the short half-life of 5-FU and the percentage of tumor cells in the cell cycle: prolonging the drug administration time might increase tumoral cytotoxicity [2]. This high-dose regimen avoids the modulation of 5-FU metabolism by leucovorin (LV) [3], and the ranges of response rate and median survival found in several phase II studies were 29–39% and 11–15 months, respectively [26].

Irinotecan, an inhibitor of topoisomerase I, was introduced into clinical practice for the treatment of advanced CRC refractory to 5-FU [7, 8]. Clinical research continued with the evaluation of a combination of irinotecan plus 5-FU/LV as first-line treatment for advanced CRC: two phase III trials showed the superiority of this combined chemotherapy over 5-FU/LV alone using two distinct 5-FU/LV regimens: Mayo Clinic bolus regimen [9] and the de Gramont infusional regimen [10]. Therefore, a combination treatment with irinotecan plus 5-FU/LV was recommended as the reference first-line chemotherapy for metastatic CRC [11].

In a previous randomized clinical trial conducted in advanced CRC patients, we found a higher response rate (30.3%) for the TTD regimen (5-FU 3.5 g/m2) than for the Mayo Clinic bolus regimen (19.2%). No differences were found between the time to progression (TTP), survival and toxicity of the two regimens [6]. Therefore, the TTD regimen may constitute a feasible alternative to other 5-FU/LV modulated regimens for combining chemotherapy with irinotecan as first-line treatment for advanced CRC.

We conducted a phase I trial to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of weekly irinotecan combined with 5-FU 3 g/m2 given as a weekly 48-h i.v. infusion (TTD regimen) to treat different gastrointestinal solid tumors. Additional phase II research was conducted in order to determine the activity and toxicity of the dose recommended from the phase I trial as first-line chemotherapy for patients with advanced CRC.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Selection of patients for phases I and II
This phase I/II trial was approved by the health authorities and ethics committees of the centers involved in the research (four centers in the phase I study and 10 centers in the phase II study), and written informed consent was obtained from all patients. The phase I cohort included patients with histologically confirmed solid tumors not curable with surgery or radiotherapy, or unresponsive to standard chemotherapy (maximum of one previous palliative line). The patients in the phase II cohort showed histologically confirmed advanced colorectal carcinoma with at least one measurable lesion (chemotherapy-naïve or with prior adjuvant chemotherapy ≥6 months before inclusion). An interval of 4 weeks must have elapsed since the end of other treatments (6 weeks for mitomycin C, nitrosureas or non-extensive radiotherapy).

Common inclusion criteria for phases I and II were as follows: age between 18 and 70 years; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; a life expectancy ≥12 weeks; and adequate bone marrow function (neutrophil count ≥2000/mm3, platelet count ≥100 000/mm3, hemoglobin ≥10 g/dl), renal function (serum creatinine ≤125 µmol/l) and liver function [bilirubin level ≤1.25 x upper normal limit (ULN), serum transaminases ≤3 x ULN and prothrombin time ≥50%]. If liver metastases were present, bilirubin levels could be ≤1.5 x ULN and serum transaminases ≤5 x ULN.

The exclusion criteria for both phases were as follows: prior treatment with irinotecan or any other topoisomerase I inhibitor; severe toxicity with the same 5-FU schedule; symptomatic metastases in the central nervous system or carcinomatous leptomeningitis; previous cancer history (except for resolved cervical carcinoma or basal cutaneous carcinoma); a high risk of poor outcome due to concomitant nonmalignant disease (uncontrolled severe infection, major organic failure, ischemic cardiopathy, chronic inflammatory intestinal disease or chronic diarrhea syndrome); bowel obstruction or subobstruction; extensive pelvic radiotherapy; and lactating, pregnant women or patients with reproductive potential not implementing adequate contraceptive measures.

