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.
ABSTRACT: Oxaliplatin (Eloxatin) is a novel antineoplastic platinumderivative that may exert its cytotoxic effects by blocking DNAreplication/transcription, thus resulting in cell death in proliferating cells,as well as apoptosis. Oxaliplatin is often more potent than other platinums suchas cisplatin (Platinol) in vitro, and shows greater efficacy in preclinicalstudies against many tumor cell lines, including some that are resistant tocisplatin and carboplatin (Paraplatin). Oxaliplatin is approved for use with thefluoropyrimidines in the treatment of metastatic colorectal cancer in Asia,Latin America, and Europe. In light of the broad efficacy of oxaliplatin inseveral solid tumors and the encouraging preclinical data on combination therapywith novel agents (eg, thymidylate synthase inhibitors, epidermal growth factor-receptorantagonists, microtubule interactive agents), this article will review thepublished literature on novel combinations that have been tested in thelaboratory and/or the clinic. [ONCOLOGY14(Suppl 11):52-58, 2000]
Oxaliplatin(cis-[(1R,2R)]-1,2-cyclohexanediamine-N,N´ oxalato (2-)-O,O´] platinum,Eloxatin) is a novel antineoplastic platinum derivative with a1,2-diaminocyclohexane (DACH) carrier ligand. Although its precise mechanismof action is unknown, platinum compounds in general are thought to exert theircytotoxic effects through the formation of DNA adducts that block both DNAreplication and transcription, resulting in cell death in actively dividingcells as well as the induction of apoptosis.[2,3] Oxaliplatin is often morepotent than cisplatin (Platinol) in vitro, requiring fewer DNA adducts toachieve an equal level of cytotoxicity, and shows the same or greater efficacyagainst many tumor cell lines in preclinical studies, including some that areresistant to cisplatin and carboplatin (Paraplatin).[4-6]
Based on provocative responses seen in patients with metastaticcolorectal cancer, oxaliplatin has been approved for use with thefluoropyrimidines in the treatment of metastatic colorectal cancer in Asia,Latin America, and Europe. Studies with oxaliplatin have also demonstrated itsbroad efficacy in several solid tumors and yielded encouraging preclinical dataon 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 theclinic 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 byother investigators in this supplement. Because oxaliplatin is a new drug,several approaches that have the potential for clinical application are beingtested; however, data supporting these applications are still predominantlypreclinical.
In vitro and in vivo studies of oxaliplatin have shown itsadditive or synergistic cytotoxic properties with the fluoropyrimidines(fluorouracil [5-FU]), thymidylate synthase inhibitors (AG337, raltitrexed[Tomudex]), nucleoside analogs (gemcitabine [Gemzar]), topoisomerase Iinhibitors (topotecan, irinotecan [Camptosar], and SN-38), microtubule bindingagents (paclitaxel [Taxol]), and DNA modifying/alkylating agents (cisplatin andcyclophosphamide [Cytoxan, Neosar]).[7-13]
Although oxaliplatin demonstrates additive/synergistic activityin combination with many standard anticancer agents in preclinical models, somecombinations do not show increased in vivo activity and are sometimes associatedwith increased toxicity. More extensive synergy studies withirinotecan/SN-38 and oxaliplatin in HT-29 colon carcinoma cell lines and GRImouse mammary and other human tumor models suggest that there is increasedstabilization of DNA adducts in cells exposed to topoisomerase I inhibitors afterexposure to platinum. There are increased DNA topoisomerase I cleavablecomplexes that result in increased inhibition of DNA elongation and S-phasearrest.[8,9]
Other combinations include increased platinum-DNA adducts withhyperthermia exposure to cultured SW 1573 cells, potentiation ofplatinum-DNA adducts and cellular cytotoxicity when combined with antisenseoligonucleotides against XPA (or CSB), and potentiation of oxaliplatincytotoxicity by ZD1839 (Iressa), an epidermal growth factor receptor-selectivetyrosine kinase inhibitor.
The efficacy of oxaliplatin monotherapy in patients withadvanced colorectal cancer has been evaluated in several studies, and objectiveresponse 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 withirinotecan alone in patients with colorectal cancer. Nevertheless,single-agent use of oxaliplatin is not currently recommended as standard therapyexcept in some European countries for patients with dihydropyrimidinedehydrogenase deficiency, which is associated with an increased risk for severeor 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 withoxaliplatin in colorectal cancer, an obvious choice was to study combinationswith 5-FU and leucovorin in a front-line setting. These trials have beenreviewed elsewhere in this supplement; however, in summary, the response ratesvaried from 25% to 67% depending on the delivery schedules of 5-FU/leucovorin.The major toxicities of oxaliplatin/5-FU/leucovorin combination therapy werediarrhea, stomatitis, peripheral sensory neuropathy, and nausea and vomiting.Multiple reviews of these trials have been published, and confirmatory data fromrandomized trials of oxaliplatin (with or without 5-FU/leucovorin) in the UnitedStates are awaited.
