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© 2003 American Society for Clinical Oncology Safety and Toxicity Analysis of Oxaliplatin Combined With Fluorouracil or as a Single Agent in Patients With Previously Treated Advanced Colorectal Cancer
From the University of Pittsburgh Cancer Institute, Pittsburgh; University of Pennsylvania Cancer Center; Thomas Jefferson University, Philadelphia, PA; Dana Farber Harvard Cancer Center, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; USC Norris Comprehensive Cancer Center, Los Angeles, CA; Cancer Center of the Carolinas, Greenville, SC; and Ochsner Clinic Foundation, New Orleans, LA. Address reprint requests to Ramesh K. Ramanathan, MD, UPMC Cancer Pavilion; 5150 Centre Ave, #562, Pittsburgh, PA 15232; email: ramanathanrk{at}msx.upmc.edu.
Purpose: Two consecutive compassionate use studies of oxaliplatin were conducted in the United States and Canada in more than 5,000 patients with locally advanced or metastatic colorectal carcinoma who had experienced treatment failure after at least one prior chemotherapy regimen. Patients and Methods: The main focus was safety. Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin in combination with fluorouracil (FU) and with or without leucovorin (LV) in various regimens. Response data collection was not a trial objective, but time to treatment failure (TTF) was recorded in the first cohort (1,370 patients). Results: All treatment regimens were well tolerated, with an overall incidence of grade 3 or 4 hematologic toxicity of 23.2%, grade 3 or 4 treatment-related gastrointestinal toxicity of 26.4% (including diarrhea, vomiting, and mucositis), and grade 3 neurosensory toxicity 3.9%. Similar results were reported in the second cohort (3,806 patients), in which the eligibility criteria were much less restrictive. In the first cohort (in which 83% received prior irinotecan), median TTF was 14 weeks, and was similar for the five regimens combining oxaliplatin and FU with or without LV, but significantly shorter for the single-agent oxaliplatin arm. The overall dose-intensity of oxaliplatin was maintained at 85.5% (range, 80.6% to 94.3%) of that prescribed by protocol (average 36.7 mg/m2/wk). Conclusion: These data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer.
CHEMOTHERAPY OF metastatic colorectal cancer (CRC) has undergone rapid change in the last decade, with the availability of new regimens. In the United States, the regimen of irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) is widely used as first-line therapy on the basis of a randomized study showing superior survival and response rates compared with FU plus LV alone.1 The therapeutic options become fewer in the second-line setting. Single-agent irinotecan has shown activity and is superior to supportive care or infusional FU in patients who experience treatment failure after a bolus FU-based regimen.2,3 Until recently, there were no data available on the efficacy of any chemotherapeutic regimen after progression with IFL as first-line therapy. Oxaliplatin (Eloxatin; Sanofi-Synthelabo, New York, NY) is a diaminocyclohexane platinum derivative with broad-spectrum activity.4–6 The United States Food and Drug Administration in August 2002 approved oxaliplatin in combination with infusional FU and LV for the treatment of patients with advanced CRC whose disease has recurred or relapsed after initial treatment with IFL. Interim results of this North American study (EFC 4584) demonstrated that the combination of oxaliplatin with infusional FU plus LV (FOLFOX4 regimen) results in a 9.9% response rate and a 2-month improvement in radiologic time to tumor progression, which was significant compared with single-agent oxaliplatin or infusional FU.7 The FOLFOX4 regimen has also been investigated as first-line therapy with promising results. Randomized studies have shown statistically superior response rates and time to progression with acceptable toxicity for FOLFOX4 compared with FU plus LV regimens.8,9 The efficacy of oxaliplatin in first-line treatment of metastatic CRC also is supported by data from the North American Intergroup study N9741. Preliminary results of a planned interim analysis, on the basis of 795 patients, showed that patients receiving FOLFOX4 had significantly longer time to progression, better overall survival, higher response rate, and lower toxicity than patients receiving IFL.10 Before August 2002, oxaliplatin was an investigational drug in the United States. To make oxaliplatin available, a compassionate use treatment program was opened to patients with previously treated advanced or metastatic CRC. Preliminary data for 1,131 patients entered as of June 1999 have been previously reported.11 Results are presented here for the total of 5,176 patients.
In study LTS7072, 1,370 patients were registered and received treatment with at least one dose of oxaliplatin before September 1, 1999. Subsequently, 3,806 additional patients were entered onto study LTS7072A between September 1, 1999 and December 31, 2000.