Treatment for phase I
Several doses of irinotecan (from 60 to 110 mg/m2) were tested in combination with a fixed dose of 5-FU (3 g/m2). The chemotherapy dose escalation plan is shown in Table 1. The patients received weekly irinotecan given as a 30-min i.v. infusion followed immediately by 5-FU given as a 48-h i.v. infusion. Complete treatment lasted 6 weeks, and at least three patients were to be treated at each dose level. In the absence of DLT, other patients were enrolled in the next dose level. If one patient experienced a DLT, three additional patients were recruited at the same dose level. Intrapatient dose escalation was not allowed. The treatment was repeated every week to a minimum of six courses except when disease progression was detected during the study period. A follow-up of 2 weeks after the last infusion was allowed to assess any potential toxicities. Nevertheless, the treatment could be maintained if clinical beneficial effects were found, and toxicity data were recorded until disease progression in order to assess potential cumulative toxicity.


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Table 1. Dose escalation plan for the phase I studya
 
Phase I: DLT and MTD
Toxicity was evaluated during the 6 weekly infusions and for 2 weeks after the last infusion. DLT included grade 4 hematological toxicity (granulocyte level <0.5 x 109/l or platelets <25 x 109/l); grade 3/4 febrile neutropenia; sepsis concomitant with grade 3/4 neutropenia; symptomatic thrombocytopenia (hemorrhage), and any grade 3/4 non-hematological toxicity in the first course (except for alopecia and anemia). All toxicities experienced during the study were recorded and graded according to the National Cancer Institute–common toxicity criteria (NCI–CTC) [12].

The maximum tolerated dose (MTD) was defined as the dose level at which 50% of patients showed a DLT. A minimum of six studied patients were required. The recommended dose was the dose level immediately below the MTD level.

Treatment for phases IIa and IIb
Initially, patients were treated with the recommended dose obtained from the phase I study (i.e. irinotecan 80 mg/m2 and 5-FU 3 g/m2) using the same schedule described above: weekly irinotecan 30-min i.v. infusion followed immediately by 5-FU 48-h i.v. infusion (phase IIa). Treatment was administered weekly for six consecutive weeks followed by a 2-week rest period. A maximum of 24 infusions was recommended. If clinical benefits were detected, treatment could be maintained until disease progression.

However, due to the high percentage of patients showing grade 3/4 diarrhea in this initial cohort (27 from 46 patients enrolled; 59%), a second cohort of 36 patents was studied (phase IIb) using the same irinotecan and 5-FU schedule but reducing the 5-FU starting dose to 2.25 g/m2 in order to improve the tolerance to treatment.

Concomitant treatments
Except for antiemetic drugs, no other prophylactic treatments were allowed during the first course. In the event of severe cholinergic syndrome and early diarrhea related to irinotecan infusion, atropine 0.25 mg subcutaneously (s.c.) was administered as curative treatment and prophylaxis for subsequent cycles.

Specific guidelines for the curative treatment of delayed diarrhea were provided; these recommended loperamide 2 mg, every 2 h, for 12 h after the last episode of diarrhea, for a maximum of 48 consecutive hours. If diarrhea persisted for >24 h, an oral prophylactic broad-spectrum quinolone antibiotic was prescribed. If diarrhea persisted for >48 h, the patients were admitted to hospital for parenteral rehydration and treatment with another antidiarrheic drug (e.g. octreotide).

Patients with febrile neutropenia were hospitalized and treated with antibiotherapy and specific support. Nevertheless, the use of prophylactic granulocyte colony-stimulating factor (G-CSF) was not permitted.

Guidelines for dose reduction or delay
The guidelines for dose modification of the chemotherapeutic agents, irinotecan and 5-FU, due to toxicity are shown in Table 2. In the event of two consecutive dose suspensions, the following dose was reduced by 20%. In the event of hand–foot–mouth syndrome, the 5-FU dose was reduced by 20%. If the delay lasted for >2 weeks, the patient was withdrawn from the study. Treatment was also stopped in cases of angina pectoris.


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Table 2. Dose modification guidelines for toxicity
 
Criteria for antitumor response and toxicity in phase II
Response to treatment was evaluated after each treatment period and further rest (i.e. every 8 weeks) and classified according to World Health Organization (WHO) criteria [13]. All objective responses were confirmed 4 weeks later by an independent reviewer. All patients who were withdrawn from the study due to disease progression before the third treatment cycle were classified as treatment failures. Other secondary efficacy end points were duration of response (calculated from time of first objective response to progression), time to disease progression (calculated from first treatment day to progression) and survival (calculated from the start of treatment).

