- Email: [email protected]
Gemcitabine Plus Paclitaxel in Breast Cancer
Gemcitabine Plus Paclitaxel in Breast Cancer Denise A. Yardley The combining of gemcitabine and paclitaxel in chemotherapy for metastatic breast cancer is supported by sound evidence of single-agent activity, beneficial pharmacologic interaction, and largely non-overlapping toxicities. In phase II studies in both heavily pretreated patients and chemotherapy-naive patients, the combination has produced remarkably high rates of response and has been exceptionally well tolerated. A recent phase III trial of the combination as first-line treatment for metastatic breast cancer showed significant improvements in objective response, time to disease progression, and overall survival compared with paclitaxel alone, leading to the approval of gemcitabine in combination with paclitaxel for this indication. The combination was very well tolerated and was not associated with any adverse impact in quality of life compared with paclitaxel alone. Continued investigation of the role of gemcitabine/taxane combinations in early and advanced breast cancer is ongoing, including additional investigation of biweekly schedules and use of the combination as part of triplet therapy with trastuzumab. Semin Oncol 32(suppl 6):S14-S21 © 2005 Elsevier Inc. All rights reserved.
I
n 2005, more new cases of breast cancer than of any other malignancy will be diagnosed in women in the United States, with the estimated incidence exceeding 211,000 cases.1 However, advances in breast cancer therapy and management have continued to result in significant reductions in diseaserelated mortality. Therefore, it is estimated that mortality caused by lung cancer (approximately 73,000 deaths) will continue to exceed breast cancer mortality in 2005. Incremental improvements in chemotherapy have followed advances in the understanding of tumor biology. Newer, effective antineoplastic regimens are partially responsible for the improvement in survival that is evident for patients who face a new diagnosis of breast cancer. Diminishing the overall tumor burden and thereby controlling disease progression are increasingly important end points with which one can reliably measure the effectiveness of treatment early in the disease. While these desired benefits are frequently accompanied by symptom control, treatment regimens are frequently accompanied by significant toxicities. It
The Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN. Dr Yardley has received research grant support from Eli Lilly, Sanofi-Aventis, Novartis Inc, Pfizer Inc, Amgen, Genentech Inc, Keryx Biopharmaceuticals, Inc, and Abraxis Oncology. She has received honoraria as a consultant to Pfizer Inc, Genentech, Eli Lilly and Company, and Sanofi-Aventis and is a member of the Speakers Bureaus of Pfizer Inc, Eli Lilly and Company, Sanofi-Aventis, Genentech Inc, AstraZeneca, and Abraxis Oncology. Address reprint requests to Denise A. Yardley, MD, 250 25th Ave North, Suite 110, Nashville, TN 37203. E-mail: [email protected]
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0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.06.025
is thus encouraging that some newer treatments, while proving to be effective in providing symptom relief and controlling disease progression, have been associated with measurable improvements in multiple quality-of-life (QOL) parameters. For women with advanced breast cancer, the development of new and effective drugs with improved toxicity profiles is long overdue. Chemotherapy remains an essential first-line treatment component for women who confront a diagnosis of recurrent breast cancer. In the past decade, the taxanes have emerged as one of the most powerful classes of compounds, and both docetaxel and paclitaxel are welcome additions to the breast cancer patients’ treatment armamentarium. Although both taxanes disrupt the balance of microtubulin polymerization and depolymerization, deactivate Bcl-2, and induce apoptosis in tumor cells, the differences in their molecular pharmacology, pharmacokinetics, and pharmacodynamic profiles are apparent.2,3 These dissimilarities account for observed differences in their potencies, clinical activity, and toxicities, as well as their incomplete cross resistance.4-6 As a single agent, paclitaxel has produced objective response rates (RRs) of 23% to 48% in patients with anthracycline-resistant disease7-9 and 29% to 62% in patients with no prior treatment for metastatic disease.10-12 Docetaxel, which is also effective in generating responses in extensively pretreated patients with metastatic disease, has produced single-agent RRs ranging from 30% (in patients who have been treated with two or more prior regimens) to 42% (in patients with less-extensive pretreatment).13,14 As a result of their prominent monotherapy activity, efficacy in pretreated patients, and the ease
Gemcitabine plus paclitaxel in breast cancer
S15
Table 1 Phase II Studies: Gemcitabine and Paclitaxel in Metastatic Breast Cancer
Study
Gemcitabine Dose
Paclitaxel Dose
No. of Patients
Response
Delfino et al27
1,200 mg/m2 days 1, 8 every 21 days
42
Genot et al26
1,200 mg/m2 days 1, 8 every 21 days
Murad et al23*
1,000 mg/m2 days 1, 8, 15 every 28 days; 1st five patients Remaining patients days 1, 8 every 21 days
Paclitaxel 175 mg/m2 day 1 every 21 days Paclitaxel 175 mg/m2 day 1 every 21 days Paclitaxel 175 mg/m2 day 1 every 21 days
Overall RR 55% 14% CR 41% PR Overall RR 42% 6% CR 36% PR Overall RR 55% 17% CR 38% PR 21% SD
40 (36 evaluable) 29
Median Duration/ Response
Median Survival
18 mos
19 mos
344 days
NR
8 mos
12 mos
Abbreviations: CR, complete response; NR, not reported; PR, partial response; RR, response rates; SD, stable disease. *Previously treated.
with which they can be combined with other agents, the taxanes have increasingly been incorporated in clinical investigations to define their role in combination therapy and in both advanced and earlier stage disease. In initial studies of anthracycline/taxane combinations, paclitaxel/doxorubicin combinations were highly effective although somewhat plagued by the discovery of schedule-dependent cardiac toxicity reported in some trials.15 Nonetheless, the anthracyline/ taxane doublets were embraced, and investigators quickly entered them into a series of clinical trials.16-19 Perhaps the most noteworthy was the Eastern Cooperative Oncology Group 1193 trial that showed significant improvements in RR and time to disease progression (TTP), with the paclitaxel/doxorubicin doublet compared with paclitaxel monotherapy.19 However, the absence of a survival advantage, perhaps as a consequence of the lack of synergism for the taxane/anthracycline combination, diminished the zeal for further exploration of this often myelosuppressive regimen. Furthermore, with the increasing incorporation of doxorubicin into adjuvant breast cancer therapy, there was increased attention to identifying non-anthracycline– based taxane combinations. Gemcitabine is a novel pyrimidine antimetabolite that possesses a unique mechanism of action that greatly enhances its combination with a variety of chemotherapy agents, including the taxanes. Gemcitabine inhibits ribo-
nucleotide reductase, an enzyme responsible for the production of deoxynucleotide triphosphates. Requiring intracellular phosphorylation of the 2’,2’ difluorodeoxycytidine, the action of gemcitabine results in the production and accumulation of difluorodeoxycytidine triphosphate (dFdCTP). Directly competing with deoxynucleotide triphosphate (whose production is impaired by gemcitabine), gemcitabine triphosphate’s subsequent DNA incorporation as a false nucleotide results in masked chain termination.20 Preclinical studies that investigated gemcitabine in non–small cell lung cancer cell lines showed an apparent two-fold increased accumulation of dFdCTP in the presence of paclitaxel, suggesting enhanced cytotoxic effects when these agents are administered in combination.21,22 On the basis of such findings, clinical evaluation of the combination of gemcitabine and paclitaxel, each with identified single agent activity in breast cancer, was eagerly undertaken.
