SEARCH

SEARCH BY CITATION

Keywords:

  • colorectal neoplasms;
  • drug therapy;
  • Phase II;
  • irinotecan;
  • oxaliplatin

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer, and there is a strong preclinical rationale for combining these 2 agents. Therefore, a Phase II trial was designed and conducted to determine the efficacy and tolerability of combined irinotecan and oxaliplatin given every 3 weeks to patients with metastatic colorectal cancer.

METHODS

Patients with previously untreated metastatic colorectal cancer received irinotecan at a dose of 175 mg/m2 and oxaliplatin at a dose of 130 mg/m2, both given intravenously every 3 weeks. Objective responses were evaluated every 2 courses and were confirmed at least 4 weeks after the initial determination.

RESULTS

Fifty-five patients were enrolled and treated in the current trial. Of the 53 patients whose responses were evaluable, 18 (34%) achieved a partial response, 27 (51%) had stable disease, and 8 (15%) developed disease progression as their best response to the treatment. The intent-to-treat median survival for all patients was 16.4 months and the time to progression was 4.8 months. All 55 patients were available for toxicity analysis (according to version 2.0 of the National Cancer Institute Common Toxicity Criteria). The most common Grade 3-4 toxic effect was neutropenia, which was reported to occur in 22 patients (40%).

CONCLUSIONS

The combination of irinotecan and oxaliplatin appears to be safe and active when used to treat patients with metastatic colorectal cancer. Treatment results with this regimen were similar to those reported for other combined frontline chemotherapy regimens for colorectal cancer. When this particular regimen wa used, neutropenia was found to be the predominant toxicity. Cancer 2006. © 2006 American Cancer Society.

Despite more than 40 years of 5-fluorouracil (5-FU)-based treatment for metastatic colorectal cancer, this tumor continues to be a major health problem in the U.S., and it is estimated that 57,100 patients will have died of the disease in 2004.1 Except for small improvements noted with the use of continuous infusions of 5-FU and 5-FU combined with the biomodulator leucovorin, attempts at improving the efficacy of 5-FU have not produced consistent benefits.2 Furthermore, despite improved response rates with continuous infusions and leucovorin modulation, survival prolongation has been only marginal at best.3, 4 It is clear that a number of patients have colorectal cancers that have “de novo” resistance to 5-FU, and we may be reaching a time when those patients will be identified based on the molecular profile of their tumors and the presence of specific polymorphisms.5–7 In addition, a small number of patients have a deficiency of the enzyme dihydropyrimidine dehydrogenase and may have fatal toxicities with the use of any fluoropyrimidine.

Two new chemotherapy drugs, irinotecan and oxaliplatin, have become available for the treatment of colorectal cancer. Both have demonstrated activity as single agents in patients previously treated with 5-FU and in those not previously exposed to chemotherapy for metastatic disease.8, 9 In addition, both irinotecan and oxaliplatin have been combined with 5-FU and leucovorin, and both combinations have produced high objective response rates and are considered standard treatments for metastatic colorectal cancer.10, 11

A strong preclinical rationale exists for combining irinotecan and oxaliplatin. Irinotecan is converted in the liver to its active metabolite, SN-38, which acts as an inhibitor of topoisomerase I.12 SN-38 stabilizes the complex formed by DNA and topoisomerase I, leading to double-stranded DNA breaks and consequently to cell death. Oxaliplatin forms both intrastrand and interstrand DNA adducts. It has been shown that irinotecan and oxaliplatin are synergistic against the HT29 human colon carcinoma cell line, regardless of the sequence of administration.13 The inhibition of DNA and RNA synthesis lasted longer and was more pronounced when SN-38 was given after oxaliplatin. In addition, SN-38 administration delayed recovery from the DNA damage that was induced by oxaliplatin in vitro.

Although gastrointestinal toxicity and bone marrow suppression are relatively common after treatment with both irinotecan and oxaliplatin, their dose-limiting toxicities differ somewhat. The main dose-limiting toxicity for irinotecan is diarrhea; for oxaliplatin, it is peripheral neuropathy. Therefore, combining irinotecan and oxaliplatin appears to be a logical step in the development of novel chemotherapy regimens for the treatment of patients with metastatic colorectal cancer.

