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Compassionate-use oxaliplatin with bolus 5-fluorouracil/leucovorin in heavily pretreated patients with advanced colorectal cancer.

Objectives: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer was evaluated. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled.

Methods: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6.

Results: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic <3%; peripheral neuropathy 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months.

Conclusion: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.

Key Words: bolus 5-fluorouracil/leucovorin, colorectal cancer, compassionate use study, diarrhea, oxaliplatin, pretreated

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In the United States, 135,400 new cases of colorectal cancer will be diagnosed in 2001. Of these, 20 to 25% will have already disseminated beyond the colon at the time of initial presentation, most commonly, though not exclusively, to the liver. In spite of advances made in screening, diagnostic, and surgical technique over the last decade, colorectal cancer remains the third leading cause of cancer-related deaths in the USA, with an annual mortality rate exceeding 50,000. (1)

Following its introduction into clinical practice over 40 years ago, 5-fluorouracil (5-FU) had been the standard chemotherapeutic agent for treating patients with advanced colorectal carcinoma. However, as a single-agent, 5-FU was found to be only modestly beneficial, with response rates rarely exceeding 15%. (2) Several attempts have been made to increase the efficacy of 5-FU, including the addition of modulating compounds, manipulation of dosage and administration schedules, and combining 5-FU with other chemotherapeutic agents such as cisplatin and methotrexate. (3) Although these methods have succeeded in increasing the efficacy of 5-FU in terms of objective response rate, the survival of patients with advanced colorectal cancer remains quite low, rarely exceeding 12 months. Even with the introduction of new agents into the treatment armamentarium such as irinotecan and capecitabine, the median survival of patients with metastatic disease remains only in the range of 14.8 months. (4)

Oxaliplatin (OXP) is a relatively new 1,2-diaminocyclohexane (DACH) platinum compound that has demonstrated antitumor activity in a variety of neoplasms. (5,6) Of particular interest has been its antitumor activity in advanced colorectal carcinoma, which has been studied extensively by European investigators over the last 8 years. (6-17) Its postulated primary mechanism of action is similar to that of cisplatin, with the formation of intrastrand DNA adducts between two adjacent guanine residues or adjacent guanine and adenine residues. (7) Since intrastrand adducts are capable of blocking both DNA replication and transcription, this can be lethal to a proliferating carcinoma. Preclinical trials have demonstrated the antitumoral superiority of oxaliplatin to cisplatin. (18) Indeed, one of the preclinical observations that spawned oxaliplatin's clinical development was the significant in vitro antitumor effect in cisplatin-resistant cell lines. (7,8,18,19)

Early evidence of oxaliplatin activity in combination with 5-FU was provided by clinical studies employing various infusional and chronomodulated OXP/5-FU and leucovorin (LV) schedules. (15-17)

Oxaliplatin entered phase II and phase III testing in the United States in 1998, through a multi-center compassionate use program sponsored by Sanofi-Synthelabo. The Kentuckiana Cancer Institute, PLLC, participated in this program and consistently placed eligible, heavily pretreated patients with advanced colorectal cancer (CRC) on a regimen of oxaliplatin with weekly bolus 5-FU/LV (Roswell Park regimen). The results of this treatment program on 123 patients are reported herein.

Materials and Methods

Between September 25, 1998 and May 1, 2001 a total of 123 advanced CRC patients were consented and enrolled in a compassionate use study in which OXP 85 mg/[m.sup.2] was administered in combination with the Roswell Park 5-FU/LV regimen. (3) Patients were required to have Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 to 2 and have radiographically progressive CRC at the time of protocol entry. All had progressed through at least one prior 5-FU and irinotecan-containing regimen. Patients received OXP 85 mg/[m.sup.2] as a two-hour infusion on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-FU 500 mg/[m.sup.2] and LV 500 mg/[m.sup.2] were administered on day 1 of weeks 1 through 6 via bolus infusion following oxaliplatin administration. Treatment was planned for four cylces of therapy, or a total duration of 32 weeks. The protocol was approved by the Institutional Review Board of Jewish Hospital/University of Louisville, and all patients gave written informed consent before enrollment. Patients with confirmed progressive disease at any point during the study received no further treatment on the protocol. All patients were followed for survival through May 31, 2001.

