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
ABSTRACT: In recent years, the clinical application of paclitaxel (Taxol),docetaxel (Taxotere), vinorelbine (Navelbine), and trastuzumab (Herceptin) hasimproved the management of advanced breast cancer. With the introduction ofgemcitabine, a new drug with significant activity in breast cancer has becomeavailable. As a single agent, gemcitabine (Gemzar) provides response rates inthe range of 25% to 46% in breast cancer, depending on starting dose and statusof prior chemotherapy for metastatic disease. Higher response rates are observedwhen gemcitabine is combined with other classes of cytotoxic drugs. Studiesconducted in our laboratory detected high degrees of synergy between gemcitabineand cisplatin (Platinol) in a variety of human tumors in primary culture. Theseanalyses identified breast cancer as a target for this combination. Thecombination of cisplatin plus gemcitabine is active in relapsed breast cancerpatients. The activity observed in drug-resistant patients suggests relative non-crossresistance with other drug combinations. [ONCOLOGY 15(Suppl 3):28-33, 2001]
Breast cancer is among the mostcommon malignancies of western societies, with 182,800 new diagnoses and 41,200 deaths in the United Statesin 2000. The benefits associated with adjuvant hormonal andchemotherapeutic interventions have improved the survival of patients withearly-stage disease. However, patients who present with advanced disease or whorelapse following initial therapy have low survival rates that have not changedin several decades. Efforts to improve the outcome of high-risk patients withdose-intensive combinations followed by stem-cell support have, thus far, provenunsuccessful.*[4-8] In this context, the introduction of gemcitabine (Gemzar), a novel cytotoxic agent with unique modes of action and crossresistance, provides an important addition to the armamentarium for thisdisease.
In the late 1980s and early 1990s, investigators reportedactivity for gemcitabine in a variety of human tumor-cell lines and xenografts.In the early 1990s, as investigators at the Free University in Amsterdam wereexamining the basic mechanism of interaction between gemcitabine and cisplatin(Platinol) in cell line systems, our laboratory began evaluating gemcitabine in a broad array of human tumor primary culture specimens utilizing an exvivo apoptotic model. Preliminary results indicated significant correlationsbetween gemcitabine and cisplatin (P < .05) and gemcitabine and mustard alkylators(P < .01) by Pearsoncorrelation. This finding led to the analysis of gemcitabine in combinationwith other classes of cytotoxic drugs. We reported synergy between gemcitabineand cisplatin in 73% of human tumor primary cultures and, more recently,synergy between mustard alkylators and gemcitabine in 69% of human tumorspecimens. The degree of true synergy identified for cisplatin plusgemcitabine has exceeded that identified between any other classes of drugsevaluated by our laboratory to date.
Based on laboratory findings, we applied thegemcitabine/cisplatin combination in a number of tumor types, with particularattention to relapsed ovarian and breast cancers, two diseases with significantactivity and synergy in the EVA (ex vivo apoptotic) assay. Preliminary resultsin ovarian cancer have been reported. In this article, we focus on the roleof gemcitabine plus cisplatin in advanced breast cancer.
Platinum Therapy in Breast Cancer
In 1978, a phase II trial of cisplatin in relapsed breast cancerprovided no objective responses in 26 evaluable patients. This led to thevirtual disappearance of cisplatin from the breast cancer literature for adecade. When cisplatin was subsequently tested in previously untreated advancedbreast 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 (Paraplatin) in previously treated vs chemotherapy-naivebreast cancer patients have reported similar results. In a study reported byJurga et al, the 53.9% objective response rate for cisplatin in untreatedbreast cancer patients fell to 30.6% for relapsed patients.
A study of carboplatin as a single agent yielded a response rateof 35% in previously untreated breast cancer patients. However, whenclinical trials compared carboplatin in previously untreated vs previouslytreated patients, the objective response rates fell from 33% to 8% in one and32% to 0% in the second study.[18,19] It is evident that platinum activity fallsdramatically in previously treated populations, suggesting collateral resistanceto this class of drugs induced by prior exposure to cytotoxics.
In the early 1990s, as the use of platinum in breast cancergained acceptance, platinum-based combination therapies were shown to provideobjective responses in a number of trials (Table 1). Accumulated experienceindicates that platinum derivatives have activity in breast cancer, thatplatinum activity appears greater in chemotherapy-naive patients, and that someplatinum-based combinations are highly effective in this disease.