Patient selection criteria are shown in Table 1
Treatment regimens were not specified for patients enrolled onto 7072A. However, oxaliplatin doses of 85 and 130 mg/m2 were indicated for the 2- and 3-week regimens, respectively, in an outpatient setting. Oxaliplatin was administered in 250 or 500 mL of 5% glucose solution, over 2 hours. The infusion duration was increased to 6 hours if local symptoms at the infusion site or laryngopharyngeal dysesthesia occurred. The infusion line was flushed after oxaliplatin administration and before initiation of other infusions (such as FU or LV). Needles or infusion sets containing aluminum components were not used for the preparation or administration of oxaliplatin because of a risk of degradation of the chemotherapy agent. All toxicity was graded according to the National Cancer Institute common toxicity criteria 1.0 (December 19, 1996), except for neurosensory toxicity, for which a study-specific scale was used. If there was a delay in FU treatment, then administration of oxaliplatin was also delayed. If FU had to be discontinued because of toxicity, the investigator could continue with single-agent oxaliplatin. If a dosing delay of more than 4 weeks occurred because of treatment-related toxicity, the patient was removed from the study. Dose modifications of oxaliplatin or FU were made for hematologic, gastrointestinal, or neurologic toxicities on the basis of the most severe grade of toxicity that had occurred during the previous cycle. Treatment was delayed until the absolute number of neutrophils was more than 1,500/µL; platelets were more than 100,000/µL; and recovery occurred from mucositis, diarrhea, or skin toxicity to grade 1 or less. The dose of oxaliplatin was reduced if there were paresthesias persistent between cycles or paresthesias with functional impairment lasting more than 7 days. If pharyngolaryngeal dysesthesia occurred, the next dose of oxaliplatin was administered as a 6-hour rather than a 2-hour infusion. Patients were removed from the study for progressive disease, toxicity that required a dosing delay of more than 4 weeks, neurosensory toxicity specified as painful paresthesias or paresthesias with functional impairment that was persistent between cycles of oxaliplatin, or at the discretion of the investigator or the patient. Response criteria for tumor measurements were not specified because efficacy was not an objective of this study.
Data Monitoring and Quality Assurance There was no on-site monitoring of data for these studies. For study LTS7072, extensive by-cycle data were required, collected, and queried; the data were substantiated without direct review of patient charts. For study LTS7072A, only summary information was required, and this also was reviewed and queried when received. The queries that were generated consisted of requests for missing forms, missing data points, and inconsistencies in the data; all queries were followed until resolution.
Statistical Analysis
Patient Characteristics Table 3  lists patient characteristics at study entry for the 1,370 patients (LTS7072) who received at least one dose of oxaliplatin. The mean age was 60 years (range, 20 to 89 years), and 23% of patients were  70 years of age. Most patients had a performance status of 0 (33%) or 1 (55%). Excluding adjuvant chemotherapy, patients received an average of 2.3 prior chemotherapy regimens (range, 0 to 6), which included irinotecan in 83% of the patients. The baseline characteristics for patients enrolled onto LTS7072A were quite similar to those in the initial cohort. Table 2 also lists the number of patients in the various treatment regimens. The most frequently selected regimen was Roswell Park (43% to 45% of patients in both cohorts).
Comparison of demographic characteristics of patients enrolled onto LTS7072 selected to receive the single-agent arm versus the five arms containing FU showed that the proportion of patients age 70 years was significantly higher in the single-agent arm (P = .02). The proportion of patients with a performance status of 2 was also significantly higher in this arm (P < .0001). However, there was no significant difference in the proportion of patients who had at least two prior treatment regimens (P = .10).
Treatment With Oxaliplatin
Dosing delays, expressed as percentage of patients receiving a given cycle who had dose delays, are summarized for cycles 2, 3, and 6. These cycles were selected to evaluate dose delays in early compared with later treatment cycles. As may be anticipated, the percentage of patients experiencing dose delays increased from 13% for cycle 2 to 31% for cycle 6. More patients receiving the daily for 5 days regimen required dosing delays than did patients receiving the other regimens.
Time to Treatment Failure
Death was listed as the reason for discontinuation of study treatment in 5% and 7% of patients enrolled onto LTS7072 and LTS7072A, respectively. When deaths of patients enrolled onto the study and within 30 days of the last dose of study drug are considered, the total number of deaths for those enrolled onto LTS7072 was 118 patients (9%; Table 5 ). The causes of death in these 118 patients were listed as progressive disease in 73.7% and adverse event in 14.4%; 11.9% were categorized as being due to multiple other causes. Ten deaths (0.9%) were considered to be possibly related to treatment. These included neutropenic sepsis or septic shock (n = 5); diarrhea, dehydration, nausea, or vomiting (n = 3); colitis and perforated viscus attributed to FU toxicity (n = 1); and ventricular tachycardia in a patient who had vomiting, diarrhea, and dehydration. In LTS7072A, of the 221 patients whose reason for discontinuation of study treatment was death, in only 16 patients (0.7%) was the relationship to study drug considered to be likely (Table 6). In 13 patients the cause was gastrointestinal (diarrhea, dehydration, volume depletion, nausea, and vomiting). Two deaths were due to neutropenia complicated by sepsis or pneumonia, and in one patient the cause was anaphylactic shock.
