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Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: A multicenter phase II trial
Annals of Oncology 10: 211-215,1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: A multicenter phase II trial
'Department of Medical Oncology, University General Hospital of Heraklion; 2Oncology Unit of 'Marika Heliadis' Hospital of Athens; First Department of Medical Oncology, 'Agios SavasAnticancer Hospital of Athens; "Medical Oncology Unit of the National Health Insurance, Athens; 5 First Department of Medical Oncology, 'Agii AnargyrV Cancer Hospital of Athens; ('Department of Bioslalistics, School of Medicine, University of Crete, Greece 3
Summary Purpose: The activity of the docetaxel-gemcitabine combination in women with disease progression after initial chemotherapy for metastatic breast cancer (MBC) was investigated in a multicenter phase II study. Patients and methods: Fifty-two patients with metastatic breast cancer who had disease relapse or progression after completion of an anthracycline-based front-line regimen were treated with gemcitabine 900 mg/m 2 on day 1 and day 8 and docetaxel 100 mg/m 2 on day 8. G-CSF 150 ucg/m 2 /d s.c. was given from day 9 to day 16 and the treatment was repeated every three weeks. The patients' median age was 57 years and the performance status (WHO) was 0 for 26, 1 for 20 and 2 for 6 patients. The treatment was second-line for 27 (52%) and 3s third-line for 25 (48%) patients. All patients were evaluable for response and toxicity. Results: Complete response occurred in seven (14%) patients and partial response in 21 (40%) for an overall response rate of 54% (95% confidence interval (95% CI): 40%-67%). Fifteen (29%) patients had stable disease and nine (17%) pro-
Introduction Since metastatic breast cancer remains incurable despite temporary regression of the disease with endocrine therapy or chemotherapy, palliation of symptoms and prolongation of high-quality life become the major therapeutic goals in the treatment of these patients [1]. Combination chemotherapy used as first-line treatment for metastatic disease usually results in 35%-75% objective responses; however, the complete response rate is relatively low (approximately 10%) and the average duration of response only eight months [2]. Moreover, when disease progression occurs, a standard second-line combination chemotherapy produces objective responses in 20%45% of patients depending on whether or not an anthracycline was included in the initial treatment [3,4].
gressive disease. Of 25 patients previously treated with taxanes, 11 (44%) responded (1 CR, 10 PR). Interestingly, in four patients with disease progression while receiving docetaxel or paclitaxel monotherapy, the docetaxel + gemcitabine combination achieved partial responses. Responses were observed at all metastatic sites (local disease 62%, lymph nodes 58%, skin 44%, lung 47% and liver 36%) with a median duration of response of 3.6 months (range 1-16) and a median time to disease progression of eight months (range 2-18.5). Grade 3 neutropenia developed in 10 (19%) and grade 4 in five (10%) patients. Neutropenia was associated with infection in four patients without toxic deaths. Grade 3 thrombocytopenia developed in nine (17%) patients and grade 4 in two (4%). Nonhematologic toxicity was usually mild. Conclusion: The docetaxel-gemcitabine combination is an active and well tolerated salvage treatment in .patients with MBC. Previous treatment with taxanes does not preclude a good clinical response to this regimen.
Key words: docetaxel, gemcitabine, metastatic breast cancer
Docetaxel (taxotere; Rhone-Poulenc Rorer, Antony, France) is a new hemi-synthetic taxane with significant antineoplastic activity [5] and manageable toxicity consisting primarily of myelosuppression (mainly neutropenia). As front-line monotherapy for MBC, it produced an overall response rate of 59%, and as second-line an objective response rate of 49% [6]. Even for patients who had failed prior anthracycline treatment, the objective response rate was 41% [7]. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, USA) is a novel nucleoside analogue of deoxycytidine [8] with a broad range of activity against various tumors[9] and an especially favorable toxicity profile of mild myelosuppression and minimal non-hematologic toxicity [10]. In advanced breast cancer, response rates, when it was used as a single agent, ranged from 25%-46%, depend-
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D. Mavroudis,1 N. Malamos,2 A. Alexopoulos,3 Ch. Kourousis,1 S. Agelaki,1 E. Sarra,1 A. Potamianou,4 Ch. Kosmas,2 G. Rigatos,3 Th. Giannakakis,5 K. Kalbakis,1 F. Apostolaki,2 J. Vlachonicolis,6 S. Kakolyris,1 G. Samonis1 & V. Georgoulias1 for the Greek Breast Cancer Cooperative Group
212 Response evaluation All patients had tumor measurements (by physical examination, CTor MRI) performed within 14 days of registration and subsequently after every three cycles of treatment. Hematologic toxicity was monitored by weekly blood counts except in instances of grade 4 or febrile neutropenia where daily monitoring was performed. Standard evaluation by history, physical examination and routine laboratory tests was performed before each treatment. Imaging studies with ultrasounds or computed tomography scans were performed after every three chemotherapy cycles. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were assessed by International Union Against Cancer (UICC) criteria [15]. The duration of response was measured from the first documentation of response to disease progression. Time to progression was determined by the interval between the initiation of therapy to the first date that disease progression was objectively documented. The follow-up time was measured from the day of first treatment administration to last contact or death.
