1 Department of Medical Oncology, National Cancer Research Institute, Genova; 2 Clinical Trials Unit, NCI, Naples; 3 Istituto Nazionale Riposo e Cura per l'anziano, Oncologia, Roma; 4 Department of Oncology-Hematology, Azienda Ospedaliera S. Carlo, Potenza; 5 Department of Oncology, Ospedale Fatebenefratelli, Roma; 6 Medical Oncology Unit University Hospital of Padua, Padova; 7 UO Oncology, Molinette Hospital, Torino; 8 U.O. Oncologia Medica, USL 1, Ospedale Civile, Sanremo (IM), Italy
* Correspondence to: Dr L. Del Mastro, Department of Medical Oncology, National Cancer Research Institute, L.go Rosanna Benzi 10, 16132 Genova, Italy. Tel: +39-010-5600666; Fax: +39-010-5600850; Email: lucia.delmastro{at}istge.it
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Abstract |
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Patients and methods: Women with stage III or IV breast cancer aged 70 years were enrolled in a phase II study aimed to evaluate both activity and toxicity of weekly paclitaxel. Among 46 planned patients, at least 18 responses and not more than seven unacceptable toxic events are required for a favourable conclusion. Paclitaxel 80 mg/m2 was administered weekly for 3 weeks every 28 days.
Results: Unacceptable toxicity occurred in seven out of 46 patients evaluated for toxicity [15.2%; exact 95% confidence interval (CI) 7.6% to 28.2%] and was represented by one case of febrile neutropenia, one case of severe allergic reaction and five cases of cardiac toxicity. Among 41 patients evaluated for response, a complete response occurred in two (4.9%) patients and a partial response in 20 (48.8%), with an overall response rate of 53.7% (exact 95% CI 38.7% to 67.9%). The median progression-free survival was 9.7 months (95% CI 8.518.7) and median survival was 35.8 months (95% CI 19not defined).
Conclusions: Weekly paclitaxel is highly active in elderly advanced breast cancer patients. Data on cardiovascular complications, however, indicate the need for a careful monitoring of cardiac function before and during chemotherapy.
Key words: breast cancer, cardiotoxicity, chemotherapy, elderly, phase II study, weekly paclitaxel
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Introduction |
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The association of anthracyclines and taxanes is considered a standard treatment [1] for metastatic breast cancer patients. However, the use of anthracycline-containing regimens in elderly patients can led to an excessively high incidence of toxicity [2
]. The use of monochemotherapy with active drugs other than anthracyclines, such as paclitaxel, may be a strategy that combines both activity and tolerability in elderly patients.
Paclitaxel administered on a weekly schedule at doses of 80100 mg/m2 has been shown to be active and well tolerated [3, 4
]. Preliminary results of a direct comparison showed superiority of weekly compared with every 3 weeks paclitaxel in terms of response rate and time to progression [5
]. Our previous dose-finding study showed that weekly paclitaxel can be safely administered to elderly breast cancer patients [6
].
Data suggesting high activity and low toxicity of weekly paclitaxel prompted the present study evaluating the safety and activity of weekly paclitaxel as first-line chemotherapy in women 70 years.
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Patients and methods |
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Geriatric assessment
At baseline a multidimensional geriatric assessment was performed as described previously [7, 8
]. Comorbidities were scored as absent/present using a predefined list of 33 possible diseases; the Charlson score [9
] was then built by summing data regarding myocardial infarction, congestive heart failure, peripheral vascular disease, cerebral vascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease and diabetes. The other pathological conditions hypothesised in the Charlson score were not taken into account because they were precluded by the exclusion criteria for the study. Geriatric scales, namely those exploring activities of daily living (ADL) [10
] and instrumental ADL (IADL) [11
] were also used. Response codes range from 0 (full ability) to 8 (full disability) for the IADL scale and from 0 to 6 for the ADL scale.
Study design and sample size
The study was designed as a multicentre, two-stage, phase II study with activity and toxicity as primary end points [12]. The primary objective was to evaluate the activity (response rate) and toxicity (within the first four cycles) of weekly paclitaxel. The following parameters were considered for calculation of sample size: 30% as the lower acceptable response rate, 50% as the auspicated response rate, 25% as the higher acceptable rate of patients with unacceptable toxicity, 5% as the auspicated rate of patients with unacceptable toxicity, 10% of risk of false-negative result, 10% of risk of false-positive result for activity and 10% of risk of false-positive result for toxicity.