Gemcitabine Activityin Breast Cancer
The activity of gemcitabine as a single agent for advancedbreast cancer has been the subject of prior investigation with responsesobserved in approximately 20% of patients.[27-33] (Other studies, however,have shown efficacy rates varying from 25% to 46%, depending on starting doseand status of prior chemotherapy for metastatic disease.[34,35]) The principaltoxicities associated with gemcitabine are generally mild to moderate inseverity and include neutropenia, thrombocytopenia, malaise, and asthenia, withrash, dyspnea, alopecia, and nausea reported less frequently. Gemcitabine’sfavorable toxicity profile has led many investigators to suggest gemcitabine asan ideal agent for combination therapy.
The results of clinical trials of gemcitabine plus paclitaxel(Taxol), docetaxel (Taxotere), vinorelbine (Navelbine),doxorubicin, and epirubicin (Ellence), as well as triple-agent regimenssuch as gemcitabine/epirubicin/paclitaxel (Taxol) (GET), have been reported.Additional trials are underway to further evaluate gemcitabine’s role in thisdisease.
The question that arises from these trials remains: How do weoptimize drug/drug interactions, based on mechanisms of action, to provide themost effective combination regimens? To address the question we examinedgemcitabine’s activity in combination with a variety of cytotoxic agents anddetermined the degree of true synergy for each doublet (Figure 1).
As can be seen, cisplatin revealed the highest degree of synergywith gemcitabine. Our group reported a formal examination of the degree ofactivity and synergy for the combination of gemcitabine plus cisplatin (Table2). This analysis revealed activity and synergy for breast cancer, a diseasenot generally targeted for this combination.
To determine the objective response rate and assess thepredictive validity of the ex vivo apoptotic predictions for this combination,we initiated a phase II trial of gemcitabine/cisplatin in relapsed breast cancerpatients. To approximate the in vitro conditions, our design incorporated a repeating doublet sequence wherein both drugs are administered together each dayof therapy. To date, three clinical trials combining cisplatin with gemcitabinein advanced breast cancer have been reported (Table 3).[42-44]
Hematologic toxicity has been the most commonly reported sideeffect with no treatment-related deaths noted in any of the studies. A moredetailed review of the phase II trial reported by our group follows.
Between May 1997 and October 1998, we conducted a phase II trialof low-dose cisplatin plus gemcitabine in a repeating doublet sequence inpatients with previously treated, relapsed breast cancer. The original trial ofcisplatin (30 mg/m2) plus gemcitabine (1,000mg/m2) administered on days 1, 8, and 15 every 28 days was modified tocisplatin (30 mg/m2) plus gemcitabine (750 mg/m2) on days 1 and 8 every 21 daysfollowing the observation of day 15 myelosuppression.
Patients and Methods
All patients had received one or more prior chemotherapyregimens for systemic recurrence and all had Eastern Cooperative Oncology Groupperformance status ≤ 3, with adequate bone marrow, hepatic, and renal function.Concurrent radiation or hormonal therapy was not allowed. Patients withclinically stable brain metastases or other sites of metastases who hadcompleted radiation therapy were permitted. Patients were eligible regardless ofthe type of prior therapy, including high-dose therapy with stem-cell rescue, orprior exposure to cisplatin or gemcitabine, provided these two drugs were not given together. Patients with accessiblesites of recurrence had tissue submitted for blinded ex vivo apoptoticlaboratory analysis of sensitivity to gemcitabine plus cisplatin. Theresults of the ex vivo apoptotic assay were not used in the selection ofpatients.
The primary end points of the trial were safety and efficacymeasured as objective response rate and time to progression. A secondary endpoint was to compare ex vivo apoptotic assay results with clinical outcome. Allpatients signed written informed consents. Patients were tested for HER2overexpression using anti-c-erbB2 mouse monoclonal IgG1.
Statistical calculations were performed using SPSS (StatisticalPackage for the Social Sciences) version 7.5. Survival curves were generatedusing the Life table function. Comparisons were performed using the Wilcoxon(Gehan) test, which compared the following subgroups: HER2 (positive vsnegative), assay (sensitive vs resistant), and number of prior treatments (1 to2 vs > 3). Results were considered significant at the .05 level.
