1 Institut Català dOncologia, Girona; 2 Instituto Valenciano de Oncología, Valencia; 3 Hospital Clínic, Valencia; 4 Hospital Germans Trias i Pujol, Badalona; 5 Hospital de la Santa Creu i Sant Pau, Barcelona; 6 Hospital Arnau de Vilanova, Valencia; 7 Hospital General Yagüe, Burgos; 8 Hospital 12 de Octubre, Madrid, Spain
Received 20 May 2003; revised 25 August 2003; accepted 4 September 2003
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ABSTRACT |
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We wanted to assess the toxicity and efficacy of paclitaxel plus gemcitabine in advanced breast cancer and to confirm whether circulating HER2 extracellular domain (ECD) correlates with treatment response.
Patients and methods:
Forty-three patients received paclitaxel 150 mg/m2 followed by gemcitabine 2500 mg/m2, both on day 1 of 14-day cycles, with a maximum of eight cycles. Serum levels of HER2 ECD were assessed by ELISA.
Results:
All patients were evaluable for toxicity and 42 for efficacy. Overall toxicity was low. Grade 3 neutropenia occurred in 12% of patients and grade 4 in 17%, and other grade 3 toxicities in <5%. One patient had an allergic infusion reaction. Overall response rate was 71% [95% confidence interval (CI) 62% to 81%], with 11 patients achieving a complete response (26%). With a median follow-up of 26 months, the median time to progression was 16.6 months. Response rate correlated significantly with HER2 ECD, with 42% of HER2 ECD-positive patients responding versus 83% of HER2 ECD-negative patients (P = 0.02). Furthermore, response duration was shorter in patients with positive HER2 ECD levels (7.9 versus 14.4 months; P = 0.04).
Conclusions:
Paclitaxel plus gemcitabine given as an every 2-weeks schedule is a well tolerated and active regimen in advanced breast carcinoma. This is an attractive combination to use when anthracyclines are not indicated, such as in HER2 positive cases that receive trastuzumab. In addition, elevated levels of HER2 ECD adversely affect the efficacy of treatment.
Key words: breast cancer, extracellular domain, gemcitabine, HER2, oncogene, paclitaxel
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Introduction |
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Gemcitabine is a cytosine arabinoside prodrug analog which shows activity in a wide range of tumors. The cytotoxicity of gemcitabine is related to the cell accumulation of gemcitabine triphosphate (dFdCTP), inducing G0/G1 and S-phase arrest in human solid tumor cells [12]. In breast carcinoma, response rates as a single agent ranged from 15% to 46% [13] with very low toxicity, even in heavily pretreated patients [14].
Paclitaxel acts by stabilizing microtubules, blocking eukaryotic cells in the G2M mitotic phase [15]. Administered as a weekly or every 3-week schedule, paclitaxel is among the most active agents in breast cancer [16, 17]. In randomized clinical trials, paclitaxel therapy is equally effective as cyclophosphamide, methotrexate, 5-FU and prednisone (CMFP) in patients with advanced breast cancer [18]. In anthracycline-naïve patients, randomized trials have shown that paclitaxel in combination with anthracyclines is equivalent [19] or superior [3] to standard cyclophosphamide, doxorubicin and fluorouracil.
The combination of gemcitabine and paclitaxel is particularly valuable because of the different mechanisms of action of each drug and their non-overlapping toxicities. In vivo research shows that paclitaxel increases the accumulation of dFdCTP [20]. In non-small-cell lung cancer cell lines, paclitaxel administered immediately before gemcitabine significantly increased dFdCTP accumulation, gemcitabine incorporation into RNA and apoptotic index [21]. In mouse models, the greatest tumor growth delay was obtained when paclitaxel was administered on days 1 and 15, with gemcitabine every 3 days [22]. The combination of paclitaxel and gemcitabine has been evaluated in a phase I study using a biweekly schedule [23], with paclitaxel as a 3-h infusion, followed by gemcitabine as a 3060 min infusion. In this trial, the dose-limiting toxicities were neutropenia and elevation of alanine aminotransferase (ALT), and the recommended dose for phase II studies was paclitaxel 150 mg/m2 plus gemcitabine 3000 mg/m2.
Response to chemotherapy can be related to HER2 oncogene expression. We have shown previously that the response of metastatic breast cancer to a combination of paclitaxel plus doxorubicin was significantly impaired in those patients with elevated levels of circulating HER2 extracellular domain (ECD) [24]. We suggested that this relationship needed confirmation in an independent patient population.
The primary objective of the phase II clinical trial presented here was to determine the antitumor activity and the toxicity profile of a biweekly regimen of paclitaxel plus gemcitabine in patients with untreated advanced breast carcinoma. The secondary objective was to establish the relationship of prospectively determined baseline HER2 ECD with the efficacy of therapy.
