Division of Medical Oncology A, National Tumour Institute, Naples, Italy
Received 15 October 2001; revised 16 November 2001; accepted 11 December 2001.
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Abstract |
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The purpose of this study was to compare the activity and toxicity of the combination of irinotecan (IRI) plus folinic acid (FA)-modulated 5-fluorouracil (5-FU) i.v. bolus with a regimen of double modulation of 5-FU with methotrexate (MTX) and FA in patients with advanced colorectal carcinoma.
Patients and methods
Two-hundred and thirty-four patients were enrolled: 118 patients received IRI 200 mg/m2 (90-min i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and 5-FU 850 mg/m2 (i.v. bolus) on day 2 (IRIFAFU), and 116 patients received MTX 750 mg/m2 (2-h i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and FU 800 mg/m2 (i.v. bolus) on day 2 (MTXFAFU). Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles. Response rate (RR) was the main end point of the study; responses were assessed every four cycles and confirmed after 2 additional months of treatment.
Results
RR was significantly greater with IRIFAFU (36%) than with MTXFAFU (20%) (P <0.001). Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity (P = 0.028). Median progression-free survival was longer with IRIFAFU than with MTXFAFU (7.2 months compared with 4.8 months; P = 0.048). Median survival time (MST) did not differ between the two arms (14.7 months compared with 14.8 months, respectively). Patients not receiving second-line chemotherapy, however, lived longer when treated in the first-line with IRIFAFU (MST 11.9 months compared with 6.4 months; P = 0.038). IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia (40% compared with 9%; P = 0.001) and diarrhoea (13% compared with 4%; P = 0.024), but a significantly lower incidence of stomatitis (3% compared with 12%; P = 0.007), than the comparative regimen.
Conclusions
IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens. IRIFAFU, however, seems easier to administer, because it does not require infusional catheter or pump devices, and it is less expensive. It may represent a new option for treating advanced colorectal carcinoma.
Key words: advanced colorectal carcinoma, combination regimen, irinotecan plus modulated 5-fluorouracil, randomised trial
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Introduction |
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Irinotecan (IRI or CPT-11) has been initially tested in 5-FU-refractory patients, obtaining a moderate activity and a survival benefit, suggesting a lack of cross-resistance between the two drugs [9, 10]. Furthermore, CPT-11 with 5-FU has been compared with 5-FU alone as first-line management of advanced colorectal cancer patients in two randomised trials [11, 12]. In one of these studies, CPT-11 125 mg/m2, FA 20 mg/m2 and 5-FU 500 mg/m2 were given together i.v. weekly for 4 of every 6 weeks [11]. In another study, patients were randomised to receive either one of two 5-FU infusional regimens (24-h weekly or 48-h every other week), or the same regimen with the addition of CPT-11 (80 mg/m2 or 180 mg/m2, respectively) [12]. In both trials, a statistically significant survival advantage was obtained with the combination regimens. We have recently explored a new scheduling of CPT-11 and FA-modulated 5-FU, administering the two cytotoxic drugs in close sequence on days 1 and 2 (CPT-11 200 mg/m2 as short i.v. infusion and 5-FU 850 mg/m2 as i.v. bolus, respectively) in a biweekly regimen, obtaining a very encouraging RR [13].
Therefore, we planned to assess the activity and toxicity of this new regimen in a randomised study, keeping our double modulation of 5-FU as reference treatment. The interim analysis of this trial has been already published [14]. Here we report the final analysis of the this trial.
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Patients and methods |
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The primary end points of this phase II/III randomised trial were: (i) to evaluate the RR and the acute toxicity profile of two new regimens in which 5-FU and LFA were combined with either CPT-11 (IRIFAFU) or Tomudex® (TOM; TOMFAFU) in patients with advanced colorectal carcinoma, and (ii) to estimate the difference in RR between each of these two experimental regimens and the reference regimen of MTX followed by LFA + 5-FU (MTXFAFU) every 2 weeks. Secondary end points were to compare the time to progression (TTP) and the overall survival of treated patients.
Patients who meet the inclusion criteria, after stratification for site of primary cancer (colon compared with rectum) and performance status (PS) [0 compared with 1 or 2 of the Eastern Cooperative Oncology Group (ECOG) scale], were randomly allocated to receive one of the three following treatments: CPT-11 200 mg/m2 as 90-min i.v. infusion on day 1, LFA 250 mg/m2 as 2-h i.v. infusion and 5-FU 850 mg/m2 i.v. bolus on day 2 every 2 weeks (IRIFAFU); TOM 3.0 mg/m2 as 15-min i.v. infusion on day 1, LFA 250 mg/m2 as 2-h i.v. infusion and 5-FU 1050 mg/m2 i.v. bolus on day 2 every 2 weeks (TOMFAFU); or MTX 750 mg/m2 as 2-h i.v. infusion on day 1, LFA 250 mg/m2 as 2-h i.v. infusion and 5-FU 800 mg/m2 i.v. bolus on day 2 every 2 weeks (MTXFAFU).
