Oxaliplatin in Tumors Other Than Colorectal Cancer
Oxaliplatin (Eloxatin) has demonstrated significant activity in a variety of tumor types in addition to colorectal cancer. Several studies have reported on the effectiveness of oxaliplatin as single-agent treatment or in
ABSTRACT: Oxaliplatin (Eloxatin) has demonstrated significant activity in a variety oftumor types in addition to colorectal cancer. Several studies have reported onthe effectiveness of oxaliplatin as single-agent treatment or in combinationwith cisplatin (Platinol) or paclitaxel (Taxol) in pretreated advanced ovariancancer patients, with promising data reported for the combination of oxaliplatinand cisplatin as first-line therapy. Other small studies have shown the activityof single-agent oxaliplatin in anthracycline-resistant metastatic breast cancerand refractory non-Hodgkin’s lymphoma. Data have also demonstrated theactivity of oxaliplatin in combination with gemcitabine (Gemzar) in advancedpancreatic cancer. In recurrent germ-cell cancer, a "biplatin" regimenof oxaliplatin plus cisplatin was found to be effective salvage therapy. Datafrom these studies indicate that oxaliplatin is active in bothplatinum-resistant disease and in tumor types that have previously beenunresponsive to platinum treatment. Moreover, it enhances the effect ofcisplatin or carboplatin, which is a striking demonstration of differingmechanisms of action. Ongoing and planned trials will evaluate the efficacy ofoxaliplatin in other disease settings and combinations. [ONCOLOGY14(Suppl 11):33-37, 2000]
Introduction
In preclinical studies, oxaliplatin (Eloxatin) has demonstratedin vivo activity that is comparable or superior to cisplatin (Platinol) atequitoxic doses in a variety of murine tumors. It is active in several tumormodels, including colon adenocarcinomas #26 and #38, L1210 leukemia, P388leukemia, Lewis lung carcinoma, B16 melanoma, M5076 reticulum cell sarcoma, andmammary 16/C models (see Table 1 and Table2). Xenograft studies have shown thesuperior activity of oxaliplatin compared with other platinum compounds inmammary and non-small-cell lung cancer, as well as in colorectal tumors.[1]
Additivity or synergistic activity in various tumors has alsobeen reported for oxaliplatin in combination with a number of agents. Theseinclude fluorouracil (5-FU) in GR mammary and human HT-29 colorectal cancer celllines, cyclophosphamide (Cytoxan, Neosar) and carboplatin (Paraplatin) in L1210leukemia, paclitaxel (Taxol) in MV-522 human lung carcinomas, and irinotecan(CPT-11, Camptosar) in GR mammary tumors.[1]
Data have been reported from clinical trials of oxaliplatin fora number of cancers other than colorectal cancer. The greatest amount ofaccumulated data in this regard has been in ovarian cancer, although smallerstudies have been conducted in a variety of disease settings, including breast,pancreatic, and non-small-cell lung cancer, and in patients with lymphoma andgerm-cell tumors. These data indicate that oxaliplatin may play an importantrole in the treatment of many of these settings.
Ovarian Cancer
Oxaliplatin has been evaluated as monotherapy in pretreatedpatients with advanced ovarian cancer in a number of studies.[2-4] In theinitial 1996 phase II study by Chollet and colleagues,[2] treatment ofoxaliplatin in 34 patients (31 evaluable) with epithelial ovarian cancer wasassociated with an overall response rate of 29% and a median survival of 12months. All study patients received platinum therapy previously, and 16% hadprior treatment with a taxane; patients had a median of three prior courses ofchemotherapy. This compassionate-use trial accrued patients who were otherwiseineligible for phase II studies.
A response was observed in 6 of 13 patients (46%) withplatinum-sensitive disease (ie, relapse at > 6 months after prior platinumtreatment) and in 3 of 18 (17%) with platinum-resistant disease. Theinvestigators concluded that the data justified further confirmatory phase IIand combination chemotherapy studies.
In a recent report by Bougnoux and coworkers,[3] the overallresponse rate in a group of 48 patients (42 evaluable) with advanced ovariancancer who had been treated with single-agent oxaliplatin was 26.1%, with amedian overall survival of 15 months. All study patients had received priorplatinum treatment, and 44% had prior treatment with a taxane; patients had amedian of one prior course of chemotherapy. Response rates were 41.7% (10 of 24)in those with platinum-sensitive disease and 5.5% (1 of 18) in those withplatinum-resistant disease. These data confirmed previous reports on thesingle-agent activity of oxaliplatin in pretreated patients with advancedovarian cancer, and demonstrated a good tolerance profile.
