Evidence for in vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer

A. Alexopoulos*, D. Tryfonopoulos, M. V. Karamouzis, G. Gerasimidis, I. Karydas, K. Kandilis, J. Stavrakakis, H. Stavrinides, C. Georganta, A. Ardavanis and G. Rigatos

1st Department of Medical Oncology, St Savvas Anticancer–Oncologic Hospital, Athens, Greece

Received 16 January 2003; revised 15 September 2003; accepted 17 September 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

The docetaxel and gemcitabine combination is active as salvage therapy in taxane-resistant/refractory patients with metastatic breast cancer (MBC). We conducted a phase II study to determine if this activity is due to an in vivo synergistic effect.

Patients and methods:

Women with measurable MBC, who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment, were enrolled. Patients with progressive disease (PD) or stable disease (SD) after receiving at least four cycles of docetaxel received gemcitabine 900 mg/m2 on days 1 and 8 plus docetaxel 100 mg/m2 on day 8, every 3 weeks. Granulocyte colony-stimulating factor could be used prophylactically in patients who experienced grade 3/4 neutropenia after the first cycle.

Results:

Between January 1999 and March 2002, 173 courses of docetaxel and gemcitabine were administered to 50 patients. The median number of metastatic sites was two (range one to three). Forty-six percent of patients responded (three complete responses, 20 partial responses), whereas 28% had SD and 26% had PD. The median duration of response was 6.1 ± 2.4 months. The median time to disease progression was 7.5 months (range 1–25) and the overall median survival was 15 months (range 3–57). Neutropenia was the only National Cancer Institute Common Toxicity Criteria grade 4 toxicity (in seven patients). Hematological grade 3 toxicities included neutropenia in 12 patients, thrombocytopenia in seven and anemia in one, while non-hematological toxicities were mild and manageable.

Conclusions:

The high overall response rate of the docetaxel plus gemcitabine combination after docetaxel failure in patients with MBC can be attributed to an in vivo synergism between the two drugs. These data warrant confirmation in a randomized study.

Key words: docetaxel, gemcitabine, metastatic breast cancer, salvage therapy


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Docetaxel is an agent known for its effectiveness against anthracycline-resistant metastatic breast cancer (MBC) [1]. Nevertheless, many patients do not respond to treatment or respond poorly with a short duration of response, requiring further salvage therapeutic approaches.

Gemcitabine is a chemotherapeutic agent that has shown encouraging activity in pretreated patients with MBC [24]. Gemcitabine blocks the cells in a different cellular phase from docetaxel (G1/S instead of G2/M) [5], therefore combination therapy with these agents is a promising option. Moreover, they interact synergistically in vitro [5], which may explain their additive effects when used in combination.

Various regimens of docetaxel and gemcitabine have produced significant response rates even when administered after the failure of previous regimens, in MBC [612], non-small-cell lung cancer [13] and pancreatic adenocarcinoma [14]. In a previous study from our group, four of 11 patients who had progressed after taxane treatment responded to the combination [11]. Thus, pretreatment with taxanes did not preclude a favorable response to the combined regimen. These results led us to speculate on a possible in vivo synergistic interaction between docetaxel and gemcitabine.

We conducted a phase II clinical study to investigate further the possibility of an in vivo synergism between docetaxel and gemcitabine in women with previously treated MBC in whom docetaxel therapy had failed.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient selection
Women aged 18–75 with histologically confirmed and bidimensionally measurable MBC, who were refractory or resistant [stable disease (SD) or progressive disease (PD)] to at least four previous cycles of docetaxel monotherapy as first- or second-line treatment, were enrolled. Prior radiotherapy was allowed provided that the treatment target was outside the radiation field. Eligibility criteria required patients to have a World Health Organization performance status of 0 –2, adequate organ function, including an absolute neutrophil count ≥1500/µl, platelet count ≥100 000/µl, total serum bilirubin level ≤1.5 mg/dl, aspartate aminotransferase ≤3 x upper limit of normal, and serum creatinine concentration ≤1.5 mg/dl. Ineligibility criteria included radiotherapy to >25% of marrow-containing bone, untreated brain metastases and a history of a second malignancy other than resected basal cell and/or squamous cell carcinoma of the skin. The local Scientific and Ethics Committees approved the protocol. All patients gave written informed consent before study entry; the study was carried out according to the Declaration of Helsinki.