For phase II, according to Simon’s method [14], we defined p1p0 = 20, where p1 was the optimum drug activity (response rate = 35% as found by Douillard et al. [10] using another infusional combined regimen) and p0 was the minimum desirable activity (response rate = 15%). Thus, a maximum sample size of 47 patients was calculated assuming a two-sided protection level against type I errors of 0.05 and a withdrawal rate of 20%. Efficacy and toxicity analyses of both phase II cohorts were performed on the ‘intention-to-treat’ population (i.e. patients receiving at least one chemotherapy course). Kaplan–Meier estimations were used for the duration of response, TTP and overall survival. Adverse events were calculated by punctual estimation with a 95% confidence interval (95% CI).


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Phase I: dose-finding study
Patient and treatment characteristics. The main characteristics of the 21 patients studied are shown in Table 3. Most patients showed PS = 0 (75%) and had received prior chemotherapy (67%) or undergone surgery (95%). The most frequent tumor location was colorectal (52%), followed by gastric (24%) and rectum (24%). Four patients showed metastases to more than two organs, the liver being the most affected (62%).


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Table 3. Characteristics of patients
 
Six patients were enrolled into dose levels 1, 3 and 4, and three patients were enrolled into dose level 2 (Table 1). Nine patients (43%) did not complete treatment due to disease progression, and three patients (14%) due to adverse events (two cases of grade 3 diarrhea and one case of severe infection). A total of 10 deaths (48%) were recorded during the study, all of them due to tumor progression, except for one death caused by pneumonia. No toxic deaths were reported.

A total of 258 chemotherapy infusions were administered (median of six infusions per patient). The distribution of infusions per dose level is shown in Table 1. Irinotecan dose was reduced in 11 infusions (4%) and delayed in 64 infusions (25%); the 5-FU dose was reduced in 17 infusions (7%) and delayed in 66 infusions (26%) (Table 4).


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Table 4. Dose reductions or delays and median dose relative intensity
 
DLT and maximum tolerated dose. All patients were evaluable for toxicity. The DLTs found during the study are summarized in Table 5. Diarrhea was the most common DLT, found even at the first dose level. Nevertheless, dose level 4 was the MTD as it showed >50% of patients (five of six) affected by a DLT. Therefore, level 3 (irinotecan 80 mg/m2 and 5-FU 3 g/m2) was considered to be the recommended dose for phase II research.


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Table 5. Dose-limiting toxicities (DLT) found with combined irinotecan and high-dose 5-FU in 48-hour continuous infusion
 
Phase IIa: antitumor efficacy and toxicity in advanced CRC
Patient and treatment characteristics. The main characteristics of the 46 patients studied are shown in Table 3. Most patients showed PS = 0 (72%). All of them showed advanced, metastatic CRC. Ten patients showed metastases to more than two organs, the liver being the most affected (85%). All patients had undergone prior surgery of which 22 were curative and 24 palliative. Ten patients (22%) had received prior 5-FU-based adjuvant chemotherapy together with surgical procedures, and only two patients (4%) had received prior radiotherapy.

A total of 720 infusions were administered (median, 16 infusions/patient) (Table 4). The irinotecan dose was reduced in 43 infusions (6%) and delayed in 188 infusions (26%); the 5-FU dose was reduced in 40 infusions (6%) and delayed in 189 infusions (26%) (Table 4). Dose intensity was 64.4 mg/m2/week for irinotecan and 2445.6 mg/m2/week for 5-FU. The median relative dose intensity was 0.71 for both irinotecan and 5-FU (Table 4).

Antitumor efficacy. Table 6 shows the overall objective response found in the intention-to-treat population. Six patients were considered not evaluable for response because of withdrawal due to adverse events: intestinal obstruction, bad tolerance to treatment, grade 4 diarrhea and neutropenia and podagra, paroxysmal auricular tachycardia, and two cases of grade 3 diarrhea.


