Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Originally published as JCO Early Release 10.1200/JCO.2003.01.238 on September 8 2003

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goetz, M. P.
Right arrow Articles by Goldberg, R. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goetz, M. P.
Right arrow Articles by Goldberg, R. M.
Journal of Clinical Oncology, Vol 21, Issue 20 (October), 2003: 3761-3769
© 2003 American Society for Clinical Oncology

Phase I and Pharmacokinetic Study of Two Different Schedules of Oxaliplatin, Irinotecan, Fluorouracil, and Leucovorin in Patients With Solid Tumors

Matthew P. Goetz, Charles Erlichman, Anthony J. Windebank, Joel M. Reid, Jeffrey A. Sloan, Pamela Atherton, Alex A. Adjei, Joseph Rubin, Henry Pitot, Evanthia Galanis, Matthew M. Ames, Richard M. Goldberg

From the Division of Medical Oncology, Division of Oncology Research, Biostatistics, and Department of Neurology, Mayo Clinic, Rochester, MN.

Address reprint requests to Matthew P. Goetz, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: goetz.matthew{at}mayo.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics.

Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD.

Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen.

Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
THE FLUOROPYRIMIDINE fluorouracil (FU) is the most commonly used treatment for gastrointestinal malignancies. Because the response rate of fluorouracil is low when used as a single agent in metastatic colorectal cancer (MCC), researchers have added leucovorin (LV), which stabilizes the complex formed by FU’s metabolite fluorodeoxyuridine monophosphate and the enzyme thymidylate synthase.1–7

Irinotecan (CPT-11), a semisynthetic camptothecin derivative, is converted in vivo to SN-38, which is 1,000 times more potent as an inhibitor of topoisomerase I.8–10 SN-38 covalently stabilizes the enzyme-DNA complexes,11 resulting in strand breaks and subsequent cytotoxicity.12–15 CPT-11 has activity in a wide spectrum of human neoplasms16–23 and, as a single agent, increases survival in patients with FU-resistant MCC compared with supportive care or FU infusion.24,25 The activity of these agents and their different mechanisms of action led to their combination as first-line treatment in MCC. Saltz et al26 and Douillard et al27 reported that the combination of CPT-11, FU, and LV improves tumor control and survival when compared with FU/LV.

Oxaliplatin (trans-/-1,2-diaminocyclohexane oxalatoplatinum) is a platinum derivative with a 1,2-diaminocyclohexane carrier ligand. Platinum compounds exert their cytotoxic effects by forming DNA adducts that inhibit both DNA replication and transcription, resulting in the induction of apoptosis. In clinical trials, oxaliplatin demonstrated efficacy against MCC, both as a single agent28–32 and in combination with FU and LV.33–37 Recently, the North Central Cancer Treatment Group demonstrated that the oxaliplatin, FU, and LV regimen was superior to the CPT-11, FU, and LV regimen (IFL) regarding improvement in response rate, time to progression, overall survival, and toxicity profile.38

Preclinical studies indicate that administration sequence is important for CPT-11, FU, and oxaliplatin combinations. In HCT8 human colon cancer cell lines, SN-38 exposure followed by FU + LV results in synergy. However, simultaneous exposure or the reverse sequence of FU + LV followed by SN-38 were not synergistic.39 Other investigators40–42 have reported similar findings regarding sequence-dependent synergy. Further in vitro studies investigating combinations of FU, CPT-11, and oxaliplatin have shown that synergism occurs only when CPT-11 precedes FU/oxaliplatin exposure.43