Previous studies of this combination have attempted to maximize the dose of irinotecan, holding the dose of oxaliplatin at a lower level. We previously conducted a Phase I study that explored the tolerability and activity of treatment with combined irinotecan and oxaliplatin, with an attempt to maximize the oxaliplatin dose. Our recommended Phase II doses were 175 mg/m2 for irinotecan and 130 mg/m2 for oxaliplatin, both administered intravenously (i.v.) every 3 weeks.14 The dose-limiting toxicity of the combination was neutropenia, but the regimen was generally well tolerated, as was noted with similar combination regimens. In the current study, we used these recommended doses to conduct a Phase II trial for previously untreated patients with metastatic colorectal cancer.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Design

The study was designed as a 2-stage Phase II, nonrandomized, single-arm trial, using a combination of oxaliplatin at a dose of 130 mg/m2 followed by irinotecan at a dose of 175 mg/m2, administered i.v. in the outpatient setting every 3 weeks for a maximum of 8 courses. Additional courses were permitted for responding patients at the discretion of the attending physician. Infusions of both irinotecan (Pharmacia, Peapack, NJ) and oxaliplatin (Sanofi–Synthelabo, New York, NY) were given on Day 1 of each course.

Patients were enrolled both at the University of Texas M. D. Anderson Cancer Center and at the University of Texas Medical Branch in Galveston. The institutional review boards of both institutions approved the protocol and all patients provided written informed consent before participating.

Eligibility of Patients

Eligible patients were at least 18 years old and had pathologically confirmed metastatic adenocarcinoma of the colon or rectum with at least 1 lesion (not previously irradiated and larger than 2.0 × 2.0 cm), 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 (ANC) ≥1500/μL, a platelet count ≥100,000/μL, serum creatinine ≤2.0 mg/dL, serum bilirubin ≤1.5 mg/dL, and serum alanine aminotransferase ≤2.5 times higher than the upper limit of normal (except in those cases with liver involvement, when a value ≤5 times the upper limit of normal was accepted). Other eligibility criteria required full recovery from previous surgery (at least 2 weeks) or radiation therapy (at least 4 weeks).

No previous chemotherapy treatment for metastatic disease was allowed, but patients who had received adjuvant chemotherapy with fluoropyrimidines were eligible if the interval after the end of adjuvant therapy was >6 months. If the disease had progressed while the patient was still undergoing adjuvant chemotherapy or within 6 months of its completion, the prior chemotherapy for metastatic disease was considered a failure and the patient was ineligible for the current study. Patients who had previously been treated with irinotecan or oxaliplatin or radiation therapy to the pelvis were excluded from the study, as were pregnant and breast-feeding women. Other exclusion criteria included clinically apparent central nervous system metastases, prior malignancies (other than nonmelanoma skin cancer or in situ cervical cancer) within the previous 5 years, uncontrolled infection or diabetes mellitus, serious psychiatric disorders, myocardial infarction within the previous 6 months, heart failure, and history of epilepsy or use of anticonvulsant medications. Patients with known Gilbert syndrome were also excluded because of the known excessive irinotecan toxicity associated with this diagnosis.

Treatment

Oxaliplatin was diluted in 250 mL or 500 mL of 5% dextrose solution and infused i.v. over 120 minutes. After the oxaliplatin infusion was complete, irinotecan was diluted in 250 mL of 5% dextrose solution and infused i.v. over 30 minutes. Antiemetic premedication consisted of 10 mg of dexamethasone and a 5-hydroxytryptamine-3 antagonist. No prophylactic atropine, loperamide, or granulocyte colony-stimulating factor was used, but their therapeutic use was allowed. Patients were instructed to take loperamide for diarrhea occurring more than 8 hours after treatment. Early cholinergic symptoms were treated with i.v. atropine (at a dose of 0.25-1.0 mg), which could also be used as secondary prophylaxis for patients who had experienced these symptoms in prior courses of therapy.