Gemcitabine/ Paclitaxel in Pretreated Metastatic Breast Cancer Several investigators have evaluated the activity of gemcitabine and paclitaxel in patients with metastatic breast cancer (MBC) in phase II trials. The findings are summarized
Table 2 Phase II Randomized Study of Three Gemcitabine-Taxane Combinations in Metastatic Breast Cancer Treatment Arms*
Schedule
Response Rate
Time to Progression
Gemcitabine 1,250 Paclitaxel 175 mg/m2 over 3 hours
Days 1, 8 Day 1
49%
7.5 mos
Gemcitabine 1,000 mg/m2 Paclitaxel 100 mg/m2 over 1 hour
Days 1, 8 Days 1, 8
52%
7.0 mos
Gemcitabine 1,000 mg/m2 Docetaxel 40 mg/m2
Days 1, 8 Days 1, 8
52%
7.4 mos
mg/m2
*Repeated every 3 weeks. Data from Khoo et al.28
D.A. Yardley
Neutropenia 11% 27 (20 evaluable) Paclitaxel 150 mg/m2 days 1, 15 every 28 days 1,500 mg/m2 days 1, 15 every 28 days Vici et al24*
43 (38 evaluable) 2,500 mg/m2 day 1 every 14 days Llombart et al31
Paclitaxel 150 mg/m2 day 1 every 14 days
43 (42 evaluable) 2,500 mg/m2 day 1 every 14 days Colomer et al30
Sanchez-Rovira et
Abbreviations: CR, complete response; NR, not reported; PR, partial response; SD, stable disease; TTP, time to disease progression. *Heavily pretreated
MedianTTP:8mos
NR
Leukopenia 14% NR NR
13.4mos
NR
Neutropenia 29%
Hematologic 15% Growth factors 34% 11 mos NR
45% 16%CR 30% PR 69% 24%CR 45% PR 19%SD 68% 21%CR 47% PR 18%SD 45% 10%CR 35% PR 44
Paclitaxel 135 days 1, 15 every 28 days Paclitaxel 150 mg/m2 day 1 every 14 days
2,500 days 1, 15 every 28 days
mg/m2
al29
mg/m2
No. of Patients Paclitaxel Dose Gemcitabine Dose Study
Table 3 Phase II Studies: Biweekly Gemcitabine and Paclitaxel in Metastatic Breast Cancer
Response
Median Duration/Response
Median Survival
Hematologic Toxicity
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in Tables 1-3. Two completed phase II studies of this combination in heavily pretreated patients have shown impressive RRs of approximately 45% to 55% as secondor third-line therapy, prompting further interest and subsequent evaluations in less pretreated patients.23,24 In the first of these two studies, Murad et al23 conducted a phase II trial using gemcitabine 1,000 mg/m2 administered on days 1, 8, and 15, and paclitaxel 175 mg/m2 on day 1 of a 28-day cycle in 29 visceral disease-predominant MBC patients, the majority of whom were considered anthracycline-refractory. The first five patients experienced significant thrombocytopenia (18.5%), resulting in the elimination of the day-15 gemcitabine dose in all subsequent cycles. The remaining cohort of patients were treated on a 21-day schedule, resulting in a decline of the rate of thrombocytopenia to 5%. A remarkable overall RR of 55% was noted, including five patients who achieved complete responses (CRs). Growth factor use in one third of the patients resulted in grade 3/4 neutropenia in only 9% of courses. Using docetaxel with a regimen similar to that outlined above, Fountzilas et al25 reported results for 40 anthracycline-resistant MBC patients. The slightly inferior RR observed in this study likely reflected the poorer prognosis and greater age of the patient population. Neutropenia, a characteristic myelosuppressive effect of docetaxel, was more prominent and experienced by nearly one half of enrolled patients. Nonetheless, the duration of response and median survival of just over 1 year were consistent between the studies despite using different taxanes. The high activity of gemcitabine/taxane doublets provided additional compelling evidence of the nature of the antineoplastic activity of this combination, and warranted evaluation of these combinations as first-line MBC therapy.
Phase II Gemcitabine/ Paclitaxel First-Line MBC Trials As first-line treatment in patients with advanced breast cancer, the gemcitabine/paclitaxel combination is characterized by consistently high RRs and excellent tolerability (Table 1).23,26,27 Genot et al26 reported their results for 40 chemotherapynaive MBC patients treated with paclitaxel 175 mg/m2 on day 1 and gemcitabine 1,200 mg/m2 days 1 and 8 every 3 weeks. Forty patients were treated; 36 were evaluable for response. Two CRs and 13 partial responses were reported, resulting in an overall RR of 42%. Median TTP did not vary markedly from that reported in other phase II trials investigating the efficacy of this doublet. In a subsequent trial using the identical gemcitabine/paclitaxel schedule also as first-line MBC therapy, Delfino et al27 reported an overall RR of 55%, with 14% CRs and 41% partial responses in 42 patients, the majority of whom had received prior adjuvant therapy. The regimen was well tolerated, and toxicities consisted primarily of mild grade 3/4 hematologic toxicity, with grade 3/4 leukopenia in only 14% of patients. Regardless of the pretreatment patient characteristics, the paclitaxel/gemcitabine combina-
Gemcitabine plus paclitaxel in breast cancer tion was active, with a clearly manageable and favorable toxicity profile. Further investigation of the gemcitabine/taxane doublet in MBC was recently reported by Khoo et al,28 who addressed the mounting interest in evaluating a weekly taxane schedule in combination with gemcitabine. The study design of this three-arm, randomized phase II trial had one arm that evaluated the standard paclitaxel 175 mg/m2 day-1 dose with gemcitabine 1,250 mg/m2 days 1 and 8. The two comparator arms incorporated a weekly taxane schedule with paclitaxel at 100 mg/m2 in one of the arms, and weekly docetaxel 40 mg/m2 in the other arm, each combined with gemcitabine 1,000 mg/m2. Both agents were administered on days 1 and 8 of a 21-day cycle. No clear RR, TTP, or survival benefit was apparent between the three arms, with no benefit apparent in favor of either the weekly taxane schedule or either taxane (Table 2).28 However, use of the taxane docetaxel, despite incorporation of a weekly administration schedule typically accompanied by less hematologic toxicity, was associated with significantly more overall grade 3/4 toxicities, particularly febrile neutropenia, infections, and transfusions, as well as use of antibiotics and granulocyte colony-stimulating factor. Continued evidence emerged supporting the finding that the gemcitabine/paclitaxel doublet possesses a favorable therapeutic index, with remarkable activity and easily manageable toxicities.