Previously, we conducted a phase I trial of CPT-11 and FU/LV in which intravenous CPT-11 was given on day 1 (infusion) and FU/LV was given on days 2 to 5 (90-minute infusion) every 3 weeks.44 The ability to deliver doses of each drug approaching the single-agent doses and evidence for efficacy led us to add oxaliplatin. Therefore, we conducted a phase I study to determine whether the addition of oxaliplatin to two active CPT-11/FU/LV regimens was feasible, using the schedule previously developed44 and the IFL regimen.26 For cohort 1, we used weekly oxaliplatin, CPT-11, and bolus FU/LV (IFL regimen); in cohort 2, patients received CPT-11 and oxaliplatin on day 1, followed by FU/LV on days 2 to 5 using a 90-minute infusion. In patients enrolled at the cohort 2 maximum-tolerated dose (MTD), we examined the impact of CPT-11 on oxaliplatin pharmacokinetics and formally monitored patients for oxaliplatin-induced neuropathy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
Eligibility
Patients with histologic or cytologic confirmed measurable or assessable metastatic or locally advanced cancer for which no established life-prolonging therapy was available or patients who were unresponsive to conventional therapy were eligible for this study. Other eligibility criteria included the following: age >= 18 years; Eastern Cooperative Oncology Group performance status <= 2; estimated life expectancy of >= 12 weeks; chemotherapy, biologic therapy, or immunotherapy for more than 4 weeks (6 weeks in patients treated with mitomycin or nitrosoureas) and recovery from any toxic effects of prior treatment; <= three prior chemotherapy regimens; completion of radiation therapy >= 4 weeks before enrollment; no pelvic radiation therapy; radiation therapy to <= 25% of bone marrow; neutrophil count >= 1,500/µL; platelet count >= 150,000/µL; hemoglobin >= 9.0 g/dL; serum creatinine within institutional normals or actual or estimated creatinine clearance >= 60 mL/min (using the Cockcroft-Gault formula); direct bilirubin <= 1.5 x and AST <= 5 x the upper limit of normal; no active or uncontrolled infection; absence of pregnancy or lactation and willingness to use adequate contraception; no known CNS metastases or uncontrolled seizure disorder; no uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association classification III or IV), unstable angina pectoris, or cardiac arrhythmia; no evident peripheral neuropathy >= grade 2; absence of any history of allergy to platinum compounds, CPT-11, or to antiemetics or antidiarrheals appropriate for administration in conjunction with chemotherapy as directed by this protocol; and absence of concomitant antiretroviral therapy. For patients in cohort 2 at the MTD, willingness to provide blood specimens for pharmacokinetic analysis and to undergo neurologic evaluations was required per protocol. All patients gave written informed consent according to institutional and federal guidelines.

Dosage and Administration
CPT-11, loperamide, FU, and LV were obtained commercially. The Division of Cancer Treatment and Diagnosis of the National Cancer Institute (Bethesda, MD) supplied oxaliplatin. CPT-11 was diluted with 5% dextrose to a total volume of 500 mL. Oxaliplatin was supplied as a lyophilized powder in vials containing 50 mg and 100 mg and was reconstituted by adding 10 mL (for the 50-mg vials) or 20 mL (for the 100-mg vials) of sterile water or 5% dextrose and water (D5W), which yielded a 5-mg/mL solution. That solution was diluted in 500 mL of D5W. FU was available in 500 mg/10 mL ampules and vials and 1 gm/20 mL, 2.5 gm/50 mL, and 5 gm/100 mL vials. Leucovorin was available in 50- and 100-mg vials for injection and reconstituted with 5 and 10 mL of sterile water or bacteriostatic water, respectively, resulting in a 10-mg/mL solution. Cohort 1 and 2 patients received chemotherapy according to the schedule shown in Table 1Go using a standard cohorts-of-three phase I clinical trial design.45 When intravenous infusion was indicated, chemotherapy was infused by electronic pump.


View this table:
[in this window]
[in a new window]
  		Table 1. Treatment Schedule
 
Dose-Limiting Toxicity (DLT)
All toxicities were graded according to the National Cancer Institute common toxicity criteria (version 2). The MTD was defined as one dose level below the dose that induced DLT in at least two patients. At most, six patients were treated at each dose level. If DLT was seen in two or more patients treated at a given dose level, then three more patients were treated at the next lower dose level to more fully assess the toxicities associated with the MTD.

The following toxicities were considered dose limiting: grade 4 absolute neutrophil count or platelet count less than 25,000/µL, serum creatinine >= two times baseline, and treatment delay more than 14 days. Grade 3 or 4 nonhematologic toxicity (with the exception of nausea, vomiting, and diarrhea) was also considered dose limiting. Grade 3 or 4 nausea, vomiting, or diarrhea in patients who had received prophylaxis and treatment with an optimal antiemetic or antidiarrheal regimen were considered dose limiting. Optimal antiemetic regimens included 5-hydroxytryptamine-3 antagonists and corticosteroids. Maximal antidiarrheal therapy included 4 mg of loperamide taken at the first onset of diarrhea, followed by 2 mg every 2 hours until diarrhea resolved for at least 12 hours. Neurotoxicity was reported using the following grading scale: grade 0, no symptoms; grade 1, paresthesias/dysesthesias of short duration that resolved and did not interfere with function; grade 2, paresthesias/dysesthesias interfering with function but not activities of daily living; grade 3, paresthesias/dysesthesias with pain or with functional impairment that also interfere with activities of daily living; and grade 4, persistent paresthesias/dysesthesias that were disabling or life-threatening.

Pretreatment and Follow-Up Studies
A complete patient history, physical examination, complete blood cell count, serum electrolytes, and chemistries were performed at baseline and before each course of treatment. Complete blood counts were performed weekly during the study. Radiologic studies were performed and objective measurement of tumor mass was assessed in accordance with the revised World Health Organization criteria (Response Evaluation Criteria in Solid Tumors)46 within 2 weeks before the start of treatment and after every cycle (cohort 1) or every two cycles (cohort 2).

