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Gemcitabine Plus Cisplatin in Breast Cancer

Gemcitabine Plus Cisplatin in Breast Cancer

ABSTRACT: In recent years, the clinical application of paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and trastuzumab (Herceptin) has improved the management of advanced breast cancer. With the introduction of gemcitabine, a new drug with significant activity in breast cancer has become available. As a single agent, gemcitabine (Gemzar) provides response rates in the range of 25% to 46% in breast cancer, depending on starting dose and status of prior chemotherapy for metastatic disease. Higher response rates are observed when gemcitabine is combined with other classes of cytotoxic drugs. Studies conducted in our laboratory detected high degrees of synergy between gemcitabine and cisplatin (Platinol) in a variety of human tumors in primary culture. These analyses identified breast cancer as a target for this combination. The combination of cisplatin plus gemcitabine is active in relapsed breast cancer patients. The activity observed in drug-resistant patients suggests relative non-cross resistance with other drug combinations. [ONCOLOGY 15(Suppl 3):28-33, 2001]

Introduction

Breast cancer is among the most
common malignancies of western societies, with 182,800 new diagnoses and 41,200 deaths in the United States
in 2000.[1] The benefits associated with adjuvant hormonal[2] and
chemotherapeutic[3] interventions have improved the survival of patients with
early-stage disease. However, patients who present with advanced disease or who
relapse following initial therapy have low survival rates that have not changed
in several decades. Efforts to improve the outcome of high-risk patients with
dose-intensive combinations followed by stem-cell support have, thus far, proven
unsuccessful.*[4-8] In this context, the introduction of gemcitabine (Gemzar), a novel cytotoxic agent with unique modes of action and cross
resistance, provides an important addition to the armamentarium for this
disease.

In the late 1980s and early 1990s, investigators reported
activity for gemcitabine in a variety of human tumor-cell lines and xenografts.
In the early 1990s, as investigators at the Free University in Amsterdam were
examining the basic mechanism of interaction between gemcitabine and cisplatin
(Platinol) in cell line systems,[9] our laboratory began evaluating gemcitabine in a broad array of human tumor primary culture specimens utilizing an ex
vivo apoptotic model. Preliminary results indicated significant correlations
between gemcitabine and cisplatin (P < .05) and gemcitabine and mustard alkylators
(P < .01) by Pearson
correlation.[10] This finding led to the analysis of gemcitabine in combination
with other classes of cytotoxic drugs. We reported synergy between gemcitabine
and cisplatin in 73% of human tumor primary cultures[11] and, more recently,
synergy between mustard alkylators and gemcitabine in 69% of human tumor
specimens.[12] The degree of true synergy identified for cisplatin plus
gemcitabine has exceeded that identified between any other classes of drugs
evaluated by our laboratory to date.

Based on laboratory findings, we applied the
gemcitabine/cisplatin combination in a number of tumor types, with particular
attention to relapsed ovarian and breast cancers, two diseases with significant
activity and synergy in the EVA (ex vivo apoptotic) assay. Preliminary results
in ovarian cancer have been reported.[13] In this article, we focus on the role
of gemcitabine plus cisplatin in advanced breast cancer.

Scientific Rationale

Platinum Therapy in Breast Cancer

In 1978, a phase II trial of cisplatin in relapsed breast cancer
provided no objective responses in 26 evaluable patients.[14] This led to the
virtual disappearance of cisplatin from the breast cancer literature for a
decade. When cisplatin was subsequently tested in previously untreated advanced
breast cancer patients, Sledge et al observed responses in 9 of 19 patients
(47%),[15] identifying it as one of the more active agents in this disease.
Other investigators who compared the activity of cisplatin or carboplatin (Paraplatin) in previously treated vs chemotherapy-naive
breast cancer patients have reported similar results. In a study reported by
Jurga et al,[16] the 53.9% objective response rate for cisplatin in untreated
breast cancer patients fell to 30.6% for relapsed patients.

A study of carboplatin as a single agent yielded a response rate
of 35% in previously untreated breast cancer patients.[17] However, when
clinical trials compared carboplatin in previously untreated vs previously
treated patients, the objective response rates fell from 33% to 8% in one and
32% to 0% in the second study.[18,19] It is evident that platinum activity falls
dramatically in previously treated populations, suggesting collateral resistance
to this class of drugs induced by prior exposure to cytotoxics.