Toxicity and Hospitalizations
Figure 2
The incidence of likely drug-related hospitalizations by study and regimen are listed in Table 7 . For patients enrolled onto LTS7072, 203 (14.8%) patients were hospitalized at least once for reasons that were considered likely to be drug related. The total number of hospitalizations for reasons that were considered likely to be drug related was 226. Of these, 163 hospitalizations (72%) were related to gastrointestinal toxicity, predominantly diarrhea and dehydration. Nausea, vomiting, and mucositis requiring hospitalization occurred much less frequently. Thirty-two hospitalizations (14%) were attributed to fever, neutropenia, or infection. The remaining 31 hospitalizations (13.7%) included hypersensitivity reactions (HSRs; n = 20), laryngopharyngeal dysesthesia (n = 3), and other reasons (n = 8) including syncope, weakness, delirium, and chest pain. For study LTS7072A, 430 patients (11.3%) were hospitalized at least once for reasons considered likely to be drug-related. The total number of hospitalizations for reasons considered likely to be drug-related was 478. Of these, 361 (75.5%) were attributed to gastrointestinal toxicity, usually diarrhea and its consequences such as dehydration or hypokalemia. Thirty-two hospitalizations (6.7%) were attributed to fever, neutropenia, or infection, and 82 hospitalizations (17.2%) were attributed to various causes such as HSRs.
The purposes of these protocols were to provide oxaliplatin for compassionate use in patients with advanced CRC who had experienced treatment failure after standard therapies, and to collect safety data in this heavily pretreated population. Most chemotherapeutic trials are confined to a segment of the cancer population, which may be relatively healthy, so data from this trial are likely to reflect the toxicity of treatment seen in a general population of cancer patients. Most of the patients had received from one to three prior chemotherapy regimens. Almost all had experienced treatment failure after an FU-containing regimen, and 83% had also received prior irinotecan. Only 5% of patients had an objective response (complete response or partial response) to their last chemotherapy regimen, indicating that this was a group with refractory disease. Despite this result, the oxaliplatin dose-intensity was maintained at 80% to 94% in all arms of the study, even in patients that might be considered at high risk of treatment-related complications. The time to removal from the study was similar for the various regimens combining oxaliplatin with FU (LV), but was significantly shorter for the single-agent arm. Single-agent oxaliplatin is less efficacious than when used in combination with FU (FOLFOX4).7 However, this result may also be related to the fact that patients assigned by oncologists to single-agent oxaliplatin were significantly older and had a worse performance status than those treated with the various combination regimens. There was a relatively low occurrence of severe (grade 3 to 4) hematologic toxicity (25%) and gastrointestinal toxicity (24%), and a less than 1% incidence of death from treatment-related adverse events. The incidence of grade 3 and 4 gastrointestinal toxicities was only 18% in the FOLFOX4 regimen and compares favorably to the other four combination regimens (28% to 33%). The incidence of grade 3 neurosensory toxicity for patients enrolled onto LTS7072 and LTS7072A (4% and 3%, respectively) was lower than previously reported for oxaliplatin. This may be partly a result of a relatively short average time enrolled onto the study of 3 months, and a lower cumulative dose of oxaliplatin that was administered in these heavily pretreated patients, as opposed to the results reported in some of the previously reported trials in untreated patients.8,9 Grade 1 neurosensory toxicity was reported in 46% and 45% of the patients, and grade 2 neurosensory toxicity was reported in 11% and 13% enrolled onto LTS7072 and LTS7072A, respectively, and was rarely a cause for discontinuation of treatment. Laryngopharyngeal dysesthesia is an adverse event uniquely associated with oxaliplatin. It is characterized by subjective dysphagia and dyspnea, usually with an onset during or within hours of the oxaliplatin infusion, and is often initiated or exacerbated by exposure to cold liquids or cold air. Symptomatic treatment may include administration of anxiolytics. Extending the duration of a subsequent infusion of oxaliplatin may decrease the incidence and severity of this syndrome. Prevention and patient education are essential. The incidence of HSRs to oxaliplatin was similar to that in other published studies8,9 and HSRs were seen in about 2% of patients. HSRs occurred during or within 1 hour of the end of oxaliplatin infusion (sometimes during a subsequent LV infusion), and included fever, chills or rigors, facial flushing or erythema, hypotension or hypertension, chest or throat discomfort, stridor or laryngospasm, or severe back pain caused by hemolysis. These reactions were usually controlled with symptomatic measures, including intravenous corticosteroids, histamine blocker, and meperidine. Many patients continued to receive additional cycles of oxaliplatin after a mild or moderate HSRs, often