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Patients and methods |
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Treatment plan
Patients received paclitaxel (150 mg/m2) by intravenous (i.v.) 3-h infusion, immediately followed by gemcitabine (2500 mg/m2) administered as a 6090-min i.v. infusion. All patients received premedication with i.v. dexamethasone 20 mg, diphenhidramine 50 mg (or dexchlorpheniramine 5 mg) and cimetidine 300 mg (or ranitidine 50 mg). Patients were scheduled to receive eight cycles of chemotherapy. All patients receiving at least four doses of therapy (2 months) were evaluable for efficacy analysis.
Complete blood counts were obtained weekly. All toxicity was graded according to the National Cancer Institute-common toxicity criteria [26]. Treatment was repeated every 2 weeks if the absolute neutrophil count (ANC) was 1.5 x 109/l and the platelet count was
100 x 109/l, and the patient had recovered from all non-hematological toxicities. Both drugs were reduced by 15% if the ANC was between 1 and 1.49 x 109/l, or if the platelet count was between 75 and 99.9 x 109/l. Treatment was delayed for at least 2 days if the ANC was <1 x 109/l, or if the platelet count was <75 x 109/l. A cycle might be delayed for a maximum of 2 weeks. If febrile neutropenia was evident, a 15% reduction for both drugs was made in subsequent cycles. Gemcitabine and paclitaxel were reduced by 25% if grade 3 liver toxicity, grade 3 mucositis or any other grade 3 toxicity developed. Paclitaxel was reduced by 25% in the case of grade 2 myalgia or grade 2 peripheral neuropathy. Gemcitabine was reduced by 25% if grade 3 cutaneous rash occurred. Both drugs were discontinued in the case of symptomatic bradycardia, grade 3 myalgia, grade 3 peripheral neuropathy or any grade 4 nonhematological toxicity. Patients who received at least one full dose of paclitaxel and gemcitabine were assessable for toxicity.
The dose intensity of paclitaxel and gemcitabine was calculated as the actual dose delivered during the whole treatment period in each patient, and expressed in milligrams of drug/m2/week [27]. With a calculated treatment period of 16 weeks, the planned dose intensity of paclitaxel was 75 mg/m2/week, and the planned dose intensity of gemcitabine was 1250 mg/m2/week.
Pretreatment evaluation and criteria for response
Pretreatment evaluation included a complete history and physical examination, complete blood count (CBC) with leukocyte differential, full serum biochemistry, Karnofsky PS assessment, computed tomography (CT) scan of the thorax and abdomen, and bone scan. During therapy, in addition to weekly CBC, biweekly serum biochemistry, physical examination and toxicity assessment were performed.
Tumor evaluation was performed after cycles four and eight, and then every 23 months. All sites of disease that were measurable or assessable before the study were re-evaluated at these time points. Patients were evaluable for efficacy analysis, using the WHO response criteria, if they had received at least four cycles of therapy or showed disease progression. After conclusion of the programmed eight cycle schedule and following the evaluation of response, the decision to offer additional treatment was left to the discretion of each investigator.
In responding patients, response duration was measured from the day the patient was first documented as having a 50% tumor volume reduction until the time of disease progression. Time to progression was measured from the date of study entry until the date of progression or relapse, date of death from any cause (even if without documented progression or relapse) or date last known to be responding. Those patients who were alive and not known to have experienced disease progression were censored at the date they were last known to be alive. Actuarial survival curves were constructed using the KaplanMeier method.
HER2 ECD measurements
Serum samples were collected prospectively in all patients before the start of therapy. The levels of circulating HER2 were measured using a sandwich enzyme immunoassay, according to the manufacturers instructions (HER-2/neu Microtiter ELISA; Oncogene, Cambridge, MA, USA). Serum samples were obtained at the time of baseline evaluation. The HER2 ECD values are expressed in nanograms per milliliter (ng/ml). Positivity was defined as 30 ng/ml, based on our previous results [24].
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Results |
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Toxicity
All patients were assessable for toxicity and the worst toxicities recorded per patient are listed in Table 2. The major toxicity was neutropenia. Grade 3 neutropenia occurred in 12% of patients and grade 4 in 17%. One patient presented two episodes of febrile neutropenia that resolved with standard therapy and did not require additional G-CSF support.
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Treatment efficacy
Of the 42 patients evaluable for response, 11 achieved a complete response (CR) and 19 a partial response, for an overall response rate of 71% [95% confidence interval (CI) 62% to 81%]. Eight (19%) patients had progressive disease and five (12%) patients had stable disease, two of them lasting >6 months. Response rate was slightly higher in patients with better PS (77% in patients with PS >80% versus 55% in cases with PS of 80%), two or less metastatic lesions (74% versus 70%) and no previous adjuvant chemotherapy (75% versus 67%), but none of these differences was statistically significant. There were no differences in response rate according to estrogen receptor status. In the patients that were pretreated with anthracyclines in the adjuvant setting, the response rate was slightly lower than in the rest of patients, although, again, this difference was not significant (57% versus 79%; P = 0.1).