Pharmacologic Studies
Sample collection. Once the MTD of cohort 2 was determined, 10 patients were studied to evaluate the pharmacokinetics and pharmacodynamics of oxaliplatin in combination with CPT-11 during the first and second cycles of therapy. This assessment was performed only on cohort 2 patients because the toxicity requiring dose omissions in cohort 1 led us to focus on the every-3-week schedule as the preferred regimen to take forward. Patients received FU/LV/oxaliplatin in cycle 1, followed by CPT-11/FU/LV/oxaliplatin in cycle 2 and all subsequent cycles. Blood samples (5 mL) were drawn into heparin-containing tubes at the following times during cycles 1 and 2: before the oxaliplatin infusion, at the end of the infusion, and 0.25, 0.5, 1, 2, 4, 8, and 24 hours and 2, 4, and 21 days after the end of infusion. Blood samples were collected from the arm contralateral to the infusion line or from a peripheral vein if oxaliplatin was infused through a central line. After collection, blood samples were immediately cooled in ice water, and plasma was separated by centrifugation (1,000 to 1,200 x g for 10 minutes) in a centrifuge maintained at 4°C and transferred into plastic tubes that were stored at -70°C until analysis.

Assay methods. Elemental platinum was assayed by inductively coupled plasma mass spectrometry using a modification of a procedure previously described.47–50 In brief, a Gilson AS90 autosampler (Gilson, Inc, Middleton, WI) operating at a rate of 0.5 mL/min was used to infuse samples into a Perkin-Elmer Sciex Elan 6000 mass spectrometer (Perkin Elmer, Norwalk, CT) operating at the following settings: Ar nebulizer flow rate, 0.9 L/min; inductively coupled plasma RF power, 1,200 W; lens voltage, 8.0 V; analog stage voltage, -2,100 V; pulse stage voltage, 1,700 V; dwell time, 100 nsec/amu. Platinum was expressed as the sum of platinum species detected at 194 and 195 amu using a program that sweeps 1 to 263 amu 50 times/reading. Platinum standards (0.2 to 20 ng/mL in 0.6 M HCl) were used to confirm the linearity of the assay (R >= 0.999); and rhodium 103 served as an internal standard. Each unknown was determined in duplicate.

Elemental platinum plasma concentration data were analyzed by noncompartmental methods using the program WINNONLIN (version 1.5; Scientific Consulting Inc, Cary, NC). The apparent terminal elimination rate constants ({lambda}z) were determined by linear least-squares regression of plasma-concentration time points, which were determined to lie in the terminal log-linear region of the plasma-concentration time profiles. The apparent elimination half-life (t1/2) was calculated as 0.693/{lambda}z.

Peak plasma concentrations and the time at which they occurred were determined from individual patient platinum-concentration time curves. Area under the plasma-concentration time curves (AUC0-T) were determined using the linear trapezoidal rule from time 0 to the last sampling time at which quantifiable drug concentrations were detected (CT). Area under the platinum plasma-concentration time curves through infinite time (AUC0-{infty}) were calculated by adding CT/{lambda}z to AUC0-T. The clearance (Cl) and apparent volume of distribution (Vz) of oxaliplatin were calculated as dose/AUC0-{infty} and Cl/{lambda}z, respectively.

Peripheral Neurotoxicity Assessment
A single neurologist performed peripheral neurotoxicity assessments to monitor the development of peripheral neuropathy in cohort 2 patients enrolled at the MTD. These studies consisted of the following three components: the Neuropathy Symptoms and Change Score, a structured symptom score that quantifies the change in a patient’s neurologic symptoms; the Neuropathy Impairment Score, a scored neurologic examination emphasizing the peripheral nervous system; and the Quantitative Sensory Examination, a threshold test in which graded stimuli are applied to the left great toe. Each of these approaches has been extensively evaluated and validated for monitoring the presence and progression of peripheral neuropathy.51–53


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
Thirty-five patients (cohort 1, n = 13; cohort 2, n =2; Table 2Go) received 159 assessable courses of treatment at three different dose levels for each cohort (Table 3Go). The median age of study participants was 52 years for cohort 1 (range, 40 to 80 years) and 60.5 years for cohort 2 (range, 40 to 78 years). The median number of weeks on study was 14 for cohort 1 (range, 6 to 31 weeks) and 12 for cohort 2 (range, 3 to 69 weeks). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The most common tumor types treated included colorectal (n = 22), small bowel (n = 5), hepatobiliary (n = 3), and esophagus (n = 2).


View this table:
[in this window]
[in a new window]
  		Table 2. Patient Characteristics
 

View this table:
[in this window]
[in a new window]
  		Table 3. Dose Escalation Scheme
 
The starting dose levels for the weekly schedule were CPT-11, 100 mg/m2; oxaliplatin, 70 mg/m2; FU, 425 mg/m2; and LV, 20 mg/m2. For the 3-weekly schedule, the starting dose levels were CPT-11, 250 mg/m2; oxaliplatin, 110 mg/m2; FU, 240 mg/m2; and LV, 20 mg/m2. Both hematologic and nonhematologic DLTs were encountered at the starting dose with both schedules, and significant dose reductions were required.

