- Email: [email protected]
Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study
Annals of Oncology 11: 367-371, 2000. O 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study G. Frasci, P. Cornelia, G. D'Aiuto, R. Thomas, I. Capasso, M. Elmo, G. Botti, G. R. Cortino, L. Lapenta, V. De Rosa, R Vallone, A. Petrillo & G. Cornelia for the Southern Italy Cooperative Oncology Group (SICOG)
combination with vinorelbine. Overall, nine episodes of DLT, all of them neutropenia, occurred at the first cycle. ConsiderPurpose: The objective of this study was to determine the ing all 94 cyles, grades 3 or 4 neutropenia and thrombocytodocetaxel MTD when combined with gemcitabine or vinorelbine penia occurred in 15 (44%), and 7 (20%) patients. Non-hemain advanced breast cancer patients who had received previous tologic toxicity was mild, except for three cases of grade 2 peripheral neuropathy. All patients were assessed for response anthracycline-based chemotherapy for advanced disease. Patients and methods: Advanced breast cancer patients aged on an 'intent-to-treat' basis. Overall, five partial responses between 18 and 70 with ECOG PS 0-2 who had not responded were recorded (docetaxel + gemcitabine = 3 and docetaxel + to, or had relapsed after, first-line anthracycline-based chemo- vinorelbine = 2), for a 15% (95% CI: 5%-31%) overall response therapy, were randomized to receive either gemcitabine 1000 rate. Only 1 of 24 (4%) patients who had received weekly dosemg/m2 or vinorelbine 25 mg/m2 in combination with escalating dense paclitaxel responded to treatment. doses of docetaxel (starting from 30 mg/m2), all on days 1 and 8 Conclusions: The weekly docetaxel administration in combievery three weeks. Escalation was stopped if > 33% of patients nation with either gemcitabine or vinorelbine is a well-tolerated treated at a given dose level showed DLTat the first cycle. treatment for heavily pretreated advanced breast cancer paResults: A total of 34 patients with locally advanced (8) or tients. This approach, although sometimes capable of achievmetastatic disease (26) were treated, for a total of 94 cycles ing a major response, does not seem advisable in advanced delivered. Nineteen patients received docetaxel in combination breast cancer patients refractory to both anthracyclines and with gemcitabine and 15 with vinorelbine. All patients had paclitaxel. been pretreated with anthracyclines, and 24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of 40/m2 proved to be safe when combined on days 1 and 8 with Key words: docetaxel + gemcitabine, docetaxel + vinorelbine, gemcitabine, while a dose of 35 mg/m2 was tolerated in phase I, breast cancer Summary
Introduction
Metastatic breast cancer is essentially incurable by current chemotherapies, and patients have a median survival time of approximately two years after documentation of metastasis [1]. Many cytotoxic agents have shown some activity in advanced breast cancer, and first-line chemotherapy regimens often include anthracyclines [1, 2]. When patients present with disease progression despite previous anthracycline-based treatment, their prognoses are considered to be extremely poor, and salvage therapy has only a modest impact on outcome [3]. Of the new agents isolated in recent years, the taxanes seem to show the most promise in the treatment of breast cancer. Docetaxel has shown significant activity in the treatment of patients with metastatic breast cancer who had received previous anthracycline therapy. In four phase II studies involving 134 patients classified
as anthracycline-resistant, docetaxel produced response rates ranging from 29%-54%, with an overall response rate of 41% (95% confidence interval (95% CI): 35%50%), a median time to progression (TTP) of 4.3 months, and a median survival of 10.6 months [4]. In a recent large phase III trial single-agent docetaxel yielded overall response (ORR), TTP and overall survival rates significantly higher than the mitomycin-vinblastine combination in anthracycline-refractory breast cancer patients [5]. Vinorelbine is also an agent with significant activity in the treatment of relapsed or refractory breast cancer. In a large randomized trial vinorelbine produced a higher ORR and TTP than single-agent melphalan in the anthracycline-refractory (third-line) setting [6]. Gemcitabine (difluorodeoxycytidine, dFdC) has also shown a definite antitumor activity in advanced breast cancer patients [7]. The combination of docetaxel with either vinorelbine or gemcitabine has recently been tested, both in chemo-
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National Tumor Institute of Naples, Naples, Italy
368 naive and pretreated patients. A standard single-day docetaxel administration was always adopted [8-10]. Since it has been recently reported that the weekly schedule could improve the docetaxel therapeutical index [11], we undertook this phase I study with the objective of determining the docetaxel MTD when it is combined with either vinorelbine or gemcitabine in anthrayclinerefractory advanced breast cancer patients. Patients and methods Eligibility criteria
Treatment
Characteristic
Number of patients
Total Age (years) Median Range Estrogen receptor status Negative Positive Unknown Main site of involvement Breast (locally advanced) T4a-b-c-
34 49
33-70
T4d
Study design The starting docetaxel dose was 30 mg/m2, with an increment of 5 mg/m2 at each step. Patients were given gemcitabine (group I) or vinorelbine (group II) in combination with docetaxel. The docetaxel dose escalation was stopped if > 2 of 3 or > 3 of 6 patients had DLT at the first chemotherapy cycle. DLT was defined as grade 4 neutropenia lasting longer than seven days (or ANC < 100 lasting longer than three days), or febrile neutropenia, or grade 4 thrombocytopenia lasting longer than four days, or grade ^ 3 non-hematologic toxicity (except for nausea and alopecia). The omission of day 8 chemotherapy administration, or any delay in recycling were also considered a DLT.