The next obvious point of investigation is the combination ofoxaliplatin with 5-FU, with or without irinotecan. Several tumor models (eg,HT-29 colon carcinoma, GRI mouse mammary tumor) have shown that the combinationof irinotecan and oxaliplatin has synergistic activity. At the molecular level,there is increased stabilization of adducts in cells exposed to thetopoisomerase I inhibitor after exposure to platinum. There are increasedDNA topoisomerase I cleavable complexes that result in prolonged inhibition ofDNA elongation and S-phase arrest.[8,9]
Scheduling for Optimal Efficacy: The observed preclinicalsynergy and the potential for nonoverlapping toxicities in the combination hasstimulated several clinical studies. Various irinotecan combinations deliveredon a number of schedules, eg, every 3 weeks, weekly, or every 2 weeks, have beenstudied (Table 1).[24-27] Wasserman et alinvestigated the every-3-week schedule of irinotecan and oxaliplatin delivery.The maximum tolerated dose (recommended phase II dose) of irinotecan was 200mg/m2 with oxaliplatin administered at a doseof 85 mg/m2. Toxicities included neuropathyand gastrointestinal events. No pharmacokinetic interactions between the twodrugs were noted, and 7 of 24 patients had partial responses.
In a subsequent study, Goldwassser and colleagues described anevery-2-week schedule of irinotecan administered with oxaliplatin. The maximumtolerated dose of the combination was irinotecan at 175 mg/m2and oxaliplatin at 85 mg/m2. There was aslightly higher incidence of myelosuppressive events in this study compared withthose described in the Wasserman study; however, the regimen was well toleratedoverall, and significant responses were reported.
Rothenberg and collaborators have reported on the combination ofirinotecan and oxaliplatin using an every-2-week schedule. The maximum tolerateddose has not yet been reached at 200 mg/m2 ofirinotecan and 85 mg/m2 oxaliplatin (MaceRothenberg, personal communication).
Other studies of irinotecan in the United States include one ofa weekly schedule that is currently underway at Memorial Sloan-Kettering CancerCenter. Additional phase I and II studies have reported on the tolerabilityof this combination and also on the synergistic responses.[28,29] The toxicityof the triple combination of irinotecan, oxaliplatin, and 5-FU, with or withoutleucovorin, is predominantly dictated by the dose schedule of 5-FU/leucovorin.
The bulk of published studies indicate that it is feasible andsafe to combine these three drugs [30-33]; however, there are examples ofcombinations that are very toxic and that do not significantly increase theactivity of irinotecan and oxaliplatin. Gil-Delgado et al published a study ofthe triplet combination, which incorporated a modified de Gramont schedule(leucovorin at 200 mg/m2 followed by a 400 mg/m2bolus of 5-FU plus continuous intravenous 5-FU at 600 mg/m2)in combination with irinotecan and oxaliplatin. The triplet was very toxicmorethan 50% of patients presented with grade 3/4 diarrhea, and 1 of the 10 patientsenrolled developed septic shock.
Combinations With Oral Fluoropyrimidines
An obvious point of departure is the use of oralfluoropyrimidines in combination with oxaliplatin, with or withoutirinotecan.[27,35,36] In the United States, several groups are presentlyassessing combinations of the oral fluoropyrimidines, and the results of theseassessments will provide additional data that may be necessary as we begin tocontemplate irinotecan oral combination therapy.
Other novel regimens that may substitute for 5-FU (incombination with oxaliplatin) include combinations with raltitrexed.[37-46]Although raltitrexed has not been widely used in trials or in practice in theUnited States, it is popular in Europe where the drug is approved. Inpreclinical testing, raltitrexed and oxaliplatin are at best additive (and alsoshown to be antagonistic in two cell lines); however, given that theirtoxicities are nonoverlapping, it is reasonable to investigate the utility ofthis combination in the clinic.
In a phase I study by Fizazi et al, 30 patients (18 males/12females) with advanced cancer and a median age of 53 years (range: 32-71years) received raltitrexed as a 15-minute infusion followed by oxaliplatin over2 hours repeated every 3 weeks. The maximum tolerated dose of raltitrexed wasestablished at 3.5 mg/m2 and oxaliplatin at 130 mg/m2 with amaurosis fugax,stomatitis, and asthenia among the dose-limiting toxicities.