Hematologic Toxicity
Neutropenia was the principal hematologic toxicity observed and was dose limiting for patients in both cohorts at dose level 1 (one patient in each cohort) as well as one dose level below dose level 1 (one patient in each cohort at dose level -1; Table 4Go). Tables 4Go and 5Go summarize cycle 1 and the overall median and range for nadir neutrophil counts and the corresponding grades of neutropenia. Two episodes of febrile neutropenia (both in cohort 2), one at dose level 1 (grade 4) and one at dose level -1 (grade 3), resulted in hospitalization requiring parenteral antibiotics. However, there were no episodes of documented infections in the setting of grade 4 neutropenia. Consistent with the different schedules of drugs, neutrophil nadirs for cohort 1 typically occurred by day 28 (median), whereas the median time to neutrophil nadir for cohort 2 was shorter (15.5 days). The effect on platelets was mild for both cohorts, with a median platelet nadir of 160,000 x 109/L for cohort 1 and 204,000 109/L for cohort 2.


View this table:
[in this window]
[in a new window]
  		Table 4. Neutropenia: Cycle 1 per Patient Nadirs
 

View this table:
[in this window]
[in a new window]
  		Table 5. Neutropenia: Overall per Patient Nadirs
 
Nonhematologic Toxicity
Tables 6Go and 7Go list the treatment-related nonhematologic toxicities (cycle 1 and all cycles). Diarrhea was the most common nonhematologic side effect and occurred with equal frequency and severity in both cohorts. It was dose limiting for patients in both cohorts at dose level 1 and dose level -1 (Table 6Go). Six patients (three from each cohort) had grade 3 diarrhea necessitating hospitalization. No episodes of grade 4 diarrhea were noted. At the MTD, grade 3 diarrhea occurred in one of six patients in cohort 1 and three of 16 patients in cohort 2. Other toxicities that were dose limiting in cohort 2 included grade 3 nausea (two patients at dose level 3) and vomiting (two patients at dose level 3).


View this table:
[in this window]
[in a new window]
  		Table 6. Treatment-Related Nonhematologic Toxicity: Cycle 1 Only
 

View this table:
[in this window]
[in a new window]
  		Table 7. Treatment-Related Nonhematologic Toxicity: All Cycles
 
Cycle 1 Treatment Omission
For patients treated with the weekly regimen, six of 13 required omission of one or more of the four weekly treatments during cycle 1 because of toxicity. Compared with cohort 1 patients, only three of 22 cohort 2 patients required omission of one of the days of chemotherapy during cycle 1.

Neurotoxicity
Neurotoxicity was predominantly grade 1 and occurred with similar frequency in both cohorts (Tables 6Go and 7Go). One patient (cohort 2) experienced grade 3 neurotoxicity at the starting dose level. Using comprehensive neurotoxicity assessments, 10 cohort 2 patients enrolled at the MTD were studied at baseline and before cycle 3. Four patients had no neurologic symptoms. Five patients experienced transient numbness or hypersensitivity to cold or both for 2 to 4 days. Six patients with baseline neurologic deficit had no worsening of symptoms with therapy. Using the Neuropathy Symptoms and Change Score, the Neuropathy Impairment Score, and the Quantitative Sensory Examination, none of the 10 patients had evidence of oxaliplatin-associated neurotoxicity on follow-up testing at 3 months.

Antitumor Activity
Tumor responses in cohort 1 consisted of one partial response (colon) and two patients with prolonged (> 5 months) disease stabilization (colon). In cohort 2, one complete response (colon) and three partial responses (duodenal, n = 2; and rectal, n = 1) were observed. In addition, four patients had prolonged (> 5 months) disease stabilization (colon, n = 2; duodenal, n =1; and bile duct, n = 1).

Pharmacokinetics
The pharmacokinetics of oxaliplatin were studied in 10 patients in cohort 2 at the MTD to evaluate the effect of CPT-11 on the disposition of oxaliplatin. Patients received FU/LV/oxaliplatin in cycle 1 followed by CPT-11/FU/LV/oxaliplatin in cycle 2. Pharmacokinetic parameters for oxaliplatin are listed in Table 8Go. When administered without prior CPT-11, total plasma platinum concentrations reached 2,515 ng/mL at the end of infusion. Platinum plasma elimination was biphasic, with a t1/2 of 157 hours, and total platinum Cl was 0.213 L/h/m2. After administration of CPT-11 in cycle 2, the total platinum AUC was increased by 17% (P = .048), the total platinum half-life increased by 13% (P = .003), and the Vz remained unchanged. Although total platinum Cl was reduced by 13.6% in cycle 2, the effect was not statistically significant (P = .239).