Evaluation of Toxicity and Response

Toxicity

The use of oxaliplatin is associated with peripheral neurotoxicity, which may include paresthesias and dysesthesias of the hands, feet, and perioral region and with a distinctive laryngopharyngeal dysesthesia characterized by an acute sensation of respiratory discomfort without any objective evidence of such distress. Neurologic toxicity (i.e., peripheral neuropathy) was graded according to a specific scale that was developed for oxaliplatin and extensively used in previous trials. Other toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).

Response

After every 2 courses, the response to treatment was evaluated using the World Health Organization criteria and each patient's best response was recorded. A complete response was defined as the complete disappearance of all measurable and evaluable disease for at least 4 weeks, with no evidence of new lesions. A partial response was defined as a decrease of at least 50% in the sum of the products of the largest perpendicular dimensions of all measurable lesions for at least 4 weeks, with no evidence of new lesions or worsening of evaluable disease. Progressive disease was defined as an increase of at least 25% in the sum of the products of the largest perpendicular dimensions of all measurable lesions, the reappearance of any lesion that had disappeared, or the appearance of new lesions. Stable disease was defined as a response that did not fit into any of the other categories.

Planned dose adjustments

For Grade 3 diarrhea or diarrhea that had not returned to the baseline level by the day of the next planned treatment, the dose of irinotecan only was reduced (by 25 mg/m2). Any episode of Grade 4 diarrhea was considered cause for discontinuation of treatment. For neurologic toxicity lasting longer than 7 days, the dose of oxaliplatin only was reduced (by 25% in patients without functional impairment and by 50% in patients with functional impairment). Patients with pain or functional impairment that persisted between courses of treatment were withdrawn from the study. For patients who experienced laryngopharyngeal dysesthesia, subsequent doses of oxaliplatin were infused over 6 hours.

Treatment delays were planned for both irinotecan and oxaliplatin until the ANC was ≥1500/μL and the platelet count was ≥100,000/μL, until recovery from diarrhea to at least baseline levels, and until recovery from any treatment-related nonhematologic toxicity to Grade ≤1. Oxaliplatin-related neurologic toxicity resulted in dose reductions or discontinuations but not dose delays. Treatment could be delayed for a maximum of 2 weeks. If either drug had to be delayed for longer than 2 weeks or discontinued permanently, the affected patients were withdrawn from the study. Other reasons for withdrawal were documented disease progression, withdrawal of patient consent, patient noncompliance, and serious intercurrent illness.

Statistical Design

The primary endpoint of the trial was the response rate; a 40% response rate was considered to be of interest. Any response rate of <20% was unacceptable. Therefore, the trial was conducted using a 2-stage design, with 90% power to detect a response rate of 40% and <5% chance of continuing the trial if the response was <20%. The trial was designed to treat an initial cohort of 19 patients, with termination of the trial if there were 4 or fewer responses. If there were more than 4 responses, the trial would proceed to the second stage, with the enrollment of 35 additional patients. Secondary endpoints included median time to progression and overall survival.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Fifty-five patients were evaluated between July 2000 and December 2002. Their baseline characteristics are summarized in Table 1. A total of 224 courses of treatment were given and patients received a median of 5 courses (range, 1-13 courses). Response could not be evaluated in 2 patients (1 patient died within 2 weeks of enrollment and the second withdrew consent after the first course). Among the 53 patients with evaluable responses, the best-documented responses were partial response in 18 patients (34%), stable disease in 27 patients (51%), and progressive disease in 8 patients (15%). Time to progression and median survival were measured for all patients after the intent-to-treat analysis. The median time to progression was 4.8 months (range, 1.3-9.6 months) (Fig. 1), and the median overall survival was 16.4 months (range, 4.5-47.0 months). It is interesting to note that 19 patients (34.5%) had median survivals >20 months.

Table 1. Characteristics of the 55 Patients at Baseline
CharacteristicNumber
  1. ECOG: Eastern Cooperative Oncology Group.