With these requirements, the planned sample size was 22 patients for the first stage and 46 at the end of the study, when at least 18 responses and not more than seven unacceptable toxic events within the first four cycles of chemotherapy were required for a favourable conclusion. The first stage was considered to be successfully passed if at least eight responses and not more than four unacceptable toxic events were observed. The protocol was approved by the Protocol Review and the ethics committees of the National Cancer Research Institute of Genoa, Italy.
Treatment regimen
Paclitaxel 80 mg/m2 was administered intravenously over 1 h weekly for 3 weeks every 28 days. Premedications, given 30 to 60 min before chemotherapy, consisted of diphenhydramine 40 mg administered intramuscularly, dexamethasone 12 mg administered intravenously and ranitidine 150 mg administered intravenously. Treatment continued for a minimum of four and a maximum of six cycles. Treatment was delayed for 1 week for grade 2 neutropenia and/or grade
1 thrombocytopenia. No dose reduction was planned by protocol. Treatment was interrupted if disease progression or unacceptable toxicity occurred. The use of granulocyte colony-stimulating factor was allowed in the presence of an absolute granulocyte count <1000/mm3.
Assessment of response
According to RECIST (Response Evaluation Criteria in Solid Tumors) guidelines, tumour lesions were categorised as measurable if they could be accurately measured in at least one dimension as 20 mm with conventional techniques or as
10 mm with spiral computed tomography. All other tumour lesions, including small lesions and truly non-measurable lesions, were categorised as non-measurable lesions [13
]. Tumour measurements for response assessment were obtained every two cycles. Response evaluation was performed according to RECIST guidelines.
Assessment of toxicity
Complete blood cell count, platelet count and toxicity assessment were performed weekly, with performance status, serum chemistry and ECG assessed before each cycle. Echocardiography or MUGA with the evaluation of left ventricular ejection fraction was performed at baseline and every two cycles. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
Unacceptable toxicity, requiring interruption of the treatment at the planned dose of 80 mg/m2, was defined by the occurrence within the first four cycles of chemotherapy, of at least one of the following events: grade 3 thrombocytopenia (platelets
50 000 µl); grade 3 or 4 anemia (hemoglobin <8 g/dl); grade 4 vomiting or mucositis, or diarrhoea or constipation; organ toxicity of grade
2, excluding alopecia and neurotoxicity; toxicity of any grade that worsened general conditions thus hampering tumour assessment after two cycles.
Statistical methods
For response rate and unacceptable toxicity rate, exact 95% confidence intervals (CIs) were calculated. Time to progression was defined as the time elapsed from beginning of treatment to the date of documented disease progression, the date of death without progression or the date of the last visit for patients who had not yet progressed at the end of the study. Survival was defined as the time elapsed from beginning of treatment to the date of death or the date of the last visit for patients alive at the end of the study. Two patients who were lost immediately after registration and never starting chemotherapy were censored at time zero. Unplanned subgroup analyses were performed to generate hypotheses regarding the possibility that baseline geriatric assessment could help to predict toxicity or efficacy of treatment. Associations between Charlson index, ADL and IADL scores (all transformed in dichotomic variables), response rate and unacceptable toxicity rate were studied by contingency tables analysed by Fisher's exact test. Progression-free survival curves within the same subgroups were compared using the log-rank test. All analyses were performed using S-PLUS 6.0 Professional Release 1 (Insightful Corporation, Seattle, WA, USA).
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Results |
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Toxicity
All 46 patients who received at least one administration of chemotherapy were evaluated for toxicity. Unacceptable toxicity (Table 3) within the first four cycles occurred in seven patients (15.2%; exact 95% CI 7.6% to 28.2%) and was represented by one case of febrile neutropenia associated with lung infiltrates, one case of severe allergic reaction and five cases of cardiac toxicity, including two patients who died, one with pulmonary embolism 2 days after chemotherapy (third cycle) and one with congestive heart failure 26 days after administration of the second cycle.
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Predictive value of geriatric scales
Unplanned subgroup analyses were performed to generate hypotheses regarding the possibility that geriatric assessment can help to predict toxicity and activity of treatment. The Charlson and the IADL scales were never predictive of either toxicity or activity. On the contrary, the presence of at least one inability among those itemised in the ADL scale was significantly associated with both a lower probability of response (P=0.009, Fisher's exact test) and a shorter progression-free survival (P=0.04, log-rank test), but not with unacceptable toxicity rates.
