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Triplet Combination With Irinotecan Plus Oxaliplatin Plus Continuous-Infusion Fluorouracil and Leucovorin as First-Line Treatment in Metastatic Colorectal Cancer: A Multicenter Phase II Trial

From the Department of Medical Oncology and Department of Radiology, School of Medicine, University General Hospital of Heraklion, Crete; and Department of Medical Oncology, General Hospital of Larisa, Larisa, Greece.

Address reprint requests to Vassilis Georgoulias MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, P.O. Box 1352, Heraklion 71110, Crete, Greece; e-mail: georgsec{at}med.uoc.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC).

PATIENTS AND METHODS: Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m² as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m² as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m² preceded 5-FU administration of 400 mg/m²/d initial IV bolus dose followed by 600 mg/m²/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks.

RESULTS: All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred.

CONCLUSION: The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
COLORECTAL CANCER is the second most common cancer in developed countries, after breast cancer in females and lung cancer in males. In Europe, the predicted annual incidence is approximately 150,000 new cases, with mortality of about 80,000 to 95,000.¹ Similarly, in the United States colon cancer alone caused 56,000 deaths and 130,000 new cases per year,² making it the second most common cancer in females after breast cancer and the third most common in males after lung and prostate. Despite macroscopically curative surgical resection in 70% to 80% of cases, half of those colorectal cancer patients will develop recurrence (mostly metastatic) and will die of the disease.² For more than 40 years, fluorouracil (5-FU) was the only cytotoxic agent with significant activity in advanced colorectal cancer. Until recently, the standard therapy for metastatic colorectal cancer was 5-FU, modulated by calcium folinate (leucovorin [LV]), which typically achieved a median survival of 10 to 14 months.^3,4

Although there is no internationally accepted standard 5-FU/LV regimen, the monthly 5-day bolus North Central Treatment Group/Mayo Clinic regimen is commonly used.⁵ Recently, in a randomized study, this regimen was compared with a bimonthly schedule of LV and bolus plus infusional 5-FU (LV/5-FU2).⁶ LV/5-FU2 proved superior in terms of response rate (32.6% v 14.5%), progression-free survival (27.6 v 22 weeks), and toxicity (grade 3 to 4 in 11.1% v 22.9% of patients), but not in overall survival.⁶

Irinotecan (CPT-11) is a hemi-synthetic, water-soluble derivative of the plant alkaloid camptothecin. After conversion to its active metabolite, SN-38, CPT-11 acts by inhibiting the eukariotic enzyme DNA-topoisomerase I.^7,8 This unique mechanism of action of CPT-11 is distinct from that of 5-FU, and therefore, opens the opportunity for 5-FU and CPT-11 combinations without cross-resistance.⁹ Furthermore, the value of CPT-11 as first-line treatment of colorectal cancer has been established in two large randomized phase III trials.^10,11 These trials demonstrated that the addition of CPT-11 to 5-FU/LV significantly improved the response rate, median time to progression, and overall survival of patients with metastatic colorectal cancer. The advantage for the combination of CPT-11 and 5FU/LV was achieved with predictable and manageable toxicities and without compromising overall quality of life.^10,11

Oxaliplatin (L-OHP), a new diaminocyclohexane-platinum analog, has also shown significant activity in advanced colorectal cancer.¹² The main mechanism of action of L-OHP is similar to that of cisplatin because it induces the formation of DNA adducts leading to inhibition of DNA synthesis.¹³ Nevertheless, L-OHP has a different activity profile than cisplatin. This is because the DNA adducts of L-OHP are bulkier and more hydrophobic than those of cisplatin and, thus, the inhibitory effect on DNA synthesis is more pronounced,¹⁴ and because, unlike cisplatin, the DNA adducts of L-OHP are not recognized by the DNA mismatch repair enzymes.¹⁵

Two randomized trials have compared the combination of L-OHP with 5-FU/LV given either chronomodulated or in accordance with the De Gramont schedule, with that of the same 5-FU/LV regimen alone as first-line treatment of metastatic colorectal cancer.^16,17 The addition of L-OHP to 5-FU/LV significantly improved the overall response rate and median time to tumor progression but not the median survival time.