Study treatment
Patients were pretreated with a minimum of four cycles (maximum six cycles) of docetaxel (Taxotere®; Aventis Pharma EBEWE Arzneimittel Ges.m.b.H., Pharmaceutical Laboratories Unterach, Austria) at 100 mg/m2 in 250 ml 0.9% normal saline administered by intravenous infusion over 60 min on day 1. Premedication was given to all patients, and consisted of methylprednisolone 16 mg p.o. 12, 8 and 1 h before docetaxel infusion; methylprednisolone 8 mg b.i.d. was continued for 2 days after infusion to prevent fluid retention and hypersensitivity reactions.

Chemotherapy consisted of gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, IN, USA) at 900 mg/m2 in 250 ml 0.9% normal saline by intravenous infusion over 30 min on days 1 and 8 and docetaxel 100 mg/m2 before gemcitabine on day 8. Treatment was repeated every 3 weeks (additional pretreatment details are provided in our previous study) [11], for a total of six cycles. Treatment was discontinued in the case of disease progression, intolerable toxicity or patient refusal.

Recombinant human granulocyte colony-stimulating factor (G-CSF) (Granocyte; Aventis Pharma) 150 µg/m2 was administered subcutaneously on days 9–16, or until recovery of leukocytes, to the patients who experienced grade 3/4 neutropenia after the first cycle of chemotherapy. Treatment was repeated every 3 weeks.

Dose modifications were based on hematological and non-hematological toxicities. If the neutrophil count on day 8 of scheduled treatment was <1500/µl or the platelet count was <100 000/µl treatment was postponed 1 week without dose adjustment. In the case of a neutrophil count <500/µl lasting >4 days or complicated with fever, or a platelet count <25 000/µl, the subsequent dose of both drugs was reduced by 25%. Regarding docetaxel, 25% reduction of the previous dose was recommended in the case of grade 2 skin reactions and grade 2 neurotoxicity, whereas treatment would be stopped in the case of persistent grade 2 skin reactions and grade 3 neurotoxicity. In the case of fluid retention, no dose reduction of docetaxel was planned, although treatment with spironolactone 50 mg would be recommended.

Response and toxicity evaluations
Before each treatment, patients underwent standard evaluations, including full patient history, physical examination and routine laboratory tests. Tumor measurement was assessed by physical examination, computed tomography scan and/or ultrasound within 14 days of enrollment and subsequently after each cycle of treatment.

Complete response (CR), partial response (PR), SD and PD were assessed using the International Union against Cancer Criteria [15]. Response duration was measured from the first day of treatment to documentation of PD for CRs or PRs only. Survival was calculated from the date of registration to the date of death, irrespective of its cause. Time to disease progression was determined by the interval between the initiation of treatment to the first date that disease progression was objectively documented or treatment was discontinued. All time-to-event curves were estimated using the Kaplan–Meier method.

Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) [16]. Hematological toxicity, assessed via complete blood counts, was monitored weekly, except for patients with grade 4 or febrile neutropenia in whom monitoring was carried out daily.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
A total of 87 patients were pretreated with docetaxel monotherapy; 50 patients with MBC found to be refractory or resistant (i.e. had SD or PD) to docetaxel were enrolled in this phase II study between January 1999 and March 2002. All 50 patients were evaluable for response and toxicity. Patient characteristics are shown in Table 1. The majority of patients (84%) received prior anthracycline-containing regimens and presented with visceral metastasis, i.e. liver and/or lung involvement (74%). The median number of metastatic sites was two (range one to three).


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Table 1. Patient characteristics
 
Dose administration
A total of 173 cycles of docetaxel and gemcitabine were administered to the 50 enrolled patients. The median number of cycles per patient was 3.46 ± 1.45. Forty-six cycles (27%) of therapy were delayed due to hematological toxicity. The median number of delay days due to toxicity events was estimated to be 4 days (range 3–5). The relative dose intensities for gemcitabine and docetaxel were 84.4% and 85.1%, respectively.

Response
After docetaxel monotherapy, 30 patients (60%) had SD and 20 (40%) had PD. As shown in Table 2, there were three CRs (6%) and 20 PRs (40%) for an overall response rate of 46% (95% confidence interval 32% to 60%) following combination chemotherapy with the addition of gemcitabine. The median time to response was 5 weeks (range 3–9). Additionally, 14 patients (28%) had SD and 13 (26%) had PD. Of the 30 patients who achieved SD with initial docetaxel monotherapy, 15 achieved a response (two CRs, 13 PRs). Of the 20 patients who progressed, eight achieved a response (one CR, seven PRs) with the combination. The median duration of response was 6.1 ± 2.4 months.


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Table 2. Response after the addition of gemcitabine after docetaxel failure
 
At the time of analysis 43 patients (86%) had died. The time to disease progression was 7.5 months (range 1–25) (Figure 1) and the overall median survival of all patients was 15 months (range 3–57) (Figure 2). The patients with CR had a median time to disease progression of 9.5 months (range 7–11) and a median overall survival of 17 months (range 8–30), while patients with PR had a median time to disease progression of 9 months (range 2–25) and a median overall survival of 19 months (range 3–57).



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Figure 1. Disease-free survival of the patients enrolled in the study.

 


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Figure 2. Overall survival of the patients enrolled in the study.

 
Toxicity
All patients were assessed for toxicity. No toxic death occurred. Table 3 summarizes the hematological and non-hematological toxicities for all patients. Treatment was discontinued in only one patient, due to prolonged grade 3/4 neutropenia, while seven patients (14%) refused to continue the treatment schedule due to grade 3/4 myelotoxicity. Neutropenia was the only NCI-CTC grade 4 toxicity, occurring in seven patients. Grade 3 neutropenia occurred in 12 patients (24%), of whom four developed neutropenic fever. Additionally, grade 3 thrombocytopenia was experienced in seven patients (14%); however, no platelet transfusions were necessary. One patient (2%) experienced grade 3 anemia. Non-hematological toxicities were mild and manageable; asthenia and fluid retention were the main grade 3 toxicities.


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Table 3. National Cancer Institute Common Toxicity Criteria toxicity grades (n = 50)
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The addition of gemcitabine to docetaxel therapy resulted in a considerable overall response rate of 46% in docetaxel-refractory or -resistant patients with MBC, as all patients had either SD or PD to previous docetaxel therapy. Most notably, eight patients who progressed on docetaxel responded to the subsequent combination, with one patient achieving a CR.

The high overall response rate of the combination after docetaxel pretreatment cannot be solely attributed to gemcitabine, since gemcitabine monotherapy in anthracycline-resistant MBC and after taxane therapy has resulted in response rates of up to 29% [4, 17, 18]. Moreover, as docetaxel has been shown to provide its highest therapeutic potency as a single agent at about four cycles of a 3-week schedule [19], we decided to administer gemcitabine after at least four cycles of docetaxel to minimize the possibility that the initial docetaxel infusion may have contributed to the achieved response.

In our previous study of docetaxel plus gemcitabine in MBC patients pretreated with an anthracycline-based regimen as front-line therapy, the majority of patients who had previously responded to a taxane regimen also responded to the combination [11]. Patients presenting with SD to a taxane regimen generally did not respond to the combination, although four of 11 patients with PD responded. In the present study, eight of 20 patients who had a PD to docetaxel pretreatment responded, as well as 15 of 30 patients with SD. These results further underscore the synergistic potential of gemcitabine and docetaxel.

Although the combination of gemcitabine plus docetaxel yields higher response rates at higher docetaxel doses, its use is often limited by significant toxicities [7, 8], particularly in the absence of growth factor prophylaxis or support [7]. Neutropenia is the major dose-limiting toxicity of docetaxel, followed by diarrhea and fluid retention. Thus, depending on the dose and schedule, significant hematological toxicity may occur with the combination. The toxicity profile observed in our study with the gemcitabine plus docetaxel combination was moderate and manageable, especially considering the number of docetaxel cycles administered in total. This may be due to the prophylactic administration of G-CSF [20].

In conclusion, the high response rate observed with the combination of gemcitabine and docetaxel could indicate a synergistic clinical interaction between the two drugs. In particular, patients responded to gemcitabine plus docetaxel even after docetaxel failure. These data further demonstrate that the combination may be used as potent salvage therapy after anthracycline and/or taxane pretreatment with manageable toxicity. These encouraging results should be confirmed in a randomized study conducted in a selected population of pretreated patients.


    FOOTNOTES
 
* Correspondence to: Dr A. Alexopoulos, 171 Alexandras Street, Athens 11522, Greece; Tel: +30-210-6409381; Fax: +30-210-6420146; E-mail: empika{at}ath.forthnet.gr Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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