Treatment was administered in each arm of the trial every 14 days until a complete response (CR) was achieved (after which four additional cycles were administered), or up to a maximum of 6 months of treatment in the case of partial response (PR) or stable disease. Therapy was discontinued earlier in the presence of documented progression of disease, unacceptable toxicity, patients refusal, or when the attending physician judged that it was in the patient
s best interest. After the discontinuation of treatment, patients were controlled every 2 months to assess relapse of disease (for responder patients) or progression of disease (for patients with stable disease).
In each arm of the trial, doses were adjusted according to blood cell count performed at day 8: if a grade 4 neutropenia was detected at that time, or a febrile neutropenia occurred before recycling, the dose of cytotoxic drugs was subsequently reduced by 25%. If a grade 4 neutropenia occurred again despite this reduction, a further reduction by 25% was adopted. In case of neutropenia [absolute neutrophil count (ANC) <1500/mm3] on day 15, recycling was delayed until recovery. If a 2-week delay was required to reach an ANC value 1500/mm3, a 25% dose reduction was then adopted. If a >2-week delay was required for bone marrow recovery, the patient was discharged from the study.
Dose modifications were also planned for severe non-haematological toxicities: in case of severe diarrhoea or other toxicities grade 3 or more (except alopecia and anaemia), therapy was delayed for 12 weeks until complete recovery or grade 1 or less, then re-instituted with a 25% reduction of cytotoxic drugs.
During treatment, blood cell count was performed weekly (or more often in the presence of neutropenia), while biochemistry was repeated at each cycle. Physical status and evaluation of toxicity was assessed at each cycle. Toxicity was scored according to WHO criteria [15], and the worst toxicity suffered by each patient during the whole treatment was recorded. The cholinergic syndrome was arbitrarily scored as previously reported. Measurements of the disease with CT or MRI scan was repeated after every four cycles and at the end of treatment. Response to treatment was defined according to WHO criteria [16]. Responses were radiologically reassessed 8 weeks after their first documentation, and only confirmed responses were computed in each arm of the trial.
Duration of response was calculated from the time of the start of treatment, or from the date it was first documented (in the case of CR) to the date of documented tumour progression. TTP was calculated from the date of registration to the date of documented tumour progression, or death. Patients who discontinued the treatment early because of toxicity, refusal or reasons other than progression were considered as censored at that time interval. Overall survival time was calculated for all patients from the date of registration to the date of death for any cause, or to patients last follow-up.
To define the sample size, the two-stage design for phase III randomised trials [17] has been utilised: assuming a 15% difference in RR between the control and each experimental regimen (20% compared with 35%), the comparison on the first 48 patients per arm has an 80% power to reveal at least a 4% difference in response. If this is not the case, the study could be terminated early. This was the case for the TOMFAFU arm, which was close to accrual after interim analysis. On the contrary, accrual continued in the IRIFAFU and MTXFAFU arms to reach a total of 116 patients per arm: this final sample size gave also a sufficient power for a comparison of TTP. Indeed, anticipating a median TTP of 4 months for the MTXFAFU arm, this sample size had an 80% power to detect a 50% increase in TTP (i.e. 6 months) for IRIFAFU patients, with a type I error of 0.05 (two-sided test).
All curves were estimated with the KaplanMeier method [18], and compared with either the Wilcoxon test (which gives more weight to the earlier events) or the log-rank test [19]. All comparison were made with a two-sided test.
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Results |
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Off-study management was not planned in the protocol, and it was left to the individual choice of attending physicians. About one-third of patients received further treatment in both arms: second-line chemotherapy (40% compared with 36%), surgery (4% compared with 3%) or radiotherapy (2% in both arms), and a few patients (five in all) received a third-line chemotherapy. In the IRIFAFU arm, most second-line treatments were oxaliplatin-based (38 patients), while in the MTXFAFU arm 20 patients were treated with CPT-11, usually combined with other cytotoxic drugs, and six patients received oxaliplatin-based chemotherapy, alone or in combination; nine patients underwent a combination of CPT-11 and oxaliplatin.
Activity analysis
In the IRIFAFU arm, nine CRs and 33 PRs were registered, giving an overall RR of 36% [95% confidence interval (CI) = 28% to 44%]. Twelve patients obtained a minor response, and 16 patients showed a stabilisation lasting at least 6 months, giving an overall tumour growth control in 70 of 118 patients (59%) (Table 2). All major responses were registered after a median of 3.3 months of treatment (range 2.07.3 months), and lasted a median of 10.2 months (range 4.025.2). In the MTXFAFU arm, four patients achieved a CR, and 19 patients were considered in PR, for an overall RR of 20% (95% CI = 13% to 27%), while an overall control of tumour growth was achieved in 55 patients (47%). Responses were registered after a median of 3.5 months (range 1.57.3) of treatment, and lasted a median of 9.3 months (range 2.724.8).