after pretreatment with high-dose dexamethasone (10 to 20 mg intravenously) and diphenhydramine. Patients with severe reactions were usually removed from the study. Acute local reactions also were observed in patients without central venous catheters, consisting of arm or hand pain, tenderness, and vein sensitivity at the site of oxaliplatin infusion. Such local reactions could usually be alleviated by increasing the duration of infusion of oxaliplatin or by increasing the volume of infusion. Infusional FU regimens are widely used in Europe, and FOLFOX4 is the most commonly used oxaliplatin plus FU regimen.8 In contrast, oncologists in North America generally use bolus FU schedules. Indeed, in this study, the majority preferred a bolus FU regimen, even though infusion schedules were available. The use of bolus FU schedules was demonstrated to be safe in this study. However, the experience in untreated patients, especially with the daily for 5 days regimen, bolus FU schedules have been mixed. The Intergroup study N9741 closed one arm with the modified Mayo Clinic schedule of FU plus oxaliplatin because of excessive toxicity.13 In contrast, a study by Ravaioli et al14 found a similar regimen to be safe and active. A weekly FU plus LV and oxaliplatin regimen was evaluated in a recently completed adjuvant study of colon cancer by the National Surgical Adjuvant Breast and Bowel Project (NSABP-C07) study group; safety results have not yet been presented. All six regimens used in this study of more than 5,000 patients had an acceptable safety profile. Therapy with single-agent oxaliplatin resulted in the lowest incidence of hospitalization. For the combination arms, the percentage of patients hospitalized for reasons that were considered likely to be drug related was lower in the FOLFOX4 arm (< 10%), which is the currently approved second-line regimen in the United States, than other regimens in both cohorts. Therefore, although the incidence of grade 3 to 4 hematologic toxicity was somewhat higher in the FOLFOX4 regimen, this regimen was associated with a lower incidence of hospitalizations, indicating that the majority of treatment-related hospitalizations resulted from gastrointestinal toxicities. The substitution of infusional regimens of FU by a weekly bolus regimen or capecitabine could result in increased patient convenience, and the efficacy of these regimens needs to be determined in randomized clinical trials. Ongoing studies are evaluating the safety, efficacy, and optimal regimens of oxaliplatin with FU, irinotecan, and capecitabine as front-line or salvage therapy for advanced or metastatic CRC.15–17
We thank Anne Kornowski, MD (Sanofi-Synthelabo), Mirjam Gerber, MD, Kathy Foard, and Beth Dershem (Prologue Research International) for their assistance in data collection and in preparation of this manuscript, and Alicia Depastino for secretarial assistance.
Supported by Sanofi-Synthelabo, New York, NY. This study was presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.
1. 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 2. 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] 3. 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] 4. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen Panel. Biochem Pharmacol 52:1855–1865, 1996[CrossRef][Medline] 5. Mani S, Graham MA, Bregman DB, et al: Oxaliplatin: A review of evolving concepts. Cancer Invest 20:246–263, 2002[CrossRef][Medline]
6. Raymond E, Chaney SG, Taamma A, et al: Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 9:1053–1071, 1998
7. Rothenburgh ML, Orza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol. 21:2059–2069, 2003
8. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947, 2000
9. 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 10. Goldberg R, Morton D, Sargent C, et al: N9741: Oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/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) 11. Mitchell EP: Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. Oncology 14:30–32, 2000 (12 suppl 11)[Medline] 12. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 13. Morton RF, Goldberg RM, Sargent DJ, et al: Oxaliplatin (OXAL) or CPT-11 combined with 5-FU/leucovorin (LV) in advanced colorectal cancer (CRC): An NCCTG/CALGB study.Proc Am Soc Clin Oncol 20:125a, 2001 (abstr 495)
14. Ravaioli A, Marangolo M, Pasquini E, et al , Bolus oxaliplatin and leucovorin with oxaliplatin as first line treatment in metastatic colorectal cancer. J Clin Oncol 20:2545–2550, 2002 15. Goldberg R: Oxaliplatin in colorectal cancer: Current studies. Oncology 14:42–47, 2000 (12 supp 11)[Medline]
16. Borner MM, Dietrich D, Stupp R, et al: Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 20:1759–1799, 2002
17. Falcone A, Masi G, Allegrini G, et al: Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: A pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006–4014, 2002 Submitted November 12, 2002; accepted April 23, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test) with respect to the baseline parameters of age, performance status (Eastern Cooperative Oncology Group), and number of prior chemotherapy regimens for LTS7072. Time to off-study and cumulative neurosensory toxicity were compared by the Kaplan-Meier method.