Response and Toxicity Analysis

Of the 123 patients accrued, only those receiving at least two eight-week treatment cycles and with adequately documented, measurable and/or evaluable disease were eligible for tumor response assessment. All patients were evaluable for treatment-related toxicities. Response evaluation was undertaken with every two cycles of treatment (ie, 16 wk) or at the discretion of the treating physician upon suspicion of disease progression. Responses were recorded per World Health Organization guidelines and toxicities were reported in accordance with National Cancer Institute common toxicity criteria. (20,21)

Results

Cohort Characteristics

Of the 123 registered patients, 101 were eligible for response. The remaining 22 patients were removed from the study before completion of the first treatment cycle due to either disease progression or the occurrence of significant treatment-related toxicities which prompted the patients to decline further treatment. Patient and disease characteristics at the time of study enrollment are summarized in Table 1.

The population of heavily pretreated advanced CRC patients included 65 men and 58 women, the majority of whom (92%) had an ECOG performance status of 0 or 1 at the time of enrollment. The principal metastatic sites in this patient population were the liver, lungs, and bone, in descending order of frequency. Seventy-five percent of patients had an elevated serum CEA level at the time of enrollment.

Toxicity

The grade 3 to 4 toxicity profile of oxaliplatin and concomitant bolus 5-FU/LV in the 123 intent-to-treat patients is presented in Table 2. The most prevalent adverse effects resulting from this treatment schedule were gastrointestinal (GI). Nearly a third (30%) of patients reported grade 3 to 4 diarrhea (9% required hospitalization and dose reduction) and 10% reported grade 3 to 4 vomiting. Although peripheral neuropathy is a known limiting toxicity for oxaliplatin, the most frequent neuropathies observed were grade 1 or 2. (6) Laryngopharyngeal dysesthesias are also frequently encountered in conjunction with oxaliplatin, yet only one patient reported such sensations. The subgroup of patients experiencing grade 3 to 4 GI toxicity was scrutinized for commonalities. No significant correlation was found between toxicity and the patient's history of prior radiotherapy, performance status upon enrollment, or their number of previous chemotherapeutic regimens.

Antitumor activity

One hundred and one patients were evaluable for objective tumor response (Table 3). An overall response rate of 6.9% was achieved with 7 partial responses of at least 2 months' duration. In addition, there was one minor response lasting 7 months, and 31 patients with disease stabilization. These 31 patients had radiographic evidence of progression of disease at the time of enrollment and then demonstrated disease stabilization with a median duration of 6.08 months. Seventy-seven of the evaluable patients had serial CEA levels available. Twenty-seven (35%) had a greater than 25% reduction, while seven (9%) achieved greater than 50% CEA reduction.

Survival

Patients were assessed for time to progression and overall survival through May 31, 2001 (32 months after the accrual of the first patient and 30 days after the accrual of the last patient). The median time to progression of all evaluable patients was 3.6 months from receiving the first dose of OXP/5-FU/LV. Sixty percent of patients were removed from the study before finishing their second treatment cycle. Of those, 83% were removed due to disease progression; 17% withdrew from the study in response to experiencing significant toxicities, most commonly gastrointestinal. The median overall survival of all patients accrued to the study was 6.5 months.

Discussion

This analysis of 123 patients with advanced, heavily pretreated colorectal cancer, enrolled into a Sanofi-Synthelabo sponsored compassionate-use program with oxaliplatin with bolus 5-fluorouracil/leucovorin represents the first large scale US experience with this new generation platinum compound. Phase II trials evaluating oxaliplatin either alone or in combination with 5-FU in patients with colorectal cancer have appeared in the European literature since 1993. (22-28) Although phase I testing of oxaliplatin had been performed with various dosing schedules, a consensus emerged recommending either 130 mg/[m.sup.2] every three weeks, or 85 mg/[m.sup.2] every 2 weeks for phase II trials. (23,24) When combined with 5-FU in the relapsed setting, de Gramont et al (25) championed the use of OXP 85 to 100 mg/[m.sup.2] every two weeks, together with biweekly bolus/infusional 5-FU (de Gramont regimen). These authors have reported objective response rates in the range of 20 to 58%, which were significantly higher than the 10% response rate when oxaliplatin was administered as a single agent in this patient population. (24)