Patients and methods Patient selection Patients with histologically confirmed and bidimensionally measurable metastatic adenocarcinoma of the breast, relapsing or not responding to initial chemotherapy that included anthracydines, were enrolled. Postmenopausal women who failed at least one hormonal therapy were also eligible. Prior radiotherapy was allowed provided the treatment target was outside the radiation fields. In addition, at least four weeks had to have passed since the last chemotherapy or hormonal treatment. Patients should have a performance status (WHO) of 0-2 and adequate organ function, including an absolute neutrophil count S=l,500/ul, platelet count > 100,000/ul, total bilirubin level <1.5 mg/dl, AST =S three times the upper limit of normal, and serum creatinine concentration ^ 1.5 mg/dl. Other factors that rendered the patient ineligible included radiotherapy to > 25% of marrow-containing bone, untreated brain metastases, a history of a second malignancy other than resected basal cell and/or squamous cell carcinoma of the skin. The protocol was approved by the Scientific and Ethics Committees of the participating institutions in the Greek Cooperative Group for Breast Cancer. All patients signed an informed consent prior to study entry.
Treatment Patients received gemcitabine (Gemzar; Eli Lilly, Indianapolis, USA) 900 mg/m 2 (in 250 ml 0.9% normal saline) by intravenous (i.v.) infusion over 30 min on days 1 and 8 and docetaxel (Taxotere; RhonePoulenc Rorer, Antony, France) 100 mg/m 2 (in 250 ml 0.9% normal saline) by i.v. infusion over 60 min on day 8. All patients were premedicated with dexamethasone 16 mg p.o. 12, eight and one hour prior to docetaxel infusion and continued dexamethasone 8 mg b.i.d. for three days afterwards to prevent fluid retention and hypersensitivity reactions. rhG-CSF (Granocyte; Rhone-Poulenc Rorer) 150 (icg/m2/d s.c. was given to all patients from day 9 to day 16 of each cycle or, occasionally, up to day 20 in patients with sustained grade 3-4 neutropenia beyond day 16. Treatment was repeated every three weeks. All toxicity was graded according to the National Cancer Institute common toxicity criteria [14]. Dose modification for hematologic toxicity was as follows: for grade 4 neutropenia (lasting more than five days) or febrile neutropenia both drug doses were reduced by 25% on day 8; for grade 3 neutropenia or grade 3 or 4 thrombocytopenia, the docetaxel dose was reduced by 20% and the gemcitabine dose by 15%. Neurosensory and/or neuromotor peripheral neuropathy meant removal from the study for grades 3 or 4 and a 25% docetaxel dose reduction for patients with grade 2 toxicity.
Statistical analysis
The probability of survival was estimated by the method of Kaplan and Meier [16], and confidence intervals for response rates were calculated using methods for exact binomial confidence intervals [17].
Results Patient characteristics Between June 1996 and February 1998, 52 patients with measurable metastatic breast cancer were enrolled in this multicenter phase II study. All patients were evaluable for response and toxicity. The patients' characteristics are shown in Table 1. Thirty-nine patients (75%) had visceral disease and most of them (30 patients) had lung metastasis as the predominant site. For 27 women the treatment was a second-line chemotherapy regimen and for the other 25 it was ^ third-line. The median interval between the end of the first-line treatment and study entry was six months (range 4-240 weeks). All patients had previously been treated with anthracydines as front-line treatment for metastatic disease, and 25 had also received taxane-based chemotherapy. Twenty-five (48%) patients had disease not responding to initial chemotherapy and 27 (52%) patients had disease relapsing after an initial response to front-line chemotherapy. Response and survival A total of 250 courses of docetaxel and gemcitabine were administered to 52 patients. The median number of courses per patient was 5 (range 1-9). There were seven complete responses (CRs, 14%) and 21 partial responses (PRs, 40%) among the 52 evaluable patients. The overall response rate was 54% (95% CI: 40%-67%). Additionally, 15 patients (29%) had stable disease and nine patients (17%) progressive disease. Of 25 patients who had previously received a taxane-based front-line regimen, 11 (44%, 1 CR and 10 PRs) responded to the treatment (Table 2). Interestingly, in four patients who
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ing on the dose administered and whether patients have previously received chemotherapy [11,12]. Due to their remarkable activity, different mechanisms of action, and favorable toxicity profile, we evaluated, in a phase II trial, the activity and tolerability of the docetaxel-gemcitabine combination as salvage treatment in women with metastatic breast cancer. Since docetaxelinduced neutropenia generally occurs five to eight days after the infusion, we decided to administer docetaxel on the 8th day of the cycle in order to maintain the weekly dosing of gemcitabine. This administration schedule was based on our previous experience of low toxicity with this drug combination in treating patients with advanced non-small-cell lung cancer [13].