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Table 6. Antitumoral efficacy found in the two phase II cohorts (intention-to-treat population)
 
One patient (2%) showed a complete response and 28 patients (61%) showed a partial response. Therefore, the overall response rate was 63% (95% CI 48% to 77%). Response was confirmed in 20 patients (including the patient with complete response), therefore giving a rate of confirmed response of 44% (95% CI 29% to 59%). The median duration of response (whether confirmed or not) was 8.4 months. Stable disease was observed in eight patients (17%) and three patients (7%) progressed during study treatment.

Time to disease progression and survival. After a median follow-up of 17.7 months, the median TTP was 11.7 months (95% CI 9.4–14.3) and the median overall survival was 23.8 months (95% CI 16.5–36.6) (Table 6).

Toxicity. The most common grade 3/4 toxicity was delayed diarrhea, which affected 59% of patients (Table 7). Three of these patients, with grade 3 (two cases) or grade 4 (one case) diarrhea, finally had to discontinue treatment despite previous dose reduction or delay and concomitant treatment with loperamide. Other toxicities showing a high incidence were neutropenia (17% of patients), nausea/vomiting (17% of patients) and asthenia (17% of patients). One patient showing grade 4 neutropenia withdrew from the study, and only one case of grade 4 febrile neutropenia was found. Two patients showed cardiovascular toxicity consisting of grade 3 sinusoid tachycardia and grade 4 arrhythmia. No toxic deaths were reported.


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Table 7. Grade 3/4 treatment-related toxicity during phase II
 
Phase IIb: antitumor efficacy and toxicity in advanced CRC
Patient and treatment characteristics. The main characteristics of the 36 patients studied were quite similar to that of the other phase II cohort studied (Table 3). Most patients showed PS = 0 (70%); all of them showed advanced, metastatic CRC; six patients showed metastases to more than two organs, the liver being the most affected (83%); all of them had undergone prior surgery of which 10 were curative and 26 palliative. Ten patients (28%) had received prior 5-FU-based adjuvant chemotherapy together with surgical procedures and seven patients (19%) had received prior radiotherapy.

A total of 818 infusions were administered (median, 24 infusions/patient) (Table 5). The irinotecan and 5-FU doses were reduced or delayed in a lower percentage of infusions compared with the phase IIa cohort (Table 4). Dose intensity was 77.3 mg/m2/week for irinotecan and 2134.2 mg/m2/week for 5-FU. In comparison with that reported in phase IIa cohort, these reported absolute doses were significantly higher for irinotecan (P <0.005), but lower for 5-FU (P <0.0001). The median relative dose intensity was 0.79 for irinotecan and 0.77 for 5-FU (Table 4).

Antitumoral efficacy. Four patients were considered not evaluable for response, but only one case was withdrawn due to adverse events (asthenia, anorexia and depression). One patient (3%) showed a complete response and 14 patients (39%) showed a partial response [overall response rate of 43% (95% CI 25% to 59%)]. Response was confirmed in 10 patients with partial response [rate of 28% (95% CI 14% to 45%)]. The median duration of response was 8.3 months and the median duration of confirmed response was 14.3 months. Stable disease was observed in 13 patients (36%) and four patients (11%) progressed during study treatment (Table 6).

Time to disease progression and survival. After a median follow-up of 15.8 months, the median TTP was 9.2 months (95% CI 7.5–10.4) and median overall survival was 17.2 months (95% CI 12.4–25.7) (Table 6).

Toxicity. Similar to what was found in the other phase II cohort, diarrhea was again the grade 3/4 toxicity with the highest incidence (56% of patients), followed by asthenia (17%), neutropenia (11%) and anorexia (11%) (Table 7). Nevertheless, most diarrhea was grade 3 (16 patients, 44%) in contrast with that found in the phase IIa cohort (diarrhea grade 3 in 14 patients; 30%). Moreover, cases of diarrhea showed the best management of toxicity and this was reflected in better treatment compliance: no patients belonging to this cohort withdrew from the study due to diarrhea or neutropenia. No cases of febrile neutropenia or toxic deaths were reported. Cardiovascular events were reduced to one case of heart failure.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The aim of the first part of this study (phase I) was to define the maximal dose achievable during the first chemotherapy course: irinotecan 80 mg/m2 combined with 5-FU 3 g/m2 was the dose recommended for further research, i.e. phase II. The irinotecan 80 mg/m2 dose chosen for combination with weekly TTD regimen (a high-dose 5-FU schedule) was lower than the 125 mg/m2 dose used for weekly second-line irinotecan monotherapy [1518], or the 125 mg/m2 used in the phase III study on irinotecan combined with the Mayo Clinic bolus regimen in the first-line setting of CRC [9]. The other phase III trial on biweekly irinotecan combined with the de Gramont 5-FU–LV regimen used a higher dose of irinotecan: 180 mg/m2 [10]. A similar irinotecan dose (80 mg/m2) was used by Douillard et al. for combination therapy following the weekly German AIO regimen [10], and in a recent study which has confirmed the clinical benefit of irinotecan combined with the AIO regimen [19].