Phase II Trials of Biweekly Gemcitabine/Taxanes The biweekly gemcitabine/paclitaxel administration schedule has generated considerable interest (Table 3).24,29-31 In previously treated MBC patients, Sanchez-Rovira et al29 assessed a biweekly dose of paclitaxel 135 mg/m2 and gemcitabine 2,500 mg/m2 given on days 1 and 15. In spite of the fact that more than 90% of patients received prior anthracycline-based therapy, a striking RR of 45% was evident, with seven CRs. Despite the degree of pretreatment, grade 3/4 hematologic events occurred in 15% of patients. To maintain dose intensity, only 34% of patients used growth factor support. In the trial of Vici et al24 27 anthracycline-pretreated patients, the majority of whom also received prior treatment with the taxane docetaxel, were treated with gemcitabine 1,500 mg/m2 and paclitaxel at 150 mg/m2 administered on days 1 and 15 at 28-day intervals. Twenty patients were evaluable for efficacy, showing an overall RR of 45%, with two CRs (21%) reported. Growth factor support mandated days 7 to 9 and 20 to 22 resulted in only 11% of patients experiencing grade 3/4 neutropenia. This encouraging and consistent activity with the biweekly gemcitabine/paclitaxel schedule in heavily pretreated MBC patients led to growing enthusiasm in evaluating this appealing doublet as first-line therapy in MBC. Both Colomer et al30 and Llombart et al31 investigated identical gemcitabine/paclitaxel biweekly schedules as first-line treatment in MBC. Using a day-1 gemcitabine dose of 2,500 mg/m2 with paclitaxel 150 mg/m2 delivered every 2 weeks, remarkable respective RRs
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Figure 1 Study JHQG: Phase III trial comparing gemcitabine plus paclitaxel versus paclitaxel alone.
of 69% and 68% were achieved in chemotherapy-naive MBC patients. Surprisingly, despite a two-fold increase in the gemcitabine dose, grade 3/4 hematologic toxicities were minimal and achieved without prophylactic growthfactor support. In this era of dose intensity, enthusiasm for the biweekly gemcitabine/paclitaxel schedule continues to escalate.
Novel Phase II Gemcitabine/ Paclitaxel Combinations The combination of gemcitabine and paclitaxel is effective in both chemotherapy-naive and heavily pretreated patients. The RR of 55% achieved for the doublet in anthracycline pretreated patients23 may be particularly appreciated in view of the low phase III single-agent activity of paclitaxel after doxorubicin failure.32 Although combination chemotherapy results in higher RRs, recent efforts to improve survival have focused on biologically based therapies such as trastuzumab, a humanized monoclonal antibody directed against the HER2/neu onco-protein. Slamon et al33 conducted a randomized phase III trial in patients with HER2– over-expressing breast cancer, and showed that trastuzumab added to chemotherapy resulted in a higher RR, longer duration of response, and more importantly, a 6-month improvement in overall survival (OS) compared with patients treated with chemotherapy alone. Given the concentration-dependent synergistic interaction of gemcitabine with trastuzumab,34 as well as that previously established between trastuzumab and paclitaxel, the effects of the triplet combination of gemcitabine, paclitaxel, and trastuzumab against HER2– overexpressing breast cancer was investigated. Miller et al35 reported a 67% RR with a median OS just under 2 years when using the triplet. This significant activity was confirmed by Colomer et al,36 who reported a RR of 78%. As the role of targeted therapy continues to evolve, the augmented activity associated with this triplet makes it an attractive first-line treatment option in patients with HER2-amplified breast cancer.
D.A. Yardley
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Phase III Trial of Gemcitabine/ Paclitaxel as First-Line Therapy in MBC Based on the significant antitumor activity that was reported from the phase II studies of the gemcitabine/paclitaxel doublet, Albain et al37 and O’Shaughnessy et al38 conducted a prospective, phase III randomized trial (JHQG) to evaluate the benefit of gemcitabine when added to standard-dose paclitaxel (Fig 1). While an interim OS analysis has been performed following the favorable TTP results that emerged from the first planned interim analysis, final analysis of the study’s predefined primary endpoint of survival will take place in 2005, once the protocol predefined number of events (n ⫽ 440) have occurred. From August 1999 through April 2002, 98 centers in 19 countries enrolled and randomized 529 women with measurable MBC and a Karnofsky performance status ⱖ70% to receive paclitaxel monotherapy at 175 mg/m2 on day 1 or paclitaxel 175 mg/m2 day 1 with gemcitabine 1,250 mg/m2 on days 1 and 8; cycles were administered in both arms every 21 days until disease progression. The treatment arms were balanced for all patient and demographic characteristics. Patients had a median age of 53 years, and over 70% of patients had visceral metastases, with two or more organ systems involved in 76%. Prior anthracycline use was documented in 96% of patients, and one half of the study patients in both arms had received prior hormonal therapy. Objective RR was significantly increased with combination treatment (39.3% v 25.6%, P ⫽ .0007). Median TTP mirrored the superior overall RR observed for the combination–5.4 months versus 3.5 months (P ⫽ .0013), a highly significant improvement. Unlike what has been observed with other taxane combinations (eg, the anthracycline/taxane doublets), gemcitabine appeared to add little in the way of either hematologic or nonhematologic toxicity, with overall grade 3/4 events being relatively uncommon. The reported toxicities were minimal, expected, and easily manageable. Grade 4 neutropenia was observed in only 17% of patients who received the doublet compared with an incidence of 7% in patients receiving single-agent paclitaxel. However, febrile neutropenia was extremely infrequent in both arms, occurring in only 5% and 2%, respectively. Perhaps most unexpected was the lack of severe thrombocytopenia, an observation that suggested a “platelet-sparing” effect associated with paclitaxel when combined with gemcitabine. Nonhematologic toxicity was modest in both arms with less than 10% grade 3/4 adverse events in both arms. These results are all in the context of a greater than 90% delivered dose intensity for gemcitabine/paclitaxel combination; only 7% of gemcitabine doses were omitted with 8% reduced because of toxicity. A subset of patients underwent a variety of evaluations, including QOL measurements performed at baseline, before each cycle, and as patients went off study. According to the Brief Pain Inventory administered to a subset of 290 patients, lower pain scores were shown for gemcitabine/paclitaxeltreated patients, while paclitaxel patients had essentially unchanged pain scores.39 As a result, there was a significant reduction in analgesic use in 25% of patients receiving gem-
citabine/paclitaxel. In addition, a majority of enrolled patients underwent a four-scale QOL assessment implementing the Rotterdam Symptom Checklist tool that evaluated activity level, physical symptom distress, psychologic distress, and overall valuation of life. No significant differences emerged across different time points between the treatment arms. However, a statistically significant improvement in QOL was experienced at cycles 5 and 6 (P ⫽ .005 and .036, respectively) when compared with baseline by patients treated with the gemcitabine/paclitaxel doublet. This comes somewhat as a surprise because at cycles 5 and 6 patients typically are experiencing cumulative chemotherapy toxicities that often negatively impact QOL. The gemcitabine/paclitaxel doublet appears to defy one of the major criticisms of combination therapy–specifically, when two or more drugs are administered together there are risks of producing increased toxicity and impairments in QOL that often outweigh the marginal efficacy benefits. The high degree of statistical significance shown for most endpoint comparisons supports the gemcitabine/paclitaxel combination as effective, with a higher chance of and longer duration of disease control; this increased effectiveness was achieved without incurring considerably more toxicity or sacrificing QOL. On May 19, 2004, gemcitabine, in combination with paclitaxel, received US Food and Drug Administration approval for the first-line treatment of patients with MBC after failure of prior anthracycline-containing adjuvant chemotherapy.