213 Table 1. Patient characteristics.
Prior regimen
Prior response
Response to D + G
Taxol-based (n = 16)"
5CR 4 PR 2SD 5PD 3 PR 4SD 6PD
1 CR, 3 PR, 1 SD 3 PR, 1 SD 2SD 1 PR, 3 SD, 1 PD 2 PR, 1 SD 4SD 3 PR, 2 SD, 1 PD
52 57 39-75 26 20 6
Taxotere-based (n = 13)"
19 33
Abbreviations: CR - complete response; PR - partial response; SD stable disease; PD - progressive disease. * Four patients had previous treatment with both Taxol and taxoterebased regimens.
46 34 28 6 23 52 52 25 7 20 10 15 5 7 6 11 32 20 13 19 14 30 9 4 17 17 18
Abbreviations: CR - complete response; PR - partial response; SD stable disease; PD - progressive disease. a Four patients had previous treatment with both taxol and taxoterebased regimens.
previously had progressive disease treated with either paclitaxel (one patient) or docetaxel (three patients) monotherapy, the combination of docetaxel + gemcitabine achieved partial responses (four PRs). Response rates were 36% for liver, 47% for lung, 44% for skin, 58% for lymph nodes and 62% for local disease. After a median follow-up time of seven months (range 1-19 months), 19 (37%) patients have died. The Kaplan-Meier estimated probability of a one-year survival for the group as a whole was 55% (Figure 1). The median duration of response was 3.6 months (range 1-16) and the median time to tumor progression eight months (range 2-18.5). In the subgroup analysis of responses we observed a
V
\
Figure 1. Kaplan-Meier estimated probability of survival for the 52 patients with metastatic breast cancer treated with the combination of docetaxel + gemcitabine.
response rate of 46% (one CR, six PR) among 15 patients with progressive disease as best response to front-line anthracycline-based treatment, and a response rate of 57% (6 CR, 15 PR) among the 37 patients who had an initial response before developing progressive disease (P = 0.3). Similarly, the response rate was 36% (four PR) for the 11 patients who had progressive disease after a taxane-based regimen and 50% (one CR, eight PR) for the 18 patients who had disease progression following an initial response (P — 0.4). Of 32 patients who received the study treatment < 6 months from previous chemotherapy, 17 (53%, 5 CR and 12 PR) responded. Of 20 patients who received the treatment > 6 months after their last chemotherapy, 11 (55%, two CR and nine PR) responded (P = 0.9). Toxicity The treatment had to be delayed in 35 of 250 (14%) administered courses due to toxicity (Table 3). The median interval between courses was 23 days (range 2 1 39). In only two patients was treatment discontinued due to toxicity, consisting of recurrent hypersensitivity reactions in one patient and prolonged grade 3 neutropenia and thrombocytopenia in a second patient. Hematologic toxicity included five (10%) patients with grade 4 and 10 (19%) with grade 3 neutropenia. In addition,
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Number of patients Age (in years) Median Range Performance status (WHO) 0 1 2 Menopausal status Premenopausal Postmenopausal Prior treatment Surgery Radiation Hormonal Tx Neoadjuvant chemoTx Adjuvant chemoTx ChemoTx for metastatic disease Anthracyclines for metastatic disease Taxanes for metastatic disease Response to previous anthracycline-based regimen CR PR SD PD Response to previous taxane-based regimena CR PR SD PD Interval from last chemotherapy to study entry $ 6 months _ > 6 months Measurable disease sites Local Lymph nodes Liver Lung Skin Mediastinum Number of disease sites per patient 1 2 >3
Table 2. Responses to docetaxel + gemcitabine (D + G) in patients with prior taxane-based front-line therapy.
214 Table 3. Toxicity. Toxicity
NCI grade (number of patients, %) 1
12(23) 10(19) 5(10) 9(17) 20 (39) 3(6) 23(44) 9(17) 2(4) 14(27) 12(23) 1(2) 13(25) 8(15) 9(17) 4(8) 1(2) 4(8) 4(8) 1(2) 10(19) 6(12) 8 (15) mild 7 (13) mild 2 (4) mod 17(33) 16(31) 1(2) 4(8) 17(33)
two patients (4%) developed grade 4 and nine (17%) grade 3 thrombocytopenia; three patients (6%) presented grade 3 anemia. In four patients (8%) neutropenia was associated with fever and 17 patients (33%) developed non-neutropenic infections. Admission to the hospital for the treatment of infections or toxicities was required for 11 patients. Three patients required RBC transfusions and two patients platelet transfusions. Non-hematologic toxicity was generally mild to moderate and transient (Table 3). Due to lack of severe toxicity, 30 of the 52 patients tolerated the full planned doses of the two drugs and 80% of docetaxel and 85% of gemcitabine protocol planned doses were actually administered to the patients. The median dose intensity was 26.5 (range 11-33) and 513 (range 227-600) mg/m 2 /wk for docetaxel and gemcitabine, respectively.