The repeating doublet schedule of cisplatin/gemcitabineadministered on days 1, 8, and 15 every 28 days was modified to days 1 and 8every 21 days due to day 15 myelosupression, as mentioned earlier. Thismodification occurred after the accrual of patient 12. The schedules wereotherwise identical and were administered as follows.
All patients received hydration with D5½NS (dextrose in 0.5%normal saline) at 200 mL over 1 hour. Patients were premedicated with IVgranisetron (Kytril) at 1 mg and IV dexamethasone at 10 mg. Cisplatin at 30 mg/m2 was administered in 250 mL of normal saline with 12.5 g of mannitol and 1g of MgSO4 over 1 hour. A second hydration with 250 mL of D5½NS over 1 hour wasfollowed by gemcitabine at 750 mg/m2 in 250 mL of normal saline over 1 hour.Patients with two or more prior chemotherapy regimens were started at agemcitabine dose of 600 mg/m2. All treatments were administered on an outpatientbasis.
Between May 1997 and October 1998, 31 patients entered thestudy. One patient developed brain metastases at the second week and wasconsidered not evaluable. The remaining 30 patients who received at least onecycle of therapy are included. There were 3 (10%) complete responses and 12(40%) partial responses for an overall objective response rate of 50%. Two offour patients accrued following relapse from high-dose therapy with stem-cellsupport had objective responses. Responses were observed in soft tissue, lung,liver, and bone. No responses were observed in the central nervous system. Ofthe 30 patients, 8 developed central nervous system metastases, 6 of whom hadobjective systemic responses at the time of central nervous system relapse.Among responding patients (complete and partial responses), there was amedian time to progression of 23.5 weeks, with a mean of 25 weeks.
Toxicity was primarily hematologic with grade 3 and 4 leukopeniain 13%, neutropenia in 10%, anemia in 4%, and thrombocytopenia in 31% oftreatment cycles. The most frequent subjective side effect reported by 44% ofthe patients was mild-to-moderate fatigue; 36% of patients reported moderatenausea without vomiting. Overall, the regimen proved to be quite tolerable.
Of the 22 patients for whom tissue blocks were evaluable, 5 werepositive and 17 negative for HER2 overexpression. This precluded analysis of theimpact of HER2 overexpression on response to this combination. A comparison of anumber of prior treatments (1 or 2 vs 3 or more) and time to progression (14 vs22 weeks) did not achieve significance (P < .32). However, ex vivo apoptoticassay sensitivity to the drug combination correlated significantly (P < .03)with time to treatment progression (15 vs 36 weeks).
Gemcitabine’s Place in Combination Therapy
In a series of clinical trials, single-agent gemcitabine hasprovided objective responses in approximately 25% to 46% of patients withadvanced breast cancer. The drug has a relatively mild toxicity profile,activity in solid tumors, and non-cross resistance with other classes ofdrugs. Yet, it is gemcitabine’s utility in combination therapy,specifically with cisplatin, that may hold the greatest clinical potential.
Resistance to cisplatin is primarily mediated by nucleotideexcision repair and mismatch repair. After DNA platination, DNApolymerases incorporate nucleosides into sites of DNA damage. Evidencesupporting the role of nucleotide excision repair in the synergy betweencisplatin and gemcitabine has recently been provided. Using mismatch repairdeficient cell lines, Yang has shown that antisense ERCC1 RNA abrogates thecytotoxic synergism between cisplatin and gemcitabine.
To enhance difluorodeoxycytidine triphosphate (dFdCTP)incorporation, in keeping with in vitro observations, cisplatin/gemcitabine wasadministered in a repeating doublet sequence in two of the reported trials andas a 4-day cisplatin infusion with gemcitabine on days 2 and 8 in one trial. Therationale for the combination is the repeated induction of genomic insultfollowed by repair inhibition. Studies conducted in our laboratory haveindicated that synergy persists for these drugs even at low cisplatinconcentrations (ie, 1.65 mg/mL continuous exposures in fixed ratios withgemcitabine). Prior observations in the A2780 ovarian carcinoma cell linerevealed that wild-type and cisplatin-resistant subclones were sensitive, yetgemcitabine-resistant subclones were resistant to the two-drug combination.Cells with efficient DNA repair may be uniquely sensitive to agents that targetexcision repair processes.