In the early 1990s, as the use of platinum in breast cancer
gained acceptance, platinum-based combination therapies were shown to provide
objective responses in a number of trials (Table 1). Accumulated experience
indicates that platinum derivatives have activity in breast cancer, that
platinum activity appears greater in chemotherapy-naive patients, and that some
platinum-based combinations are highly effective in this disease.

Gemcitabine Activity
in Breast Cancer

The activity of gemcitabine as a single agent for advanced
breast cancer has been the subject of prior investigation with responses
observed in approximately 20% of patients.[27-33] (Other studies, however,
have shown efficacy rates varying from 25% to 46%, depending on starting dose
and status of prior chemotherapy for metastatic disease.[34,35]) The principal
toxicities associated with gemcitabine are generally mild to moderate in
severity and include neutropenia, thrombocytopenia, malaise, and asthenia, with
rash, dyspnea, alopecia, and nausea reported less frequently. Gemcitabine’s
favorable toxicity profile has led many investigators to suggest gemcitabine as
an ideal agent for combination therapy.

The results of clinical trials of gemcitabine plus paclitaxel
(Taxol),[36] docetaxel (Taxotere),[37] vinorelbine (Navelbine),[38]
doxorubicin,[39] and epirubicin (Ellence),[40] as well as triple-agent regimens
such as gemcitabine/epirubicin/paclitaxel (Taxol) (GET), have been reported.[41]
Additional trials are underway to further evaluate gemcitabine’s role in this
disease.

The question that arises from these trials remains: How do we
optimize drug/drug interactions, based on mechanisms of action, to provide the
most effective combination regimens? To address the question we examined
gemcitabine’s activity in combination with a variety of cytotoxic agents and
determined the degree of true synergy for each doublet (Figure 1).

As can be seen, cisplatin revealed the highest degree of synergy
with gemcitabine. Our group reported a formal examination of the degree of
activity and synergy for the combination of gemcitabine plus cisplatin (Table
2
).[10] This analysis revealed activity and synergy for breast cancer, a disease
not generally targeted for this combination.

To determine the objective response rate and assess the
predictive validity of the ex vivo apoptotic predictions for this combination,
we initiated a phase II trial of gemcitabine/cisplatin in relapsed breast cancer
patients. To approximate the in vitro conditions, our design incorporated a
repeating doublet
sequence wherein both drugs are administered together each day
of therapy. To date, three clinical trials combining cisplatin with gemcitabine
in advanced breast cancer have been reported (Table 3).[42-44]

Hematologic toxicity has been the most commonly reported side
effect with no treatment-related deaths noted in any of the studies. A more
detailed review of the phase II trial reported by our group follows.

Repeating Doublet Gemcitabine/Cisplatin

Between May 1997 and October 1998, we conducted a phase II trial
of low-dose cisplatin plus gemcitabine in a repeating doublet sequence in
patients with previously treated, relapsed breast cancer. The original trial of
cisplatin (30 mg/m2) plus gemcitabine (1,000
mg/m2) administered on days 1, 8, and 15 every 28 days was modified to
cisplatin (30 mg/m2) plus gemcitabine (750 mg/m2) on days 1 and 8 every 21 days
following the observation of day 15 myelosuppression.

Patients and Methods

All patients had received one or more prior chemotherapy
regimens for systemic recurrence and all had Eastern Cooperative Oncology Group
performance status ≤ 3, with adequate bone marrow, hepatic, and renal function.
Concurrent radiation or hormonal therapy was not allowed. Patients with
clinically stable brain metastases or other sites of metastases who had
completed radiation therapy were permitted. Patients were eligible regardless of
the type of prior therapy, including high-dose therapy with stem-cell rescue, or
prior exposure to cisplatin or gemcitabine, provided these two drugs were not given together. Patients with accessible
sites of recurrence had tissue submitted for blinded ex vivo apoptotic
laboratory analysis of sensitivity to gemcitabine plus cisplatin.[45] The
results of the ex vivo apoptotic assay were not used in the selection of
patients.

The primary end points of the trial were safety and efficacy
measured as objective response rate and time to progression. A secondary end
point was to compare ex vivo apoptotic assay results with clinical outcome. All
patients signed written informed consents. Patients were tested for HER2
overexpression using anti-c-erbB2 mouse monoclonal IgG1.[46]

Statistical calculations were performed using SPSS (Statistical
Package for the Social Sciences) version 7.5. Survival curves were generated
using the Life table function. Comparisons were performed using the Wilcoxon
(Gehan) test, which compared the following subgroups: HER2 (positive vs
negative), assay (sensitive vs resistant), and number of prior treatments (1 to
2 vs > 3). Results were considered significant at the .05 level.

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