Discussion Encouraged by the low toxicity profile of gemcitabine, we designed an administration schedule that would permit delivery of both drugs on day 8 after a first dose of gemcitabine on day 1. Our previous experience using the same regimen in patients with advanced non-smallcell lung cancer was very gratifying since the combination showed antitumor activity and low toxicity [13]. Similarly, in this phase II study we observed a high response rate with the combination of docetaxel and gemcitabine as 2s second-line treatment in women with metastatic breast cancer. The treatment was well tolerated and toxicity was seldom caused treatment delay or dose reduction. Since the expected neutropenia from the 100 mg/m 2 docetaxel dose alone is much higher, the low toxicity we observed in our study may be due to the prophylactic administration of G-CSF [18]. The observed overall response rate of 54% with a median time to disease progression of eight months are among the highest described in the literature [3]. This is especially important since our patients primarily had visceral disease which had relapsed after an anthracycline-based
Acknowledgements This work was supported in part by a grant from the Cretan Association for Biomedical Research (CABR).
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Neutropenia Anemia Thrombocytopenia Nausea/vomiting Diarrhea Mucositis Neurotoxicity Allergic reactions Fluid retention Asthenia Fever with neutropenia Non-neutropenic fever
- and in many cases also after a taxane-based - chemotherapy, and therefore belonged to a poor-prognosis group. Our results are intriguing because of the high response rate (44%) we observed in patients previously treated with taxanes. Some patients who had previously responded to either taxol or taxotere showed a good response to the docetaxel-gemcitabine combination, suggesting that the sensitivity to the taxanes may still be present at the time of disease recurrence. Patients with stable disease during prior taxane treatment did not respond also to the docetaxel-gemcitabine combination. On the other hand, for patients with disease progression under paclitaxel or docetaxel treatment who showed a good response to the docetaxel-gemcitabine combination (4 of 11 patients; response rate 36%), this can only be explained by one of the following two possibilities. The response was due either to in vivo synergism between docetaxel and gemcitabine or to exclusive tumor sensitivity to gemcitabine. It is unlikely that docetaxel alone would produce similar results since 13 of the patients had previously received docetaxel-based treatments and responses occurred even in those who had previously failed to respond. Despite the theoretical backround for possible synergistic activity between gemcitabine and docetaxel (e.g., different cellular mechanisms of action), a synergism between the two drugs has not been observed in in vitro experiments [19]. Moreover, in a recent report, concurrent or sequential treatment of various cell lines with gemcitabine and paclitaxel showed an antagonistic effect [20]. Since our study was not designed to test cross-resistance between taxanes and gemcitabine or in vivo synergism between the two drugs, our results should be viewed as preliminary and interpreted with great caution, with the understanding that further studies are needed to address these issues. In the past, several investigators have questioned the efficacy and value of second- and third-line regimens for patients who have previously failed anthracyclines [21, 22]. A number of studies having demonstrated the noncross-resistant activity of the taxanes in anthracyclinerefractory disease [4, 7], the taxanes are now part of the second- or even first-line regimens [23, 24]. Our study has shown that for patients who have previously failed anthracycline - and in some cases also taxane - combinations, a salvage regimen of docetaxel with gemcitabine achieved durable responses in half of the treated patients. Whether or not this treatment would also lead to prolongation of survival can only be answered by prospective randomized studies. Furthermore, the obvious advantages of high activity, modest toxicity and high tolerability of this regimen should be weighed against the high cost of treatment.
215 Dr. E. Sana and Dr. D. Mavroudis are recipients of a fellowship from the CABR.
References
Received 7 September 1998; accepted 1 December 1998.
Correspondence to: Dr. D. Mavroudis Department of Medical Oncology University General Hospital of Heraklion P.O. Box 1352 71110 Heraklion, Crete Greece
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1. Vogel CL, Azevedo S, Hilsenbeck S et al. Survival after first recurrence of breast cancer: The Miami experience. Cancer 1992; 70:129-35. 2. Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: Present and future prospects. Semin Oncol 1995; 22 (Suppl 5): 5-21. 3. Vogel CL. Current status of salvage chemotherapy for refractory advanced breast cancer. Oncology 1996; 10 (Suppl 6): 7-15. 4. Abrams JS, Vena DA, Baltz J et al. Paclitaxel activity in heavily pretreated breast cancer: A National Cancer Institute Treatment Referral Center Trial. J Clin Oncol 1995; 13 (8): 2056-65. 5. Bissery MC, Guenard D, Gueritte-Voegelein Fet al. Experimental antitumor activity of taxotere (RPR56976, NSC628503) a Taxol analogue. Cancer Res 1991; 51: 4845-52. 6. Ravdin PM, Valero V. Review of docetaxel (taxotere), a highly active new agent for the treatment of metastatic breast cancer. Semin Oncol 1995; 22 (2, Suppl 4): 17-21. 7. Ravdin PM. Docetaxel (taxotere) for the treatment of anthracycline-resistant breast cancer. Semin Oncol 1997; 24 (4, Suppl 10): 18-21. 8. Huang P, Chubb S, Hertel L et al. Action of 2,2-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991; 51: 6110-7. 9. Merriman RL, Hertel LW, Schultz RM et al. Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Invest New Drugs 1996; 14: 243-7. 10. Poplin EAD, Corbett T, Flaherty L et al. Difluorodeoxycytidine (dFdC, gemcitabine): A phase I study. Invest New Drugs 1992; 10: 165-70. 11. Carmichael J, Walling J. Advanced breast cancer: Investigational role of gemcitabine. Eur J Cancer 1997; 33 (Suppl I): S27-30. 12. Carmichael J, Possinger K, Phillip P et al. Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 1995; 13 (11): 2731-6. 13. Georgoulias V, Kourousis Ch, Androulakis N et al. Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: A multicenter phase II trial. J Clin Oncol (in press).
