Eloxatin approved for first line treatment of advanced colorectal cancer

Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 14 de marzo del 2004

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Eloxatin approved for first line treatment of advanced colorectal cancer By Julia Draznin Maltzman, MD

Approved

Eloxatin (oxaliplatin, Sanofi-Synthelabo) along with 5-fluorouracil and leucovorin (5-FU/LV) was recently approved by the FDA as first like treatment for advanced colorectal cancer. The combination commonly referred to as FOLFOX, has previously been used as the approved second line treatment for patients who recurred or progressed after treatment with 5-FU/LV. Eloxatin was approved for second line use in colorectal cancer in August 2002.

The data

The approval for first line indication was based on the results form the North American, multi-center, randomized, open-label, controlled intergroup study, N9741, led by the North Central Cancer Treatment Group (NCCTG). Money and support for this effort came from the NCI. This trial was a large and coordinated trial with seven arms at different times during the conduct of the study. Four of these arms were later closed due to changes in the standard of care or toxicity profile. In the end, the trial compared the efficacy and safety of two experimental regimens – eloxatin in combination with infusional 5-FU/LV (FOLFOX4) every two weeks and the combination of eloxatin plus irinotecan (IROX) every three weeks, with an approved control regimen of irinotecan plus 5FU/LV (IFL). Participants in the trial consisted of 795 randomized patients previously untreated for locally advanced or metastatic colorectal cancer. The three arms were equally divided with similar patient profiles: IFL had 264 participants, 269 patients received FOLFOX, and IROX had 265 patients participating.

The overall median survival time following FOLFOX was 19.4 months compared to 14.6 months with IFL (P<0.0001). The IROX regimen had intermediate survival – 17.0 months. In addition to the 35% improvement in survival over the IFL regimen, patients on the FOLFOX regimen had a significantly higher overall tumor response rate in patients with measurable disease. A 45% response rate was noted for FOLFOX as opposed to a 33% response rate for IFL. (IROX exhibited a 30% response rate). A response rate was defined as the sum of both a partial response and a complete response. FOLFOX also achieved a longer time to tumor progression than IFL – 8.7 months versus 6.9 months. IROX preformed similarly to IFL with a 6.7-month time to tumor progression. Furthermore, this effect seemed to hold true for all age groups and was unaffected by prior adjuvant therapy.

Judging by the toxicity profiles for each regimen, FOLFOX emerged as the most favorable treatment. Grade 3 or greater toxicities were evaluated and FOLFOX only had an increased rate of parasthesias over the other two alternative therapies. Surprisingly, there was a higher rate of neutropenia with the FOLFOX regimen, however there were considerably fewer febrile neutropenic events with FOLFOX when compared to either IFL or IROX.

Quality of life was also assessed and no difference was seen among the three treatment options. Quality of life was assessed in a number of different ways including a symptom distress scale.

This pivotal trial demonstrated that patients who received FOLFOX as the first-line treatment had a significant improvement in survival compared with patients treated with IFL. Toxicity data favored FOLFOX over IROX which led to the formers acceptance as the approved first line therapy for metastatic colorectal cancer.

Mechanism of action

Eloxatin is a new generation platin compound. It is a cousin of cisplatin and carboplatin. Like its cousins, eloxatin has a central platinum group that works by intercalating itself into the cells DNA and forming crosslinks both within the DNA strand and among different strands of DNA. The crosslinks result in DNA breakage and ultimately cell death. The mechanism of eloxatin is not cell cycle specific so it can work on even slowly replicating tumors.

In preclinical studies, eloxatin showed synergistic activity in vitro with 5-FU. In other words, the combination of both compounds worked much better than either one alone. The synergy seen in the laboratory ultimately led to its use in clinical trials and resulted in the development of the FOLFOX regimen.

Unlike cisplatin, eloxatin does not cause renal failure and most people do not experience much nausea at all. Eloxatin has its own unique side effects, the most important of which is a neuropathy.

Neuropathy

Eloxatin is associated with two types of peripheral sensory neuropathies: an acute, reversible type and a persistent type associated with prolonged use. Acute and persistent neuropathies occurred in 56% and 48% (all grades) of previously untreated patients. The acute neuropathy is often described as an electric shock felt by the patient exacerbated by cold temperatures. (Such as when reaching for a cold soda in the refrigerator). The persistent neuropathy will manifest itself as difficulties in manipulating small object such as buttons or putting on earrings.

The Future

Eloxatin has captured much of the market in metastatic colorectal cancer. Trials are on-going that are examining the role of eloxatin in adjuvant therapy. There have been several very good and convincing studies showing a benefit to the FOLFOX combination in stage III disease.

Another largely untapped area will be to examine the efficacy and the benefit of eloxatin in combinations with some of the more targeted therapeutic approaches. Such combinations as eloxatin and vascular endothelial growth factor (VEGF) inhibitors or eloxatin with the monoclonal antibodies would be important to evaluate.


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