Schedule-dependent cytotoxic interactions for the combination of thymidylate synthase inhibitors with SN-38 and L-OHP have been reported in an in vitro model.¹⁸ Synergistic effects were demonstrated only when SN-38 was started 24 to 48 hours before the L-OHP-5-FU/LV exposure in WIDR and SW620 human colorectal cancer cell lines. These data suggest that CPT-11, L-OHP, and 5-FU are active drugs in the treatment of metastatic colorectal cancer, with different mechanisms of action and nonoverlapping toxicities. Based on the Goldie and Coldman¹⁹ hypothesis, the development of drug-resistant clones could be minimized by the early tumor exposure to as many active agents as possible. Therefore, the early administration of three active agents may be a way to avoid the emergence of chemoresistant clones. A prior phase I study of the three-drug combination as first-line treatment in patients with unresectable MCC has been performed and showed that the regimen is feasible and is associated with acceptable toxicity.²⁰ A multicenter phase II study was conducted by the Greek Cooperative Group for Colorectal Cancer to assess the efficacy and safety of the triplet CPT-11 plus L-OHP plus 5-FU/LV de Gramont regimen administered every 2 weeks as first-line treatment in patients with advanced colorectal cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Patients with histologically proven metastatic adenocarcinoma of the colon or rectum were enrolled. Previous chemotherapy for metastatic disease was not allowed. Patients who had received prior adjuvant 5-FU–based chemotherapy were eligible if they had remained free of disease for at least 6 months after the completion of adjuvant therapy. Patients with operable metastatic disease were excluded from the study. Other eligibility criteria included the following: age 18 to 75 years, performance status (World Health Organization) 0 to 2; at least one bidimensionally measurable lesion of 2 cm; a life expectancy of at least 3 months; adequate hematologic parameters (absolute neutrophil count 1.5 x 10⁹/L and platelets 100 x 10⁹/L); creatinine and total bilirubin 1.25 times the upper limit of normal; aspartate and ALT 3.0 times the upper limit of normal; absence of active infection or malnutrition (loss of more than 20% of the body weight); absence of a second primary tumor other than nonmelanoma skin cancer or in situ cervical carcinoma. Patients treated with palliative radiotherapy had to have measurable metastatic disease outside the irradiation fields. Patients with severe cardiac dysfunction, liver metastases involving more than 50% of the liver parenchyma, chronic diarrhea, or prior irradiation affecting more than 30% of the active bone marrow were excluded. The study was approved by the ethics and scientific committees of each participating center. All patients gave written informed consent to participate in the study.

Chemotherapy
CPT-11 was given at a dose of 150 mg/m² as a 30-minute intravenous (IV) infusion on day 1. LV was given at a dose of 200 mg/m² as a 2-hour IV infusion, followed by 5-FU 400 mg/m² as IV bolus, and then 600 mg/m² as a 22-hour continuous IV infusion, on days 2 and 3. L-OHP was administered on day 2 at the dose of 65 mg/m² as a 2-hour IV infusion in parallel with LV but using different lines. Routine antiemetic prophylaxis with a 5-hydroxytryptamine-3-receptor antagonist was used. Treatment was administered every 2 weeks until disease progression or unacceptable toxicity occurred or until the patient declined further.

Patients were assessed for toxicity before each cycle using the National Cancer Institute common toxicity criteria. Chemotherapy was delayed until recovery if neutrophils were less than 1.5 x 10⁹/L or platelets less than 100 x 10⁹/L or for significant persisting nonhematologic toxicity. CPT-11 was administered according to the guidelines used for CPT-11 monotherapy, including recommendations for using atropine and loperamide. Doses of all drugs were reduced by 15% in subsequent cycles in case of grade 4 neutropenia or 3 to 4 thrombocytopenia lasting for more than 3 days or in case of febrile neutropenia. No prophylactic administration of granulocyte colony-stimulating factor (G-CSF) was allowed. G-CSF was used for the treatment of febrile neutropenia. Doses of CPT-11 and 5-FU were reduced by 15% in subsequent cycles in case of grade 3 to 4 diarrhea. The 5-FU dose was reduced if grade 3 to 4 stomatitis or dermatitis occurred. L-OHP dose was reduced by 15% in cases of persistent ( 14 days) paresthesia or temporary (7 to 14 days) painful paresthesia or functional impairment. In cases of persistent ( 14 days) painful paresthesia or functional impairment, L-OHP was omitted in subsequent cycles from the regimen until recovery.

Patient Evaluation
Pretreatment evaluation included a detailed medical history and physical examination, a complete blood cell count with differential and platelet count, whole blood chemistry, determination of serum levels of carcinoembryonic antigen, and computed tomography (CT) scans of the chest and abdomen. Pretreatment evaluation had to be performed within 2 weeks before study entry. During treatment, a complete blood cell count with differential and platelet count was performed weekly, and in cases of grade 3 to 4 neutropenia, thrombocytopenia, or febrile neutropenia, it was performed daily until hematologic recovery. In addition, patients were clinically assessed and routine biochemical tests were performed before each treatment cycle. Response to treatment was evaluated after six 2-week cycles (3 months) or sooner if clinically indicated.