14. Ajani JA, Welch SR, Raber MN et al. Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 1990; 8: 147-59. 15. Evaluation of the cancer patient and the response to treatment. In Monfardini S, Brunner K, Crowther D et al. (eds): UICC-Manual of Adult and Paediatric Medical Oncology. Berlin, Germany: Springer 1987; 22-38. 16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1959; 53: 457-81. 17. Cox DR. The Analysis of Binary Data. London, UK: Methuen 1970. 18. Gilbert CVredenburgh J, Rizzieri D et al.The effect of G-CSFon docetaxel (taxotere) associated neutropenia during therapy for breast cancer. Proc Am Soc Clin Oncol 1998,17: 91a (Abstr 352). 19. Giaccone. Personal communication. 20. Theodossiou C, Cook J, Fisher J et al. Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines. Int J Oncol 1998; 12: 825-32. 21. Porkka K, Blomquvist C, Rissamen P et al. Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer. J Clin Oncol 1994; 12 (8): 1639-47. 22. Benner SE, Fetting JH, Brenner MH. A stopping rule for standard chemotherapy for metastatic breast cancer. Lessons from a survey of Maryland medical oncologists. Cancer Invest 1994; 12 (5): 451-5. 23. Reichman BS, Seidman AD, Crown JPA et al. Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1993; 11: 1943-51. 24. Seidman AD, Reichman BS, Crown JPA et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol 1995; 13:1152-9.
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Original article Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: A multicenter phase II trial
'Department of Medical Oncology, University General Hospital of Heraklion; 2Oncology Unit of 'Marika Heliadis' Hospital of Athens; First Department of Medical Oncology, 'Agios SavasAnticancer Hospital of Athens; "Medical Oncology Unit of the National Health Insurance, Athens; 5 First Department of Medical Oncology, 'Agii AnargyrV Cancer Hospital of Athens; ('Department of Bioslalistics, School of Medicine, University of Crete, Greece 3
Summary Purpose: The activity of the docetaxel-gemcitabine combination in women with disease progression after initial chemotherapy for metastatic breast cancer (MBC) was investigated in a multicenter phase II study. Patients and methods: Fifty-two patients with metastatic breast cancer who had disease relapse or progression after completion of an anthracycline-based front-line regimen were treated with gemcitabine 900 mg/m 2 on day 1 and day 8 and docetaxel 100 mg/m 2 on day 8. G-CSF 150 ucg/m 2 /d s.c. was given from day 9 to day 16 and the treatment was repeated every three weeks. The patients' median age was 57 years and the performance status (WHO) was 0 for 26, 1 for 20 and 2 for 6 patients. The treatment was second-line for 27 (52%) and 3s third-line for 25 (48%) patients. All patients were evaluable for response and toxicity. Results: Complete response occurred in seven (14%) patients and partial response in 21 (40%) for an overall response rate of 54% (95% confidence interval (95% CI): 40%-67%). Fifteen (29%) patients had stable disease and nine (17%) pro-
Introduction Since metastatic breast cancer remains incurable despite temporary regression of the disease with endocrine therapy or chemotherapy, palliation of symptoms and prolongation of high-quality life become the major therapeutic goals in the treatment of these patients [1]. Combination chemotherapy used as first-line treatment for metastatic disease usually results in 35%-75% objective responses; however, the complete response rate is relatively low (approximately 10%) and the average duration of response only eight months [2]. Moreover, when disease progression occurs, a standard second-line combination chemotherapy produces objective responses in 20%45% of patients depending on whether or not an anthracycline was included in the initial treatment [3,4].
gressive disease. Of 25 patients previously treated with taxanes, 11 (44%) responded (1 CR, 10 PR). Interestingly, in four patients with disease progression while receiving docetaxel or paclitaxel monotherapy, the docetaxel + gemcitabine combination achieved partial responses. Responses were observed at all metastatic sites (local disease 62%, lymph nodes 58%, skin 44%, lung 47% and liver 36%) with a median duration of response of 3.6 months (range 1-16) and a median time to disease progression of eight months (range 2-18.5). Grade 3 neutropenia developed in 10 (19%) and grade 4 in five (10%) patients. Neutropenia was associated with infection in four patients without toxic deaths. Grade 3 thrombocytopenia developed in nine (17%) patients and grade 4 in two (4%). Nonhematologic toxicity was usually mild. Conclusion: The docetaxel-gemcitabine combination is an active and well tolerated salvage treatment in .patients with MBC. Previous treatment with taxanes does not preclude a good clinical response to this regimen.
