Abstract
Gemcitabine and paclitaxel are active drugs in the treatment of patients with metastatic breast cancer which seem to have synergistic anticancer activity. Seven Phase II trials of gemcitabine/paclitaxel and one Phase III trial have been published. Two dosing or admistration schedules have been preferred in the clinical development of the combinations: gemcitabine on days 1 and 8 plus paclitaxel on day 1 or 8, every 3 weeks or gemcitabine plus paclitaxel on day 1, every 2 weeks. In first-line Phase II trials, up to 71% of patients responded to gemcitabine/paclitaxel therapy. Response rates were lower among patients who had received previous chemotherapy for metastatic disease (46%). Responses were observed in patients refractory to docetaxel monotherapy. Toxicity of gemcitabine/paclitaxel regimens has been low, with infrequent neutropenia or nonhematologic toxicity. In the randomized Phase III registration trial, the gemcitabine/paclitaxel combination demonstrated a clear advantage over paclitaxel alone in terms of the primary end point of survival and other efficacy end points, with manageable toxicity. Gemcitabine/paclitaxel showed a survival advantage of approximately 22% over paclitaxel alone (hazard ratio of 0.775). Gemcitabine plus paclitaxel represents an active and well-tolerated treatment alternative for first-line treatment of anthracycline-treated metastatic breast cancer. Triplet combinations, in which an anthracycline or trastuzumab are added to gemcitabine/paclitaxel, are being explored in the metastatic and neoadjuvant settings with excellent results. In addition, gemcitabine/paclitaxel is being evaluated in two large adjuvant multicenter studies.
Patients with metastatic breast cancer who receive combination chemotherapy have improved relapse-free and overall survival rates [1,2], and some have long-term remissions [3]. Most node-negative and -positive patients with operable breast cancer receive adjuvant anthracycline-containing chemotherapy [4]. Strong biologic [5] and clinical [6] data demonstrate that patients with metastatic disease previously treated with anthracyclines have a worse prognosis and lower chance of benefit from anthracycline-containing regimens. Therefore, alternative chemotherapies are needed for advanced breast cancer, among which are combinations of taxanes with newer agents such as gemcitabine.
The taxanes, either as single agents or in combination with other drugs, have become the standard front-line therapy for patients progressing after anthracycline chemotherapy [7]. There is a clear need for active combinations that do not include anthracyclines in this population.
Gemcitabine is a cytosine arabinoside prodrug analog with activity in a wide range of tumors. The cytotoxicity of this agent is related to the cellular accumulation of gemcitabine triphosphate (dFdCTP) and gemcitabine diphosphate, inducing a G0/G1 and S mitotic phase arrest in human solid tumor cells. Gemcitabine triphosphate competes with deoxycitidine triphosphate for incorporation into DNA, and gemcitabine diphosphate inhibits ribonucleotide reductase. Intracellular accumulation of gemcitabine diphosphate may be saturable and can increase with longer infusion times. Gemcitabine is rapidly metabolized in the blood, liver, kidneys and other tissues to the inactive compoud deoxydifluorouridine [8]. Single-agent gemcitabine-induced response rates range from 15 to 46% in advanced breast cancer patients [9], with minimal toxicity even in heavily pretreated cases [10].
Paclitaxel acts by stabilizing microtubules and blocking eukaryotic cells in the G2/M mitotic phase [7,11]. The taxanes have been shown to be among the most active therapies for advanced breast cancer [7], and are also presently used adjuvantly in node-positive breast carcinoma [12].
The use of gemcitabine combined with paclitaxel is particularly appealing clinically, as the drugs have different mechanisms of action and nonoverlapping toxicities. In vivo, paclitaxel increases accumulation of dFdCTP [13]. In cancer cell lines, paclitaxel administered immediately before gemcitabine significantly increased dFdCTP accumulation, gemcitabine incorporation into RNA and apoptotic index (143). In vivo, gemcitabine had no effect on paclitaxel plasma pharmacokinetics [15]. The combination of gemcitabine with a taxane has been found to be synergistic in vitro [16,17]. In vitro, the synergistic anticancer effects of gemcitabine and paclitaxel are particularly marked when paclitaxel is given before gemcitabine [16]. Following intravenous administration in a 30 min infusion, the peak concentrations reach a plateau after approximately 15 min, and the median maximum drug level after the first dose (Cmax) was 61 μmol/l. The area under the plasma concentration–time curve (AUC) was 3.8–25 mg/h/l. The Cmax for gemcitabine triphosphate was reached less than 30 min after the end of a gemcitabine infusion.