Phase II Study
The European Organization for Research and Treatment of Cancer(EORTC) gynecologic cancer cooperative group recently performed an open-label,randomized, phase II study comparing oxaliplatin at 130 mg/m2 every 3 weeks(2-hour infusion) and paclitaxel at 175 mg/m2 every 3 weeks (3-hour infusion) inpatients with pretreated advanced ovarian cancer.[4] Eligibility criteriaincluded metastatic epithelial ovarian carcinoma, measurable disease, one or twoprior courses of a platinum-containing chemotherapy, and a platinum-freeinterval of ≤ 12 months.
The characteristics of the 41 patients who were randomized topaclitaxel and the 45 who were randomized to oxaliplatin were comparable withregard to median age (62 vs 59 years), World Health Organization (WHO)performance status (PS) 0/1 (85% vs 84%), serous histologic subtype (73% vs73%), one to two prior chemotherapy courses (73%/27% vs 64%/36%), andplatinum-free intervals of < 6 months/6 to 12 months (76%/24% vs 71%/29%)(see Table 3). Patients were treated until disease progression ordiscontinuation due to excessive toxicity.
The reported overall response rates were 17% in the paclitaxelarm and 16% in the oxaliplatin arm, with a median time to progression of 14 and12 weeks, respectively, and median overall survival durations of 8.5 and 9.6months, respectively (see Table 4).[4] In general, grade 3/4 toxicities weremore common in the paclitaxel arm than in oxaliplatin recipients, withneutropenia occurring in 22% vs 0%, arthralgia/myalgia in 12% vs 0%, alopecia in54% vs 0%, sensory neurotoxicity in 7% vs 9%, motor neurotoxicity in 7% vs 0%,and nausea/vomiting in 5% vs 11%.[4]
Oxaliplatin inCombination Regimens
A number of investigators have assessed the utility ofoxaliplatin in combination chemotherapy for ovarian cancer. There isconsiderable rationale for combination platinum ("biplatin") regimens,including synergistic activity, absence of cross-resistance, and the ability toincrease platinum dose intensity. Soulie and collaborators[5] treated 25 heavilypretreated patients (13 with cisplatin-refractory disease) with oxaliplatin at130 mg/m2 (2-hour infusion) plus cisplatin at 100 mg/m2; any dose reductionsmaintained the 1.3 to 1 dose ratio.
Dose-limiting toxicities consisted of grade 3 cumulativeperipheral sensory neuropathy, which resolved within a few months afterdiscontinuation of treatment, and grade 3/4 neutropenia and/or thrombocytopenia,which occurred in 35% to 40% of patients. The overall response rate in 22measurable/evaluable patients was 40% (95% confidence interval [CI]: 21%-61%),with complete responses reported in 8% and partial responses in 32%. The medianduration of response was 4 months. Objective responses were observed in 58% ofpatients (7/12; 95% CI: 28%-85%) with potentially platinum-sensitive diseaseand in 23% (3/13; 95% CI: 5%-54%) with platinum-resistant disease. Soulie etal concluded that these encouraging results provided the basis for newfirst-line and second-line combination regimens in ovarian carcinoma.[5]
Compassionate-Use Study
In a compassionate-use study of oxaliplatin and paclitaxel,Kalla and coworkers[6] assessed a combination of oxaliplatin and paclitaxel in37 pretreated patients with recurrent ovarian cancer. Twenty patients wererefractory to platinum compounds, 16 were sensitive, and one was unclassified.All patients had received one prior treatment regimen, and 12 had received bothcisplatin and carboplatin therapy. Oxaliplatin (100-135 mg/m2) and paclitaxel(135-175 mg/m2) were administered sequentially on the same day, with the cyclerepeated every 3 to 4 weeks.
The main grade 3/4 toxicity was neutropenia (16%/13%).Peripheral neurotoxicity, the most common side effect, occurred in 94% ofpatients (grade 2/3 in 12 and 6 patients). The overall response rate was 41%,with patients in the evaluable cohort achieving a response rate of 48% andplatinum-resistant patients, a response rate of 33%. The median progression-freesurvival was 9.4 months and the median overall survival was 25 months. Thiscombination is very promising after platinum failure.
Phase II/III Trial
Misset and colleagues[7] have reported the final results of aphase II/III trial comparing oxaliplatin vs cisplatin in 177 previouslyuntreated patients with stage IIc, III, and IV advanced ovarian cancer. Botharms included cyclophosphamide at 1,000 mg/m2 with either oxaliplatin at 130mg/m2 (n = 85) or cisplatin at 100 mg/m2 (n = 92). A total of 453 cycles in 85patients were evaluable for toxicity in the oxaliplatin arm vs 455 cycles in 92patients in the cisplatin arm. Significant differences in toxicities includedgrade 3/4 anemia, 5 patients in the oxaliplatin arm vs 31 patients in thecisplatin arm (P < .0001); grade 3/4 vomiting, 22 vs 51 patients,respectively (P < .0001); and grade 3/4 leukopenia, 32 vs 51 patients,respectively (P < .042). Peripheral neuropathy was mild (grade 1-2), with onegrade 3 neuropathy in the cisplatin arm. Creatinine clearance at the end oftreatment favored the oxaliplatin arm, confirming its lack of nephrotoxicity.