Key words: docetaxel, gemcitabine, metastatic breast cancer
Docetaxel (taxotere; Rhone-Poulenc Rorer, Antony, France) is a new hemi-synthetic taxane with significant antineoplastic activity [5] and manageable toxicity consisting primarily of myelosuppression (mainly neutropenia). As front-line monotherapy for MBC, it produced an overall response rate of 59%, and as second-line an objective response rate of 49% [6]. Even for patients who had failed prior anthracycline treatment, the objective response rate was 41% [7]. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, USA) is a novel nucleoside analogue of deoxycytidine [8] with a broad range of activity against various tumors[9] and an especially favorable toxicity profile of mild myelosuppression and minimal non-hematologic toxicity [10]. In advanced breast cancer, response rates, when it was used as a single agent, ranged from 25%-46%, depend-
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D. Mavroudis,1 N. Malamos,2 A. Alexopoulos,3 Ch. Kourousis,1 S. Agelaki,1 E. Sarra,1 A. Potamianou,4 Ch. Kosmas,2 G. Rigatos,3 Th. Giannakakis,5 K. Kalbakis,1 F. Apostolaki,2 J. Vlachonicolis,6 S. Kakolyris,1 G. Samonis1 & V. Georgoulias1 for the Greek Breast Cancer Cooperative Group
212 Response evaluation All patients had tumor measurements (by physical examination, CTor MRI) performed within 14 days of registration and subsequently after every three cycles of treatment. Hematologic toxicity was monitored by weekly blood counts except in instances of grade 4 or febrile neutropenia where daily monitoring was performed. Standard evaluation by history, physical examination and routine laboratory tests was performed before each treatment. Imaging studies with ultrasounds or computed tomography scans were performed after every three chemotherapy cycles. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were assessed by International Union Against Cancer (UICC) criteria [15]. The duration of response was measured from the first documentation of response to disease progression. Time to progression was determined by the interval between the initiation of therapy to the first date that disease progression was objectively documented. The follow-up time was measured from the day of first treatment administration to last contact or death.
Patients and methods Patient selection Patients with histologically confirmed and bidimensionally measurable metastatic adenocarcinoma of the breast, relapsing or not responding to initial chemotherapy that included anthracydines, were enrolled. Postmenopausal women who failed at least one hormonal therapy were also eligible. Prior radiotherapy was allowed provided the treatment target was outside the radiation fields. In addition, at least four weeks had to have passed since the last chemotherapy or hormonal treatment. Patients should have a performance status (WHO) of 0-2 and adequate organ function, including an absolute neutrophil count S=l,500/ul, platelet count > 100,000/ul, total bilirubin level <1.5 mg/dl, AST =S three times the upper limit of normal, and serum creatinine concentration ^ 1.5 mg/dl. Other factors that rendered the patient ineligible included radiotherapy to > 25% of marrow-containing bone, untreated brain metastases, a history of a second malignancy other than resected basal cell and/or squamous cell carcinoma of the skin. The protocol was approved by the Scientific and Ethics Committees of the participating institutions in the Greek Cooperative Group for Breast Cancer. All patients signed an informed consent prior to study entry.
Treatment Patients received gemcitabine (Gemzar; Eli Lilly, Indianapolis, USA) 900 mg/m 2 (in 250 ml 0.9% normal saline) by intravenous (i.v.) infusion over 30 min on days 1 and 8 and docetaxel (Taxotere; RhonePoulenc Rorer, Antony, France) 100 mg/m 2 (in 250 ml 0.9% normal saline) by i.v. infusion over 60 min on day 8. All patients were premedicated with dexamethasone 16 mg p.o. 12, eight and one hour prior to docetaxel infusion and continued dexamethasone 8 mg b.i.d. for three days afterwards to prevent fluid retention and hypersensitivity reactions. rhG-CSF (Granocyte; Rhone-Poulenc Rorer) 150 (icg/m2/d s.c. was given to all patients from day 9 to day 16 of each cycle or, occasionally, up to day 20 in patients with sustained grade 3-4 neutropenia beyond day 16. Treatment was repeated every three weeks. All toxicity was graded according to the National Cancer Institute common toxicity criteria [14]. Dose modification for hematologic toxicity was as follows: for grade 4 neutropenia (lasting more than five days) or febrile neutropenia both drug doses were reduced by 25% on day 8; for grade 3 neutropenia or grade 3 or 4 thrombocytopenia, the docetaxel dose was reduced by 20% and the gemcitabine dose by 15%. Neurosensory and/or neuromotor peripheral neuropathy meant removal from the study for grades 3 or 4 and a 25% docetaxel dose reduction for patients with grade 2 toxicity.
Statistical analysis
The probability of survival was estimated by the method of Kaplan and Meier [16], and confidence intervals for response rates were calculated using methods for exact binomial confidence intervals [17].