Results Demographics Between September 1997 and June 1999, 34 patients with locally advanced (8) or metastatic (26) breast cancer were enrolled in this study. Table 1 outlines the main patient characteristics. Five of the eight patients without distant metastases had inflammatory breast cancer. In patients with metastatic disease the main site of disease
8 3 5
Lung Liver Bone Soft tissue Previous treatment Cisplatin—epirubicin—paclitaxel High-dose epirubicin
4 6 12 4 24 4 6
FEC
Response to previous treatment Yes
< 3-month relapse-free > 3-month relapse-free No
Eligible patients were alternately enrolled in one of the following groups: I) docetaxel + gemcitabine; II) docetaxel + vinorelbine. In both gToups patients received escalating doses of docetaxel (starting from 30 mg/m2) as a one-hour infusion, followed by gemcitabine 1000 mg/m2 over 30 minutes (I) or vinorelbine 25 mg/m2 (II) on days 1 and 8 every three weeks. Premedication for hypersensitivity reactions and fluid retention consisted of oral dexamethasone 12 hours and 4 hours before docetaxel administration and for 3 days after treatment. At least three cycles were delivered. In patients showing a major response an additional three cycles were administered. Chemotherapy was given at full doses if neutrophils were 5* 2000/mm3, and platelets > 100,000/mm3. In the presence of grade 1 neutropenia or thrombocytopenia chemotherapy was omitted on day 1, while on day 8 it was given at 75% of the planned dose.
11 18 5
13 5 8 21
involvement was visceral in 10 cases, bone in 12 cases, and soft tissue in the remaining 4 cases. Previous treatment for the advanced disease had consisted of a cisplatin (30 mg/m2)-epirubicin (50 mg/m2)-paclitaxel (120 mg/m2) weekly administration with G-CSF support in 24 of 34 patients [14]. The remaining 10 patients had received a standard cyclophosphamide-epirubicinfluorouracil regimen (6) or epirubicin at the dose of 120 mg/m2 (4). In 12 of the 34 patients adjuvant chemotherapy had also been performed. Twenty-one patients had not responded to previous anthracycline-based therapy. In the remaining 13 patients, the relapse had occurred within 3 months (5 cases) or more (8 cases) after suspension of the previous chemotherapy. Dose escalation data (Table 2) a) Docetaxel—gemcitabine
Nineteen patients were enrolled in this group through four different docetaxel dose levels, for a total of fiftythree cycles delivered. The docetaxel dose escalation proceeded to the dose of 45 mg/m2. No DLT occurred at the first cycle in the three patients treated at the docetaxel dose of 30 mg/m2, while episodes of DLT occurred in each of the first cycles of the 35 mg/m2 and 40 mg/m2 doses, in both cases grades ^ 2 neutropenia on day 8. Four patients entered at the dose level of 45 mg/m2. In two cases the day 8 chemotherapy administration was omitted at the first cycle due to grade ^ 2 neutropenia, and in a third case an episode of febrile neutropenia occurred.
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Candidates for this study were women with histologicaHy/cytologically-proven locally-advanced or metastatic breast cancer who had not responded to, or had relapsed after, anthracycline-based chemotherapy for advanced disease. Previous exposure to paclitaxel was also allowed. Other requirements included measurable or assessable disease, age ^ 70 years, ECOG performance status $ 2, and adequate hematologdc, renal and hepatic functions. All patients gave their witnessed and written informed consent, and the protocol was approved by the Ethics Committee for Biological Research of the National Tumor Institute of Naples.
Table 1. Patient characteristics.