Two patients with cisplatin-resistant mesothelioma had a partialresponse, and although pharmacokinetic interaction studies were performed, thepharmacokinetic data were not reported in the abstract.
In a subsequent phase II study, this combination wasadministered to 50 patients (37 males/13 females) with predominantlychemotherapy-naive malignant mesothelioma. The objective response rate was 28.6%(95% confidence interval: 9.2%-47.9%), and the stable disease rate was 54.2%.Of 15 (31.3%) chemotherapy-naive patients, 5 had a partial response, and 1 of 11patients with cisplatin-refractory cancer had a partial response.
The toxicities reported in this trial included grade 3 asthenia(2 patients), neutropenia (1 patient), diarrhea (1 patient), and grade 2 anemia.Neutropenia, vomiting, nausea, and paresthesia were uncommon.
Raltitrexed in Advanced Cancer: Responses in patients withmesotheliomas have been reported in subsequent phase II studies.[42,43] Theregimen is tolerable for delivery on an outpatient basis with limited sideeffects, in particular hematologic effects and alopecia. Fluorouracil has beenadded to raltitrexed and oxaliplatin. This triplet combination (with leucovorinincluded) may be given at the doses recommended for the individual drugs.
In a phase I study in patients with advanced cancer, oxaliplatinat 85 mg/m2 was followed by raltitrexed at 2.5 to 3mg/m2 (day 1), and by a2-hour infusion of leucovorin at 250 mg/m2, then by 5-FU at doses ranging from750 to 1,050 mg/m2 (day 2) repeated every 2 weeks. The dose-limiting toxicitiesdefining the maximum tolerated dose of oxaliplatin at 85 mg/m2, raltitrexed at 3mg/m2, and 5-FU at 900 mg/m2 included neutropenia, diarrhea, and stomatitis.
Of 18 evaluable patients (11%), two achieved a partial responsewhile 13 showed a minor response (1 patient) or stable disease (12 patients). Itwas concluded that full doses of all cytotoxic agents could be safelyadministered every 2 weeks.
Gemcitabine and Oxaliplatin
Preclinical synergy has been demonstrated with the combinationof gemcitabine and oxaliplatin. Once again both drugs have toxicities thatare nonoverlapping. Several reports, mostly in abstract form, have shown thefeasibility of combining these two drugs.
Phase I Trial: Mavroudis et al reported on a phase I trialof the combination of oxaliplatin and gemcitabine in which gemcitabine wasadministered on days 1 and 8 as a 30-minute infusion at doses ranging between1,000 and 1,600 mg/m2 followed by oxaliplatin as a2-hour infusion at doses ranging from 60 to 110 mg/m2 repeated every 3weeks. The maximum tolerated dose has not been reached, and accrualcontinues with patients receiving gemcitabine at a dose of 1,600 mg/m2 andoxaliplatin at a dose of 110 mg/m2. Other investigators have shown lowermaximally tolerated doses of gemcitabine; however, overall the toxicities, asexpected, include myelosuppression and neuropathy.[48,49]
The combination of oxaliplatin with gemcitabine is appealingbecause it may be used for a variety of solid tumors (eg, lung, breast,ovarian), including the typically chemoresistant tumors like pancreaticcancer. We have used the broad applicability of this regimen to combine itfurther with 5-FU, making this triplet useful for many solid tumors. The basisfor the combination of 5-FU and gemcitabine stems from our earlier experiencewith this combination using several schedules of infusional 5-FU in combinationwith weekly gemcitabine (either on days 1 and 8 or days 1, 8, and 15).
In our prior studies, we concluded that gemcitabine is bestdelivered in combination with infusional 5-FU on days 1 and 8 onlywefrequently had to omit day 15 dosing due to toxicity. Furthermore, there areknown pharmacokinetic interactions with 5-FU and gemcitabine.
Current Phase I Trial: At Albert Einstein College ofMedicine, we have embarked on a phase I trial (T99-0023) of the combination ofgemcitabine, oxaliplatin, and 5-FU sponsored by the Cancer Therapy EvaluationProgram (CTEP), National Cancer Institute (NCI). The study aims to describe thetoxicities and maximum tolerated doses of the individual drugs given incombination. The trial is using the NCI accelerated titration design format withexpansion of the recommended phase II dose to a minimum of 12 patients in orderto better study toxicities. We have also incorporated into the study assessmentsfor pharmacokinetic interactions between these drugs as well as assessments forinteractions in drug sequence.