The World Health Organization criteria were used to assess tumor response. Complete response was defined as the complete disappearance of all clinically assessable disease for at least 4 weeks, and partial response was defined as a decrease of at least 50% of the sum of the products of the diameters of measurable lesions for at least 4 weeks. CT scans were repeated 4 weeks later to confirm a response. All CT scans were reviewed by an external panel of radiologists. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% of measurable lesions, and progressive disease was defined as an increase of at least 25% of the measurable lesions or the appearance of new malignant lesion(s).

The duration of response was measured from the first documentation of response to disease progression. The time to tumor progression was determined by the interval between the initiation of treatment and the date when disease progression was first documented. Survival was measured form the date of registration to date of death. The follow-up time was measured from the day of first treatment administration to the last contact or death.

Patients’ quality of life was assessed at baseline and every 8 weeks during the study using the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The Global Health Status/Quality of Life scale was selected as the primary end point.²¹ Tumor related symptoms were assessed at baseline and before each cycle.

Statistical Considerations
The study followed a two-step design according to which if an objective response rate exceeding 40% was observed in the first 15 patients, an additional 15 patients should be enrolled. The probability of survival was estimated by the Kaplan-Meier method,²² and the confidence intervals (CI) for response rates were calculated using methods for exact binomial CIs.²³

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients Characteristics
From October 1999 to April 2001, 31 patients with MCC were enrolled onto the study. The patients had not received prior chemotherapy for metastatic disease. The median age was 60 years (range, 25 to 75 years), 26 (84%) of the patients had a performance status of 0 to 1, and the median number of involved sites was two per patient (Table 1). Approximately half of the patients (14 patients, 45%) had received prior 5-FU–based adjuvant chemotherapy. None of the patients had previously received CPT-11 or L-OHP. The median time elapsed between first diagnosis of metastasis and study entry was 1 month (range, 0 to 3 months), whereas the median time between initial disease diagnosis and the first metastasis was 19.4 months (range, 7 to 88 months). All patients were assessable for toxicity and 30 for response to treatment. One patient was not assessable for response because of absence of bidimensionally measurable disease, and in the intent-to-treat analysis, he was considered a progressor.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curve for the 31 patients receiving the triplet combination.

Compliance With the Treatment
At the time of this analysis, 27 patients (87%) have discontinued treatment for the following reasons: progressive disease in 12 patients (39%), unacceptable toxicity in two (6%), and patient withdrawal in 13 (42%). The 13 patients who withdrew from the study had received a median of 12 cycles of chemotherapy (range, five to 18 cycles). Nine patients had achieved a partial remission, and three had stable disease after six to 12 cycles of chemotherapy without any further improvement in the tumor response with additional cycles of treatment. All these patients had no excessive toxicity but refused further treatment after discussing the results with their physicians. One patient refused to continue after five cycles of therapy because of personal reasons. This patient was evaluated after cycle 5, and he had a stable disease. Three hundred eighty-two courses of chemotherapy have been administered (median, 12 courses per patient; range, four to 18 courses). Sixty-nine courses (18%) were delayed for a median of 4 days (range, 1 to 6 days) because of hematologic (n = 27, 7%) and nonhematologic (n = 7, 2%) toxicity; 32 courses (8%) were delayed because of reasons unrelated to disease or treatment, ie, pending imaging studies for response evaluation. The median interval between cycles was 16 days (range, 14 to 20 days). Dose reduction was required in 34 cycles (9%) because of hematologic (n = 17 cycles; 4.5%) and nonhematologic toxicity (n = 14 cycles; 4%). G-CSF was administered in 28 cycles (7.3%) for the treatment of severe or febrile neutropenia. The delivered relative dose-intensity was 85% for CPT-11, 84% for L-OHP, and 88% for 5-FU/LV of the protocol-planned doses.

Quality of Life and Relief of Symptoms
One hundred thirty-one questionnaires were completed from 30 patients. The rate of form return was 82%. The Global Health Status/Quality of Life mean scale score remain unchanged, with a slight improvement during the treatment (Fig 2). Sixteen patients (52%) had at least one disease-related symptom at baseline. Fourteen patients had presented with abdominal pain. Pain relief (decrease of the drug doses or discontinuation of analgesic therapy) was observed in 12 patients (85%). Eight of those patients had achieved a partial response, and four had present stable disease. In one patient with gastrointestinal bleeding and two with fever, complete resolution of their symptoms was observed. All these patients had a partial response.