369 Table 2. Dose escalation results. Docetaxel dose
No. of pts
Cycles
Type
Response
0 1 1 3
Day 8 omissiun Day 8 omission 2 day 8 omission 1 febrile neutropenia
0 1 2 0
0 1 3
Day 8 omission Day 8 omission Day 22 omission Febrile neutropenia
0 2 0
Docetaxel-gemcitabine 30 35 40 45
mg/m 2 mg/m 2 mg/m 2 mg/m 2
3 6 6 4
8 19 16 10
Docetaxel-vinorelbine 30 mg/m 2 35 mg/m 2 40 mg/m 2
3 6 6
6 16 19
b) Docetaxel-vinorelbine Fifteen patients were enrolled in this group through three different docetaxel dose levels, for a total of fortyone cycles delivered. The docetaxel dose escalation proceeded to the dose of 40 mg/m2. No DLT occurred at the first cycle in the three patients treated at the docetaxel dose of 30 mg/m2, while one episode of DLT occurred in the first cycle in the six patients treated at the dose of 35 mg/m2, a grade 3 neutropenia on day 8. Six patients entered at the dose level of 40 mg/m2. There were three episodes of DLT at the first cycle, a grade 4 neutropenia, omission of day 8 chemotherapy administration, and incomplete hematologic recovery on day 21. Overall toxicity No toxic deaths were observed. Overall, grades 3 or 4 neutropenia occurred in 7 of 19 (37%) patients receiving docetaxel-gemcitabine (in only 2 cases was it of grade 4), and 8 of 15 (53%) patients who received docetaxelvinorelbine (3 cases of grade 4), and only two episodes of neutropenic sepsis were observed (both in the vinorelbine group). Thrombocytopenia, of grades 3 or 4, in 3 (16%) of the 19 patients treated with docetaxelgemcitabine and 4 (26%) of the 15 patients who received docetaxel-vinorelbine, was less relevant. Only one patient (who had received 4 cycles of docetaxel-gemcitabine) showed severe anemia requiring a packed red blood-cell transfusion. Non-hematologic toxicity was negligible in the majority of patients. Mild fluid retention occurred in only three patients (docetaxel-gemcitabine two patients, docetaxel-vinorelbine one patient). Severe emesis occurred in only one patient of the last docetaxel-gemcitabine cohort. Fatigue was more frequent, occurring in 7 of the 19 (37%) patients treated with docetaxel-gemcitabine, and 6 of 15 (40%) of those receiving docetaxelvinorelbine, but was severe in only 2 cases (one in each group). Peripheral neuropathy was observed in a total of 16 (47%) patients; 6 of 19 (32%) treated with docetaxelgemcitabine and 10 of 15 (66%) treated with docetaxel-
Response All of the 34 enrolled patients were evaluated for response on an 'intent-to-treat' basis. A total of nine patients (docetaxel-gemcitabine 5 and docetaxelvinorelbine 4) received fewer than three chemotherapy cycles because of the occurrence of early disease progression. No complete responses were registered among the 25 patients assessed for response after 3 cycles. An overall offivepatients showed a partial response (docetaxel-gemcitabine 3 and docetaxel-vinorelbine 2) for a 15% ORR (95% CI: 5%-31%). Response occurred in liver in three cases, and in lung and soft tissue in the others. Responses were observed at the docetaxel dose of 35 mg/m2 (3 patients) and 40 mg/m2 (2 patients) (Table 2). One partial response was observed among the twentyfour patients (4%) who had received weekly dose-dense paclitaxel, while four objective responses were recorded for the remaining ten patients (40%) who had previously received an anthracycline-based treatment not including paclitaxel. Four of the five responders had shown response to previous treatment (3 had had > 3-month relapse-free intervals), while only one response occurred among the 21 patients who had failed to respond to the previous anthracycline-based chemotherapy.
Discussion On the basis of the results of this study we believe that an effective docetaxel dose can be administered in combination with either vinorelbine or gemcitabine in heavily pretreated breast cancer patients on the days 1 and 8 - every-three-week schedule. Indeed, a total docetaxel dose of 80 mg/m2 can be safely delivered over three weeks in combination with gemcitabine, while a slightly lower dose (70 mg/m2) has been proven safe in combination with vinorelbine. Moreover, even in the last cohorts of patients of both groups the occurrence of life-threatening hematologic or non-hematologic toxicity was very uncommon, with DLT in most cases being a moderate but prolonged neutropenia which impaired the administration of chemotherapy at the scheduled time. Indeed, it is noteworthy that less than 20% of patients (5 of 34) suffered grade 4 neutropenia, and that there were only two episodes of neutropenic sepsis. This result appears to be of interest when compared with the much higher incidence of grade 4 neutropenia (>50% even in
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DLT
vinorelbine. One patient of the latter group refused to continue the treatment after the fourth cycle because of the occurrence of grade 2 peripheral neuropathy. Fourteen of the sixteen patients showing neurotoxicity had previously received weekly cisplatin-epirubicin-paclitaxel. Protracted constipation was observed in two patients receiving docetaxel-gemcitabine and four patients treated with docetaxel-vinorelbine.