The DLT for irinotecan plus TTD regimen found in the phase I study was diarrhea. This finding is in accordance with previous phase I trials evaluating weekly irinotecan with 24-h infusional 5-FU/LV-modulated regimens, which also reported diarrhea as the DLT [20], but differs from phase I studies with weekly irinotecan combined with bolus 5-FU/LV, where neutropenia was the DLT and diarrhea was common but rarely dose-limiting [21].

The results obtained in the first phase II cohort revealed a marked antitumor activity of the combined irinotecan plus TTD regimen chemotherapy as first-line treatment for advanced CRC. An overall confirmed response rate of 44% was found together with almost 20% of patients showing stable disease. Therefore, this combined chemotherapy provided a meaningful rate of tumor control. A finding especially relevant is that the response rate was associated with a TTP of 11.7 months and an overall survival of 23.8 months. These efficacy values are better than those reported with the TTD regimen alone in previous phase II trials: a response rate of 29–39% and an overall survival of 11–15 months [26]. Moreover, the efficacy values reported here are higher than those described in previous phase III studies that evaluated combinations of irinotecan and 5-FU/LV as first-line chemotherapy for advanced CRC patients: response rate of 35% and 39%, TTP of 6.7 and 6.0 months, and overall survival of 17.4 and 14.8 months, respectively [9, 10] (Figure 1).



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Figure 1. Comparison of response rate, duration of response, time to progression, and overall survival found in previous studies on combined irinotecan plus 5-FU/LV (Mayo Clinic bolus regimen [9] and de Gramont infusional regimen [10]) and in the two phase II cohorts of the present trial. Values shown are medians.

 
Nevertheless, the high antitumor activity found for irinotecan plus TTD regimen was associated with a high incidence of severe toxicity, especially grade 3/4 diarrhea which affected 59% of patients. No toxic deaths were found, but diarrhea led to the withdrawal of three patients despite dose reduction or curative treatment with loperamide. This finding prompted the enrolment of a second cohort of advanced CRC patients in which the irinotecan dose remained unchanged but the 5-FU starting dose was reduced from 3 to 2.25 g/m2. A recent trial evaluating the clinical benefit of irinotecan combined with the German AIO regimen required a reduction of the initial 5-FU dose from 2.3 to 2 g/m2 due to some toxic deaths [19]. Following the 5-FU reduction, but maintaining the same irinotecan dose (80 mg/m2), rates of grade 3/4 diarrhea were reduced.

In the present study, the aim of this 5-FU starting dose reduction (to improve the tolerance of this combined chemotherapy) was achieved. The high incidence of patients reporting grade 3/4 diarrhea did not decrease substantially (56% versus 59% of patients), but the overall incidence of grade 4 diarrhea was lower (11% versus 28%). Most patients showed grade 3 diarrhea, which was successfully corrected by dose adjustment; in this way, no patients discontinued treatment. Moreover, the incidence of the most relevant non-hematological toxicity (i.e. neutropenia) was notably reduced (11% versus 17%) and no cases of febrile neutropenia were reported in the second cohort. The overall toxicity profile agrees with that reported in previous phase III trials with combined irinotecan and 5-FU/LV as first-line chemotherapy for advanced CRC, although these large trials showed a lower incidence of diarrhea (22.7% and 44.4%), but a higher incidence of neutropenia (53.8% versus 28.8%) [9, 10].