In 1999, Brienza et al (15) published a European multi-center compassionate use program experience of oxaliplatin with bolus/infusion 5-FU in 206 5-FU pretreated patients with advanced CRC. The majority of their patient population had received only one (53%) or two (23%) prior chemotherapy regimens and almost all received some form of infusional 5-FU together with oxaliplatin. A response rate of 25.5% in 98 evaluable patients was reported, and although the incidence of grade 3 to 4 hematologic and peripheral neurotoxicity was in line with previously reported European data, a somewhat higher incidence of grade 3 to 4 diarrhea (28% of patients) was noted. Interestingly, despite their improved response rate, the median time to progression in their 98 evaluable patients was 4.1 months, as compared with 3.6 months in our patient population.

Alternatively, Levi et al (26,29) reported the use of oxaliplatin together with 5-FU and leucovorin using a chronomodulated approach, again reporting response rates in the range of 29 to 55%. (27) These response rates are markedly better than those achieved in our patient population (6.9%) using a similar oxaliplatin dose but a bolus-only administration of 5-FU. This difference may in part be secondary to the multiple prior chemotherapeutic regimens that our patient population had received before entering into the oxaliplatin study (89% having received two or more previous regimens), thus reflecting patients with more inherently resistant tumors. In addition, the use of a bolus-only administration of 5-FU rather than a bolus/continuous infusion (de Gramont regimen) or a chronomodulated continuous infusion in conjunction with oxaliplatin may result in a diminished therapeutic efficacy of the combined regimen.

The toxicity profile of oxaliplatin with bolus 5-FU/LV (Roswell Park schedule) in our heavily pretreated population was characterized by significant diarrhea and nausea (grade 3-4 in 30% and 10% of patients, respectively). The former contributed to hospitalization as well as dose reduction for 9% of patients.

European phase II and III studies employing OXP 85 mg/[m.sup.2] together with the de Gramont regimen report grade 3 to 4 diarrhea in only 5 to 12%. However, they do report a higher incidence of neutropenia (15-42%) and thromobocytopenia (2.5-7%) as well as peripheral neuropathy (18-28%). (25,28) In light of the comparable oxaliplatin dosing in our patient cohort, we attribute the different toxicity profile to the bolus administration of 5-FU, although the decreased incidence of peripheral neuropathy was unexpected.

Indeed, the controversy between bolus and continuous infusion 5-FU when used as a single agent in advanced colorectal cancer is longstanding in the oncologic literature. (30,31) Although a high response rate and a more favorable toxicity profile versus bolus schedules have been shown with the infusional administration of 5-FU when used as a single agent, this failed to translate into a significant overall survival benefit in a randomized study of 179 previously untreated patients. (30) In addition, although a metaanalysis of seven randomized trials demonstrated a slight improvement in overall survival in favor of an infusional schedule, this disappeared when studies using leucovorin modulation were included. (31)

With regard to combined OXP/5-FU/LV regimens, European investigators have limited themselves to infusional 5-FU regimens, and no formal randomized comparison exists with oxaliplatin-containing 5-FU bolus-only regimens. Hochster et al (32) have reported preliminary data utilizing oxaliplatin with weekly bolus 5-FU and low-dose leucovorin every 3 of 4 weeks in an ongoing single arm study in newly diagnosed advanced colorectal cancer patients. An objective response rate greater than 50% was reported in that patient population, with nausea and diarrhea being the most pronounced toxicities reported to date (grade 3-4 toxicity in 15% and 22%, respectively). In a phase III setting, de Gramont et al (28) demonstrated a statistically significant improvement in response rate (51% versus 22%, P < 0.001) and median progression-free survival (9.0 versus 6.2 mo, P < 0.001) of oxaliplatin with bolus/infusion 5-FU (de Gramont regimen) and leucovorin as compared with 5-FU/LV alone in the first line treatment of patients with advanced colorectal cancer. However, no improvement in overall survival could be demonstrated (16.2 mo versus 14.7 mo). Although both of these studies revealed improved responses over our experience, our patient population had failed two to five prior treatment modalities, again suggesting an inherently resistant disease process.