370 is expected to happen with more prolonged infusion or dose-dense weekly administration). On the basis of these considerations, it could be argued that neither the docetaxel-gemcitabine nor the docetaxel-vinorelbine combinations should be recommended for breast cancer patients with previous treatment with anthracycline and paclitaxel, especially when given at a high-dose intensity. On the other hand, the evidence of 4 partial responses among 10 patients not previously treated with paclitaxel makes it reasonable to seek further evaluation of these two regimens in anthracycline-pretreated patients. In conclusion, the results of this study suggest that splitting the administration of docetaxel between days 1 and 8 of an every-three-week cycle allows its combination with either gemcitabine or vinorelbine. With both of these regimens hematologic and nonhematologic toxicities are manageable, although some concerns may remain about neurotoxicity in patients receiving docetaxel-vinorelbine, especially those pretreated with paclitaxel and cisplatin. The possible role of these two regimens needs to be explored in anthracycline-resistant patients, although minimal or no activity is expected in patients with previous exposure to high-dose-intensity paclitaxel. References 1. Flamm Honig S. Treatment of metastatic disease. In Harris JR, Hellman S, Henderson IC et al. (eds): Breast Diseases. Philadelphia, Pennsylvania: Lippincott 1996; 669-734. 2. Hoogstraten B, George SL, Samal B et al. Combination chemotherapy and adnamycin in patients with advanced breast cancer: A Southwest Oncology Group study. Cancer 1976; 38: 13-20. 3. Sedlacek SM. Salvage therapy for metastatic disease. Semin Oncol 1990; 17 (Suppl 7): 45-9. 4. Van Oosterom AT. Docetaxel (taxotere): An effective agent in the management of second-line breast cancer. Semin Oncol 1995; 22 (Suppl 13): 22-8. 5. Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 1999; 17:1413-24. 6. Jones S, Winer E, Vogel C et al. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 1995; 13: 2567-74. 7. Carmichel J, Possinger K, Phillip P et al. Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731-6. 8. Escudero P, Bueso P, Mayordomo Jl et al. Docetaxel + vinorelbine is an active combination for patients with anthracyclinerefractory breast cancer. Results of a phase II trial. Proc Am Soc Clin Oncol 1998; 17: 139a. 9. De Paz L, Lluch A, Martin M et al. A phase II study of docetaxel and vinorelbine in metastatic breast cancer. Proc Am Soc Clin Oncol 1999; 18: 119. 10. Mavroudis D, Kouroussis Ch, Malamos N et al. A phase II trial of docetaxel and gemcitabine as second-line treatment in metastatic breast cancer. Proc Am Soc Clin Oncol 1998; 17:158a. 11. Briasoulis E, Karavasilis V, Anastasopoulos D et al. Weekly docetaxel in minimally pretreated cancer patients: A dose-escalation study focused on feasibility and cumulative toxicity of longterm administration. Ann Oncol 1999; 10: 701-6.
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chemo-nalve patients) reported with the standard singleday every-three week administration [12]. The better toxicity profile associated with the weekly docetaxel administration has been confirmed in a recently published study. A weekly dose of 50 mg/m2 (giving a three-week cumulative dose of 150 mg/m2) was the MTD, and even at this level no episodes of grade 4 neutropenia were observed, the DLT also being a prolonged moderate neutropenia causing > 2-week treatment delay in this study [11]. The weekly fractionation results in a even more dramatic change of the paclitaxel therapeutic index. In fact, an almost three-times higher dose intensity with the weekly schedule than that generally obtained with the single-day every-three-week administration was delivered [13]. Moreover, with this schedule we even managed to deliver cumulative three-week doses of paclitaxel, epirubicin, and cisplatin of 320 mg/m2, 150 mg/m2, and 90 mg/m2 [14]. Nonhematologic toxicity was also not troublesome in the majority of patients. Peripheral neuropathy was sometimes relevant, especially in the vinorelbine group, but that almost always occurred in patients who had pre-existing grade 1 neuropathy as a consequence of the previous cisplatin- and paclitaxel-including treatment. The low number of patients treated prevents us from making an accurate comparison of the toxicity profiles of the two groups. However, the addition of vinorelbine seems to produce a higher incidence of severe neutropenia, and relevant neurotoxicity; therefore, the dose of docetaxel which can be safely combined with vinorelbine is slightly lower than that advisable in combination with gemcitabine. Although evaluation of the antitumor activity of these two new regimens was not the primary aim of this study, we believe that our activity data allow us to speculate on this issue. The overall response rate of the study population as a whole does not appear particularly encouraging if compared with that reported with docetaxel alone (30%) in a recently published large phase III trial [5]. However, there are relevant differences between the two study populations. First of all it must be stated that 70% (24 of 34) of our patients had been previously treated with a very aggressive weekly polychemotherapy regimen which included epirubicin, paclitaxel and cisplatin, all together [14]. Only one partial response (4%) was recorded in this subgroup, while 4 of 10 (40%) of the remaining patients responded. The previous exposure to a very high-dose intensity of epirubicin (50 mg/m2/ week), and of paclitaxel (120 mg/m2/week), could explain the disappointing response rate in the former group. At the MD Anderson a 17.4% ORR was reported in paclitaxel-resistant breast cancer patients with singleagent docetaxel, but no responses were observed in those who had received the paclitaxel 24-hour infusion [15]. This finding suggests that the possibility of responding to docetaxel is very low in patients who have previously received a maximal paclitaxel exposure (such as
371 12. Fumoleau P, Chevallier B, Kerbrat P et al. A multicentre phase II study of the efficacy and safety of docetaxel as first-line treatment of advanced breast cancer. Report of the Clinical Screening group of the EORTC. Ann Oncol 1996; 7: 165-71. 13. Akerley W, Glantz M, Choy H et al. Phase I trial of weekly paclitaxel in advanced lung cancer. J Clin Oncol 1998; 16: 153-8. 14. Frasci G, D'Aiuto G, Cornelia P et al. Cisplatin-epirubicinpaclitaxel weekly administration in advanced breast cancer: A phase I study of the Southern Italy Cooperative Oncology Group. Breast Cancer Res Treat 1999; 56: 239-52. 15. Valero V, Jones SE, Von Hoff DD et al. A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 1998; 16: 3362-8.
