Gemcitabine (Gemzar) and paclitaxel are active drugs in the treatmentof metastatic breast cancer. Phase I clinical trials data have suggestedthat the gemcitabine plus paclitaxel combination is safe in breastcancer patients. Two doses/administration schedules have been preferredin subsequent phase II and III trials: gemcitabine on days 1 and8 plus a taxane on day 1, every 3 weeks; or gemcitabine plus a taxaneon days 1 and 14, every 4 weeks. In phase II trials, 114 of 221 patients(52%) responded to gemcitabine/paclitaxel therapy. Response rates werelower among patients who received previous chemotherapy for metastaticdisease (response rates: 45%, second line and 70%, first line).Toxicity of gemcitabine/paclitaxel regimens has generally been low, withfew cases of neutropenia or nonhematologic toxicity. Results of therandomized phase III registration trial show a clear advantage forgemcitabine plus paclitaxel over paclitaxel alone in time to disease progression,objective response, and overall survival. Triplet combinations,in which an anthracycline is added to gemcitabine/paclitaxel, are beingexplored in the metastatic and neoadjuvant settings.
Gemcitabine (Gemzar) and paclitaxel are active drugs in the treatment of metastatic breast cancer. Phase I clinical trials data have suggested that the gemcitabine plus paclitaxel combination is safe in breast cancer patients. Two doses/administration schedules have been preferred in subsequent phase II and III trials: gemcitabine on days 1 and 8 plus a taxane on day 1, every 3 weeks; or gemcitabine plus a taxane on days 1 and 14, every 4 weeks. In phase II trials, 114 of 221 patients (52%) responded to gemcitabine/paclitaxel therapy. Response rates were lower among patients who received previous chemotherapy for metastatic disease (response rates: 45%, second line and 70%, first line). Toxicity of gemcitabine/paclitaxel regimens has generally been low, with few cases of neutropenia or nonhematologic toxicity. Results of the randomized phase III registration trial show a clear advantage for gemcitabine plus paclitaxel over paclitaxel alone in time to disease progression, objective response, and overall survival. Triplet combinations, in which an anthracycline is added to gemcitabine/paclitaxel, are being explored in the metastatic and neoadjuvant settings.
Patients with metastatic breast cancer who receive combination chemotherapy have improved relapse-free and overall survival rates,[1-5] and some have long-term remissions. Currently, patients with early breast cancer commonly receive adjuvant therapy, which includes anthracyclines in cases of high risk of relapse. Although anthracycline-related cumulative toxicities can often be avoided, strong biologic and clinical[9-11] data show that patients with metastatic disease previously treated with anthracyclines in earlier disease stages have a worse prognosis and lower chance of benefit from anthracycline-containing regimens than do chemotherapynaive patients. Therefore, alternative chemotherapies are needed for advanced breast cancer, among which are combinations of taxanes with newer agents such as gemcitabine (Gemzar). The taxanes, either as single agents or combined with other drugs, have become the standard front-line therapy for patients whose disease progresses after anthracycline chemotherapy. The combination of paclitaxel and doxorubicin has been shown to be less active in patients who have previously received adjuvant anthracycline treatment. There is a clear need for active combinations that do not include anthracyclines in this population. Appeal of Combination Therapy Gemcitabine is a cytosine arabinoside prodrug analog with activity in a wide range of tumors. Cytotoxicity of this agent is related to the cellular accumulation of gemcitabine triphosphate (dFdCTP), inducing a G0/G1 and S phase arrest in human solid tumor cells. Single-agent gemcitabine induced response rates ranging from 15% to 46% in breast cancer patients, with minimal toxicity, even in heavily pretreated patients.[ 14] Paclitaxel acts by stabilizing microtubules, blocking eukaryotic cells in the G2/M mitotic phase. When administered on a weekly or every-3- week schedule, paclitaxel has been shown to be among the most active therapies for breast cancer.[16,17] In randomized clinical trials, paclitaxel was equal in efficacy to CMFP (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil [5-FU], prednisone) in patients with advanced breast cancer. In randomized trials involving anthracycline-naive patients, results with paclitaxel combined with anthracyclines were equivalent[ 19] or superior to those achieved with standard cyclophosphamide, doxorubicin, and 5-FU. Use of gemcitabine combined with paclitaxel is particularly appealing because the drugs have different mechanisms of action and nonoverlapping toxicities. In vivo, paclitaxel increases the accumulation of dFdCTP. In non-small-cell lung cancer cell lines, paclitaxel administered immediately before gemcitabine significantly increased the accumulation of dFdCTP, the incorporation of gemcitabine into RNA, and the apoptotic index. In the mouse model, the greatest delay in tumor growth was obtained when paclitaxel was administered on days 1 and 15, with gemcitabine given every 3 days. In addition to the well-established days 1 and 8 schedules, the paclitaxel/ gemcitabine combination was also evaluated in a phase I study using an every-2-week schedule. Paclitaxel was infused over 3 hours, followed by gemcitabine as a 30- to 60-minute infusion. Dose-limiting toxicities were neutropenia and alanine transaminase (SGPT) elevations. Doses recommended for biweekly phase II studies were 150 mg/m2 for paclitaxel plus 3,000 mg/m2 for gemcitabine. Phase II Trials of Gemcitabine With Paclitaxel Six phase II trials have explored the combination of gemcitabine with paclitaxel. Doses, schedules, and response rates are summarized in Table 1. Three trials were performed in patients receiving first-line treatment for metastatic breast cancer, and three trials involved second- or third-line therapy. Administration schedules were every 3 weeks and every 2 weeks (biweekly) in three trials each. Overall response rates ranged from 40% to 71%, with the highest rates observed in studies of chemotherapy-naive patients (responses are summarized in Table 2).