Discussion While there is still much controversy regarding the respective roles of combination versus single-agent chemotherapy in the management of patients with MBC, the recently completed multinational JHQG trial evaluating the gemcitabine/ paclitaxel doublet as compared with single-agent paclitaxel continues to distinguish itself from other randomized comparator trials evaluating disparate treatment strategies. When considering the goals of combination therapy, one must try to remain clear on the rationale that underlies antineoplastic combination strategies. Ideally, the optimal combination regimen should satisfy a number of principles before embarking on demonstrating efficacy. Specifically, each component should be administered at the full known effective dose when combined with other agents, as is evident for both gemcitabine and paclitaxel in the aforementioned JHQG trial; perhaps just as important, this should not come at the cost of increased toxicity or impaired dose intensity. As has been so often evident, combination regimens often use less than the established optimal effective doses of the respective chemotherapy agents, frequently in efforts to minimize overlapping toxicities. Dosing compromises are commonly accompanied by inferior outcomes; these inferior outcomes can lead to misleading conclusions regarding the ability of combination chemotherapy to deliver superior outcomes. Ideally, the components of combination therapy should show non-overlapping safety profiles; they should also exhibit additive or synergistic effects and minimal or no cross-resistance. For patients who will most benefit from combination treat-
Gemcitabine plus paclitaxel in breast cancer
S19
Figure 2 Design of the paclitaxel, anthracycline, gemcitabine, and cyclophosphamide (tAnGo) trial of adjuvant therapy in early-stage breast cancer. C, cyclophosphamide; E, epirubicin; G, gemcitabine; T, paclitaxel.
ment, such as younger patients with symptomatic disease, a high disease burden, or short disease-free interval, gemcitabine/paclitaxel offers the appropriate patient a higher chance of disease control and longer duration of control without incurring considerably more toxicity. Distinguishing this doublet from so many others in the management of MBC is the fact that the RR benefit achieved by the doublet has translated into not only a TTP benefit but also an OS benefit at the price of modest toxicity without evident QOL disadvantages. It is hoped that the efficacy documented in MBC for the gemcitabine/paclitaxel combination, escalating its entry into adjuvant and neoadjuvant breast cancer trials, will translate
into curative outcomes for those newly diagnosed women with early stage breast cancer. Early in 2005, the United Kingdom is expected to complete its accrual to their “tAnGo” (paclitaxel, Anthracycline, Gemcitabine, cyclophosphamide) breast cancer trial evaluating the gemcitabine/paclitaxel combination following four cycles of epirubicin/cyclophosphamide (Fig 2). Likewise, the National Surgical Adjuvant Breast and Bowel Project elected to incorporate this exciting doublet in their upcoming node-positive breast cancer trial. Following four cycles of doxorubicin/cyclophosphamide, patients will receive four cycles of either single-agent paclitaxel or gemcitabine/paclitaxel (Fig 3). A biweekly schedule of ad-
Figure 3 Integration of gemcitabine/paclitaxel combination in the National Surgical Adjuvant Breast and Bowel Project B38 Lymph Node-Positive Adjuvant Breast Cancer Trial.
D.A. Yardley
S20 ministration has been chosen for these two arms, while a third arm will administer six cycles of docetaxel, doxorubicin, and cyclophosphamide on an every-3-week basis. In combination with trastuzumab, the gemcitabine/paclitaxel doublet shows promising activity with RRs ranging between 67% to 78% and an estimated median survival exceeding 2 years.40 While the benefits of combination therapy may remain marginal in the metastatic setting, earlier-stage disease may be more suited to showing a survival advantage, thus possibly sparing women from ever having to experience recurrent disease. The current trials underway are carefully posed to be better able to further define gemcitabine’s evolving role in all stages of breast cancer.
Conclusion First-line gemcitabine plus paclitaxel in MBC has shown potent antitumor activity, yielding superior responses, TTP, and OS as compared with paclitaxel monotherapy. A high degree of statistical significance was shown for most endpoint comparisons in the setting of good tolerability. The favorable therapeutic index of the gemcitabine/paclitaxel regimen supports its use as a new and evolving treatment option for MBC patients. The exciting phase III data remain a motivating force supporting the evaluation of this active and well-tolerated doublet in earlier-stage disease with hopes of incrementally increasing the curative potential for women with early stage breast cancer. From its inception, gemcitabine has shown significant activity in multiple tumor types, accompanied by preservation of multiple QOL parameters. As its role in the patient diagnosed with breast cancer continues to evolve, we eagerly and enthusiastically await the unveiling of gemcitabine’s next chapter in the management of the patient with breast cancer.