Results Patient characteristics Between June 1996 and February 1998, 52 patients with measurable metastatic breast cancer were enrolled in this multicenter phase II study. All patients were evaluable for response and toxicity. The patients' characteristics are shown in Table 1. Thirty-nine patients (75%) had visceral disease and most of them (30 patients) had lung metastasis as the predominant site. For 27 women the treatment was a second-line chemotherapy regimen and for the other 25 it was ^ third-line. The median interval between the end of the first-line treatment and study entry was six months (range 4-240 weeks). All patients had previously been treated with anthracydines as front-line treatment for metastatic disease, and 25 had also received taxane-based chemotherapy. Twenty-five (48%) patients had disease not responding to initial chemotherapy and 27 (52%) patients had disease relapsing after an initial response to front-line chemotherapy. Response and survival A total of 250 courses of docetaxel and gemcitabine were administered to 52 patients. The median number of courses per patient was 5 (range 1-9). There were seven complete responses (CRs, 14%) and 21 partial responses (PRs, 40%) among the 52 evaluable patients. The overall response rate was 54% (95% CI: 40%-67%). Additionally, 15 patients (29%) had stable disease and nine patients (17%) progressive disease. Of 25 patients who had previously received a taxane-based front-line regimen, 11 (44%, 1 CR and 10 PRs) responded to the treatment (Table 2). Interestingly, in four patients who
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ing on the dose administered and whether patients have previously received chemotherapy [11,12]. Due to their remarkable activity, different mechanisms of action, and favorable toxicity profile, we evaluated, in a phase II trial, the activity and tolerability of the docetaxel-gemcitabine combination as salvage treatment in women with metastatic breast cancer. Since docetaxelinduced neutropenia generally occurs five to eight days after the infusion, we decided to administer docetaxel on the 8th day of the cycle in order to maintain the weekly dosing of gemcitabine. This administration schedule was based on our previous experience of low toxicity with this drug combination in treating patients with advanced non-small-cell lung cancer [13].
213 Table 1. Patient characteristics.
Prior regimen
Prior response
Response to D + G
Taxol-based (n = 16)"
5CR 4 PR 2SD 5PD 3 PR 4SD 6PD
1 CR, 3 PR, 1 SD 3 PR, 1 SD 2SD 1 PR, 3 SD, 1 PD 2 PR, 1 SD 4SD 3 PR, 2 SD, 1 PD
52 57 39-75 26 20 6
Taxotere-based (n = 13)"
19 33
Abbreviations: CR - complete response; PR - partial response; SD stable disease; PD - progressive disease. * Four patients had previous treatment with both Taxol and taxoterebased regimens.
46 34 28 6 23 52 52 25 7 20 10 15 5 7 6 11 32 20 13 19 14 30 9 4 17 17 18
Abbreviations: CR - complete response; PR - partial response; SD stable disease; PD - progressive disease. a Four patients had previous treatment with both taxol and taxoterebased regimens.
previously had progressive disease treated with either paclitaxel (one patient) or docetaxel (three patients) monotherapy, the combination of docetaxel + gemcitabine achieved partial responses (four PRs). Response rates were 36% for liver, 47% for lung, 44% for skin, 58% for lymph nodes and 62% for local disease. After a median follow-up time of seven months (range 1-19 months), 19 (37%) patients have died. The Kaplan-Meier estimated probability of a one-year survival for the group as a whole was 55% (Figure 1). The median duration of response was 3.6 months (range 1-16) and the median time to tumor progression eight months (range 2-18.5). In the subgroup analysis of responses we observed a
V
\
Figure 1. Kaplan-Meier estimated probability of survival for the 52 patients with metastatic breast cancer treated with the combination of docetaxel + gemcitabine.
response rate of 46% (one CR, six PR) among 15 patients with progressive disease as best response to front-line anthracycline-based treatment, and a response rate of 57% (6 CR, 15 PR) among the 37 patients who had an initial response before developing progressive disease (P = 0.3). Similarly, the response rate was 36% (four PR) for the 11 patients who had progressive disease after a taxane-based regimen and 50% (one CR, eight PR) for the 18 patients who had disease progression following an initial response (P — 0.4). Of 32 patients who received the study treatment < 6 months from previous chemotherapy, 17 (53%, 5 CR and 12 PR) responded. Of 20 patients who received the treatment > 6 months after their last chemotherapy, 11 (55%, two CR and nine PR) responded (P = 0.9). Toxicity The treatment had to be delayed in 35 of 250 (14%) administered courses due to toxicity (Table 3). The median interval between courses was 23 days (range 2 1 39). In only two patients was treatment discontinued due to toxicity, consisting of recurrent hypersensitivity reactions in one patient and prolonged grade 3 neutropenia and thrombocytopenia in a second patient. Hematologic toxicity included five (10%) patients with grade 4 and 10 (19%) with grade 3 neutropenia. In addition,
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Number of patients Age (in years) Median Range Performance status (WHO) 0 1 2 Menopausal status Premenopausal Postmenopausal Prior treatment Surgery Radiation Hormonal Tx Neoadjuvant chemoTx Adjuvant chemoTx ChemoTx for metastatic disease Anthracyclines for metastatic disease Taxanes for metastatic disease Response to previous anthracycline-based regimen CR PR SD PD Response to previous taxane-based regimena CR PR SD PD Interval from last chemotherapy to study entry $ 6 months _ > 6 months Measurable disease sites Local Lymph nodes Liver Lung Skin Mediastinum Number of disease sites per patient 1 2 >3
Table 2. Responses to docetaxel + gemcitabine (D + G) in patients with prior taxane-based front-line therapy.
