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 (Gemzar), a novel cytotoxic agent with unique modes of action and cross
resistance, provides an important addition to the armamentarium for this
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, 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 (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.
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 (Taxotere), vinorelbine (Navelbine),
doxorubicin, and 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
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
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.
1. Cancer Facts & Figures 2000. Atlanta, American Cancer
2. Systemic treatment of early breast cancer by hormonal,
cytotoxic, or immune therapy. Lancet 339(8784):423-424,1992.
3. Baum M: Polychemotherapy for early breast cancer: An overview
of the randomized trials. Lancet 352:930-942, 1998.
4. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Phase III
randomized trial of high-dose chemotherapy and stem cell support shows no
difference in overall survival or severe toxicity compared to maintenance
chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil for women
with metastatic breast cancer who are responding to conventional induction
chemotherapy (abstract 1). Proc Am Soc Clin Oncol 18:1a, 1999.
5. Peters W, Rosner G, Vredenburgh J, et al: A prospective,
randomized comparison of two doses of combination alkyating agents as
consolidation after CAF in high-risk primary breast cancer involving ten or more
axillary lymph nodes: Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13
(abstract 2). Proc Am Soc Clin Oncol 18:1a, 1999.
6. The Scandinavian Breast Cancer Study Group 9401: Results from
a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb
supported by autologous bone marrow stem cells versus dose escalated and
tailored FEC therapy (abstract 3). Proc Am Soc Clin Oncol 18:2a, 1999.
7. Bezwoda WR: Randomized, controlled trial of high dose
chemotherapy versus standard dose chemotherapy for high risk, surgically
treated, primary breast cancer (abstract 4). Proc Am Soc Clin Oncol 18:2a, 1999.
8. Stadtmauer EA, O’Neill A, Goldstein LJ, et al:
Conventional-dose chemotherapy compared with high-dose chemotherapy plus
autologous hematopoietic stem-cell transplantation for metastatic breast cancer.
Philadelphia Bone Marrow Transplant Group. N Engl J Med 342(15):1069-1076, 2000.
9. Peters GJ, Bergman AM, Ruiz van Helperen VWT, et al:
Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol
22(4 suppl 11):72-79, 1995.
10. Nagourney RA, Evans SS, Makalinao AJ, et al: Gemcitabine
activity in primary cultures of human cancer (abstract 2161). Proc Am Assoc
Cancer Res 37:318, 1996.
11. Nagourney RA, Su Yz, Link J, et al: Gemcitabine synergy with
cisplatin: Clinical and laboratory correlates (abstract 2118). Proc Am Assoc
Cancer Res 39:310, 1998.
12. Evans SS, Chow C, Danskin JW, et al: Gemcitabine synergy
with nitrogen mustard in human tumors (abstract 3891). Proc Am Assoc Cancer Res
13. Nagourney RA: Gemcitabine and cisplatin "repeating
doublet" therapy in heavily pretreated, relapsed ovarian cancer (abstract
54). Cancer Invest 18(1):69-70, 2000.
14. Yap HY, Salem P, Hortobagyi GN, et al: Phase II study of
cisdichlorodiaminocisplatinum (II) in advanced breast cancer. Cancer Treat Rep
15. Sledge G, Loehrer PJ, Roth BJ, et al: Cisplatin as
first-line therapy for metastatic breast cancer. J Clin Oncol 6(12):1811-1814,
16. Jurga L, Misurova E, Kovac V, et al: The role of cisplatin
in chemotherapy of advanced breast cancer. Neoplasma 41(6):347-352, 1994.
17. Martin M, Diaz-Rubio E, Casado A, et al: Carboplatin: An
active drug in metastatic breast cancer. J Clin Oncol 10(3):433-437, 1992.
18. Martin M, Diaz-Rubio E, Casado A, et al: Phase II study of
carboplatin in advanced breast cancer: Preliminary results. Semin Oncol 18
(suppl 2):23-27, 1991.
19. O’Brien ME, Talbot DC, Smith IE: Carboplatin in the
treatment of advanced breast cancer: A phase II study using a
pharmacokinetically guided dose schedule. J Clin Oncol 11(11):2112-2117, 1993.
