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Novel Combinations With Oxaliplatin

Novel Combinations With Oxaliplatin

ABSTRACT: Oxaliplatin (Eloxatin) is a novel antineoplastic platinum derivative that may exert its cytotoxic effects by blocking DNA replication/transcription, thus resulting in cell death in proliferating cells, as well as apoptosis. Oxaliplatin is often more potent than other platinums such as cisplatin (Platinol) in vitro, and shows greater efficacy in preclinical studies against many tumor cell lines, including some that are resistant to cisplatin and carboplatin (Paraplatin). Oxaliplatin is approved for use with the fluoropyrimidines in the treatment of metastatic colorectal cancer in Asia, Latin America, and Europe. In light of the broad efficacy of oxaliplatin in several solid tumors and the encouraging preclinical data on combination therapy with novel agents (eg, thymidylate synthase inhibitors, epidermal growth factor-receptor antagonists, microtubule interactive agents), this article will review the published literature on novel combinations that have been tested in the laboratory and/or the clinic. [ONCOLOGY 14(Suppl 11):52-58, 2000]

Introduction

Oxaliplatin
(cis-[(1R,2R)]-1,2-cyclohexanediamine-N,N´ oxalato (2-)-O,O´] platinum,
Eloxatin) is a novel antineoplastic platinum derivative with a
1,2-diaminocyclohexane (DACH) carrier ligand.[1] Although its precise mechanism
of action is unknown, platinum compounds in general are thought to exert their
cytotoxic effects through the formation of DNA adducts that block both DNA
replication and transcription, resulting in cell death in actively dividing
cells as well as the induction of apoptosis.[2,3] Oxaliplatin is often more
potent than cisplatin (Platinol) in vitro, requiring fewer DNA adducts to
achieve an equal level of cytotoxicity, and shows the same or greater efficacy
against many tumor cell lines in preclinical studies, including some that are
resistant to cisplatin and carboplatin (Paraplatin).[4-6]

Based on provocative responses seen in patients with metastatic
colorectal cancer, oxaliplatin has been approved for use with the
fluoropyrimidines in the treatment of metastatic colorectal cancer in Asia,
Latin America, and Europe. Studies with oxaliplatin have also demonstrated its
broad efficacy in several solid tumors and yielded encouraging preclinical data
on combination therapy with novel agents (eg, thymidylate synthase inhibitors,
epidermal growth factor-receptor antagonists, microtubule interactive agents).

Novel drug combinations with oxaliplatin that have entered the
clinic may be grouped as follows:

  • Combinations with topoisomerase inhibitors

  • Combinations with novel thymidylate synthase inhibitors

  • Combinations with DNA interactive agents

  • Combinations with microtubule interactive agents

  • Other novel combinations

Many of the above combinations have been described in detail by
other investigators in this supplement. Because oxaliplatin is a new drug,
several approaches that have the potential for clinical application are being
tested; however, data supporting these applications are still predominantly
preclinical.

Preclinical Studies of Novel Combinations

In vitro and in vivo studies of oxaliplatin have shown its
additive or synergistic cytotoxic properties with the fluoropyrimidines
(fluorouracil [5-FU]), thymidylate synthase inhibitors (AG337, raltitrexed
[Tomudex]), nucleoside analogs (gemcitabine [Gemzar]), topoisomerase I
inhibitors (topotecan, irinotecan [Camptosar], and SN-38), microtubule binding
agents (paclitaxel [Taxol]), and DNA modifying/alkylating agents (cisplatin and
cyclophosphamide [Cytoxan, Neosar]).[7-13]

Although oxaliplatin demonstrates additive/synergistic activity
in combination with many standard anticancer agents in preclinical models, some
combinations do not show increased in vivo activity and are sometimes associated
with increased toxicity.[14] More extensive synergy studies with
irinotecan/SN-38 and oxaliplatin in HT-29 colon carcinoma cell lines and GRI
mouse mammary and other human tumor models suggest that there is increased
stabilization of DNA adducts in cells exposed to topoisomerase I inhibitors after
exposure to platinum. There are increased DNA topoisomerase I cleavable
complexes that result in increased inhibition of DNA elongation and S-phase
arrest.[8,9]

Other combinations include increased platinum-DNA adducts with
hyperthermia exposure to cultured SW 1573 cells,[15] potentiation of
platinum-DNA adducts and cellular cytotoxicity when combined with antisense
oligonucleotides against XPA (or CSB),[16] and potentiation of oxaliplatin
cytotoxicity by ZD1839 (Iressa), an epidermal growth factor receptor-selective
tyrosine kinase inhibitor.[17]