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every two weeks in advanced breast cancer. Proc Am Soc Clin Oncol 19:110a, 2000 (abstr 426) Paridaens R, Biganzoli L, Bruning P, et al: Paclitaxel versus doxorubicin as first-line single agent chemotherapy for metastatic breast cancer: A European organization for research and treatment of cancer randomized study with cross-over. J Clin Oncol 18:724-733, 2000 Slamon D, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 Pegram M, Konecny G, O’Callaghan C, et al: Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 96:739-749, 2004 Miller K, Sisk J, Gize G, et al: Phase II study of gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer: A Hoosier Oncology Group trial. Breast Cancer Res Treat 76:S113, 2002 (suppl 1) (abstr 437) Colomer R, Mayordomo J, Calvo L, et al: HER2 ECD-positive metastatic breast cancer treated with gemcitabine, paclitaxel plus trastuzumab (GTH). Breast Cancer Res Treat 88:S127, 2004 (suppl 1) (abstr 3046)
S21 37. Albain K, Nag S, Calderillo-Riuz 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. Proc Am Soc Clin Oncol 23:5, 2004 (abstr 510) 38. O’Shaughnessy J, Nag S, Calderillo-Riuz G, et al: Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast cancer (MBC): Interim results of a global phase III study. Proc Am Soc Clin Oncol 22:7, 2003 (abstr 25) 39. Moinpour C, Wu J, Donaldson G, et al: Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pretreated metastatic breast cancer (MBC): Quality of life (QoL) and pain palliation results from the global phase III study. Proc Am Soc Clin Oncol 23:32, 2004 (abstr 621) 40. Miller K, Sisk J, Ansari R, et al: Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. Oncology 15:38-40, 2001 (suppl 3)
I
n 2005, more new cases of breast cancer than of any other malignancy will be diagnosed in women in the United States, with the estimated incidence exceeding 211,000 cases.1 However, advances in breast cancer therapy and management have continued to result in significant reductions in diseaserelated mortality. Therefore, it is estimated that mortality caused by lung cancer (approximately 73,000 deaths) will continue to exceed breast cancer mortality in 2005. Incremental improvements in chemotherapy have followed advances in the understanding of tumor biology. Newer, effective antineoplastic regimens are partially responsible for the improvement in survival that is evident for patients who face a new diagnosis of breast cancer. Diminishing the overall tumor burden and thereby controlling disease progression are increasingly important end points with which one can reliably measure the effectiveness of treatment early in the disease. While these desired benefits are frequently accompanied by symptom control, treatment regimens are frequently accompanied by significant toxicities. It
The Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN. Dr Yardley has received research grant support from Eli Lilly, Sanofi-Aventis, Novartis Inc, Pfizer Inc, Amgen, Genentech Inc, Keryx Biopharmaceuticals, Inc, and Abraxis Oncology. She has received honoraria as a consultant to Pfizer Inc, Genentech, Eli Lilly and Company, and Sanofi-Aventis and is a member of the Speakers Bureaus of Pfizer Inc, Eli Lilly and Company, Sanofi-Aventis, Genentech Inc, AstraZeneca, and Abraxis Oncology. Address reprint requests to Denise A. Yardley, MD, 250 25th Ave North, Suite 110, Nashville, TN 37203. E-mail: [email protected]
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0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.06.025
is thus encouraging that some newer treatments, while proving to be effective in providing symptom relief and controlling disease progression, have been associated with measurable improvements in multiple quality-of-life (QOL) parameters. For women with advanced breast cancer, the development of new and effective drugs with improved toxicity profiles is long overdue. Chemotherapy remains an essential first-line treatment component for women who confront a diagnosis of recurrent breast cancer. In the past decade, the taxanes have emerged as one of the most powerful classes of compounds, and both docetaxel and paclitaxel are welcome additions to the breast cancer patients’ treatment armamentarium. Although both taxanes disrupt the balance of microtubulin polymerization and depolymerization, deactivate Bcl-2, and induce apoptosis in tumor cells, the differences in their molecular pharmacology, pharmacokinetics, and pharmacodynamic profiles are apparent.2,3 These dissimilarities account for observed differences in their potencies, clinical activity, and toxicities, as well as their incomplete cross resistance.4-6 As a single agent, paclitaxel has produced objective response rates (RRs) of 23% to 48% in patients with anthracycline-resistant disease7-9 and 29% to 62% in patients with no prior treatment for metastatic disease.10-12 Docetaxel, which is also effective in generating responses in extensively pretreated patients with metastatic disease, has produced single-agent RRs ranging from 30% (in patients who have been treated with two or more prior regimens) to 42% (in patients with less-extensive pretreatment).13,14 As a result of their prominent monotherapy activity, efficacy in pretreated patients, and the ease
Gemcitabine plus paclitaxel in breast cancer
S15
Table 1 Phase II Studies: Gemcitabine and Paclitaxel in Metastatic Breast Cancer
Study
Gemcitabine Dose
Paclitaxel Dose
No. of Patients
Response
Delfino et al27
1,200 mg/m2 days 1, 8 every 21 days
42
Genot et al26
1,200 mg/m2 days 1, 8 every 21 days
Murad et al23*
1,000 mg/m2 days 1, 8, 15 every 28 days; 1st five patients Remaining patients days 1, 8 every 21 days
Paclitaxel 175 mg/m2 day 1 every 21 days Paclitaxel 175 mg/m2 day 1 every 21 days Paclitaxel 175 mg/m2 day 1 every 21 days
Overall RR 55% 14% CR 41% PR Overall RR 42% 6% CR 36% PR Overall RR 55% 17% CR 38% PR 21% SD
40 (36 evaluable) 29
Median Duration/ Response
Median Survival
18 mos
19 mos
344 days
NR
8 mos
12 mos
Abbreviations: CR, complete response; NR, not reported; PR, partial response; RR, response rates; SD, stable disease. *Previously treated.
with which they can be combined with other agents, the taxanes have increasingly been incorporated in clinical investigations to define their role in combination therapy and in both advanced and earlier stage disease. In initial studies of anthracycline/taxane combinations, paclitaxel/doxorubicin combinations were highly effective although somewhat plagued by the discovery of schedule-dependent cardiac toxicity reported in some trials.15 Nonetheless, the anthracyline/ taxane doublets were embraced, and investigators quickly entered them into a series of clinical trials.16-19 Perhaps the most noteworthy was the Eastern Cooperative Oncology Group 1193 trial that showed significant improvements in RR and time to disease progression (TTP), with the paclitaxel/doxorubicin doublet compared with paclitaxel monotherapy.19 However, the absence of a survival advantage, perhaps as a consequence of the lack of synergism for the taxane/anthracycline combination, diminished the zeal for further exploration of this often myelosuppressive regimen. Furthermore, with the increasing incorporation of doxorubicin into adjuvant breast cancer therapy, there was increased attention to identifying non-anthracycline– based taxane combinations. Gemcitabine is a novel pyrimidine antimetabolite that possesses a unique mechanism of action that greatly enhances its combination with a variety of chemotherapy agents, including the taxanes. Gemcitabine inhibits ribo-
nucleotide reductase, an enzyme responsible for the production of deoxynucleotide triphosphates. Requiring intracellular phosphorylation of the 2’,2’ difluorodeoxycytidine, the action of gemcitabine results in the production and accumulation of difluorodeoxycytidine triphosphate (dFdCTP). Directly competing with deoxynucleotide triphosphate (whose production is impaired by gemcitabine), gemcitabine triphosphate’s subsequent DNA incorporation as a false nucleotide results in masked chain termination.20 Preclinical studies that investigated gemcitabine in non–small cell lung cancer cell lines showed an apparent two-fold increased accumulation of dFdCTP in the presence of paclitaxel, suggesting enhanced cytotoxic effects when these agents are administered in combination.21,22 On the basis of such findings, clinical evaluation of the combination of gemcitabine and paclitaxel, each with identified single agent activity in breast cancer, was eagerly undertaken.