During the phase I escalation of the trial, we studied thefollowing schedules:
In cycle 1: Oxaliplatin over 2 hours followed by gemcitabineover 30 minutes followed by infusional 5-FU
In cycle 2: Gemcitabine over 30 minutes followed byoxaliplatin over 2 hours followed by infusional 5-FU
All subsequent cycles incorporate the cycle 1 schedule of drugdelivery. Detailed pharmacokinetic studies were conducted during cycles 1 and 2for ultrafilterable and total platinum, gemcitabine (and its metabolites), and5-FU. Thus far, 12 patients have been treated with varying dose levels (Table2).
We have established the maximum tolerated dose of thecombination of oxaliplatin, 5-FU, and gemcitabine, and on preliminary review,the regimen appears to be well suited for outpatient therapy. The toxicities arepredominantly diarrhea and neutropenia; however, these data have to be viewedwith caution as the trial is ongoing.
Combinations With the Taxanes
Combination therapy with the taxanes is important, especially aswe expand the use of oxaliplatin. Several phase I trials of docetaxel (Taxotere)combinations that assessed an every-3-week docetaxel/oxaliplatin schedule havebeen reported. In one study, the recommended phase II dose of the combinationwas 75 mg/m2 of docetaxel with 80 mg/m2 of oxaliplatin. In ovariancarcinoma, a dose-finding study of the paclitaxel/oxaliplatin combination usedan every-3-week schedule and yielded a 48% response rate, with a responseobserved in platinum-resistant patients.[53,54]
There was no apparent increase in the incidence ofmyelosuppression or neuropathy as compared with the taxanes given alone;however, this finding was preliminary and must be viewed with caution. There area number of other oxaliplatin combinations (eg, vinorelbine [Navelbine],cisplatin [Platinol], multitargeted folate antagonists), and among them are theoptimizing agents used for the treatment of colorectal cancer.[55-58]
Several questions, however, regarding the use and development ofoxaliplatin for solid tumors remain unanswered. There have been a proliferation ofphase I studies with a number of combinations and schedules being tested. Forexample, in colorectal cancer, several irinotecan combinations are beingclinically explored. The question is which schedule or combination will assumethe lead in the development of oxaliplatin in combination with irinotecan? Ifany particular schedule is chosen, where will the combination of irinotecan andoxaliplatin fall within the treatment schemes now available for colorectalcancer (eg, the current standard for frontline treatment of metastatic diseaseis irinotecan given with 5-FU and leucovorin)? Cooperative group studies arecurrently underway and poised to help answer some of these questions.
This review hopes to stimulate the reader to look for othernovel combinations with oxaliplatin based on the current knowledge of themechanism of action of oxaliplatin. Departing from existing combinations andindications for clinical use, there are data suggesting that oxaliplatin may bean effective radiation sensitizer. Other combinations are currently beingdeveloped and have their roots in basic concepts of receptor-enhancedchemosensitivity and reduced nucleotide excision repair of platinum-DNAadducts.[16,60-92]
Receptor-enhanced chemosensitivity has potential clinicalapplications based on the fact that (1) the dose-effect relationship ofanti-HER2/neu antibody plus cisplatin is synergistic; (2) this synergism isspecific for cells that overexpress the HER2/neu receptor; (3) the combinationof cisplatin plus anti-HER2/neu antibody results in a two-log increase in cellkilling; and (4) the combination yields pathologic complete remissions againstHER2/neu-overexpressing human breast carcinoma xenografts in athymic nudemice.[83-87]
Furthermore, given the similarity of oxaliplatin tocisplatin-induced DNA lesions,  we hypothesize that strategies forinhibiting DNA repair will augment the efficacy of cisplatin as well asoxaliplatin and newer generation platinum agents. In fact, we have demonstratedthe synergistic cytotoxicity of oxaliplatin and trastuzumab (Herceptin) inHER2-overexpressing SKBR-3 breast carcinoma cells (Lu Y, Mani S, Bregman DB,unpublished data). In addition, we recently reported that A2780/CP70 cellstreated with antisense oligonucleotides targeting Xeroderma pigmentosum group Acomplementing protein (XPA) showed enhanced sensitivity to cisplatin andoxaliplatin.
To date, studies of nucleotide excision repair (NER) have takenadvantage of genetic mutants in humans, yeast, and rodents. Now, with theclinical development of anti-HER2 antibodies, miscellaneous agents withdemonstrated anti-NER activity such as UCN-01, and the development of antisenseoligonucleotides targeting specific NER proteins, pharmacologic reagents will beavailable to complement the genetic tools available for the study of nucleotideexcision repair. Moreover, these combinations may prove useful to furtherenhance the selective cytotoxic potential of oxaliplatin.
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