Clinical Data

The efficacy of oxaliplatin monotherapy in patients with
advanced colorectal cancer has been evaluated in several studies, and objective
response rates achieved with oxaliplatin as first-line therapy averaged 18%
while those of oxaliplatin as second-line therapy averaged 10%.[18-21]
Furthermore, this single-agent response rate is comparable to that achieved with
irinotecan alone in patients with colorectal cancer.[22] Nevertheless,
single-agent use of oxaliplatin is not currently recommended as standard therapy
except in some European countries for patients with dihydropyrimidine
dehydrogenase deficiency, which is associated with an increased risk for severe
or lethal 5-FU toxicity, or in patients with 5-FU-related cardiotoxicity.

Combinations With 5-FU and Leucovorin

Given the relatively high response rates reported with
oxaliplatin in colorectal cancer, an obvious choice was to study combinations
with 5-FU and leucovorin in a front-line setting. These trials have been
reviewed elsewhere in this supplement; however, in summary, the response rates
varied from 25% to 67% depending on the delivery schedules of 5-FU/leucovorin.
The major toxicities of oxaliplatin/5-FU/leucovorin combination therapy were
diarrhea, stomatitis, peripheral sensory neuropathy, and nausea and vomiting.
Multiple reviews of these trials have been published, and confirmatory data from
randomized trials of oxaliplatin (with or without 5-FU/leucovorin) in the United
States are awaited.[23]

Oxaliplatin/Fluorouracil/Irinotecan

The next obvious point of investigation is the combination of
oxaliplatin with 5-FU, with or without irinotecan. Several tumor models (eg,
HT-29 colon carcinoma, GRI mouse mammary tumor) have shown that the combination
of irinotecan and oxaliplatin has synergistic activity. At the molecular level,
there is increased stabilization of adducts in cells exposed to the
topoisomerase I inhibitor after exposure to platinum. There are increased
DNA topoisomerase I cleavable complexes that result in prolonged inhibition of
DNA elongation and S-phase arrest.[8,9]

Scheduling for Optimal Efficacy: The observed preclinical
synergy and the potential for nonoverlapping toxicities in the combination has
stimulated several clinical studies. Various irinotecan combinations delivered
on a number of schedules, eg, every 3 weeks, weekly, or every 2 weeks, have been
studied (Table 1).[24-27] Wasserman et al
investigated the every-3-week schedule of irinotecan and oxaliplatin delivery.
The maximum tolerated dose (recommended phase II dose) of irinotecan was 200
mg/m2 with oxaliplatin administered at a dose
of 85 mg/m2.[24] Toxicities included neuropathy
and gastrointestinal events. No pharmacokinetic interactions between the two
drugs were noted, and 7 of 24 patients had partial responses.

In a subsequent study, Goldwassser and colleagues described an
every-2-week schedule of irinotecan administered with oxaliplatin. The maximum
tolerated dose of the combination was irinotecan at 175 mg/m2
and oxaliplatin at 85 mg/m2.[25] There was a
slightly higher incidence of myelosuppressive events in this study compared with
those described in the Wasserman study; however, the regimen was well tolerated
overall, and significant responses were reported.

Rothenberg and collaborators have reported on the combination of
irinotecan and oxaliplatin using an every-2-week schedule. The maximum tolerated
dose has not yet been reached at 200 mg/m2 of
irinotecan and 85 mg/m2 oxaliplatin (Mace
Rothenberg, personal communication).

Other studies of irinotecan in the United States include one of
a weekly schedule that is currently underway at Memorial Sloan-Kettering Cancer
Center.[24] Additional phase I and II studies have reported on the tolerability
of this combination and also on the synergistic responses.[28,29] The toxicity
of the triple combination of irinotecan, oxaliplatin, and 5-FU, with or without
leucovorin, is predominantly dictated by the dose schedule of 5-FU/leucovorin.

The bulk of published studies indicate that it is feasible and
safe to combine these three drugs [30-33]; however, there are examples of
combinations that are very toxic and that do not significantly increase the
activity of irinotecan and oxaliplatin. Gil-Delgado et al published a study of
the triplet combination, which incorporated a modified de Gramont schedule
(leucovorin at 200 mg/m2 followed by a 400 mg/m2
bolus of 5-FU plus continuous intravenous 5-FU at 600 mg/m2)
in combination with irinotecan and oxaliplatin. The triplet was very toxic—more
than 50% of patients presented with grade 3/4 diarrhea, and 1 of the 10 patients
enrolled developed septic shock.[34]

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