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. The benefits associated with adjuvant hormonal and chemotherapeutic 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(Drug information on 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(Drug information on cisplatin) (Platinol) in cell line systems, 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. 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 and, more recently, synergy between mustard alkylators and gemcitabine in 69% of human tumor specimens. 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. In this article, we focus on the role of gemcitabine plus cisplatin in advanced breast cancer.
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. 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%), identifying it as one of the more active agents in this disease. Other investigators who compared the activity of cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin) in previously treated vs chemotherapy-naive breast cancer patients have reported similar results. In a study reported by Jurga et al, 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. 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), docetaxel(Drug information on docetaxel) (Taxotere), vinorelbine (Navelbine), doxorubicin(Drug information on doxorubicin), and epirubicin(Drug information on epirubicin) (Ellence), as well as triple-agent regimens such as gemcitabine/epirubicin/paclitaxel (Taxol) (GET), have been reported. 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). 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.
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. 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.
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.