The combination was generally well tolerated, particularly in the firstline setting. In the study by Sanchez- Rovira et al assessing second- or third-line gemcitabine/paclitaxel, 15% of patients had grade 3 or 4 hematologic toxicity, and 34% required granulocyte colony-stimulating factor (G-CSF [Neupogen]) support. Murad et al observed grade 3 or 4 neutropenia in 35% of patients, neutropenic fever in 7%, and neuropathy in 7%. Colomer et al observed grade 4 neutropenia in 17% of patients. Nonhematologic toxicities occurred in less than 5% of cases, except for elevated liver enzyme levels (8%). Preliminary reports by Delfino et al, Vici et al, and Genot et al, presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2002, showed manageable toxicities.[27-30] Colomer at al also observed that patients with elevated levels of circulating HER2 extracellular domain (ECD) had poorer response to therapy (83% vs 42%, P = .02). This finding confirmed results of an earlier study[26,31] and is the basis for a subsequent phase II clinical trial of gemcitabine and paclitaxel plus trastuzumab (Herceptin) in HER2 ECDpositive patients. In addition, interesting pharmacogenomics studies are being performed in patients with primary breast cancer who are receiving neoadjuvant treatment with the gemcitabine/paclitaxel combination.[ 32]
Phase III Trial of Gemcitabine and Paclitaxel Early results of a randomized comparison of gemcitabine/paclitaxel vs paclitaxel alone have been published in abstract form.[33,34] This study compared the combination with paclitaxel in 529 metastatic breast cancer patients previously treated with an anthracycline but no previous chemotherapy for advanced disease. Study objectives were overall survival, progression-free survival, overall response rate, quality of life, pain palliation, toxicity, and time to progressive disease (primary interim analysis objective). The study design is shown in Figure 1. Results for the multicenter JHQG trial presented by O'Shaughnessy at the ASCO annual meeting in 2003 favored the gemcitabine/paclitaxel combination (n = 267) over paclitaxel (n = 262). The median time to progression was 5.4 months (95% CI = 4.6-6.1 mo) for gemcitabine/ paclitaxel and 3.5 months (95% CI = 2.9-4.0 mo) for paclitaxel (P = .0013). The hazard ratio of being progression-free at 6 months was 0.734 (95% CI = 0.607-0.889; P = .0015), with an increased probability of ~50% for the combination. The disease progression-free survival was significantly better with gemcitabine/ paclitaxel (P = .0021). The overall response rate was 39.3% (95% CI = 33.5%-45.2%) for gemcitabine/ paclitaxel and 25.6% (95% CI = 20.3%- 30.9%) for paclitaxel (P = .0007). Furthermore, the combination was associated with a trend toward numerical improvements in analgesic level, pain relief, and global quality of life (P = NS). Grade 4 hematologic toxicity (by Common Toxicity Criteria) was more pronounced with gemcitabine/ paclitaxel than with paclitaxel (17.2% vs 6.6% neutropenia, 1.1% vs 0.4% anemia, 0.4% vs 0% thrombocytopenia, 0.4% vs 0% febrile neutropenia). Nonhematologic toxicity was manageable in both arms. There was one toxic death per arm. Conclusions from this study were that gemcitabine plus paclitaxel demonstrated significant efficacy advantages over paclitaxel alone in patients with metastatic breast cancer, and toxicity was as expected and manageable. During the 2004 ASCO annual meeting, Albain et al presented the initial report of overall survival for this study. The overall survival hazard ratio (HR) was 0.775, significantly in favor of gemcitabine plus paclitaxel (P = .018). A statistically significant advantage of gemcitabine plus paclitaxel over paclitaxel was also reported (18.5 months vs 15.8 months, HR = .775, P = .018). One-year survival was significantly increased for the gemcitabine/paclitaxel arm (70.7% vs 60.9%; P = .019), and the HR favoring the combination persisted (Cox regresion) even after adjusting for baseline covariates: 0.740 (P = .006). Thirty-eight percent of patients receiving gemcitabine plus paclitaxel ceased therapy due to disease progression, vs 55% in the paclitaxel arm, and therapy ended due to adverse events in 6.7% of patients receiving gemcitabine plus paclitaxel, vs 5.0% of those in the paclitaxel arm. Thus, the survival advantage reported in this study has