The gemcitabine/paclitaxel combination has been explored clinically in different schedules, including the well-established schedule of taxane on day 1 and gemcitabine on days 1 and 8 [18]. The doses recommended for this schedule are paclitaxel 150–175 mg/m2 or docetaxel 75–100 mg/m2 plus gemcitabine 900–1250 mg/m2. Growth factor (granulocytecolony stimulating factor [G-CSF]) support is not usually used in paclitaxel combinations. These drugs have also been evaluated in Phase I studies using a biweekly schedule [19,20]. As a single drug, a Phase I study showed that biweekly gemcitabine could be delivered in doses up to 5700 mg/m2 [21]. When paclitaxel and gemcitabine were combined biweekly, dose-limiting toxicities were febrile neutropenia and, in one study, alanine transaminase (ALT) elevations. Doses recommended for biweekly Phase II studies are paclitaxel 150 mg/m2 plus gemcitabine 3000 mg/m2 [19] or 2500 mg/m2 [20].
Phase II trials of gemcitabine/paclitaxel
Seven Phase II trials have explored the combination of gemcitabine with paclitaxel. Doses, schedules, response rates and toxicities are summarized in Table 1 [22–28]. Three trials were performed in patients receiving first-line treatment for metastatic breast cancer and four trials involved second- or third-line therapy. Administration schedules were every 3 weeks or every 2 weeks. Overall response rates ranged 40–71%, with higher rates observed in the first-line setting (75/123, 61%) compared with those observed in second-line therapy (59/129, 46%). The study by Alexopoulos and colleagues is particularly interesting, since it was performed in patients pretreated with docetaxel, and three of the 13 observed responses occurred in docetaxel-refractory patients [25].
Phase II clinical trials of gemcitabine/paclitaxel doublets in metastatic breast cancer.
With G-CSF.
FN: Febrile neutropenia; G-CSF: Granulocyte-colony stimulating factor; NR: Not reported.
Colomer and colleagues also observed that patients with elevated levels of circulating HER-2 extracellular domain (ECD) had a poorer response to therapy (83 vs 42%, p = 0.02). This was the basis for a subsequent Phase II clinical trial of gemcitabine and paclitaxel plus trastuzumab in HER-2 ECD-positive patients [26].
Phase III trial of gemcitabine/paclitaxel
Early results of a multi-institutional, randomized study of gemcitabine/paclitaxel versus paclitaxel alone have been published in abstract form [29]. This registration study compared gemcitabine/paclitaxel with paclitaxel alone in 529 metastatic breast cancer patients predominatly pretreated with anthracyclines as adjuvant/neoadjuvant therapy. The primary study end point was overall survival. Secondary objectives were: time to disease progression, progression-free survival, overall response rate, quality of life and pain palliation.
The interim analysis presented at the American Society of Clinical Oncology (ASCO) in 2004 unequivocally favors the gemcitabine/paclitaxel combination [29]. The overall survival of gemcitabine/paclitaxel was statistically superior to that of paclitaxel alone (log rank p = 0.018) (Figure 1), with a survival advantage of approximately 22% over paclitaxel alone (hazard ratio [HR] = 0.775). Median suvival was 18.5 months (95% confidence interval [CI]: 16.5–21.2) for gemcitabine/ paclitaxel and 15.8 months (95% CI: 14.4–17.4) for paclitaxel alone. All the other efficacy variables analyzed also favored the gemcitabine/paclitaxel arm (Table 2). The survival advantage found in this study has definitively established a role for gemcitabine in the treatment of metastatic breast cancer and has resulted in the approval of gemcitabine in combination with paclitaxel for the treatment of first-line metastatic breast cancer by the regulatory agencies in Europe and the USA.