View larger version (12K): [in this window] [in a new window]   Fig 2. Variation of the Global Health Status mean scale score during treatment with the triplet combination.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

However, in the United States, the combination of weekly CPT-11 and bolus 5-FU and LV (Saltz regimen)¹⁰ was approved as first-line treatment of metastatic colorectal carcinoma. The response rate of this combination was 39%, the median duration of response was 9.2 months, the median time to disease progression was 7.0 months, and the median survival time was 14.8 months with a higher toxicity (0.9% treatment-related deaths rate).¹⁰ Because the inclusion criteria were similar in both studies, a combined analysis was carried out that confirmed the results of the above two randomized trials.²⁴

More recently, Sargent et al²⁵ reported their preliminary estimates of 60-day death rates from any cause in two ongoing studies with CPT-11, LV, and 5-FU in the treatment of colorectal cancer. In both studies, a higher death rate was observed in the treatment arm with the Saltz regimen. Based on these results, the enrollment onto the N9741 and C89803 trials was suspended. Although the investigation for the increased mortality has not been completed, preliminary analysis suggests that the higher grade 3 to 4 neutropenia and diarrhea rates observed with the Saltz regimen may be the major contributing factor.

The present multicenter phase II trial demonstrates that the three-drug combination of CPT-11, L-OHP, and 5-FU/LV produced a high response rate (58.1%) with a median duration of response of 11 months and a median time to disease progression of 13 months. After a median follow-up of 11 months, the median survival time has not yet been reached, but the projected probability of 1-year survival (75%) was very promising. These efficacy results are among the highest reported in the literature for any chemotherapy regimen in MCC. The patients’ characteristics were similar to that of the Douillard et al¹⁰ and Saltz et al studies¹¹ because it concern the median age of the treated patients, the median time from initial diagnosis to first metastasis, the proportion of patients who had received prior adjuvant chemotherapy, and the extension of the disease. Recently, the preliminary results from four other phase I or II studies with the same four-drug combination, but different treatment schedules, have been reported (as abstracts).^27-30 The response rates ranged from 39% to 69%. The reported median time to disease progression ranged from 11.8 to 14 months. In addition, the Global Health Status/Quality of Life remained constant or presented a slight improvement during the treatment, and the majority of the patients had improvement of their tumor-related symptoms. Although the present study has the limitations of any phase II study (limited number of patients, selection bias), the patient population was representative for this particular disease.

The selection of the particular schedule used in the present study was based on preclinical evidence of maximum synergism.^18,31 These studies have reported that synergistic effects were observed only when SN-38 was started 24 to 48 hours before L-OHP and 5-FU/LV.

The toxicity profile of the triplet combination was relatively mild. As expected, the main toxicities were neutropenia and diarrhea. Grade 3 to 4 neutropenia was observed in 14 patients (45%); however, febrile neutropenia occurred in only two patients (6%). G-CSF was used in 28 cycles (7.3%) for the treatment of febrile or severe neutropenia. Severe thrombocytopenia was practically absent. No patient required RBC or platelet transfusions. Only three admissions were required for the treatment of therapy-related toxicity. Grade 3 to 4 diarrhea occurred in 10 patients (32%), similar to what has been reported in previous irinotecan studies.²⁶ The main nonhematologic toxicity was peripheral sensory neuropathy and fatigue. Grade 3 to 4 neuropathy was observed in three patients (10%), whereas grade 2 was observed in six (19%), and was characterized by cold-induced paresthesias and dysthesias in the extremities, which is characteristic of L-OHP neurotoxicity.¹⁷ Grade 2 to 3 fatigue was observed in 16 patients (52%), as reported by other irinotecan studies.²⁶ All but one of 13 patients who decided to withdraw from the protocol did so after achieving a plateau in the tumor response with at least 12 cycles of treatment. These patients did not have any excessive toxicity but decided to discontinue the treatment after discussing the results with their physicians.

In conclusion, this study reports that the triplet combination of CPT-11 plus L-OHP plus bolus and infusional 5-FU with LV modulation, is a well-tolerated and highly active regimen for the front-line treatment of metastatic colorectal cancer. A large randomized trial is needed to compare the efficacy of this triple with a double, standard chemotherapy regimen (CPT-11/L-OHP/5-FULV v CPT-11/5-FULV) in patients with advanced colorectal cancer.

	ACKNOWLEDGMENTS

 
Supported in part by a grant from the Cretan Association for Biomedical Research (CABR). J.S. and N.V. were recipients of a CABR clinical fellowship.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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15. Scheff ED, Howell SB: Computer modeling of the primary cisplatin and oxaliplatin DNA adducts and relevance to mismatch repair recognition. Proc Am Assoc Cancer Res 39: 158, 1998 (abstr 3745)

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Submitted August 2, 2001; accepted November 26, 2001.

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