20. Crown J, Hakes T, Reichman B, et al: Phase II trial of
carboplatin and etoposide in metastatic breast cancer. Cancer 71(4):1254-1257,
21. Jones AL, Smith IE, O’Brien ME, et al: Phase II study of
continuous infusion fluorouracil with epirubicin and cisplatin in patients with
metastatic and locally advanced breast cancer: An active new regimen. J Clin
Oncol 12(6):1259-1265, 1994.
22. Gelmon KA, O’Reilly SE, Tolcher AW, et al: Phase I/II
trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast
cancer. J Clin Oncol 14(4):1185-1191, 1996.
23. Iaffaioli RV, Tortoriello A, Facchini G, et al: A phase II
study of carboplatin and vinorelbine as second-line treatment for advanced
breast cancer. Br J Cancer 72(5):1256-1258, 1995.
24. Bonnefoi H, Smith IE, O’Brien ME, et al: Phase II study of
continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of
cisplatin) in patients with metastatic/locally advanced breast cancer
(infusional EcarboF): A very active and well-tolerated outpatient regimen. Br J
Cancer 73(3):391-396, 1996.
25. Klaasen U, Wilke H, Weyhofen R, et al: Phase II study with
cisplatin and paclitaxel in combination with weekly high-dose 24 h infusional
5-fluorouracil/leucovorin for first-line treatment of metastatic breast cancer.
Anticancer Drugs 9(3):203-207, 1998.
26. Fountzilas G, Dimopoulos AM, Papadimitriou C, et al:
First-line chemotherapy with paclitaxel by 3-hour infusion and carboplatin in
advanced breast cancer (final report): A phase II study conducted by the
Hellenic Cooperative Oncology Group. Ann Oncol 9(9):1031-1034, 1998.
27. Carmichael J, Possinger K, Phillip P, et al: Advanced breast
cancer: A phase II trial with gemcitabine. J Clin Oncol 13(11):2731-2736, 1995.
28. Possinger K, Kaufmann M, Coleman R, et al: Phase II study of
gemcitabine as first-line chemotherapy in patients with advanced or metastatic
breast cancer. Anticancer Drugs 10(2):155-162, 1999.
29. Blackstein M, Vogel CL, Ambinder R, et al: Phase II study of
gemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol
30. Akrivakis K, Schmid P, Flath B, et al: Prolonged infusion of
gemcitabine in stage IV breast cancer: A phase I study. Anticancer Drugs
31. Speilmann M, Llombart-Cussac A, Kalla S, et al: Single-agent
gemcitabine is active in previously treated metastatic breast cancer. Ann Oncol
32. Schmid P, Akrivakis K, Flath B, et al: Phase II trial of
gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs
33. Brodowicz T, Moslinger R, Herscovici V, et al: Second- and
third-line treatment of metastatic breast cancer with gemcitabine (abstract
180). Eur J Cancer 34(suppl 5):S44, 1998.
34. Carmichael J, Walling J: Advanced breast cancer:
Investigational role of gemcitabine. Eur J Cancer 33(suppl 1):S27-S31, 1997.
35. Arning M, Blatter J: Gemcitabine in solid tumorsPresent
status and future development. Oncology 20:297-304, 1997.
36. Colomer R, Llombart A, Lluch A, et al:
Paclitaxel/gemcitabine administered every 2 weeks in advanced breast cancer:
Preliminary results of a phase II trial. Semin Oncol 27(1 suppl 2):20-24, 2000.
37. Mavroudis D, Malamos N, Alexopoulos A, et al: Salvage
chemotherapy in anthracycline-pretreated metastatic breast cancer patients with
docetaxel and gemcitabine: A multicenter phase II trial. Greek Breast Cancer
Cooperative Group. Ann Oncol 10(2):211-215, 1999.
38. Haider K, Komek GV, Kwasny W, et al: Treatment of advanced
breast cancer with gemcitabine and vinorelbine plus human granulocyte
colony-stimulating factor. Breast Cancer Res Treat 55(3):203-211, 1999.