Response was reviewed according to both surgical assessment andobjective response criteria. A surgical response was noted in 32 of 50 patients(64%) in the oxaliplatin arm, and in 33 of 49 patients (67%) in the cisplatinarm. A clinical response was noted in 23 of 69 patients (33%) and in 29 of 69patients (42%) in the two groups, respectively. This recent update showssurvival favoring the oxaliplatin arm, with median survival of 36 months vs 25months in the cisplatin arm. Progression-free survival was 13 months in botharms. The authors concluded that the safety and efficacy of the oxaliplatincombination confirm the interest of oxaliplatin combined with new agents activein advanced ovarian cancer.
Oxaliplatin With Paclitaxel
Kalla and colleagues[8] assessed combinations of oxaliplatin at100 or 130 mg/m2 and paclitaxel at 135 or 175mg/m2 in 23 evaluable patientswith heavily pretreated advanced ovarian carcinoma. All had undergone priortreatment with cisplatin or carboplatin, with 2, 10, and 11 patients havingreceived one, two, or three (or more) prior regimens, respectively, and 8 havingreceived high-dose chemotherapy.
Among the four dose groups, the frequencies of grade 3/4granulocytopenia, thrombocytopenia, emesis, and neurotoxicity were as follows:oxaliplatin at 100 mg/m2 plus paclitaxel at 135mg/m20%, 22%, 5%, and 5%,respectively (n = 4); oxaliplatin at 130 mg/m2 plus paclitaxel at 135mg/m259%,4%, 0%, and 27%, respectively(n = 5); oxaliplatin at 100 mg/m2 plus paclitaxel at 175mg/m214%, 0%, 3%,and 29%, respectively (n = 7); and oxaliplatin at 130 mg/m2 plus paclitaxel at175 mg/m224%, 0%, 0%, and 11%, respectively (n = 7).
Among 18 evaluable patients, the response rate was 50%,including a complete response in three patients (17%), partial response in sixpatients (33%), and stable disease in six patients (33%). Median time toprogression was 9 months (range, 5 to 30 months), with the median overallsurvival exceeding 13 months. The investigators concluded that the combinationswere feasible at the full recommended doses for both agents. In this heavilypretreated population (all exposed to prior platin therapies), there was asignificant response rate.
Oxaliplatin Triplet
Delaloge and coworkers[9] performed a feasibility trial in 15patients with platinum-sensitive disease using the combination of oxaliplatin at100 mg/m2 day 2 (2- to 6-hour infusion), paclitaxel at 135mg/m2 day 1 (24-hourinfusion), and cisplatin at 75 mg/m2 day 2 (4-hour infusion), with cyclesrepeated every 3 weeks for six planned cycles. Eight patients werechemotherapy-naive, and seven had received one prior platinum regimen.
Grade 3/4 toxicities (evaluated in 67/70 cycles for first- andsecond-line patients) included febrile neutropenia in 51% and thrombocytopeniain 9% of cycles. Sensory neuropathy ³ grade 3 occurred in 13 of 15 patients(87%) and resulted in a discontinuation of treatment in one study subject;neuropathy was reversible in all cases. No renal or ototoxicity was observed.Also, there were no deaths attributable to toxicity.
Overall, complete responses were observed in 87.5% of thechemotherapy-naive patients (7/8); responses seen in 85.7% of pretreatedpatients (6/7 second-line), including three complete responses. Median time toprogression exceeded 11 months in 6 of 8 patients (range of 11+ to14+ months).The authors indicated that the triple combination was both feasible and active,with neutropenia and cumulative but reversible neurosensory toxicity being doselimiting. Based on these data, a phase II study has been planned of this tripletin the first-line setting.
Anthracycline-ResistantMetastatic Breast Cancer
In a study by Garufi and coworkers,[10] 14 patients withanthracycline-resistant metastatic breast cancer received oxaliplatin as eithersecond-line (n = 4, prior epirubicin[Ellence]) or third-line therapy (n = 10,prior CMF [cyclophosphamide/methotrexate/fluorouracil]). Grade 3/4thrombocytopenia was observed in one patient, and grade 3/4 acute dysesthesiareactions occurred in three patients (related to the duration of infusion);grade 1/2 neurologic cumulative toxicity developed in four patients at eachgrade. Partial responses were observed in three patients (21.4%) and stabledisease in one; progressive disease was observed in nine patients. These datasuggest that further studies in metastatic breast cancer are warranted.
Germ-Cell Cancer
Soulie et al[11] published data from a study of 13 patients withrecurrent, mostly cisplatin-refractory germ-cell tumors, who received a combinedsalvage regimen. Oxaliplatin at 130 mg/m2 and cisplatin at 100mg/m2, with orwithout a third anticancer agent, was given every 3 or 4 weeks; 12 patients hadreceived prior platinum therapy and eight had platinum-refractory disease. Intotal, seven, one, and four of the patients had received three or more, two, andone prior course of chemotherapy, respectively, with seven having receivedhigh-dose chemotherapy. Progressive disease was the best response to the lastplatinum regimen in eight patients. A platinum-free interval of < 6 months(range: 1-36 months) prior to study treatment was reported for six patients.
Treatment was individualized according to pretreatment andclinical characteristics, and it was associated with an overall response rate of54%(7/13), including two long-term complete responses (³ 5 yr) and four partialresponses (lasting 4 to 8 months) among the eight patients withplatinum-refractory disease. The median survival for the study group was 8months. Combined toxicity included grade 4 neutropenia in 78% and grade 4thrombocytopenia in 74% of the cycles. The authors suggested further evaluationof combination therapy with oxaliplatin for advanced germ-cell cancer.
Non-Small-Cell Lung Cancer
In 18 patients with stage IIIa, IIIb, and IV non-small-celllung cancer, de Cremoux and co-investigators[12] conducted an evaluation ofregimens consisting of a combination of oxaliplatin 130 mg/m2 day 1 (2-hourinfusion) and vinorelbine (Navelbine) at five dose levels ranging from 22 mg/m2to 34 mg/m2 on days 1 and 8 in 3-week cycles. Available data from the first fourvinorelbine dose groups indicated that grade 3/4 neutropeniathe main toxicityoccurredin two of three patients receiving vinorelbine at 22 mg/m2, zero of fourreceiving 24 mg/m2, three of five receiving 26mg/m2, and three of threereceiving 28 mg/m2. Grade 1/2 peripheral neuropathy was observed in twopatients.
The response rate among 15 evaluable patients was 40% (6/15),with one complete response, five partial responses, and stable disease in threepatients. Progressive disease was observed in six patients. Based on these dataand determinations of the maximum tolerated dose and recommended doses, theinvestigation will progress to phase II studies.
Non-Hodgkin’s Lymphoma
Germann and collaborators[13] are currently assessing a regimenof single-agent oxaliplatin at 100 to 130 mg/m2 every 3 weeks (2-hour infusionalong with antiemetic medication) in patients with refractory or recurrentnon-Hodgkin’s lymphoma. Preliminary findings in 22 evaluable patients, who hada median of two prior chemotherapy regimens (range, one to seven regimens),included an overall response rate of 40% (95% CI: 21%-64%), with one completeresponse and eight partial responses. The median duration of response was 27months (range, 5 to 44 months). To date, the worst toxicity reported has beengrade 1/2 nausea/vomiting and grade 1/2 peripheral neuropathy (mostlyreversible). The authors suggested that oxaliplatin is active in salvageregimens for non-Hodgkin’s lymphoma, and the data warrant further phase IIstudies.
Conclusions
As a single agent and in several combinations that have beenexamined in clinical trials, oxaliplatin exerts significant activity in avariety of tumor types, in addition to colorectal cancer. This activity hasincluded demonstrable effects in platinum-resistant disease and in tumor typesthat have heretofore been unresponsive to platinum compounds. Phase II trials ofoxaliplatin in additional disease states are planned or ongoing, as are studiesof additional oxaliplatin-including combinations. In addition, oxaliplatinappears capable of potentiating cisplatin ("biplatin" combination) inrefractory germ-cell tumors.
References
1. Investigator Brochure, Sanofi Synthelabo.
2. Chollet P, Bensmaine MA, Brienza S, et al: Single-agentactivity of oxaliplatin in heavily pretreated advanced epithelial ovariancancer. Ann Oncol 7:1065-1070, 1996.
3. Bougnoux P, Dieras V, Petit T, et al: A multicenter phase IIstudy of oxaliplatin (OXA) as a single agent in platinum (PT) and/or taxanes(TX) pretreated advanced ovarian cancer (AOC): Final results (abstract 1422).Proc Am Soc Clin Oncol 18:368a, 1999.
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7. Misset JL,Vennin PH, Chollet PH, et al: Multicentric phaseII-III study of oxaliplatin plus cyclophosphamide vs cisplatin pluscyclophosphamide in advanced chemonaive ovarian cancer patients: Final results(abstract 1502). Proc Am Soc Clin Oncol 16:380a, 2000.
8. Kalla S, Faivre S, Bensmaine MA, et al: Paclitaxel(PXL)-oxaliplatin (L-OHP): A feasible active combination in heavily pretreatedadvanced ovarian carcinoma (ADOVCA) patients (pts) (abstract 1378). Proc Am SocClin Oncol 17:357a, 1998.
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