Gemcitabine’s activity as an inhibitor of ribonucleotidereductase provides further pharmacokinetic advantages for this agent over thestructurally related cytosine arabinoside and cisplatin(ara-C). The higher intracellular concentrations of dFdCTP over ara-CTP and itsprolonged intracellular half-life may in part explain the superior activity ofthe gemcitabine/cisplatin doublet in breast cancer over the results obtained bythe Cancer and Leukemia Group B in a clinical trial that combined cisplatin with ara-C.
When we compared the ex vivo apoptotic results from previously treated vs previously untreated breast cancerspecimens, we found comparable degrees of sensitivity and a trend toward greatersensitivity and synergy in the previously treated group. The objective responsesobserved in two of the four patients who had relapsed following high-dosetherapy with stem-cell support in our series and the responses observed in theheavily pretreated patients in the other series indicates that prior treatmentand the development of repair-mediated resistance does not preclude benefit fromthis combination.
Optimal Treatment Regimens
Optimal doses and schedules for the combination of cisplatinplus gemcitabine remain to be determined. A comparison of schedules in non-small-celllung cancer suggested that day 15 cisplatin combined with day 1, 8, and 15 gemcitabine was superior to the scheduleemployed in this trial of breast cancer patients. Our experience withrepeating doublet schedules in this trial and in the treatment of advancedovarian cancer is consistent with prior in vitro and in vivoobservations and raises the question of whether optimal schedules may bedisease-specific.
We observed no significant correlation between the number ofprior treatment regimens, 1 or 2 vs 3 or more, and outcome (P = .32) for thedoublet sequence. The 4-day cisplatin infusion schedule reported by Doroshow etal revealed a trend favoring the minimally (zero or one regimen) over theheavily treated (two or more regimens) groups. In the two trials, all patientswho used the doublet sequence had failed one or more prior regimens formetastatic disease.
This finding raises several issues. First, patients who areminimally treated are more likely to respond to cisplatin, as we described earlier. The4-day infusion schedule is cisplatin-intensive, providing 100 mg/m2 as opposedto the 50 or 60 mg/m2 in the other schedules. Second, two of the trialsadministered the drugs together as a doublet, optimizing drug-druginteraction, while the 4-day schedule only administered the two drugs togetheronce on day 2.
Taken together, the close temporal sequencing of the two drugsin the repeating doublet schedule may hold certain advantages. The doubletschedule uses low-dose cisplatin to enhance gemcitabine incorporation andcytotoxicity. This is fundamentally different from the use of gemcitabine toenhance high-dose cisplatin cytotoxicity. In relapsed, previously treated andlargely drug-refractory patients whose resistance may be largely mediated by efficient DNArepair capacity, the doublet sequence holds theoretical advantage. Further studywill be required to determine optimal schedules of administration for theseagents.
Gemcitabine in Differing Combinations
The role of other platinum derivatives for combination withgemcitabine is of interest. Our laboratory findings comparing carboplatin withcisplatin have revealed high degrees of concordance for these agents, suggestingthat carboplatin interacts with gemcitabine in a manner similar tocisplatin. Our choice of cisplatin reflected the greater degree ofmyelosuppression associated with carboplatin. However, appropriately dosed,carboplatin may be able to be safely used in place of low-dose cisplatin in arepeating doublet sequence in breast cancer, as was recently reported for thiscombination in non-small-cell lung cancer. When we compared the degree of gemcitabine synergy with cisplatin to gemcitabine synergywith oxaliplatin, the incidence was identical at 73% for both drugs,suggesting similar degrees of clinical activity for these combinations.
The clinical activity for the combination of cisplatin plusgemcitabine in relapsed breast cancer has been associated with manageabletoxicity, primarily hematologic in the form of thrombocytopenia. In our series we observed responses in liver, lung, bone, and softtissue sites, indicating activity for visceral recurrences. However, we observedno activity in patients with central nervous system disease, suggesting thatthis combination does not penetrate the blood-brain barrier adequately toprovide central nervous system protection.
The correlation between ex vivo apoptotic assay and outcome inour study suggests that future studies might incorporate this or relatedtechniques into trial design, or for the selection of treatment candidates, asdescribed in a recent review.
In summary, the combination of cisplatin plus gemcitabine isactive in relapsed breast cancer patients. The activity observed indrug-resistant patients, even following high-dose/stem-cell therapy, suggestsrelative non-cross resistance with other drug combinations. Future trialsincorporating this combination into earlier stages of the disease and forconsolidation strategies are warranted.
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