Efficacy analysis in study JHQG comparing gemcitabine/paclitaxel with paclitaxel alone.
CI: Confidence interval.
Adapted from [29].
Overall survival in Study JHQG, a Phase III trial of gemcitabine/paclitaxel versus paclitaxel alone in metastatic breast cancer patients.
Tolerability of the gemcitabine/paclitaxel doublet
In Phase II trials, the combination was generally well tolerated, particularly in the first-line setting. Murad and colleagues observed grade 3/4 neutropenia in 35% of patients, neutropenic fever in 7% and neuropathy in 7% [22]. In the study by Sanchez-Rovira and colleagues assessing second- or third-line gemcitabine/paclitaxel, 15% of patients had grade 3/4 hematologic toxicity and 34% required G-CSF support [23]. Colomer and colleagues observed grade 4 neutropenia in 17% of patients, and nonhematologic toxicities occurred in less than 5% of cases, except for elevated liver enzyme levels (8%) [26]. Delfino and colleagues found a 13% incidence of grade 3/4 neutropenia and thrombocytopenia and infrequent nonhematologic toxicities [27]. Preliminary reports by Vici and colleagues, Genot and colleagues and Alexopoulos and colleagues presented at the 2002 and 2005 ASCO meetings showed manageable toxicities [24,25,28].
In the Phase III trial comparing gemcitabine/paclitaxel with paclitaxel alone, grade 3/4 hematologic toxicities (by common toxicity criteria) were more pronounced with the combination than with paclitaxel alone: febrile neutropenia 5 versus 1%, neutropenia 48 versus 11% and thrombocytopenia 5 versus 0%. Nonhematologic toxicity was manageable in both arms, with similar toxicity values for neuropathy and slightly higer values for fatigue (6 vs 1%). There was one toxic death in each arm.
Triplet combinations of gemcitabine/paclitaxel plus an anthracycline or trastuzumab
The addition of an anthracycline to the gemcitabine/paclitaxel combination in patients with metastatic breast cancer has been explored in Phase II trials, with excellent objective response rates of 83% achieved with gemcitabine, doxirubicin and paclitaxel (GAT) [30] and 92% achieved with gemcitabine, epirubicin and paclitaxel (GET) [31] in single-institution studies, and 71% achieved with GET in a multicenter study [32]. The schedules and efficacy of these trials is summarized in Table 3. There was a somewhat greater toxicity than that observed with the gemcitabine/paclitaxel combination. The results of a randomized comparison of GET versus 5-fluorouracil, epirubicin and cyclophosphamide (FEC) did not show a therapeutic advantage for GET in advanced breast cancer [33]. The contribution of gemcitabine to the well-established paclitaxel–trastuzumab regimen used in HER-2-positive metastatic breast carcinoma has been reported preliminarily by two research groups, with excellent results. Sledge and colleagues reported a 63% response rate using a days 1 and 8 schedule [34] and Colomer and colleagues reported a 78% response rate with a biweekly administration [35].
Phase II clinical trials of gemcitabine/paclitaxel triplets in metastatic breast cancer.
Phase III trial comparing GET with FEC; the figures shown belong to the GET arm.
FEC: 5-fluorouracil, epirubicin and cyclophosphamide; GET: Gemcitabine, epirubicin and paclitaxel; ORR: Overall response rate.
Phase II combinations of gemcitabine/paclitaxel in primary breast cancer.
In the breast, includes microscopic foci (<1mm).
ORR: Overall response rate; pCR: Pathologic complete response.
Executive summary
Gemcitabine is a nucleotide analog prodrug that inhibits DNA synthesis through its active metabolites gemcitabine triphosphate and gemcitabine diphosphate.
Gemcitabine triphosphate competes with deoxycitidine triphosphate for incorporation into DNA and gemcitabine diphosphate inhibits ribonucleotide reductase.
In vitro, gemcitabine and paclitaxel have synergistic anticancer effects, particularly the paclitaxel–gemcitabine sequence.
In vivo, gemcitabine had no effect on paclitaxel plasma pharmacokinetics.
In vivo, paclitaxel increased accumulation of gemcitabine triphosphate.
Gemcitabine is presently indicated for the treatment of cancer of the lung, breast, ovary and bladder.