Another beneficial effect of reducing the 5-FU starting dose was that patients received more infusions (median of 24 versus 16 infusions), whereas the number of dose reductions or delays due to toxicity were reduced to almost half of that found in the first cohort (Table 4). Apart from a high antitumor efficacy, other advantages of the present combined chemotherapy are that no biochemical modulation of 5-FU with leucovorin was required (therefore reducing the treatment cost), and also the treatment duration was longer when compared with other combined schedules. However, as the present combined chemotherapy is a weekly regimen, the total number of visits must be taken into account when assessing the final balance between advantages and disadvantages of this treatment.

Some toxicity concerns related to irinotecan plus bolus 5-FU/LV have been raised due to an unexpected number of deaths found in some trials [22, 23], most of them related to a ‘vascular syndrome’ characterized by either acute myocardial infarction, pulmonary embolism or cerebral accident developing in the early days after the beginning of the treatment [24]. These deaths led to the temporary suspension of enrolment in these trials [23], and close monitoring, withholding therapy in the presence of unresolved drug-related toxicity and aggressive use of antibiotics were encouraged [22]. Nevertheless, none of these concerns about safety have been reported in trials using the irinotecan plus infusional de Gramont schedule [10], now a common standard for advanced CRC treatment in European countries. We did not report here any deaths related to vascular syndrome, thus supporting the cardiovascular safety of combined irinotecan plus 5-FU chemotherapy when 5-FU is given as a continuous infusion, even using a high-dose schedule.

Tolerance of treatment was improved in the second cohort of patients treated with irinotecan plus the modified TTD regimen (5-FU 2.25 g/m2, 48-h i.v. infusion), but all measures of antitumor efficacy were lower compared with those found in the first cohort: response rate of 28% versus 44%, TTP of 9.2 versus 11.7 months, and overall survival of 17.2 versus 23.8 months. Reduced efficacy in phase IIb cohort could also be due to reduced dose intensity. The reported absolute doses in the phase IIb cohort were significantly lower for 5-FU (mean decrease of 13%) compared with phase IIa; however, absolute irinotecan dose was significantly higher for irinotecan (mean increase of 20%). A plausible effect on efficacy results due to different baseline patient factors between cohorts should not be discarded. However, parameters of antitumor activity were lower but confidence intervals overlapped (Table 6). In Figure 1, our results are compared with those of previous phase III studies of first-line irinotecan plus 5-FU/LV combined chemotherapy [9, 10]. Response rate, progression-free survival and overall survival appear to be within the limits of these previous clinical trials. The results of TTP (9.2–11.7 months) and overall survival (>17 months) found in the present study are quite promising.

In conclusion, we found weekly irinotecan 80 mg/m2 plus TTD regimen (5-FU 2.25 g/m2 given as a 48-h i.v. infusion) to be a feasible and an active combined chemotherapy for the first-line treatment of advanced colorectal cancer. The reduction in the 5-FU starting dose from 3 to 2.25 g/m2 improved tolerance (i.e. decreased grade 4 diarrhea and reduced grade 3/4 neutropenia) and treatment compliance, but also reduced both response rate and survival. Nevertheless, the TTP found for both 5-FU doses (9–11.7 months) clearly indicated antitumoral activity of this combined regimen. Further randomized clinical trials would be required to better define the most suitable schedule for advanced CRC treatment by comparing the present combined chemotherapy with other standard irinotecan plus 5-FU/LV first-line chemotherapies. The TTD group is now developing a phase III trial comparing the TTD regimen with Douillard’s combined infusional regimen on a non-inferiority basis; further research could contemplate the substitution of 5-FU continuous infusion by oral fluoropyrimidines in combined regimens against colorectal cancer.


    Acknowledgements
 
The authors wish to thank Vicente Alfaro (Prous Science) for his help in the creation of this manuscript.


    FOOTNOTES
 
* Correspondence to: Dr Enrique Aranda, Servicio de Oncología Médica, Hospital Universitario Reina Sofía, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain. Tel: +34-957-011626; Fax: +34-957-011626; E-mail: earandaa{at}seom.org Back


    REFERENCES
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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