View this table:
[in this window]
[in a new window]
  		Table 8. Summary of Total Platinum Pharmacokinetics (n = 10)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
In patients with MCC, two phase III trials have demonstrated that the combination of CPT-11 and FU/LV is superior to FU/LV in terms of response rates, time to progression, and overall survival.26,27 In the United States, many oncologists use the IFL regimen,26 which combines weekly CPT-11 and bolus FU and LV. In Europe, CPT-11 is commonly combined with the de Gramont schedule (FU/LV every 2 weeks)54 or the Arbeitsgemeinshaft Internische Oncologie schedule55 (once-weekly FU/LV).27 A recently presented North Central Cancer Treatment Group study, however, demonstrated that, in first-line therapy of MCC, the combination of oxaliplatin/FU/LV is superior to the IFL regimen, with improvement in response rate, time to progression, overall survival, and toxicity profile.38

The activity of CPT-11 and oxaliplatin in MCC, both as single agents and in combination with FU/LV, has created intense interest in combining oxaliplatin with CPT-11/FU/LV. Several phase I and II studies have been reported using various different treatment schedules. Souglakos et al56 published phase II data of CPT-11 (150 mg/m2, day 1) and oxaliplatin (65 mg/m2, day 2) in combination with the biweekly de Gramont regimen. Grade 3/4 toxicities included neutropenia (45% of patients, 6% febrile) and diarrhea (32%). Becouarn et al57 published phase II data using the biweekly de Gramont regimen in combination with alternating CPT-11 (day 1) and oxaliplatin (day 15). Rates of grade 3/4 neutropenia were similar (53%), although the incidence of grade 3/4 diarrhea (19%) was somewhat lower.

Phase I/II studies with weekly bolus FU have also been reported. Rubio et al,58 using an every-3-week regimen of weekly bolus FU/LV (500 mg/m2) and day-1 oxaliplatin (85 mg/m2) and CPT-11 (150 mg/m2), reported significant rates of grade 3/4 neutropenia (57%), febrile neutropenia (29%), and diarrhea (29%), necessitating omission of the day-8 dose of FU. However, Roth et al59 reported a lower incidence of neutropenia (17%) and diarrhea (20%) using an every-5-week regimen of alternating weeks of oxaliplatin (70 mg/m2, days 1 and 15) and CPT-11 (80 mg/m2, days 8 and 22) given with weekly FU (days 1, 8, 15, and 22).

In this study, we evaluated two schedules of oxaliplatin, FU/LV, and CPT-11. The recommended phase II doses for the weekly schedule are CPT-11, 75 mg/m2; oxaliplatin, 50 mg/m2; FU, 320 mg/m2; and LV, 20 mg/m2. The recommended phase II doses for the every-3-week schedule are CPT-11, 175 mg/m2; oxaliplatin, 85 mg/m2; FU, 240 mg/m2; and LV, 20 mg/m2. It is notable that when oxaliplatin is combined with weekly CPT-11/FU/LV, the MTD of CPT-11 (75 mg/m2) and FU (320 mg/m2) is significantly lower than the corresponding IFL schedule from which it originated (125 and 500 mg/m2, respectively).26 Similar to the original phase III data in which Saltz et al26 reduced doses in more than 50% of patients during course 1 of therapy, we found that six of 13 patients treated with the weekly regimen required omission of one or more of the four weekly treatments during cycle 1 because of toxicity. For cohort 2, the MTD of CPT-11 (175 mg/m2) was also lower than in our corresponding phase I study (275 mg/m2); however, the FU dose was not different (240 mg/m2).44 Compared with cohort 1 patients, only three of 22 cohort 2 patients required omission of one of the days of chemotherapy during cycle 1. The need for dose reductions and dose omissions led us to pursue the cohort 2 protocol for future studies.

The results of recent CPT-11 clinical trials have demonstrated that the major DLTs of CPT-11, diarrhea and myelosuppression, are, in part, genetically determined by the polymorphic hepatic uridine diphosphate glucuronosyl-transferase 1A1 (UGT1A1) enzyme that is responsible for the glucuronidation of SN-38.60,61 In this study, the presence of the UGT1A1*28 polymorphism may have accounted for some of the gastrointestinal and hematologic toxicity seen at the initial dose levels, which prompted dose de-escalation. The MTD we have defined does not take into consideration the effect of UGT1A*28 polymorphism that is common in the white population. Therefore, the dose of CPT-11 may need to be modified according to the presence of this polymorphism when this is determined prospectively.