Conclusion

We conclude from our experience in 123 heavily pretreated colorectal cancer patients that the combination of oxaliplatin with weekly bolus-only 5-FU and leucovorin has only modest therapeutic benefit. The GI toxicity profile resulting from this dosing schedule is significantly worse than reported with bolus/infusion 5-FU (de Gramont) regimens in conjunction with oxaliplatin, and quite possibly results in lower objective response rate. This study therefore supports the use of the de Gramont regimen, even in the US setting. However, further studies are needed to clarify the optimal dose and scheduling of oxaliplatin and 5-FU in colorectal cancer.
Table 1. Patient and disease characteristics (a)

 Total Percentage
Characteristics (n = 123) (%)

Sex
 Male 65 53
 Female 58 47
Race
 White 115 93
 African-American 7 6
 Asian 1 1
PS (ECOG)
 0-1 113 92
 2-3 10 8
Primary tumor
 Colon 88 72
 Rectum 32 26
 Pseudomyxoma peritonei 3 2
Metastatic sites
 Liver only 33 27
 Lung only 7 6
 Other 5 4
 Multiple sites 78 63
Elevated CEA (> 2X the upper normal limit) 92 75
Number of prior chemotherapeutic regimens
 1 14 11
 2 70 57
 3 26 21
 4+ 13 11
Prior radiation 24 20

(a) PS (ECOG), Eastern Cooperative Oncology Group performance status;
CEA, carcinoembryonic antigen.

Table 2. Toxicity (a)

Toxicity Grade 3-4 (%) (b)

Gastrointestinal
 Nausea 9.8
 Vomiting 10.7
 Diarrhea 30.3
Hematological
 Neutropenia 1.6
 Thrombocytopenia 2.5
Peripheral neuropathy 2.5
Dehydration 6.6
Fatigue 4.1
Laryngopharyngeal dysesthesias 0.8

(a) Based on National Cancer Institute common toxicity criteria.
(b) n = 123.

Table 3. Response to treatment for 101 evaluable patients (a)

Antitumor response:
patient's best response on study (%) Response TTP in months:
CR PR MR SD PD rate (%) mean (min-max)

0 6.9 0.9 30.7 61.4 6.9 3.6 (0.6-11.8)

Survival in
months: mean CEA
 (min-max) response (b) (%)

6.5 (0.3-24.5) 35

(a) CR, complete response; PR, partial response; MR, minimal response;
SD, stable disease; PD, progressive disease; TTP, time to progression;
CEA, carcinoembryonic antigen.
(b) CEA response = 25% or greater reduction in serum CEA levels.


Accepted April 7, 2004.

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17. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-Fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). Eur J Cancer 1999;35:1338-1342.

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25. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999;17:3560-3568.

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RELATED ARTICLE: Key Points

* Oxaliplatin and bolus 5-FU/leucovorin does exhibit modest benefit in heavily pretreated patients with colorectal cancer.

* Oxaliplatin and bolus 5-FU/leucovorin causes considerable toxicity, primarily gastrointestinal, in the heavily pretreated colorectal cancer patient.

* It appears that the use of a biweekly oxaliplatin with weekly bolus 5-FU/leucovorin regimen in the management of advanced colorectal cancer is considerably more toxic than oxaliplatin/infusional 5-FU regimens, and quite possibly less effective.

Renato V. LaRocca, MD, Shawn D. Glisson, MD, Jeffrey B. Hargis, MD, Rodney E. Kosfeld, MD, Karen E. Leaton, RN, OCN, Rebecca M. Hicks, and Falguni Amin-Zimmerman, MD

From the Kentuckiana Cancer Institute, PLLC, and the Radiation Oncology Department, University of Louisville, James Graham Brown Cancer Center.

This multicenter phase II/III compassionate use program was funded by Sanofi-Synthelabo.

Reprint requests to Falguni Amin-Zimmerman, MD, Radiation Oncology Department, University of Louisville, James Graham Brown Cancer Center, 529 South Jackson Street, Louisville, KY 40202.
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Title Annotation:Original Article
Author:Amin-Zimmerman, Falguni
Publication:Southern Medical Journal
Date:Sep 1, 2004
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