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Safety analysis
Comparison of toxicity (Table 3) showed that neutropenia of any type, and severe neutropenia, significantly affected more patients treated with IRIFAFU (P = 0.001); no difference, however, in occurrence of complicated neutropenia was observed. Any grade of thrombocytopenia was more frequent with MTXFAFU (P = 0.005). As for non-haematological toxicity, the proportion of patients suffering severe diarrhoea was three-fold greater in the IRIFAFU than in the MTXFAFU arm (P = 0.024), but occurrence of stomatitis of any grade in the MTXFAFU arm was twice that in the IRIFAFU arm (P = 0.002); moreover, the proportion of patients suffering from severe stomatitis was four-fold greater in the MTXFAFU arm (P = 0.007). Derangement of liver enzymes occurred in twice as many patients in the MTXFAFU arm (P = 0.05).
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Discussion |
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In this study, we have demonstrated that the proportion of complete and partial responses was significantly greater with IRIFAFU. Taking into account also the patients showing a tumour shrinkage that did not qualify for a major response, we are confident that the RR of the experimental regimen was not overestimated in this trial. It is also worth noting the activity of this regimen in hepatic metastases (40%), regardless of the extent of liver involvement. Multivariate analysis, including possible confounding factors, confirmed the significantly higher activity of the IRIFAFU regimen.
This greater activity was obtained at a price of acceptable toxicity. Despite the frequent occurrence of severe neutropenia, neutropenic fever/infections were seldom reported. Other haematological toxicities were negligible. Diarrhoea was troublesome in some patients, and it was responsible for an early death in this study. The whole occurrence of severe diarrhoea (<14%), although greater than that produced by the MTXFAFU regimen, did not, however, seem higher than reported with other standard weekly or monthly 5-FU i.v. bolus regimens. Occurrence of severe stomatitis was substantially lower with the IRIFAFU than with the MTXFAFU regimen. Excluding hair loss, less than one-third of patients treated with IRIFAFU suffered an adverse event of grade 3 or greater, and the proportion of patients dying early (within 2 months from initial therapy) from possible treatment-related side-effects was <3%.
Our study was also powered to detect a 50% increase in median TTP (from 4 to 6 months) with the experimental treatment. Actually, a 50% increase in TTP was produced by the IRIFAFU treatment. This difference was significant when assessed with the Wilcoxon test, but not with the log-rank test. Indeed, TTP curves diverged from 2 to 8 months from initial therapy, than gradually approached again to overlap at 12 months and thereafter.
We have tried to report our results in the context of two other large trials comparing a combination regimen of CPT-11 plus modulated 5-FU with modulated 5-FU alone in advanced colorectal cancer [11, 12] (Table 4). In the Saltz trial, the combination regimen produced a significantly greater RR (39% compared with 21%), and a significantly longer TTP (7.0 months compared with 4.3 months) and MST (14.8 months compared with 12.6 months) than the Mayo regimen. This regimen was characterised by much more severe diarrhoea (23% compared with 13%), but significantly less stomatitis (2% compared with 17%) in comparison with the reference regimen. Severe neutropenia affected about 54% of patients, but grade 4 incidence was lower than that reported with the monthly regimen (24% compared with 42.5%). In this study, drug-related deaths occurred in <1% of treated patients. An alert has recently been raised, however, on the basis of unexpectedly high proportions of early deaths reported when using this regimen in ongoing trials in the adjuvant (4.8%) as well in the metastatic setting (2.2%) [23].
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In conclusion, the IRIFAFU biweekly i.v. bolus regimen was more active than the MTXFAFU regimen, because it produced a significantly greater RR, and a longer median time to treatment failure and TTP. The use of a more active regimen as a front-line approach seemed to improve the outcome of patients who, for any reason, were not submitted to second-line chemotherapy. This regimen caused more diarrhoea and neutropenia, but less thrombocytopenia and stomatitis, than the comparative regimen, and it was generally well tolerated by patients. It may represent a new option for treating advanced colorectal cancer patients, and it is now the reference regimen for our Cooperative Group.