Received 9 December 1999; accepted 3 January 2000. Correspondence to: G. Frasci, MD Division of Medical Oncology A National Tumor Institute Via Mariano Semmola 80131 Naples Italy E-mail: [email protected]
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Short report Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study G. Frasci, P. Cornelia, G. D'Aiuto, R. Thomas, I. Capasso, M. Elmo, G. Botti, G. R. Cortino, L. Lapenta, V. De Rosa, R Vallone, A. Petrillo & G. Cornelia for the Southern Italy Cooperative Oncology Group (SICOG)
combination with vinorelbine. Overall, nine episodes of DLT, all of them neutropenia, occurred at the first cycle. ConsiderPurpose: The objective of this study was to determine the ing all 94 cyles, grades 3 or 4 neutropenia and thrombocytodocetaxel MTD when combined with gemcitabine or vinorelbine penia occurred in 15 (44%), and 7 (20%) patients. Non-hemain advanced breast cancer patients who had received previous tologic toxicity was mild, except for three cases of grade 2 peripheral neuropathy. All patients were assessed for response anthracycline-based chemotherapy for advanced disease. Patients and methods: Advanced breast cancer patients aged on an 'intent-to-treat' basis. Overall, five partial responses between 18 and 70 with ECOG PS 0-2 who had not responded were recorded (docetaxel + gemcitabine = 3 and docetaxel + to, or had relapsed after, first-line anthracycline-based chemo- vinorelbine = 2), for a 15% (95% CI: 5%-31%) overall response therapy, were randomized to receive either gemcitabine 1000 rate. Only 1 of 24 (4%) patients who had received weekly dosemg/m2 or vinorelbine 25 mg/m2 in combination with escalating dense paclitaxel responded to treatment. doses of docetaxel (starting from 30 mg/m2), all on days 1 and 8 Conclusions: The weekly docetaxel administration in combievery three weeks. Escalation was stopped if > 33% of patients nation with either gemcitabine or vinorelbine is a well-tolerated treated at a given dose level showed DLTat the first cycle. treatment for heavily pretreated advanced breast cancer paResults: A total of 34 patients with locally advanced (8) or tients. This approach, although sometimes capable of achievmetastatic disease (26) were treated, for a total of 94 cycles ing a major response, does not seem advisable in advanced delivered. Nineteen patients received docetaxel in combination breast cancer patients refractory to both anthracyclines and with gemcitabine and 15 with vinorelbine. All patients had paclitaxel. been pretreated with anthracyclines, and 24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of 40/m2 proved to be safe when combined on days 1 and 8 with Key words: docetaxel + gemcitabine, docetaxel + vinorelbine, gemcitabine, while a dose of 35 mg/m2 was tolerated in phase I, breast cancer Summary
Introduction
Metastatic breast cancer is essentially incurable by current chemotherapies, and patients have a median survival time of approximately two years after documentation of metastasis [1]. Many cytotoxic agents have shown some activity in advanced breast cancer, and first-line chemotherapy regimens often include anthracyclines [1, 2]. When patients present with disease progression despite previous anthracycline-based treatment, their prognoses are considered to be extremely poor, and salvage therapy has only a modest impact on outcome [3]. Of the new agents isolated in recent years, the taxanes seem to show the most promise in the treatment of breast cancer. Docetaxel has shown significant activity in the treatment of patients with metastatic breast cancer who had received previous anthracycline therapy. In four phase II studies involving 134 patients classified
as anthracycline-resistant, docetaxel produced response rates ranging from 29%-54%, with an overall response rate of 41% (95% confidence interval (95% CI): 35%50%), a median time to progression (TTP) of 4.3 months, and a median survival of 10.6 months [4]. In a recent large phase III trial single-agent docetaxel yielded overall response (ORR), TTP and overall survival rates significantly higher than the mitomycin-vinblastine combination in anthracycline-refractory breast cancer patients [5]. Vinorelbine is also an agent with significant activity in the treatment of relapsed or refractory breast cancer. In a large randomized trial vinorelbine produced a higher ORR and TTP than single-agent melphalan in the anthracycline-refractory (third-line) setting [6]. Gemcitabine (difluorodeoxycytidine, dFdC) has also shown a definite antitumor activity in advanced breast cancer patients [7]. The combination of docetaxel with either vinorelbine or gemcitabine has recently been tested, both in chemo-
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National Tumor Institute of Naples, Naples, Italy
368 naive and pretreated patients. A standard single-day docetaxel administration was always adopted [8-10]. Since it has been recently reported that the weekly schedule could improve the docetaxel therapeutical index [11], we undertook this phase I study with the objective of determining the docetaxel MTD when it is combined with either vinorelbine or gemcitabine in anthrayclinerefractory advanced breast cancer patients. Patients and methods Eligibility criteria
Treatment
Characteristic
Number of patients
Total Age (years) Median Range Estrogen receptor status Negative Positive Unknown Main site of involvement Breast (locally advanced) T4a-b-c-
34 49
33-70
T4d
Study design The starting docetaxel dose was 30 mg/m2, with an increment of 5 mg/m2 at each step. Patients were given gemcitabine (group I) or vinorelbine (group II) in combination with docetaxel. The docetaxel dose escalation was stopped if > 2 of 3 or > 3 of 6 patients had DLT at the first chemotherapy cycle. DLT was defined as grade 4 neutropenia lasting longer than seven days (or ANC < 100 lasting longer than three days), or febrile neutropenia, or grade 4 thrombocytopenia lasting longer than four days, or grade ^ 3 non-hematologic toxicity (except for nausea and alopecia). The omission of day 8 chemotherapy administration, or any delay in recycling were also considered a DLT.