In several Phase II clinical trials, gemcitabine plus paclitaxel has shown response rates of up to 71%, particularly when used as first-line therapy.
The combination of gemcitabine plus paclitaxel in a multicenter, randomized Phase III study was shown to be significantly more active than paclitaxel alone in the treatment of patients with metastatic breast carcinoma who had received prior adjuvant or neoadjuvant anthracyclines.
Gemcitabine is now also indicated in the first-line treatment of metastatic breast cancer (in combination with paclitaxel).
Recommended doses are gemcitabine 1250 mg/m2 on days 1 and 8, and paclitaxel 175 mg/m2 on day 1, every 3 weeks.
An alternative schedule of administration is gemcitabine 2500 mg/m2 plus paclitaxel 1 50 mg/m2 on days 1 and 1 5, every 28 days.
The recommended order of administration is paclitaxel followed by gemcitabine.
The combination of gemcitabine/paclitaxel is generally well-tolerated.
The most frequent grade 3/4 side effect is neutropenia.
Sensory neuropathy and other toxicities occur in less than 10% of patients.
Gemcitabine/taxanes in the neoadjuvant & adjuvant settings
There are three reported trials of gemcitabine/paclitaxel doublets or triplets in the treatment of primary breast cancer. Clinical response rates were generally in the range of 80–90%, with pathologic complete responses (pCRs) of approximately 20%. In a very interesting pharmacogenomic study using the biweekly gemcitabine/paclitaxel schedule, Llombart-Cussac and colleagues showed a 20% pCR rate [36]. Sanchez-Rovira and colleagues, who used GAT [37], and Conte and colleagues, who used GET [38], reported pCR rates of 17 and 15%, respectively.
Two large adjuvant clinical trials are exploring gemcitabine/paclitaxel regimens in the sequential, postoperative treatment of breast cancer. The tAnGo study, which is being conducted by Cancer Research UK and other European cooperative groups, is using a regimen of epirubicin/cyclophosphamide followed by gemcitabine/paclitaxel or paclitaxel alone [39]. The gemcitabine regimen is 1250 mg/m2 administered on days 1 and 8 and the paclitaxel regimen is 175 mg/m2 administered on day 1, every 3 weeks. The primary end point of this trial is disease-free survival. A preliminary safety evaluation of the first 130 cases demonstrated that adding gemcitabine to paclitaxel did not induce new or unexpected toxicities in the lung, heart, liver or skin. The accrual in this study stopped a few months ago after achieving the accrual goal of 3000 patients. The National Surgical Adjuvant Breast and bowel Project (NSABP) B-38, which is currently recruiting patients, will be using a three-arm design comparing a standard docetaxel, doxorubicin and cyclophosphamide (TAC) regimen with a dose-dense sequential doxorubicin and cyclophosphamide (AC) regimen followed by paclitaxel (which requires G-CSF support) and with a sequential regimen of dose-dense AC followed by a biweekly gemcitabine (2000 mg/m2) plus paclitaxel (175 mg/m2) regimen (without G-CSF) [40].
Conclusion
In conclusion, the combination of gemcitabine/paclitaxel opens a new therapeutic option in patients with metastatic breast cancer, at the expense of a very small increase in toxicity. Gemcitabine/paclitaxel has unequivocally demonstrated an increase in overall survival of approximately 22% in advanced breast cancer. The regulatory agencies in Europe and the USA (the European Medicines Agency [EMEA] and the US Food and Drug Administration [FDA]) have considered this increase to be clinically meaningful and, presently, gemcitabine/paclitaxel is indicated for first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy.
Future perspective
In the next few years, the integration of gemcitabine in the clinical setting will build on the gemcitabine/paclitaxel combination. The triplet combinations of gemcitabine/paclitaxel plus anthracyclines have increased the response rate and have shown great promise in the neoadjuvant setting. In addition, gemcitabine/paclitaxel plus trastuzumab has shown remarkable response rates in HER-2-positive patients. Finally, the use of gemcitabine/paclitaxel is currently being explored in a sequential fashion with other established chemotherapy regimens in two large, randomized, multi-institutional trials in Europe and the USA.