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Acknowledgements |
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The following investigators (and Institutions) are co-authors of this trial: P. Comella, R. Casaretti, A. Avallone, M. Montella, G. Comella (National Tumour Institute, Naples); F. De Vita, M. Orditura, G. Catalano (2nd University Medical School, Naples); L. De Lucia (City Hospital, Caserta); E. Crucitta, V. Lorusso, M. De Lena (Oncology Institute, Bari); M. Biglietto (Cardarelli Hospital, Naples); A. Farris, G. Sanna, M. G. Sarobba (University Medical School, Sassari); F. Del Gaizo, C. Belli (City Hospital, Avellino); S. Palmeri, A. Russo, N. Pizzardi, V. Accurso (University Medical School, Palermo); A. Iannelli (City Hospital, Siderno); S. Mancarella, F. Musca (City Hospital, Campi Salentino); S. Tafuto, A. Gravina (City Hospital, Pozzuoli); L. Maiorino, G. Leopaldi (San Gennaro Hospital, Naples); G. P. Ianniello (City Hospital, Benevento); F. Buzzi (City Hospital, Terni); C. Brunetti (City Hospital, Manduria); D. Muci (City Hospital, Nardò); S. Leo (IRCCS, Castellana Grotte); G. De Cataldis (Da Procida Hospital, Salerno); F. Avino, L. De Luca (Pellegrini Hospital, Naples); E. Greco, C. Aiello (City Hospital, Lametia).
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Footnotes |
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References |
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2. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992; 10: 896903.[Abstract]
3. Advanced Colorectal Cancer Meta-Analysis Project. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994; 12: 960969.[Abstract]
4. Comella P, Lorusso V, Casaretti R et al. Concurrent modulation of 5-fluorouracil with methotrexate and l-leucovorin: An effective and moderately toxic regimen for the treatment of advanced colorectal carcinoma. A multicenter phase II study of the Southern Italy Cooperative Oncology Group. Tumori 1999; 85: 465472. [ISI][Medline]
5. Abad A, Garcia P, Gravalos C et al. Sequential methotrexate, 5-fluorouracil (5-FU), and high-dose leucovorin versus 5-FU and high-dose leucovorin versus 5-FU alone for advanced colorectal cancer. Cancer 1995; 75: 12381244.[ISI][Medline]
6. Glimelius B. Biochemical modulation of 5-fluorouracil: A randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer. Ann Oncol 1993; 4: 235250.[Abstract]
7. Polyzos A, Tsavaris N, Giannopoulos C et al. Biochemical modulation of fluorouracil: comparison of methotrexate, folinic acid, and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial. Cancer Chemother Pharmacol 1996; 38: 292297.[ISI][Medline]
8. Sobrero A, Zaniboni A, Frassineti GL et al. Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a randomized study. Ann Oncol 2000; 11: 14131420.[Abstract]
9. Rougier P, Van Cutsem E, Bajetta E et al. Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998; 352: 14071412.[ISI][Medline]
10. Cunningham D, Pyrhonen S, James RD et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 14131418.[ISI][Medline]
11.
Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905914.
12. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer. A multicentre randomised trial. Lancet 2000; 355: 10411047.[ISI][Medline]
13. Comella P, Casaretti R, De Vita F et al. Concurrent irinotecan and 5-fluorouracil plus levo-folinic acid given every other week in the first-line management of advanced colorectal carcinoma: a phase I study of the Southern Italy Cooperative Oncology Group. Ann Oncol 1999; 10: 915921.[Abstract]
14. Comella P, De Vita F, Mancarella S et al. Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase IIIII randomized study. Ann Oncol 2000; 11: 13231333.[Abstract]
15. Miller AB, Hoogstraten B, Staquet M, Winkler V. Reporting results of cancer treatment. Cancer 1981; 47: 207214.[ISI][Medline]
16. Guichard S, Cussac D, Hennebelle I et al. Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT29 in vitro and in vivo. Int J Cancer 1997; 27: 729734.
17. Thall PF, Simon R, Ellenberg SS. A two-stage design for choosing among experimental treatments and a control in clinical trials. Biometrics 1989; 45: 537547.[ISI][Medline]
18. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
19. Haybittle JL. Significance testing in comparison of survival curves from clinical trials of cancer treatment. Eur J Cancer Clin Oncol 1986; 11: 12791283.
20. Mullany S, Svingen PA, Kaufmann SH et al. Effect of adding topoisomerase I poison 7-ethyl-10-hydrossycamtpthecin (SN-38) to 5-fluorouracil and folinic acid in HCT8 cells: elevated dTTP pools and enhanced cytotoxicity. Cancer Chemother Pharmacol 1998; 42: 391399. [ISI][Medline]
21. Mans DRA, Grivicich I, Peters GJ et al. Sequence-dependent growth inhibition and DNA damage formation by the irinotecan-5-fluorouracil combination in human colon carcinoma cell lines. Eur J Cancer 1999; 35: 18511861.[ISI][Medline]
22.
Cao S, Rustum YM. Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 2000; 60: 37173721.
23.
Sargent DJ, Niedzwiecki D, OConnel MJ et al. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001; 345: 144145.