Results Demographics Between September 1997 and June 1999, 34 patients with locally advanced (8) or metastatic (26) breast cancer were enrolled in this study. Table 1 outlines the main patient characteristics. Five of the eight patients without distant metastases had inflammatory breast cancer. In patients with metastatic disease the main site of disease
8 3 5
Lung Liver Bone Soft tissue Previous treatment Cisplatin—epirubicin—paclitaxel High-dose epirubicin
4 6 12 4 24 4 6
FEC
Response to previous treatment Yes
< 3-month relapse-free > 3-month relapse-free No
Eligible patients were alternately enrolled in one of the following groups: I) docetaxel + gemcitabine; II) docetaxel + vinorelbine. In both gToups patients received escalating doses of docetaxel (starting from 30 mg/m2) as a one-hour infusion, followed by gemcitabine 1000 mg/m2 over 30 minutes (I) or vinorelbine 25 mg/m2 (II) on days 1 and 8 every three weeks. Premedication for hypersensitivity reactions and fluid retention consisted of oral dexamethasone 12 hours and 4 hours before docetaxel administration and for 3 days after treatment. At least three cycles were delivered. In patients showing a major response an additional three cycles were administered. Chemotherapy was given at full doses if neutrophils were 5* 2000/mm3, and platelets > 100,000/mm3. In the presence of grade 1 neutropenia or thrombocytopenia chemotherapy was omitted on day 1, while on day 8 it was given at 75% of the planned dose.
11 18 5
13 5 8 21
involvement was visceral in 10 cases, bone in 12 cases, and soft tissue in the remaining 4 cases. Previous treatment for the advanced disease had consisted of a cisplatin (30 mg/m2)-epirubicin (50 mg/m2)-paclitaxel (120 mg/m2) weekly administration with G-CSF support in 24 of 34 patients [14]. The remaining 10 patients had received a standard cyclophosphamide-epirubicinfluorouracil regimen (6) or epirubicin at the dose of 120 mg/m2 (4). In 12 of the 34 patients adjuvant chemotherapy had also been performed. Twenty-one patients had not responded to previous anthracycline-based therapy. In the remaining 13 patients, the relapse had occurred within 3 months (5 cases) or more (8 cases) after suspension of the previous chemotherapy. Dose escalation data (Table 2) a) Docetaxel—gemcitabine
Nineteen patients were enrolled in this group through four different docetaxel dose levels, for a total of fiftythree cycles delivered. The docetaxel dose escalation proceeded to the dose of 45 mg/m2. No DLT occurred at the first cycle in the three patients treated at the docetaxel dose of 30 mg/m2, while episodes of DLT occurred in each of the first cycles of the 35 mg/m2 and 40 mg/m2 doses, in both cases grades ^ 2 neutropenia on day 8. Four patients entered at the dose level of 45 mg/m2. In two cases the day 8 chemotherapy administration was omitted at the first cycle due to grade ^ 2 neutropenia, and in a third case an episode of febrile neutropenia occurred.
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Candidates for this study were women with histologicaHy/cytologically-proven locally-advanced or metastatic breast cancer who had not responded to, or had relapsed after, anthracycline-based chemotherapy for advanced disease. Previous exposure to paclitaxel was also allowed. Other requirements included measurable or assessable disease, age ^ 70 years, ECOG performance status $ 2, and adequate hematologdc, renal and hepatic functions. All patients gave their witnessed and written informed consent, and the protocol was approved by the Ethics Committee for Biological Research of the National Tumor Institute of Naples.
Table 1. Patient characteristics.