214 Table 3. Toxicity. Toxicity
NCI grade (number of patients, %) 1
12(23) 10(19) 5(10) 9(17) 20 (39) 3(6) 23(44) 9(17) 2(4) 14(27) 12(23) 1(2) 13(25) 8(15) 9(17) 4(8) 1(2) 4(8) 4(8) 1(2) 10(19) 6(12) 8 (15) mild 7 (13) mild 2 (4) mod 17(33) 16(31) 1(2) 4(8) 17(33)
two patients (4%) developed grade 4 and nine (17%) grade 3 thrombocytopenia; three patients (6%) presented grade 3 anemia. In four patients (8%) neutropenia was associated with fever and 17 patients (33%) developed non-neutropenic infections. Admission to the hospital for the treatment of infections or toxicities was required for 11 patients. Three patients required RBC transfusions and two patients platelet transfusions. Non-hematologic toxicity was generally mild to moderate and transient (Table 3). Due to lack of severe toxicity, 30 of the 52 patients tolerated the full planned doses of the two drugs and 80% of docetaxel and 85% of gemcitabine protocol planned doses were actually administered to the patients. The median dose intensity was 26.5 (range 11-33) and 513 (range 227-600) mg/m 2 /wk for docetaxel and gemcitabine, respectively.
Discussion Encouraged by the low toxicity profile of gemcitabine, we designed an administration schedule that would permit delivery of both drugs on day 8 after a first dose of gemcitabine on day 1. Our previous experience using the same regimen in patients with advanced non-smallcell lung cancer was very gratifying since the combination showed antitumor activity and low toxicity [13]. Similarly, in this phase II study we observed a high response rate with the combination of docetaxel and gemcitabine as 2s second-line treatment in women with metastatic breast cancer. The treatment was well tolerated and toxicity was seldom caused treatment delay or dose reduction. Since the expected neutropenia from the 100 mg/m 2 docetaxel dose alone is much higher, the low toxicity we observed in our study may be due to the prophylactic administration of G-CSF [18]. The observed overall response rate of 54% with a median time to disease progression of eight months are among the highest described in the literature [3]. This is especially important since our patients primarily had visceral disease which had relapsed after an anthracycline-based
Acknowledgements This work was supported in part by a grant from the Cretan Association for Biomedical Research (CABR).
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Neutropenia Anemia Thrombocytopenia Nausea/vomiting Diarrhea Mucositis Neurotoxicity Allergic reactions Fluid retention Asthenia Fever with neutropenia Non-neutropenic fever
- and in many cases also after a taxane-based - chemotherapy, and therefore belonged to a poor-prognosis group. Our results are intriguing because of the high response rate (44%) we observed in patients previously treated with taxanes. Some patients who had previously responded to either taxol or taxotere showed a good response to the docetaxel-gemcitabine combination, suggesting that the sensitivity to the taxanes may still be present at the time of disease recurrence. Patients with stable disease during prior taxane treatment did not respond also to the docetaxel-gemcitabine combination. On the other hand, for patients with disease progression under paclitaxel or docetaxel treatment who showed a good response to the docetaxel-gemcitabine combination (4 of 11 patients; response rate 36%), this can only be explained by one of the following two possibilities. The response was due either to in vivo synergism between docetaxel and gemcitabine or to exclusive tumor sensitivity to gemcitabine. It is unlikely that docetaxel alone would produce similar results since 13 of the patients had previously received docetaxel-based treatments and responses occurred even in those who had previously failed to respond. Despite the theoretical backround for possible synergistic activity between gemcitabine and docetaxel (e.g., different cellular mechanisms of action), a synergism between the two drugs has not been observed in in vitro experiments [19]. Moreover, in a recent report, concurrent or sequential treatment of various cell lines with gemcitabine and paclitaxel showed an antagonistic effect [20]. Since our study was not designed to test cross-resistance between taxanes and gemcitabine or in vivo synergism between the two drugs, our results should be viewed as preliminary and interpreted with great caution, with the understanding that further studies are needed to address these issues. In the past, several investigators have questioned the efficacy and value of second- and third-line regimens for patients who have previously failed anthracyclines [21, 22]. A number of studies having demonstrated the noncross-resistant activity of the taxanes in anthracyclinerefractory disease [4, 7], the taxanes are now part of the second- or even first-line regimens [23, 24]. Our study has shown that for patients who have previously failed anthracycline - and in some cases also taxane - combinations, a salvage regimen of docetaxel with gemcitabine achieved durable responses in half of the treated patients. Whether or not this treatment would also lead to prolongation of survival can only be answered by prospective randomized studies. Furthermore, the obvious advantages of high activity, modest toxicity and high tolerability of this regimen should be weighed against the high cost of treatment.
215 Dr. E. Sana and Dr. D. Mavroudis are recipients of a fellowship from the CABR.
References
Received 7 September 1998; accepted 1 December 1998.
Correspondence to: Dr. D. Mavroudis Department of Medical Oncology University General Hospital of Heraklion P.O. Box 1352 71110 Heraklion, Crete Greece
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