Gemcitabine/ Paclitaxel in Pretreated Metastatic Breast Cancer Several investigators have evaluated the activity of gemcitabine and paclitaxel in patients with metastatic breast cancer (MBC) in phase II trials. The findings are summarized
Table 2 Phase II Randomized Study of Three Gemcitabine-Taxane Combinations in Metastatic Breast Cancer Treatment Arms*
Schedule
Response Rate
Time to Progression
Gemcitabine 1,250 Paclitaxel 175 mg/m2 over 3 hours
Days 1, 8 Day 1
49%
7.5 mos
Gemcitabine 1,000 mg/m2 Paclitaxel 100 mg/m2 over 1 hour
Days 1, 8 Days 1, 8
52%
7.0 mos
Gemcitabine 1,000 mg/m2 Docetaxel 40 mg/m2
Days 1, 8 Days 1, 8
52%
7.4 mos
mg/m2
*Repeated every 3 weeks. Data from Khoo et al.28
D.A. Yardley
Neutropenia 11% 27 (20 evaluable) Paclitaxel 150 mg/m2 days 1, 15 every 28 days 1,500 mg/m2 days 1, 15 every 28 days Vici et al24*
43 (38 evaluable) 2,500 mg/m2 day 1 every 14 days Llombart et al31
Paclitaxel 150 mg/m2 day 1 every 14 days
43 (42 evaluable) 2,500 mg/m2 day 1 every 14 days Colomer et al30
Sanchez-Rovira et
Abbreviations: CR, complete response; NR, not reported; PR, partial response; SD, stable disease; TTP, time to disease progression. *Heavily pretreated
MedianTTP:8mos
NR
Leukopenia 14% NR NR
13.4mos
NR
Neutropenia 29%
Hematologic 15% Growth factors 34% 11 mos NR
45% 16%CR 30% PR 69% 24%CR 45% PR 19%SD 68% 21%CR 47% PR 18%SD 45% 10%CR 35% PR 44
Paclitaxel 135 days 1, 15 every 28 days Paclitaxel 150 mg/m2 day 1 every 14 days
2,500 days 1, 15 every 28 days
mg/m2
al29
mg/m2
No. of Patients Paclitaxel Dose Gemcitabine Dose Study
Table 3 Phase II Studies: Biweekly Gemcitabine and Paclitaxel in Metastatic Breast Cancer
Response
Median Duration/Response
Median Survival
Hematologic Toxicity
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in Tables 1-3. Two completed phase II studies of this combination in heavily pretreated patients have shown impressive RRs of approximately 45% to 55% as secondor third-line therapy, prompting further interest and subsequent evaluations in less pretreated patients.23,24 In the first of these two studies, Murad et al23 conducted a phase II trial using gemcitabine 1,000 mg/m2 administered on days 1, 8, and 15, and paclitaxel 175 mg/m2 on day 1 of a 28-day cycle in 29 visceral disease-predominant MBC patients, the majority of whom were considered anthracycline-refractory. The first five patients experienced significant thrombocytopenia (18.5%), resulting in the elimination of the day-15 gemcitabine dose in all subsequent cycles. The remaining cohort of patients were treated on a 21-day schedule, resulting in a decline of the rate of thrombocytopenia to 5%. A remarkable overall RR of 55% was noted, including five patients who achieved complete responses (CRs). Growth factor use in one third of the patients resulted in grade 3/4 neutropenia in only 9% of courses. Using docetaxel with a regimen similar to that outlined above, Fountzilas et al25 reported results for 40 anthracycline-resistant MBC patients. The slightly inferior RR observed in this study likely reflected the poorer prognosis and greater age of the patient population. Neutropenia, a characteristic myelosuppressive effect of docetaxel, was more prominent and experienced by nearly one half of enrolled patients. Nonetheless, the duration of response and median survival of just over 1 year were consistent between the studies despite using different taxanes. The high activity of gemcitabine/taxane doublets provided additional compelling evidence of the nature of the antineoplastic activity of this combination, and warranted evaluation of these combinations as first-line MBC therapy.
Phase II Gemcitabine/ Paclitaxel First-Line MBC Trials As first-line treatment in patients with advanced breast cancer, the gemcitabine/paclitaxel combination is characterized by consistently high RRs and excellent tolerability (Table 1).23,26,27 Genot et al26 reported their results for 40 chemotherapynaive MBC patients treated with paclitaxel 175 mg/m2 on day 1 and gemcitabine 1,200 mg/m2 days 1 and 8 every 3 weeks. Forty patients were treated; 36 were evaluable for response. Two CRs and 13 partial responses were reported, resulting in an overall RR of 42%. Median TTP did not vary markedly from that reported in other phase II trials investigating the efficacy of this doublet. In a subsequent trial using the identical gemcitabine/paclitaxel schedule also as first-line MBC therapy, Delfino et al27 reported an overall RR of 55%, with 14% CRs and 41% partial responses in 42 patients, the majority of whom had received prior adjuvant therapy. The regimen was well tolerated, and toxicities consisted primarily of mild grade 3/4 hematologic toxicity, with grade 3/4 leukopenia in only 14% of patients. Regardless of the pretreatment patient characteristics, the paclitaxel/gemcitabine combina-
Gemcitabine plus paclitaxel in breast cancer tion was active, with a clearly manageable and favorable toxicity profile. Further investigation of the gemcitabine/taxane doublet in MBC was recently reported by Khoo et al,28 who addressed the mounting interest in evaluating a weekly taxane schedule in combination with gemcitabine. The study design of this three-arm, randomized phase II trial had one arm that evaluated the standard paclitaxel 175 mg/m2 day-1 dose with gemcitabine 1,250 mg/m2 days 1 and 8. The two comparator arms incorporated a weekly taxane schedule with paclitaxel at 100 mg/m2 in one of the arms, and weekly docetaxel 40 mg/m2 in the other arm, each combined with gemcitabine 1,000 mg/m2. Both agents were administered on days 1 and 8 of a 21-day cycle. No clear RR, TTP, or survival benefit was apparent between the three arms, with no benefit apparent in favor of either the weekly taxane schedule or either taxane (Table 2).28 However, use of the taxane docetaxel, despite incorporation of a weekly administration schedule typically accompanied by less hematologic toxicity, was associated with significantly more overall grade 3/4 toxicities, particularly febrile neutropenia, infections, and transfusions, as well as use of antibiotics and granulocyte colony-stimulating factor. Continued evidence emerged supporting the finding that the gemcitabine/paclitaxel doublet possesses a favorable therapeutic index, with remarkable activity and easily manageable toxicities.