369 Table 2. Dose escalation results. Docetaxel dose
No. of pts
Cycles
Type
Response
0 1 1 3
Day 8 omissiun Day 8 omission 2 day 8 omission 1 febrile neutropenia
0 1 2 0
0 1 3
Day 8 omission Day 8 omission Day 22 omission Febrile neutropenia
0 2 0
Docetaxel-gemcitabine 30 35 40 45
mg/m 2 mg/m 2 mg/m 2 mg/m 2
3 6 6 4
8 19 16 10
Docetaxel-vinorelbine 30 mg/m 2 35 mg/m 2 40 mg/m 2
3 6 6
6 16 19
b) Docetaxel-vinorelbine Fifteen patients were enrolled in this group through three different docetaxel dose levels, for a total of fortyone cycles delivered. The docetaxel dose escalation proceeded to the dose of 40 mg/m2. No DLT occurred at the first cycle in the three patients treated at the docetaxel dose of 30 mg/m2, while one episode of DLT occurred in the first cycle in the six patients treated at the dose of 35 mg/m2, a grade 3 neutropenia on day 8. Six patients entered at the dose level of 40 mg/m2. There were three episodes of DLT at the first cycle, a grade 4 neutropenia, omission of day 8 chemotherapy administration, and incomplete hematologic recovery on day 21. Overall toxicity No toxic deaths were observed. Overall, grades 3 or 4 neutropenia occurred in 7 of 19 (37%) patients receiving docetaxel-gemcitabine (in only 2 cases was it of grade 4), and 8 of 15 (53%) patients who received docetaxelvinorelbine (3 cases of grade 4), and only two episodes of neutropenic sepsis were observed (both in the vinorelbine group). Thrombocytopenia, of grades 3 or 4, in 3 (16%) of the 19 patients treated with docetaxelgemcitabine and 4 (26%) of the 15 patients who received docetaxel-vinorelbine, was less relevant. Only one patient (who had received 4 cycles of docetaxel-gemcitabine) showed severe anemia requiring a packed red blood-cell transfusion. Non-hematologic toxicity was negligible in the majority of patients. Mild fluid retention occurred in only three patients (docetaxel-gemcitabine two patients, docetaxel-vinorelbine one patient). Severe emesis occurred in only one patient of the last docetaxel-gemcitabine cohort. Fatigue was more frequent, occurring in 7 of the 19 (37%) patients treated with docetaxel-gemcitabine, and 6 of 15 (40%) of those receiving docetaxelvinorelbine, but was severe in only 2 cases (one in each group). Peripheral neuropathy was observed in a total of 16 (47%) patients; 6 of 19 (32%) treated with docetaxelgemcitabine and 10 of 15 (66%) treated with docetaxel-
Response All of the 34 enrolled patients were evaluated for response on an 'intent-to-treat' basis. A total of nine patients (docetaxel-gemcitabine 5 and docetaxelvinorelbine 4) received fewer than three chemotherapy cycles because of the occurrence of early disease progression. No complete responses were registered among the 25 patients assessed for response after 3 cycles. An overall offivepatients showed a partial response (docetaxel-gemcitabine 3 and docetaxel-vinorelbine 2) for a 15% ORR (95% CI: 5%-31%). Response occurred in liver in three cases, and in lung and soft tissue in the others. Responses were observed at the docetaxel dose of 35 mg/m2 (3 patients) and 40 mg/m2 (2 patients) (Table 2). One partial response was observed among the twentyfour patients (4%) who had received weekly dose-dense paclitaxel, while four objective responses were recorded for the remaining ten patients (40%) who had previously received an anthracycline-based treatment not including paclitaxel. Four of the five responders had shown response to previous treatment (3 had had > 3-month relapse-free intervals), while only one response occurred among the 21 patients who had failed to respond to the previous anthracycline-based chemotherapy.
Discussion On the basis of the results of this study we believe that an effective docetaxel dose can be administered in combination with either vinorelbine or gemcitabine in heavily pretreated breast cancer patients on the days 1 and 8 - every-three-week schedule. Indeed, a total docetaxel dose of 80 mg/m2 can be safely delivered over three weeks in combination with gemcitabine, while a slightly lower dose (70 mg/m2) has been proven safe in combination with vinorelbine. Moreover, even in the last cohorts of patients of both groups the occurrence of life-threatening hematologic or non-hematologic toxicity was very uncommon, with DLT in most cases being a moderate but prolonged neutropenia which impaired the administration of chemotherapy at the scheduled time. Indeed, it is noteworthy that less than 20% of patients (5 of 34) suffered grade 4 neutropenia, and that there were only two episodes of neutropenic sepsis. This result appears to be of interest when compared with the much higher incidence of grade 4 neutropenia (>50% even in
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DLT
vinorelbine. One patient of the latter group refused to continue the treatment after the fourth cycle because of the occurrence of grade 2 peripheral neuropathy. Fourteen of the sixteen patients showing neurotoxicity had previously received weekly cisplatin-epirubicin-paclitaxel. Protracted constipation was observed in two patients receiving docetaxel-gemcitabine and four patients treated with docetaxel-vinorelbine.