Median age, y (range)51 (25–75)
Sex 
 Female21 (38%)
 Male34 (62%)
ECOG performance status 
 032 (58%)
 123 (42%)
Ethnic group 
 White47 (85%)
 Black6 (11%)
 Hispanic2 (4%)
Prior therapy 
 Surgery48 (87%)
 Radiotherapy1 (2%)
 Adjuvant chemotherapy8 (15%)
thumbnail image

Figure 1. Median time to progression curve determined using the Kaplan-Meier technique. The median was 4.8 months.

Download figure to PowerPoint

Toxic effects could be evaluated in all 55 enrolled patients. The most significant finding was neutropenia, which tended to be more protracted as the treatment continued, consistent with a pattern of cumulative toxicity. Twenty-two of the 55 patients (40%) developed Grade 3 or 4 neutropenia as the treatment continued. Other Grade 3 and 4 toxic effects were diarrhea in 14 patients (25%), nausea in 14 patients (25%), vomiting in 13 patients (24%), and thrombocytopenia in 5 patients (9%). Severe neuropathy was reported in 6 patients (11%), a proportion consistent with that reported in studies of other oxaliplatin-based regimens. Toxicities, particularly neutropenia, led to treatment delays in 18 patients (33%) and dose reductions in 38 patients (69%). However, both delays and dose reductions tended to occur relatively late, after several courses of therapy had been given, consistent with the cumulative toxicity previously noted with these chemotherapy agents. Delays were required in 25 of the 225 courses (11%), and dose reductions were required in 68 courses (30%). Ten patients (18%) discontinued the treatment due to toxicity.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This Phase II study confirmed the feasibility and activity of this combination of irinotecan and oxaliplatin given every 3 weeks. The fact that 85% of the patients evaluated for response had either a partial response or stable disease as their best response demonstrates that this particular schedule of irinotecan plus oxaliplatin is active in metastatic colorectal cancer and may represent an option for selected patients.

The findings of the current study add to the already available data regarding the combined use of irinotecan and oxaliplatin using alternative schedules. Wasserman et al.15, 16reported the results from a study of 39 patients who were included in a combined analysis of 2 Phase I studies conducted simultaneously in France. As in our study, irinotecan and oxaliplatin were given every 3 weeks, and neutropenia, nausea, vomiting, diarrhea, and peripheral neuropathy were found to be the most frequent Grade 3 and 4 toxic effects. The doses recommended for subsequent Phase II studies were 200 mg/m2 of irinotecan and 85 mg/m2 of oxaliplatin. This 21-day schedule was recently investigated as 1 of the 3 arms in the NCCTG 9741 Phase III trial, which randomly assigned previously untreated patients with metastatic colorectal cancer to receive either the conventional IFL regimen (weekly irinotecan combined with bolus 5-FU and leucovorin), the FOLFOX 4 regimen (oxaliplatin combined with bolus and infusional 5-FU and leucovorin, administered every 2 weeks), or the IROX regimen previously reported by Wasserman et al.16 The patients on the FOLFOX 4 arm were found to have a statistically significantly greater response rate compared with patients on the IFL and IROX arms (45%, 31%, and 34%, respectively). However, although the difference in median survival between the FOLFOX 4 and IFL arms was quite impressive (19.5 months compared with 14.8 months; P = .0001); the difference between the FOLFOX 4 and the IROX arms was not found to be statistically significant (19.5 months compared with 17 months; P = .09). In addition, the median survival was at least numerically better for those patients who received IROX than for those who received IFL.16

Although the median time to progression was somewhat disappointing, both the response rate and the median survival in our own Phase II trial were found to be nearly identical to those reported for the patients who received IROX in the N9741 trial, showing a very encouraging consistency of results despite the small difference in the dosing of both active drugs. Qualitative analysis of the toxicity profile in our trial does not reveal appreciable differences compared with the toxicity profiles of the different schedules previously reported for combinations of irinotecan and oxaliplatin, and the finding that neutropenia was the most notable toxicity in the current study agrees with the reported findings from similar trials.15–17 Although neutropenia was the most common toxic effect, and episodes of Grade 3 or 4 neutropenia were recorded in 40% of the patients, there were no fatalities associated with treatment in this particular trial. The cumulative nature of the toxicity is not surprising and is consistent with the cumulative toxicity reported in previous trials of oxaliplatin-based regimens.