definitively established a role for gemcitabine in the treatment of metastatic breast cancer. Triplet Combinations of Gemcitabine and Paclitaxel Plus an Anthracycline 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 response rates of 90.2% in the neoadjuvant study reported at the European Breast Cancer Conference in 2004 by Gennari et al and 80% achieved by Sanchez-Rovira and colleagues in the metastatic setting and somewhat greater toxicity than observed with gemcitabine/paclitaxel. In the multicenter Italian study by Gennari et al, of the 41 patients who completed the gemcitabine/epirubicin [Ellence]/paclitaxel regimen and underwent surgery, 6 (14.6%) had a pathologic complete response; three were down- graded to negative axillary nodes. Although results of a randomized comparison of GET (gemcitabine/epirubicin/ paclitaxel) vs FEC (5-FU/epirubicin/ cyclophosphamide), presented at the ASCO annual meeting in 2002, did not show a therapeutic advantage for GET in advanced breast cancer,[ 37] these triplet combinations are being explored in the neoadjuvant setting, with impressive response rates reported.  Further research from other investigators, expected in the near future, will provide additional information on the use of gemcitabine and taxanes with and without other chemotherapy agents in patients with metastatic breast cancer. Conclusion Gemcitabine and paclitaxel possess activity against metastatic breast cancer, with low toxicity with gemcitabine/ paclitaxel regimens. Phase III data show a clear advantage for gemcitabine plus paclitaxel over paclitaxel alone in parameters such as time to disease progression, overall survival, and objective response. Moreoever, triplet combinations, with an anthracycline being added to gemcitabine/ paclitaxel, are being explored in the metastatic and neoadjuvant settings.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Harris JR, Marrow M, Bonadonna G: Cancer of the breast, in Devita Jr VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 4th ed, pp 1264-1332. Philadelphia, Lippincott, 1993.
2. Ackland SP, Anton A, Btreitbach GP, et al: Dose-intense epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: A randomized multinational study. J Clin Oncol 19:943-953, 2001.
3. Jassem J, Piernkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001.
4. Nabholtz JM, Riva A: Taxane/ anthracycline combinations: Setting a new standard in breast cancer. Oncologist 6(suppl 3):5- 12, 2001.
5. A'Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67:801-805, 1993.
6. Rahman ZU, Frye DK, Smith TL, et al: Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: A reference. Cancer 85:104- 111, 1999.
7. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651-2658, 1998.
8. LÃ¶nn U, LÃ¶nn S, Nilsson B, et al: Higher frequency of gene amplification in breast cancer patients who received adjuvant chemotherapy. Cancer 77:107-112, 1996.
9. Venturini M, Bruzzi P, Del Mastro L, et al: Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer. J Clin Oncol 14:764-773, 1996.
10. Pierga JY, Asselain B, Jouve M, et al: Effect of adjuvant chemotherapy on outcome in patients with metastatic breast carcinoma treated with first-line doxorubicin-containing chemotherapy. Cancer 91:1079-1089, 2001.
11. Lluch A, Ojeda B, Colomer R, et al: Doxorubicin and paclitaxel in advanced breast carcinoma: Importance of prior adjuvant anthracycline therapy. Cancer 89:2169-2175, 2000.
12. Kaye SB: New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer 78(suppl 3):1-7, 1998.
13. Seidman AD: The evolving role of gemcitabine in the management of breast cancer. Oncology 60:189-198, 2001.
14. Spielmann M, Llombart-Cussac A, Kalla S, et al: Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology 60:303-307, 2001.
15. Rowinsky EK: The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353-374, 1997.
16. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858- 1867, 1996.
17. Seidman AD, Hudis CA, Albanell J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353- 3361, 1998.
18. Bishop JF, Dewar J, Toner G, et al: A randomized study of paclitaxel versus cyclophosphamide/ methotrexate/5-fluorouracil/ prednisone in previously untreated patients with advanced breast cancer: Preliminary results. Taxol Investigational Trials Group, Australia/ New Zealand. Semin Oncol 24(suppl 17):5-9, 1998.
19. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 20:3114-3121, 2002.
20. Kroep JR, Giaccone G, Tolis C, et al: Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines. Br J Cancer 83:1069-1076, 2000.
21. Kroep JR, Giaccone G, Voorn DA, et al: Gemcitabine and paclitaxel: Pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer. J Clin Oncol 17:2190-2197, 1999.
22. Cividalli A, Mauro F, Livdi E, et al: Schedule dependent toxicity and efficacy of combined gemcitabine/paclitaxel treatment in mouse adenocarcinoma. J Cancer Res Clin Oncol 126:461-467, 2000.
23. Rothenberg ML, Sharma A, Weiis JR, et al: Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors. Ann Oncol 9:133-138, 1998.
24. Sanchez-Rovira P, Medina JB, Mohedano N, et al: Results from a phase II study of gemcitabine in combination with paclitaxel in metastatic breast cancer (abstract). Ann Oncol 9(suppl 4):A77P, 1998.
25. Murad AM, Guimaraes RC, Aragao BC, et al: Phase II trial of the use of paclitaxel and gemcitabine as a salvage treatment in metastatic breast cancer. Am J Clin Oncol 24:264-268, 2001.
26. Colomer R, Llombart-Cussac A, Lluch A, et al: Biweekly paclitaxel plus gemcitabine in advanced breast cancer: Phase II trial and predictive value of HER2 extracellular domain (ECD). Ann Oncol 15: 201-206, 2004.
27. Delfino C, Caccia GM, Riva Gonzales L, et al: Gemcitabine plus paclitaxel administered as first-line chemotherapy for patients with advanced breast cancer (ABC) (abstract 2025). Proc Am Soc Clin Oncol 21:53b, 2002.
28. Vici P, Foggi P, Capomolla E, et al: Biweekly paclitaxel/gemcitabine (P/G) as salvage treatment in breast cancer patients (pts): Preliminary results (abstract 2054). Proc Am Soc Clin Oncol 21:61b, 2002.
29. Genot J-Y, Tubiana-Hulin M, Tubiana- Mathieu N, et al: Gemcitabine and paclitaxel in metastatic breast cancer: A phase II study in the first line setting (abstract 2002). Proc Am Soc Clin Oncol 21:48b, 2002.
30. Delfino C, Caccia G, Gonzales LR, et al: Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced breast cancer. Oncology 66:18-23, 2004.
31. Colomer R, Montero S, Lluch A, et al: Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 6:2356-2362, 2000.
32. Llombart-Cussac A, Moreno-Bueno G, Ruiz A, et al: Gene expression profiling for the prediction of response to neoadjuvant paclitaxel and gemcitabine in breast cancer (BC): Preliminary results from a phase II trial (abstract 580). Proc Am Soc Clin Oncol 23:22, 2004.
33. O'Shaughnessy J, Nag S, Calderillo- Ruiz G, et al: Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast can cer (MBC): Interim results of a global phase III study (abstract 25). Proc Am Soc Clin Oncol 22:7, 2003.
34. Albain KS, Nag S, Calderillo-Ruiz G, et al: Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival (abstract 510). Proc Am Soc Clin Oncol 23:5, 2004.
35. Gennari A, Santoro A, Bottini A, et al: Gemcitabine/epirubicin/paclitaxel (GET) as primary chemotherapy in stage II-IIIA operable breast cancer: Final results of a multicenter Italian study (abstract 64). Proc Eur Breast Cancer Conf 2004.
36. Sanchez-Rovira P, Jaen A, Gonzalez E, et al: Phase II trial of gemcitabine/doxorubicin/ paclitaxel administered every other week in patients with metastatic breast cancer. Clin Breast Cancer 1:226-232, 2000.
37. Zielinski C, Beslija S, Mrsic-Krmpotic Z, et al: Gemcitabine/epirubicin/paclitaxel vs 5-fluorouracil/epirubicin/cyclophosphamide as first-line treatment in metastatic breast cancer: Demographics of a randomized, multicenter phase III trial of the Central European Cooperative Oncology Group (CECOG) (abstract 26). Proc Am Soc Clin Oncol 22:7, 2003.
38. Sanchez-Rovira P, Ramirez C, DueÃ±as R, et al: HER2-status as a predictive factor for pathological complete response in primary breast cancer patients treated with gemcitabine- Adriamycin-Taxol as neoadjuvant treatment (abstract 240). Proceedings of the San Antonio Breast Cancer Symposium. Br east Cancer Res Treat 69:246, 2001.