Previous pharmacokinetic studies evaluating single-agent oxaliplatin (130 mg/m2 every 3 weeks) have not demonstrated significant platinum accumulation in plasma ultrafiltrate.62 However, studies combining CPT-11 and oxaliplatin indicate that the sequence of administration of CPT-11 and oxaliplatin may be important. Wasserman et al63 reported two phase I studies using oxaliplatin followed by CPT-11. Pharmacokinetic studies showed no evidence for platinum accumulation. Similarly, Kemeny et al64 reported phase I results using weekly oxaliplatin and CPT-11, with the same sequence of oxaliplatin followed by CPT-11. When pharmacokinetic parameters were compared with historical controls, ultrafiltrable platinum t1/2, Vz, and Cl were similar to values obtained using single-agent platinum. In contrast, Gil-Delgado et al65 reported phase I evidence for platinum accumulation only when CPT-11 preceded oxaliplatin. When CPT-11 was administered before oxaliplatin, compared with after oxaliplatin, ultrafiltrable platinum Cl was significantly lower (23.24 L/h v 27.87L/h, respectively).

Consistent with the findings of Gil-Delgado, we found evidence for platinum accumulation in cycle 2 (17% increase in AUC) when CPT-11 is administered before oxaliplatin. Glomerular filtration is the principal mechanism of platinum elimination62; therefore, we evaluated but found no statistical differences in the renal function of patients between baseline and cycle 2. Furthermore, because platinum binds extensively to plasma proteins,62,66 we compared baseline and cycle 2 albumin and total protein levels but could not identify a relationship to explain second-cycle platinum accumulation.

Neurotoxicity is the principal toxicity and DLT of oxaliplatin, with two distinct syndromes, acute neurosensory toxicity, characterized by paresthesias and dysesthesias occurring shortly after infusion, and long-term toxicity, characterized by a sensory neuropathy that occurs with chronic dosing of oxaliplatin.67 In this study, we prospectively monitored for the development of early peripheral neuropathy in cohort 2 patients enrolled at the MTD using three different validated neurologic examinations. Although 50% of these patients experienced transient numbness or hypersensitivity to cold or both, no patients had evidence for the chronic form of oxaliplatin-derived neurotoxicity. Because the number of cycles and cumulative dose of oxaliplatin were small, conclusions cannot be drawn about the potential risk for development of the chronic form of oxaliplatin-induced neurotoxicity, which has generally been noted after cumulative doses of more than 600 mg/m2. However, the finding of second-cycle platinum accumulation in this schedule raises the potential for enhanced cumulative neurotoxicity when CPT-11 is combined with oxaliplatin.

The antitumor activity seen in patients with small bowel cancer who received the every-2-week regimen is worth noting. A protocol for this combination for small bowel cancers is currently in development in the North Central Cancer Treatment Group. In addition, a study of the cohort 2 regimen in first-line therapy of advanced colorectal cancer is planned.

In summary, we have shown that the combination of oxaliplatin with CPT-11/FU/LV, when administered in two different treatment schedules, is feasible and associated with similar types and frequencies of toxicities. We are planning further phase II trials to assess whether the lower doses required when these four drugs are combined in the cohort 2 regimen will result in effective therapy that bears comparison with current standard regimens.


   AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS’ DISCLOSURES OF...
REFERENCES
 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the past 2 years: Richard Goldberg, Sanofi-Synthelabo, Pharmacia; performed contract work within the past 2 years: Richard Goldberg, Sanofi-Synthelabo, Pharmacia; received more than $2,000 a year from a company for either of the past 2 years: Richard Goldberg, Sanofi-Synthelabo, Pharmacia.


   ACKNOWLEDGMENTS
 
We thank Michelle Daiss and Sacha Nelson (Protocol Development Coordinators), Debra Sprau and Carol Andrist (Certified Research Associates), and the patients who participated in this trial.


   NOTES
 
Supported in part by grant Nos. CA15083 and CA69912 and grant No. M01 RR00585 from the Mayo Clinic General Clinical Research Center, Rochester, MN.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS’ DISCLOSURES OF...
 REFERENCES
 
1. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: A randomized trial. J Clin Oncol 7:1437–1446, 1989[Abstract]

2. Doroshow JH, Multhauf P, Leong L, et al: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8:491–501, 1990[Abstract]

3. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6:469–475, 1988[Abstract]

4. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5:1559–1565, 1987[Abstract/Free Full Text]

5. Petrelli N, Douglass HO, Jr, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial—Gastrointestinal Tumor Study Group. J Clin Oncol 7:1419–1426, 1989[Abstract]

6. Poon MA, O’Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407–1418, 1989[Abstract]

7. Valone FH, Friedman MA, Wittlinger PS, et al: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 7:1427–1436, 1989[Abstract]

8. Kaneda N, Nagata H, Furuta T, et al: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 50:1715–1720, 1990[Abstract/Free Full Text]

9. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187–4191, 1991[Abstract/Free Full Text]