Phase II Trials of Biweekly Gemcitabine/Taxanes The biweekly gemcitabine/paclitaxel administration schedule has generated considerable interest (Table 3).24,29-31 In previously treated MBC patients, Sanchez-Rovira et al29 assessed a biweekly dose of paclitaxel 135 mg/m2 and gemcitabine 2,500 mg/m2 given on days 1 and 15. In spite of the fact that more than 90% of patients received prior anthracycline-based therapy, a striking RR of 45% was evident, with seven CRs. Despite the degree of pretreatment, grade 3/4 hematologic events occurred in 15% of patients. To maintain dose intensity, only 34% of patients used growth factor support. In the trial of Vici et al24 27 anthracycline-pretreated patients, the majority of whom also received prior treatment with the taxane docetaxel, were treated with gemcitabine 1,500 mg/m2 and paclitaxel at 150 mg/m2 administered on days 1 and 15 at 28-day intervals. Twenty patients were evaluable for efficacy, showing an overall RR of 45%, with two CRs (21%) reported. Growth factor support mandated days 7 to 9 and 20 to 22 resulted in only 11% of patients experiencing grade 3/4 neutropenia. This encouraging and consistent activity with the biweekly gemcitabine/paclitaxel schedule in heavily pretreated MBC patients led to growing enthusiasm in evaluating this appealing doublet as first-line therapy in MBC. Both Colomer et al30 and Llombart et al31 investigated identical gemcitabine/paclitaxel biweekly schedules as first-line treatment in MBC. Using a day-1 gemcitabine dose of 2,500 mg/m2 with paclitaxel 150 mg/m2 delivered every 2 weeks, remarkable respective RRs
S17
Figure 1 Study JHQG: Phase III trial comparing gemcitabine plus paclitaxel versus paclitaxel alone.
of 69% and 68% were achieved in chemotherapy-naive MBC patients. Surprisingly, despite a two-fold increase in the gemcitabine dose, grade 3/4 hematologic toxicities were minimal and achieved without prophylactic growthfactor support. In this era of dose intensity, enthusiasm for the biweekly gemcitabine/paclitaxel schedule continues to escalate.
Novel Phase II Gemcitabine/ Paclitaxel Combinations The combination of gemcitabine and paclitaxel is effective in both chemotherapy-naive and heavily pretreated patients. The RR of 55% achieved for the doublet in anthracycline pretreated patients23 may be particularly appreciated in view of the low phase III single-agent activity of paclitaxel after doxorubicin failure.32 Although combination chemotherapy results in higher RRs, recent efforts to improve survival have focused on biologically based therapies such as trastuzumab, a humanized monoclonal antibody directed against the HER2/neu onco-protein. Slamon et al33 conducted a randomized phase III trial in patients with HER2– over-expressing breast cancer, and showed that trastuzumab added to chemotherapy resulted in a higher RR, longer duration of response, and more importantly, a 6-month improvement in overall survival (OS) compared with patients treated with chemotherapy alone. Given the concentration-dependent synergistic interaction of gemcitabine with trastuzumab,34 as well as that previously established between trastuzumab and paclitaxel, the effects of the triplet combination of gemcitabine, paclitaxel, and trastuzumab against HER2– overexpressing breast cancer was investigated. Miller et al35 reported a 67% RR with a median OS just under 2 years when using the triplet. This significant activity was confirmed by Colomer et al,36 who reported a RR of 78%. As the role of targeted therapy continues to evolve, the augmented activity associated with this triplet makes it an attractive first-line treatment option in patients with HER2-amplified breast cancer.
D.A. Yardley
S18
Phase III Trial of Gemcitabine/ Paclitaxel as First-Line Therapy in MBC Based on the significant antitumor activity that was reported from the phase II studies of the gemcitabine/paclitaxel doublet, Albain et al37 and O’Shaughnessy et al38 conducted a prospective, phase III randomized trial (JHQG) to evaluate the benefit of gemcitabine when added to standard-dose paclitaxel (Fig 1). While an interim OS analysis has been performed following the favorable TTP results that emerged from the first planned interim analysis, final analysis of the study’s predefined primary endpoint of survival will take place in 2005, once the protocol predefined number of events (n ⫽ 440) have occurred. From August 1999 through April 2002, 98 centers in 19 countries enrolled and randomized 529 women with measurable MBC and a Karnofsky performance status ⱖ70% to receive paclitaxel monotherapy at 175 mg/m2 on day 1 or paclitaxel 175 mg/m2 day 1 with gemcitabine 1,250 mg/m2 on days 1 and 8; cycles were administered in both arms every 21 days until disease progression. The treatment arms were balanced for all patient and demographic characteristics. Patients had a median age of 53 years, and over 70% of patients had visceral metastases, with two or more organ systems involved in 76%. Prior anthracycline use was documented in 96% of patients, and one half of the study patients in both arms had received prior hormonal therapy. Objective RR was significantly increased with combination treatment (39.3% v 25.6%, P ⫽ .0007). Median TTP mirrored the superior overall RR observed for the combination–5.4 months versus 3.5 months (P ⫽ .0013), a highly significant improvement. Unlike what has been observed with other taxane combinations (eg, the anthracycline/taxane doublets), gemcitabine appeared to add little in the way of either hematologic or nonhematologic toxicity, with overall grade 3/4 events being relatively uncommon. The reported toxicities were minimal, expected, and easily manageable. Grade 4 neutropenia was observed in only 17% of patients who received the doublet compared with an incidence of 7% in patients receiving single-agent paclitaxel. However, febrile neutropenia was extremely infrequent in both arms, occurring in only 5% and 2%, respectively. Perhaps most unexpected was the lack of severe thrombocytopenia, an observation that suggested a “platelet-sparing” effect associated with paclitaxel when combined with gemcitabine. Nonhematologic toxicity was modest in both arms with less than 10% grade 3/4 adverse events in both arms. These results are all in the context of a greater than 90% delivered dose intensity for gemcitabine/paclitaxel combination; only 7% of gemcitabine doses were omitted with 8% reduced because of toxicity. A subset of patients underwent a variety of evaluations, including QOL measurements performed at baseline, before each cycle, and as patients went off study. According to the Brief Pain Inventory administered to a subset of 290 patients, lower pain scores were shown for gemcitabine/paclitaxeltreated patients, while paclitaxel patients had essentially unchanged pain scores.39 As a result, there was a significant reduction in analgesic use in 25% of patients receiving gem-