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Discussion |
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This phase II trial focused exclusively on elderly patients and its design took into account both toxicity and activity as criteria for recommendation about the treatment with weekly paclitaxel. We planned to consider weekly paclitaxel clinically interesting and useful for future metastatic breast cancer trials in the elderly if no more than 25% and possibly only 5% of patients experienced unacceptable toxicity, and if not less than 30% and possibly 50% of patients obtained an objective response. The actual figures we observed in the study were 15% unacceptable toxicity and 54% objective response; therefore, on the basis of our premise weekly paclitaxel can be considered a useful regimen for elderly advanced breast cancer patients. Notably, there was a relevant rate of unacceptable cardiovascular toxicity (five patients) ranging from grade 2 to 5. Two patients had a decrease in resting ejection fraction, one patient had acute myocardial infarction and two patients had fatal cardiovascular toxicity consisting of congestive heart failure (one patient) and pulmonary embolism (one patient). Two additional patients developed severe cardiotoxicity (one grade 2 and one grade 3) after the fifth cycle. In addition, grade 1 cardiotoxicity (i.e. asymptomatic decline of resting ejection fraction 10% but
20% of baseline value) was observed in five patients (11%). Overall, cardiotoxicity of any grade developed in 12 patients (26%). Specifically, grade 5, 4, 3, 2 and 1 cardiotoxicity occurred in two (4%), one (2%), one (2%), three (7%) and five (11%) patients, respectively. No cases of cardiotoxicity were observed in previous studies with weekly paclitaxel administered in metastatic breast cancer patients [3
, 4
]. The different profile of cardiotoxicity observed in our study may have various explanations. The majority of the events (eight out of 12; 67%) were grade 1 (five cases) and grade 2 (three cases) cardiotoxicity, i.e. laboratory decline of resting ejection fraction without clinical symptoms. These events were recorded because a routine MUGA or echocardiographic evaluation was performed in our study every two cycles. In the previous studies such a routine monitoring of cardiac function was not carried out, so such a toxicity could not be recorded. The 9% incidence of clinically overt cardiotoxic events observed in our study and not previously described may be related to the higher risk of cardiotoxicity of our patients as compared with patients treated in other studies. A major risk of developing cardiotoxicity is older age: the median age of our patients was 74 years (range 7087) compared with a mean age of 60 years (range 3188) reported in the study by Perez et al. [4
] and a median age of 57 years (range 3574) in the study by Seidman et al. [3
]. Moreover other cardiotoxicity risk factors, such as hypertension, were present in up to 63% of our patients. Such differences in patients' characteristics, mainly related to the enrolment in our study of true elderly patients, may explain the difference in cardiotoxicity and strongly indicate that results in terms of toxicity from studies performed in young patients cannot automatically be transferred to elderly patients.
The mortality rate (4%) during chemotherapy observed in our study is similar to that reported in the study by Chen et al. [20], where 5% of 59 elderly patients died after starting chemotherapy. Cardiovascular complications, in particular, were also the main cause of death in clinical trials on elderly patients not receiving chemotherapy. Castiglione et al. [21
] reported 2% of cardiovascular mortality in breast cancer elderly patients undergoing adjuvant endocrine therapy with tamoxifen and prednisone for 1 year.
We observed a response rate of 54% in the overall population (stage III plus stage IV) and of 44% in stage IV patients. This percentage is similar to that recently reported with weekly paclitaxel in a phase III study not focused on elderly patients, i.e. 40% [5]. On the other hand, the activity observed in our study is higher than that obtained in other studies in which elderly metastatic breast cancer patients were treated with monochemotherapy with drugs such as docetaxel (response rate 25%) [22
], doxifluoridine (27%) [23
], mitoxantrone (25%) [24
], vinorelbine (38%) [25
] and capecitabine (36%) [26
]. Moreover, a clinically very interesting long progression-free survival (9.7 months) and overall survival (36 months) were observed in this setting of metastatic breast cancer patients.
Our data indicate that weekly paclitaxel is a highly active treatment in elderly patients with advanced breast cancer. Data on cardiovascular complications, however, indicate the need for careful monitoring of cardiac function before and during chemotherapy.
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Acknowledgements |
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Notes |
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Received for publication July 18, 2004. Accepted for publication October 1, 2004.
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