10. Rivory LP, Riou JF, Haaz MC, et al: Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res 56:3689–3694, 1996[Abstract/Free Full Text]

11. Pommier Y, Tanizawa A, Kohn KW: Mechanisms of topoisomerase I inhibition by anticancer drugs. Adv Pharmacol 29B:73–92, 1994

12. Hsiang YH, Lihou MG, Liu LF: Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077–5082, 1989[Abstract/Free Full Text]

13. Holm C, Covey JM, Kerrigan D, et al: Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49:6365–6368, 1989[Abstract/Free Full Text]

14. Shin CG, Snapka RM: Exposure to camptothecin breaks leading and lagging strand simian virus 40 DNA replication forks. Biochem Biophys Res Commun 168:135–140, 1990[CrossRef][Medline]

15. Kaufmann SH: Cell death induced by topoisomerase-targeted drugs: More questions than answers. Biochim Biophys Acta 1400:195–211, 1998[Medline]

16. Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer—CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 11:909–913, 1993[Abstract/Free Full Text]

17. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128–1135, 1996[Abstract/Free Full Text]

18. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer. J Clin Oncol 10:16–20, 1992[Abstract]

19. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10:1225–1229, 1992[Abstract/Free Full Text]

20. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910–2919, 1997[Abstract]

21. Taguchi T, Tominaga T, Ogawa M, et al: [A late phase II study of CPT-11 (irinotecan) in advanced breast cancer. CPT-11 Study Group on Breast Cancer]. Gan To Kagaku Ryoho 21:1017–1024, 1994[Medline]

22. Takeuchi S, Dobashi K, Fujimoto S, et al: A late phase II study of CPT-11 on uterine cervical cancer and ovarian cancer. Research Groups of CPT-11 in Gynecologic Cancers. Gan To Kagaku Ryoho 18:1681–1689, 1991[Medline]

23. Bleiberg H: CPT-11 in gastrointestinal cancer. Eur J Cancer 35:371–379, 1999[CrossRef][Medline]

24. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407–1412, 1998[CrossRef][Medline]

25. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418, 1998[CrossRef][Medline]

26. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914, 2000[Abstract/Free Full Text]

27. 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 355:1041–1047, 2000[CrossRef][Medline]

28. Becouarn Y, Rougier P: Clinical efficacy of oxaliplatin monotherapy: Phase II trials in advanced colorectal cancer. Semin Oncol 25:23–31, 1998[Medline]

29. Diaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9:105–108, 1998[Abstract/Free Full Text]

30. Levi F, Perpoint B, Garufi C, et al: Oxaliplatin activity against metastatic colorectal cancer: A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate. Eur J Cancer 9A:1280–1284, 1993

31. Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95–98, 1996[Abstract/Free Full Text]

32. Raymond E, Faivre S, Woynarowski JM, et al: Oxaliplatin: Mechanism of action and antineoplastic activity. Semin Oncol 25:4–12, 1998[Medline]

33. Levi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:893–900, 1992[CrossRef][Medline]

34. Levi F, Zidani R, Brienza S, et al: A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy. Cancer 85:2532–2540, 1999[CrossRef][Medline]

35. Levi FA, Zidani R, Vannetzel JM, et al: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst 86:1608–1617, 1994[Abstract/Free Full Text]

36. Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 350:681–686, 1997[CrossRef][Medline]

37. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147, 2000[Abstract/Free Full Text]

38. Goldberg R, Morton R, Sargent D, et al: N9741: Oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC): Initial toxicity and response data from a GI intergroup study. Proc Am Soc Clin Oncol 21:128a, 2002 (abstr 511)

39. Mullany S, Svingen PA, Kaufmann SH, et al: Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: Elevated dTTP pools and enhanced cytotoxicity. Cancer Chemother Pharmacol 42:391–399, 1998[CrossRef][Medline]

40. Mans DR, 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 35:1851–1861, 1999[CrossRef][Medline]

41. Pavillard V, Formento P, Rostagno P, et al: Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity. Biochem Pharmacol 56:1315–1322, 1998[CrossRef][Medline]

42. Guichard S, Cussac D, Hennebelle I, et al: Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT-29 in vitro and in vivo. Int J Cancer 73:729–734, 1997[CrossRef][Medline]

43. Fischel JL, Rostagno P, Formento P, et al: Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: Results on human colon cancer cell lines. Br J Cancer 84:579–585, 2001[CrossRef][Medline]

44. Goldberg RM, Kaufmann SH, Atherton P, et al: A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin. Ann Oncol 13:1674–1680, 2002[Abstract/Free Full Text]

45. Simon R, Freidlin B, Rubinstein L, et al: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147, 1997[Abstract/Free Full Text]

46. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216, 2000[Abstract/Free Full Text]