From the analysis of the current study data and the results of the other studies discussed, it is clear that the combination of irinotecan and oxaliplatin is safe and active in the treatment of patients with metastatic colorectal cancer, including those whose disease has progressed after 5-FU therapy. It has been shown that tumors that overexpress thymidylate synthase, the main molecular target of 5-FU, are often resistant to 5-FU.18, 19 In addition, tumor levels of other enzymes involved in the metabolism of 5-FU, such as dihydropyrimidine dehydrogenase and thymidine phosphorylase, may influence the response to 5-FU.5 Therefore, it may be possible to identify patients with 5-FU-resistant tumors by molecular analysis and then treat them up front with a combination of irinotecan and oxaliplatin. This strategy may be particularly applicable to patients with low-volume metastatic disease who may be candidates for curative surgery after downstaging with chemotherapy. Patients with dihydropyrimidine dehydrogenase deficiency might also benefit from a regimen that does not expose them to fluoropyrymidines, because exposure to these agents could result in fatal toxicities.20

The results of the current study affirm that the combination of irinotecan and oxaliplatin is safe and active in the treatment of patients with metastatic colorectal cancer and that this treatment is feasible for the vast majority of patients. This combination may become the preferred frontline regimen for colorectal tumors believed to be resistant to 5-FU. The convenience of a 21-day schedule and the relatively good safety profile make this combination particularly well suited for use as a platform for newer combinations with molecular-targeted agents.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Jemal A, Tiwari RC, Murray T, et al. Cancer statistics. CA Cancer J Clin. 2004; 54: 829.
  • 2
    Ardalan B, Luis R, Jaime M, et al. Biomodulation of fluorouracil in colorectal cancer. Cancer Invest. 1998; 16: 237251.
  • 3
    Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol. 1998; 16: 301308.
  • 4
    Poon MA, O'Connell MJ, Wieand HS, et al. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991; 9: 19671972.
  • 5
    Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res. 2000; 6: 13221327.
  • 6
    Lenz HJ. The use and development of germline polymorphisms in clinical oncology. J Clin Oncol. 2004; 22: 25192521.
  • 7
    Stoehlmacher J, Park DJ, Zhang W, et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer. 2004; 91: 344354.
  • 8
    Goldberg RM. Current approaches to first-line treatment of advanced colorectal cancer. Clin Colorectal Cancer. 2004; 4(Suppl 1): S9S15.
  • 9
    Hoff PM, Pazdur R. Progress in the development of novel treatments for colorectal cancer. Oncology (Huntingt). 2004; 18: 705708.
  • 10
    Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000; 343: 905914.
  • 11
    Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22: 229237.
  • 12
    Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 1988; 48: 17221726.
  • 13
    Zeghari-Squalli N, Raymond E, Cvitkovic E, et al. Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res. 1999; 5: 11891196.
  • 14
    Hoff PM, Saad ED, Pazdur R, et al. Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer. Invest New Drugs. 2004; 22: 307313.
  • 15
    Wasserman E, Cuvier C, Lokiec F, et al. Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics. J Clin Oncol. 1999; 17: 17511759.
  • 16
    Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22: 2330.
  • 17
    Kemeny N, Tong W, Gonen M, et al. Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer. Ann Oncol. 2002; 13: 14901496.
  • 18
    Leichman CG, Lenz HJ, Leichman L, et al. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol. 1997; 15: 32233229.
  • 19
    Johnston PG, Lenz HJ, Leichman CG, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995; 55: 14071412.
  • 20
    Morrison GB, Bastian A, Dela Rosa T, et al. Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncol Nurs Forum. 1997; 24: 8388.