After a median follow-up of 26 months (range 332), the median duration of response in responding patients was 13.4 months (95% CI 11.818.2), the median time to progression was 16.6 months (95% CI 8.524.7) and the median overall survival has not been reached. The 2-year actuarial overall survival was 62%. Since time to progression might not have been exclusively a result of the study regimen, as consolidation therapies were allowed after the end of the paclitaxelgemcitabine regimen, we recorded additional therapies before progression. In total, 14 patients underwent some form of consolidation therapy while in response or stable disease, including surgery (liver, one; breast, two), hormonal therapy (three), high-dose chemotherapy with stem cell support (five), radiotherapy (four) and additional chemotherapy (one). More than eight cycles of the investigation schedule were given in three patients.
Correlation of circulating HER2 ECD and treatment efficacy
HER2 ECD was tested in 42 patients. Treatment efficacy correlated significantly with HER2 ECD levels. While 83% of the HER2 ECD negative patients had an objective response, only 42% of the HER2 ECD positive cases had a response (Table 3). This difference was significant (P = 0.02). Furthermore, when we compared the duration of response in the patients with elevated or non-elevated levels of circulating HER2 ECD, we found that there were statistically significant differences. Response duration was shorter in patients with positive HER2 ECD levels (7.9 versus 14.4 months; P = 0.04). Figure 1 illustrates that elevated circulating HER2 ECD levels are associated with a shorter response duration.
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Discussion |
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The optimal combination of gemcitabine with paclitaxel has not been defined, and the dose schedule is an issue of research. The paclitaxelgemcitabine combination that was developed in non-small-cell lung cancer uses a three-weekly schedule of paclitaxel 175 mg/m2 on day 1 and gemcitabine 10001250 mg/m2 on days 1 and 8. A first trial in advanced breast cancer [28] proved that this combination was active and safe as salvage therapy. A similar regimen of paclitaxel plus gemcitabine has been compared with single-agent paclitaxel as front-line therapy in advanced breast cancer in a large phase III trial. The every-2-week schedule that we used followed a phase I trial of this schedule [23], and offers some advantages in relation to the standard 3-weekly schedule. First, the dose intensity is increased by 25% for paclitaxel (from 58 to 75 mg/m2/week) and almost 50% for gemcitabine (from 666833 to 1250 mg/m2/week). Second, the schedule exploits the synergistic potential observed in preclinical studies. The underlying mechanism for increased dFdCTP accumulation by paclitaxel is not known, and several speculations have been done [28]. In line with this proposed synergism of action, the response rate that was observed in our study was markedly higher than has been observed with either paclitaxel or gemcitabine as single agents [4, 11]. Whether this is related to additive or synergistic effects was not addressed by our study, but further exploration of this regimen in advanced breast cancer is justified by our results.
The toxicity in this study was low and delivered dose intensities were >90% of those planned. Two studies have explored similar biweekly regimens of paclitaxel plus gemcitabine. Isla et al. [30] performed a phase II trial in advanced non-small-cell lung cancer using paclitaxel 150 mg/m2 plus gemcitabine 2000 mg/m2 every 2 weeks. Sternberg et al. [31] have recently published the results of a study of paclitaxel 150 mg/m2 plus gemcitabine 25003000 mg/m2 every 2 weeks in advanced bladder carcinoma. In line with the results from our trial, hematological and non-hematological toxicities were low and no severe adverse events or toxic deaths related to treatment were noted.
We have found that HER2 ECD expression correlates with a diminished efficacy of chemotherapy. This validates our previous description of this correlation in a population of patients with advanced breast cancer that were treated with paclitaxel and doxorubicin [24]. In that study, we reported that HER2 ECD levels correlated with only two variables in advanced breast cancer: HER2 overexpression in the primary carcinoma, and the extension of metastatic disease. Other authors have described that HER2 ECD positivity correlates with resistance to hormonal therapy in advanced breast cancer [32, 33]. Whether the association of HER2 ECD reflects a general resistance to therapy or whether it is associated to paclitaxel-containing regimens will need further studies using non-paclitaxel-containing chemotherapy regimens.
In conclusion, the combination chemotherapy of biweekly gemcitabine plus paclitaxel is an active and tolerable regimen for patients with advanced breast cancer. Because these two drugs have mechanisms of action that differ from that of anthracyclines and alkylating agents, this is an attractive regimen to explore after adjuvant anthracyclines have been used (both in the metastatic setting or as sequential adjuvant therapy), or in cases in which anthracyclines should not be preferred, such as in combination with anti-HER2 antibodies in patients with HER2 overexpressing tumors. Based on the results reported here, we are presently conducting a clinical trial of paclitaxel plus gemcitabine combined with trastuzumab in patients with advanced breast cancer that are HER2 positive as defined by HER2 ECD status.
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Acknowledgements |
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FOOTNOTES |
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