47. Tothill P: Evaluation of methods of bone mass measurement. Basic Life Sci 55:107–116, 1990[Medline]

48. Cassetta B, Roncadin M, Montanari G, et al: Determination of platinum in biological fluids by ICP-mass spectrometry. At Spectrosc 12:81–86, 1991

49. Robbins ME, Bywaters TB, Jaenke RS, et al: Long-term studies of cisplatin-induced reductions in porcine renal functional reserve. Cancer Chemother Pharmacol 29:309–315, 1992[CrossRef][Medline]

50. Allain P, Berre S, Mauras Y, et al: Evaluation of inductively coupled mass spectrometry for the determination of platinum in plasma. Biol Mass Spectrom 21:141–143, 1992[CrossRef][Medline]

51. Pitot HC, McElroy EA Jr, Reid JM, et al: Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. Clin Cancer Res 5:525–531, 1999[Abstract/Free Full Text]

52. Dyck PJ, Kratz KM, Lehman KA, et al: The Rochester Diabetic Neuropathy Study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 41:799–807, 1991[Abstract/Free Full Text]

53. Dyck PJ, Karnes JL, O’Brien PC, et al: Detection thresholds of cutaneous sensation in humans, in Peipheral Neuropathy (ed 3). Philadelphia, PA, W.B. Saunders Co, 1993, pp 706–728

54. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808–815, 1997[Abstract/Free Full Text]

55. Kohne CH, Schoffski P, Wilke H, et al: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 16:418–426, 1998[Abstract]

56. Souglakos J, Mavroudis D, Kakolyris S, et al: 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. J Clin Oncol 20:2651–2657, 2002[Abstract/Free Full Text]

57. Becouarn Y, Gamelin E, Coudert B, et al: Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 19:4195–4201, 2001[Abstract/Free Full Text]

58. Rubio G, Chacon M, Coppola F, et al: CPT-11/oxaliplatin (OXA) plus folinic acid (FA)/5-FU bolus (triple combination): An active and feasible combination in metastatic colorectal cancer (CRC) patients (pts). Proc Am Soc Clin Oncol 21:110b, 2002 (abstr 2254)

59. Roth AD, Seium Y, Ruhstaller T, et al: Oxaliplatin (OXA) combined with irinotecan (CPT-11) and 5-FU/leucovorin (OCFL) in metastatic colorectal cancer (MCRC): A phase I–II study. Proc Am Soc Clin Oncol 21:143a, 2002 (abstr 570)

60. Ando Y, Saka H, Ando M, et al: Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: A pharmacogenetic analysis. Cancer Res 60:6921–6926, 2000[Abstract/Free Full Text]

61. Iyer L, Das S, Janisch L, et al: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47, 2002[CrossRef][Medline]

62. Graham MA, Lockwood GF, Greenslade D, et al: Clinical pharmacokinetics of oxaliplatin: A critical review. Clin Cancer Res 6:1205–1218, 2000[Abstract/Free Full Text]

63. 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 17:1751–1759, 1999[Abstract/Free Full Text]

64. 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 13:1490–1496, 2002[Abstract/Free Full Text]

65. Gil-Delgado M, Bastian G, Guinet F, et al: Final results of oxaliplatin (LOHP) + irinotecan (CPT-11) and FU-FOL (LV5FU2) combination and pharmacokinetic (PK) analysis in advanced colorectal cancer (ACRC) patients (pts). Proc Am Soc Clin Oncol 20:140a, 2001 (abstr 558)

66. Uriens S, Tillement J: In vitro binding of oxaliplatin to human serum proteins: Drug interactions. Debiopharm Study Report No. LPH9922, Lausanne, Switzerland, 1995

67. Cavaletti G, Tredici G, Petruccioli MG, et al: Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 37:2457–2463, 2001[Medline]

Submitted January 31, 2003; accepted May 29, 2003.




This article has been cited by other articles:


Home page
 JCOHome page
A. Falcone, S. Ricci, I. Brunetti, E. Pfanner, G. Allegrini, C. Barbara, L. Crino, G. Benedetti, W. Evangelista, L. Fanchini, et al.
Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest
J. Clin. Oncol., May 1, 2007; 25(13): 1670 - 1676.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
G. Masi, G. Allegrini, S. Cupini, L. Marcucci, E. Cerri, I. Brunetti, E. Fontana, S. Ricci, M. Andreuccetti, and A. Falcone
First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule
Ann. Onc., December 1, 2004; 15(12): 1766 - 1772.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
C. J. A. Punt
New options and old dilemmas in the treatment of patients with advanced colorectal cancer
Ann. Onc., October 1, 2004; 15(10): 1453 - 1459.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. L. Rothenberg and J. D. Berlin
Therapeutic Strategies for Metastatic Colorectal Cancer: Simultaneous, Sequential, or Specific?
J. Clin. Oncol., October 15, 2003; 21(20): 3716 - 3717.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar