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Oxaliplatin in Tumors Other Than Colorectal Cancer

Oxaliplatin in Tumors Other Than Colorectal Cancer

ABSTRACT: 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 combination with cisplatin (Platinol) or paclitaxel (Taxol) in pretreated advanced ovarian cancer patients, with promising data reported for the combination of oxaliplatin and cisplatin as first-line therapy. Other small studies have shown the activity of single-agent oxaliplatin in anthracycline-resistant metastatic breast cancer and refractory non-Hodgkin’s lymphoma. Data have also demonstrated the activity of oxaliplatin in combination with gemcitabine (Gemzar) in advanced pancreatic cancer. In recurrent germ-cell cancer, a "biplatin" regimen of oxaliplatin plus cisplatin was found to be effective salvage therapy. Data from these studies indicate that oxaliplatin is active in both platinum-resistant disease and in tumor types that have previously been unresponsive to platinum treatment. Moreover, it enhances the effect of cisplatin or carboplatin, which is a striking demonstration of differing mechanisms of action. Ongoing and planned trials will evaluate the efficacy of oxaliplatin in other disease settings and combinations.  [ONCOLOGY 14(Suppl 11):33-37, 2000] 

Introduction

In preclinical studies, oxaliplatin (Eloxatin) has demonstrated
in vivo activity that is comparable or superior to cisplatin (Platinol) at
equitoxic doses in a variety of murine tumors. It is active in several tumor
models, including colon adenocarcinomas #26 and #38, L1210 leukemia, P388
leukemia, Lewis lung carcinoma, B16 melanoma, M5076 reticulum cell sarcoma, and
mammary 16/C models (see Table 1 and Table
2
). Xenograft studies have shown the
superior activity of oxaliplatin compared with other platinum compounds in
mammary and non-small-cell lung cancer, as well as in colorectal tumors.[1]

Additivity or synergistic activity in various tumors has also
been reported for oxaliplatin in combination with a number of agents. These
include fluorouracil (5-FU) in GR mammary and human HT-29 colorectal cancer cell
lines, cyclophosphamide (Cytoxan, Neosar) and carboplatin (Paraplatin) in L1210
leukemia, 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 for
a number of cancers other than colorectal cancer. The greatest amount of
accumulated data in this regard has been in ovarian cancer, although smaller
studies have been conducted in a variety of disease settings, including breast,
pancreatic, and non-small-cell lung cancer, and in patients with lymphoma and
germ-cell tumors. These data indicate that oxaliplatin may play an important
role in the treatment of many of these settings.

Ovarian Cancer

Oxaliplatin has been evaluated as monotherapy in pretreated
patients with advanced ovarian cancer in a number of studies.[2-4] In the
initial 1996 phase II study by Chollet and colleagues,[2] treatment of
oxaliplatin in 34 patients (31 evaluable) with epithelial ovarian cancer was
associated with an overall response rate of 29% and a median survival of 12
months. All study patients received platinum therapy previously, and 16% had
prior treatment with a taxane; patients had a median of three prior courses of
chemotherapy. This compassionate-use trial accrued patients who were otherwise
ineligible for phase II studies.

A response was observed in 6 of 13 patients (46%) with
platinum-sensitive disease (ie, relapse at > 6 months after prior platinum
treatment) and in 3 of 18 (17%) with platinum-resistant disease. The
investigators concluded that the data justified further confirmatory phase II
and combination chemotherapy studies.

In a recent report by Bougnoux and coworkers,[3] the overall
response rate in a group of 48 patients (42 evaluable) with advanced ovarian
cancer who had been treated with single-agent oxaliplatin was 26.1%, with a
median overall survival of 15 months. All study patients had received prior
platinum treatment, and 44% had prior treatment with a taxane; patients had a
median 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 with
platinum-resistant disease. These data confirmed previous reports on the
single-agent activity of oxaliplatin in pretreated patients with advanced
ovarian 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) in
patients with pretreated advanced ovarian cancer.[4] Eligibility criteria
included metastatic epithelial ovarian carcinoma, measurable disease, one or two
prior courses of a platinum-containing chemotherapy, and a platinum-free
interval of ≤ 12 months.

The characteristics of the 41 patients who were randomized to
paclitaxel and the 45 who were randomized to oxaliplatin were comparable with
regard to median age (62 vs 59 years), World Health Organization (WHO)
performance status (PS) 0/1 (85% vs 84%), serous histologic subtype (73% vs
73%), one to two prior chemotherapy courses (73%/27% vs 64%/36%), and
platinum-free intervals of < 6 months/6 to 12 months (76%/24% vs 71%/29%)
(see Table 3). Patients were treated until disease progression or
discontinuation due to excessive toxicity.

The reported overall response rates were 17% in the paclitaxel
arm and 16% in the oxaliplatin arm, with a median time to progression of 14 and
12 weeks, respectively, and median overall survival durations of 8.5 and 9.6
months, respectively (see Table 4).[4] In general, grade 3/4 toxicities were
more common in the paclitaxel arm than in oxaliplatin recipients, with
neutropenia occurring in 22% vs 0%, arthralgia/myalgia in 12% vs 0%, alopecia in
54% vs 0%, sensory neurotoxicity in 7% vs 9%, motor neurotoxicity in 7% vs 0%,
and nausea/vomiting in 5% vs 11%.[4]

Oxaliplatin in
Combination Regimens

A number of investigators have assessed the utility of
oxaliplatin in combination chemotherapy for ovarian cancer. There is
considerable rationale for combination platinum ("biplatin") regimens,
including synergistic activity, absence of cross-resistance, and the ability to
increase platinum dose intensity. Soulie and collaborators[5] treated 25 heavily
pretreated patients (13 with cisplatin-refractory disease) with oxaliplatin at
130 mg/m2 (2-hour infusion) plus cisplatin at 100 mg/m2; any dose reductions
maintained the 1.3 to 1 dose ratio.

Dose-limiting toxicities consisted of grade 3 cumulative
peripheral sensory neuropathy, which resolved within a few months after
discontinuation of treatment, and grade 3/4 neutropenia and/or thrombocytopenia,
which occurred in 35% to 40% of patients. The overall response rate in 22
measurable/evaluable patients was 40% (95% confidence interval [CI]: 21%-61%),
with complete responses reported in 8% and partial responses in 32%. The median
duration of response was 4 months. Objective responses were observed in 58% of
patients (7/12; 95% CI: 28%-85%) with potentially platinum-sensitive disease
and in 23% (3/13; 95% CI: 5%-54%) with platinum-resistant disease. Soulie et
al concluded that these encouraging results provided the basis for new
first-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 in
37 pretreated patients with recurrent ovarian cancer. Twenty patients were
refractory to platinum compounds, 16 were sensitive, and one was unclassified.
All patients had received one prior treatment regimen, and 12 had received both
cisplatin and carboplatin therapy. Oxaliplatin (100-135 mg/m2) and paclitaxel
(135-175 mg/m2) were administered sequentially on the same day, with the cycle
repeated 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% of
patients (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% and
platinum-resistant patients, a response rate of 33%. The median progression-free
survival was 9.4 months and the median overall survival was 25 months. This
combination is very promising after platinum failure.

Phase II/III Trial

Misset and colleagues[7] have reported the final results of a
phase II/III trial comparing oxaliplatin vs cisplatin in 177 previously
untreated patients with stage IIc, III, and IV advanced ovarian cancer. Both
arms included cyclophosphamide at 1,000 mg/m2 with either oxaliplatin at 130
mg/m2 (n = 85) or cisplatin at 100 mg/m2 (n = 92). A total of 453 cycles in 85
patients were evaluable for toxicity in the oxaliplatin arm vs 455 cycles in 92
patients in the cisplatin arm. Significant differences in toxicities included
grade 3/4 anemia, 5 patients in the oxaliplatin arm vs 31 patients in the
cisplatin 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 one
grade 3 neuropathy in the cisplatin arm. Creatinine clearance at the end of
treatment favored the oxaliplatin arm, confirming its lack of nephrotoxicity.

Response was reviewed according to both surgical assessment and
objective 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 cisplatin
arm. A clinical response was noted in 23 of 69 patients (33%) and in 29 of 69
patients (42%) in the two groups, respectively. This recent update shows
survival favoring the oxaliplatin arm, with median survival of 36 months vs 25
months in the cisplatin arm. Progression-free survival was 13 months in both
arms. The authors concluded that the safety and efficacy of the oxaliplatin
combination confirm the interest of oxaliplatin combined with new agents active
in advanced ovarian cancer.

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