citabine/paclitaxel. In addition, a majority of enrolled patients underwent a four-scale QOL assessment implementing the Rotterdam Symptom Checklist tool that evaluated activity level, physical symptom distress, psychologic distress, and overall valuation of life. No significant differences emerged across different time points between the treatment arms. However, a statistically significant improvement in QOL was experienced at cycles 5 and 6 (P ⫽ .005 and .036, respectively) when compared with baseline by patients treated with the gemcitabine/paclitaxel doublet. This comes somewhat as a surprise because at cycles 5 and 6 patients typically are experiencing cumulative chemotherapy toxicities that often negatively impact QOL. The gemcitabine/paclitaxel doublet appears to defy one of the major criticisms of combination therapy–specifically, when two or more drugs are administered together there are risks of producing increased toxicity and impairments in QOL that often outweigh the marginal efficacy benefits. The high degree of statistical significance shown for most endpoint comparisons supports the gemcitabine/paclitaxel combination as effective, with a higher chance of and longer duration of disease control; this increased effectiveness was achieved without incurring considerably more toxicity or sacrificing QOL. On May 19, 2004, gemcitabine, in combination with paclitaxel, received US Food and Drug Administration approval for the first-line treatment of patients with MBC after failure of prior anthracycline-containing adjuvant chemotherapy.
Discussion While there is still much controversy regarding the respective roles of combination versus single-agent chemotherapy in the management of patients with MBC, the recently completed multinational JHQG trial evaluating the gemcitabine/ paclitaxel doublet as compared with single-agent paclitaxel continues to distinguish itself from other randomized comparator trials evaluating disparate treatment strategies. When considering the goals of combination therapy, one must try to remain clear on the rationale that underlies antineoplastic combination strategies. Ideally, the optimal combination regimen should satisfy a number of principles before embarking on demonstrating efficacy. Specifically, each component should be administered at the full known effective dose when combined with other agents, as is evident for both gemcitabine and paclitaxel in the aforementioned JHQG trial; perhaps just as important, this should not come at the cost of increased toxicity or impaired dose intensity. As has been so often evident, combination regimens often use less than the established optimal effective doses of the respective chemotherapy agents, frequently in efforts to minimize overlapping toxicities. Dosing compromises are commonly accompanied by inferior outcomes; these inferior outcomes can lead to misleading conclusions regarding the ability of combination chemotherapy to deliver superior outcomes. Ideally, the components of combination therapy should show non-overlapping safety profiles; they should also exhibit additive or synergistic effects and minimal or no cross-resistance. For patients who will most benefit from combination treat-
Gemcitabine plus paclitaxel in breast cancer
S19
Figure 2 Design of the paclitaxel, anthracycline, gemcitabine, and cyclophosphamide (tAnGo) trial of adjuvant therapy in early-stage breast cancer. C, cyclophosphamide; E, epirubicin; G, gemcitabine; T, paclitaxel.
ment, such as younger patients with symptomatic disease, a high disease burden, or short disease-free interval, gemcitabine/paclitaxel offers the appropriate patient a higher chance of disease control and longer duration of control without incurring considerably more toxicity. Distinguishing this doublet from so many others in the management of MBC is the fact that the RR benefit achieved by the doublet has translated into not only a TTP benefit but also an OS benefit at the price of modest toxicity without evident QOL disadvantages. It is hoped that the efficacy documented in MBC for the gemcitabine/paclitaxel combination, escalating its entry into adjuvant and neoadjuvant breast cancer trials, will translate
into curative outcomes for those newly diagnosed women with early stage breast cancer. Early in 2005, the United Kingdom is expected to complete its accrual to their “tAnGo” (paclitaxel, Anthracycline, Gemcitabine, cyclophosphamide) breast cancer trial evaluating the gemcitabine/paclitaxel combination following four cycles of epirubicin/cyclophosphamide (Fig 2). Likewise, the National Surgical Adjuvant Breast and Bowel Project elected to incorporate this exciting doublet in their upcoming node-positive breast cancer trial. Following four cycles of doxorubicin/cyclophosphamide, patients will receive four cycles of either single-agent paclitaxel or gemcitabine/paclitaxel (Fig 3). A biweekly schedule of ad-
Figure 3 Integration of gemcitabine/paclitaxel combination in the National Surgical Adjuvant Breast and Bowel Project B38 Lymph Node-Positive Adjuvant Breast Cancer Trial.
D.A. Yardley
S20 ministration has been chosen for these two arms, while a third arm will administer six cycles of docetaxel, doxorubicin, and cyclophosphamide on an every-3-week basis. In combination with trastuzumab, the gemcitabine/paclitaxel doublet shows promising activity with RRs ranging between 67% to 78% and an estimated median survival exceeding 2 years.40 While the benefits of combination therapy may remain marginal in the metastatic setting, earlier-stage disease may be more suited to showing a survival advantage, thus possibly sparing women from ever having to experience recurrent disease. The current trials underway are carefully posed to be better able to further define gemcitabine’s evolving role in all stages of breast cancer.
Conclusion First-line gemcitabine plus paclitaxel in MBC has shown potent antitumor activity, yielding superior responses, TTP, and OS as compared with paclitaxel monotherapy. A high degree of statistical significance was shown for most endpoint comparisons in the setting of good tolerability. The favorable therapeutic index of the gemcitabine/paclitaxel regimen supports its use as a new and evolving treatment option for MBC patients. The exciting phase III data remain a motivating force supporting the evaluation of this active and well-tolerated doublet in earlier-stage disease with hopes of incrementally increasing the curative potential for women with early stage breast cancer. From its inception, gemcitabine has shown significant activity in multiple tumor types, accompanied by preservation of multiple QOL parameters. As its role in the patient diagnosed with breast cancer continues to evolve, we eagerly and enthusiastically await the unveiling of gemcitabine’s next chapter in the management of the patient with breast cancer.
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13. 14. 15.
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