39. Perez-Manga G, Lluch A, Alba E, et al: gemcitabine in
combination with doxorubicin in advanced breast cancer: Final results of a phase
II pharmacokinetic trial. J Clin Oncol 18(13):2545-2552, 2000.
40. Luftner D, Flath B, Akrivakis C, et al: Gemcitabine plus
dose-escalated epirubicin in advanced breast cancer: Results of a phase I study.
Invest New Drugs 16(2):141-146, 1998.
41. Gennari A, Donati S, Danesi R, et al: The
gemcitabine/epirubicin/paclitaxel combination in advanced breast cancer. Semin
Oncol 27(1 suppl 2):14-19, 2000.
42. Chaudhry S, Abdel-Rahman HA, Patil R, et al: Prospective
phase II study of weekly cisplatin-gemcitabine in refractory breast cancer (abstract 430). Proc Am Soc Clin
Oncol 19:111a, 2000.
43. Doroshow JH, Tetef M, Margolin K, et al: Significant
activity of gemcitabine and cisplatin in both heavily and minimally pretreated
breast cancer patients: A California Cancer Consortium/Loyola University of
Chicago trial (abstract 609H). Proc Am Soc Clin Oncol 19:155a, 2000.
44. Nagourney RA, Link J, Blitzer J, et al: Gemcitabine plus
cisplatin repeating doublet therapy in previously treated, relapsed breast
cancer patients. J Clin Oncol 18(11):2245-2249, 2000.
45. Nagourney RA, Evans SS, Mesenger JC, et al:
2-chlorodeoxyadenosine activity and cross resistance patterns in primary
cultures of human hematologic neoplasms. Br J Cancer 67:10-14, 1993.
46. Ventana Medical Systems anti-c-erbB-2 Detection Kit.
47. Waud WR, Gilbert KS, Grindley GB, et al: Lack of cross
resistance with gemcitabine against drug-resistant murine P388 leukemias. Cancer
Chemother Pharmacol 38:178-180, 1996.
48. Reed E: Platinum-DNA adduct, nucleotide excision repair, and
platinum based anti-cancer chemotherapy. Cancer Treat Rev 24(5):331-344, 1998.
49. Vaisman A,Varchenko M, Umar A, et al: The role of hMLH1,
hMLH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlation
with replicative bypass of platinum-DNA adducts. Cancer Res 58(16):3579-3585,
50. Yang LY, Li L, Jiang H, et al: Expression of ERCC1 antisense
RNA abrogates gemcitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cell lines defective in mismatch repair but
proficient in nucleotide excision repair. Clin Cancer Res 6(3):773-781, 2000.
51. Oster MW, Schilsky RL, Faraggi D, et al: Cytosine
arabinoside and cisplatin for advanced breast cancer. A phase II study of the
Cancer and Leukemia Group B. Cancer 68(8):1696-1698, 1991.
52. Abratt RP, Sandler A, Crinao L, et al: Combined cisplatin
and gemcitabine for non-small-cell lung cancer: Influence of scheduling on
toxicity and drug delivery. Semin Oncol 25(4 suppl 9):35-43, 1998.
53. Braakhuis BJ, Ruiz van Haperen VW, Welters MJ, et al:
Schedule-dependent therapeutic efficacy of the combination of gemcitabine and
cisplatin in head and neck cancer xenografts. Eur J Cancer 31A(13-14):2335-2340,
54. Evans S, Chow C, Yong-Zuang S, et al: Is cisplatin plus
gemcitabine equivalent to carboplatin plus gemcitabine? Yes and no. Proc Am Soc Clin Oncol. Submitted, 2001.
55. Yanagahara RH, Beck M: Low dose carboplatin and gemcitabine
in advanced non-small-cell lung cancer: An active combination with low
toxicity (abstract 2072). Proc Am Soc Clin Oncol 19:527a, 2000.
56. Evans SS, Chow C, Su YZ, et al: Oxaliplatin vs cisplatin activity in human tumors (abstract 894). Proc Am Soc Clin
Oncol 19:228a, 2000.
57. Cortazar P, Johnson BE: Review of the efficacy of
individualized chemotherapy selected by in vitro drug sensitivity testing for
patients with cancer. J Clin Oncol 17:1625-1631, 1999.