370 is expected to happen with more prolonged infusion or dose-dense weekly administration). On the basis of these considerations, it could be argued that neither the docetaxel-gemcitabine nor the docetaxel-vinorelbine combinations should be recommended for breast cancer patients with previous treatment with anthracycline and paclitaxel, especially when given at a high-dose intensity. On the other hand, the evidence of 4 partial responses among 10 patients not previously treated with paclitaxel makes it reasonable to seek further evaluation of these two regimens in anthracycline-pretreated patients. In conclusion, the results of this study suggest that splitting the administration of docetaxel between days 1 and 8 of an every-three-week cycle allows its combination with either gemcitabine or vinorelbine. With both of these regimens hematologic and nonhematologic toxicities are manageable, although some concerns may remain about neurotoxicity in patients receiving docetaxel-vinorelbine, especially those pretreated with paclitaxel and cisplatin. The possible role of these two regimens needs to be explored in anthracycline-resistant patients, although minimal or no activity is expected in patients with previous exposure to high-dose-intensity paclitaxel. References 1. Flamm Honig S. Treatment of metastatic disease. In Harris JR, Hellman S, Henderson IC et al. (eds): Breast Diseases. Philadelphia, Pennsylvania: Lippincott 1996; 669-734. 2. Hoogstraten B, George SL, Samal B et al. Combination chemotherapy and adnamycin in patients with advanced breast cancer: A Southwest Oncology Group study. Cancer 1976; 38: 13-20. 3. Sedlacek SM. Salvage therapy for metastatic disease. Semin Oncol 1990; 17 (Suppl 7): 45-9. 4. Van Oosterom AT. Docetaxel (taxotere): An effective agent in the management of second-line breast cancer. Semin Oncol 1995; 22 (Suppl 13): 22-8. 5. Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 1999; 17:1413-24. 6. Jones S, Winer E, Vogel C et al. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 1995; 13: 2567-74. 7. Carmichel J, Possinger K, Phillip P et al. Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731-6. 8. Escudero P, Bueso P, Mayordomo Jl et al. Docetaxel + vinorelbine is an active combination for patients with anthracyclinerefractory breast cancer. Results of a phase II trial. Proc Am Soc Clin Oncol 1998; 17: 139a. 9. De Paz L, Lluch A, Martin M et al. A phase II study of docetaxel and vinorelbine in metastatic breast cancer. Proc Am Soc Clin Oncol 1999; 18: 119. 10. Mavroudis D, Kouroussis Ch, Malamos N et al. A phase II trial of docetaxel and gemcitabine as second-line treatment in metastatic breast cancer. Proc Am Soc Clin Oncol 1998; 17:158a. 11. Briasoulis E, Karavasilis V, Anastasopoulos D et al. Weekly docetaxel in minimally pretreated cancer patients: A dose-escalation study focused on feasibility and cumulative toxicity of longterm administration. Ann Oncol 1999; 10: 701-6.
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chemo-nalve patients) reported with the standard singleday every-three week administration [12]. The better toxicity profile associated with the weekly docetaxel administration has been confirmed in a recently published study. A weekly dose of 50 mg/m2 (giving a three-week cumulative dose of 150 mg/m2) was the MTD, and even at this level no episodes of grade 4 neutropenia were observed, the DLT also being a prolonged moderate neutropenia causing > 2-week treatment delay in this study [11]. The weekly fractionation results in a even more dramatic change of the paclitaxel therapeutic index. In fact, an almost three-times higher dose intensity with the weekly schedule than that generally obtained with the single-day every-three-week administration was delivered [13]. Moreover, with this schedule we even managed to deliver cumulative three-week doses of paclitaxel, epirubicin, and cisplatin of 320 mg/m2, 150 mg/m2, and 90 mg/m2 [14]. Nonhematologic toxicity was also not troublesome in the majority of patients. Peripheral neuropathy was sometimes relevant, especially in the vinorelbine group, but that almost always occurred in patients who had pre-existing grade 1 neuropathy as a consequence of the previous cisplatin- and paclitaxel-including treatment. The low number of patients treated prevents us from making an accurate comparison of the toxicity profiles of the two groups. However, the addition of vinorelbine seems to produce a higher incidence of severe neutropenia, and relevant neurotoxicity; therefore, the dose of docetaxel which can be safely combined with vinorelbine is slightly lower than that advisable in combination with gemcitabine. Although evaluation of the antitumor activity of these two new regimens was not the primary aim of this study, we believe that our activity data allow us to speculate on this issue. The overall response rate of the study population as a whole does not appear particularly encouraging if compared with that reported with docetaxel alone (30%) in a recently published large phase III trial [5]. However, there are relevant differences between the two study populations. First of all it must be stated that 70% (24 of 34) of our patients had been previously treated with a very aggressive weekly polychemotherapy regimen which included epirubicin, paclitaxel and cisplatin, all together [14]. Only one partial response (4%) was recorded in this subgroup, while 4 of 10 (40%) of the remaining patients responded. The previous exposure to a very high-dose intensity of epirubicin (50 mg/m2/ week), and of paclitaxel (120 mg/m2/week), could explain the disappointing response rate in the former group. At the MD Anderson a 17.4% ORR was reported in paclitaxel-resistant breast cancer patients with singleagent docetaxel, but no responses were observed in those who had received the paclitaxel 24-hour infusion [15]. This finding suggests that the possibility of responding to docetaxel is very low in patients who have previously received a maximal paclitaxel exposure (such as
371 12. Fumoleau P, Chevallier B, Kerbrat P et al. A multicentre phase II study of the efficacy and safety of docetaxel as first-line treatment of advanced breast cancer. Report of the Clinical Screening group of the EORTC. Ann Oncol 1996; 7: 165-71. 13. Akerley W, Glantz M, Choy H et al. Phase I trial of weekly paclitaxel in advanced lung cancer. J Clin Oncol 1998; 16: 153-8. 14. Frasci G, D'Aiuto G, Cornelia P et al. Cisplatin-epirubicinpaclitaxel weekly administration in advanced breast cancer: A phase I study of the Southern Italy Cooperative Oncology Group. Breast Cancer Res Treat 1999; 56: 239-52. 15. Valero V, Jones SE, Von Hoff DD et al. A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 1998; 16: 3362-8.
Received 9 December 1999; accepted 3 January 2000. Correspondence to: G. Frasci, MD Division of Medical Oncology A National Tumor Institute Via Mariano Semmola 80131 Naples Italy E-mail: [email protected]
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