Annals of Oncology Advance Access originally published online on February 23, 2006
Annals of Oncology 2006 17(5):807-812; doi:10.1093/annonc/mdl013
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© 2006 European Society for Medical Oncology
Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring
1 Division of Medical Oncology C, Centro di Riferimento Oncologico, Aviano; 2 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, Aviano; 3 Epidemiology and Biostatistic Unit, Centro di Riferimento Oncologico, Aviano; 4 Cardiology Unit, Centro di Riferimento Oncologico, Aviano; 5 Division of Medical Oncology, Umberto Io Hospital, Ancona; 6 Division of Medical Oncology, General Hospital, Trento, Italy
* Correspondence to: Dr D. Crivellari, Division of Medical Oncology C, Centro di Riferimento Oncologico, Via Pedemontana Occidentale, 12, 33081 Aviano, Italy, Tel: +39 0434-659024; Fax: +39 0434 659453; E-mail: dcrivellari{at}cro.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: To determine if protracted low-dose oral idarubicin (IDA), feasible in a previous dose-finding study, would result in similar activity and a better toxicity profile in patients with metastatic breast cancer.
Patients and methods: Elderly women (
65 years) with metastatic breast carcinoma were treated with 7.5 mg/day for 21 consecutive days, every 4 weeks. After the first fourteen patients, due to excessive toxicity, the protocol was amended to 5 mg/day. IDA and Idarubicinol (IDOL) plasma concentrations (Ctrough) were investigated in all patients.
Results: Between April 1999 and June 2004, 47 elderly patients were accrued in this two-part study (14 and 33 patients respectively). The median age was 74 and 75 years respectively. Visceral involvement was present in most patients. A partial response was noted in 7/31 patients (22%; 95% CI, 9.6–41.1%). Eleven patients had stable disease (33%). At the dose of 5 mg/day the treatment was well tolerated. Neutropenia grade 4 was present in only 6% of patients; alopecia > grade 1 and cardiotoxicity did not occur. The median time to progression was 3 months and the median overall survival was 17 months. IDA Ctrough and IDOL Ctrough levels were significantly associated with haematologic toxicity.
Conclusion: This study shows that idarubicin at the dose of 5 mg/day for 21 consecutive days is feasible and effective in elderly breast cancer patients but do not demonstrate an improvement in efficacy. A determination of the IDA and IDOL plasma levels (Ctrough) is predictive for toxicity.
Key words: oral Idarubicin, elderly breast cancer patients
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Anthracyclines are among the most active agents in the treatment of breast cancer both in the metastatic and adjuvant settings [1
, 2]. Doxorubicin and epirubicin are associated with commonly reported side effects such as alopecia, vomiting, mucosal toxicities, extravasation reactions and the particularly feared cardiomyopathy. Idarubicin (IDA), a synthetic analogue of daunorubicin, differs from the parent compound by an increased lipophilicity and a better oral bioavailability [3, 4]. It is an active drug in both metastatic breast cancer and leukaemia [5–8] and appears to be less cardiotoxic than doxorubicin, particularly attractive for elderly patients [9].
We conducted a phase I study of oral IDA in patients with metastatic breast cancer (no age limits) pretreated with anthracycline-containing regimens [10] to evaluate the chronic administration of small refracted doses of the drug (from 1 mg to 10 mg/day for 21 days every 4 weeks), with the aim to simulate a continuous infusion. In order to perform the phase I study, the pharmaceutical company provided us with 1 mg capsules. Neutropenia and diarrhoea were the dose-limiting toxicities encountered at the maximum dose level of 10 mg/day. Our data showed that this treatment was feasible and well tolerated. The recommended dose for phase II trials ranged from 5 to 7.5 mg/day. We performed a phase II study with pharmacokinetic drug monitoring to evaluate the safety and activity of this schedule as first- or second-line chemotherapy for elderly patients with visceral metastatic breast cancer or resistant to hormonal treatment.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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study design
This phase II open label multi-institutional study investigated the role of protracted low-dose oral administration of IDA in patients aged 65 years or older with metastatic breast cancer. The protocol was approved by the local Ethical Committees of the participating Institutions, and the study was conducted according to Good Clinical Practice. The study involved three Institutions but only the patients treated in the main Institution (Aviano) participated in the pharmacokinetic part of the study. The protocol was amended after the first 14 patients due to severe toxicities (haematological and diarrhoea) and one toxic death. The dosage was hence reduced from 7.5 to 5 mg/day for 21 consecutive days every 4 weeks.
eligibility criteria
Women aged 65 years with histologically documented metastatic breast cancer (stage IV), not pretreated with anthracyclines, and with measurable or evaluable lesions were eligible. Patients with non-measurable disease were considered evaluable only for toxicity, pharmacokinetic evaluation, time to progression and overall survival but not for activity. Other eligibility criteria included: pre-treatment with no more than one previous regimen (e.g. CMF, Vinorelbine), ECOG performance status <2 and adequate haematological, hepatic and renal functions. A complete medical examination including existing toxicity evaluation and tumour assessment was performed as per protocol. Cardiac function was assessed at baseline by echocardiogram. Granulocyte colony stimulating factors were allowed in the presence of grade 3–4 febrile neutropenia or according to medical judgement. Patients that could not resume treatment after 15 days of interruption or had persistent side effects were taken off study.
safety and response assessment
Before each cycle, the performance status, haematology and serum chemistry profile were assessed and a physical examination was performed. Cardiac function was monitored by serial echocardiograms repeated every two cycles or if clinically indicated. Response evaluation was performed according to WHO criteria for all measurable lesions [11]. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 2.0).
drug monitoring
The plasma concentration of IDA and its principal metabolite idarubicinol (IDOL) was determined during each chemotherapy cycle by high-performance liquid chromatography (HPLC) with fluorescence detection as described in a previous paper [12]. Blood samples were collected in heparinized tubes at baseline and on days 7, 14 and 21 of each cycle immediately before the daily oral dose of IDA (Ctrough) at 09:00 h and immediately centrifuged. The plasma obtained was stored at –20°C until analysis.
statistical considerations
The study was designed as a multicentre phase II study with both safety and activity as primary end-points. A modified two-stage Simon phase II clinical trial design [13] was used to assess whether the tumour response rate of IDA was at least 10% so that at a 0.10 significance level, there would be a 90% chance of detecting a tumour response rate of at least 30%. One partial response was noted in the first nine evaluable patients. A 95% confidence interval for true response rate was constructed using the properties of the binomial distribution. The time to progression was defined as the time from registration to documented disease progression. The survival time was defined as the time from registration till death. Time-to-event distributions were estimated using the Kaplan-Meier method [14].
All pharmacokinetic data are presented as mean values ±SD, unless stated otherwise. The analysis of the differences between the mean values of IDA and IDOL Ctrough levels across days 7, 14 and 21 of the chemotherapy cycle and according to the NCI-CTC haematological toxicity criteria were evaluated by the one-way ANOVA test. To assess the statistical significance of the differences between two groups, the Student's t test was used for unpaired or paired data [15]. To test the univariate linear relationship between IDA and IDOL variables, the Pearson's correlation coefficient was calculated. A P value of <0.05 was considered statistically significant. Statistical analysis was performed with the Statistica software package (version 6.0) (Statsoft, Tulsa, OK).
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results |
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patient characteristics
Between April 1999 and June 2004, a total of 47 elderly patients with metastatic breast cancer were enrolled in this study involving three Italian Institutions. The median age was 74 years (range 67–84) in the first part of the study and 75 years (range 65–81) in the second part, while the median Karnofsky performance status was 90 (range 50–100) and 100 (range 60–100) respectively. The main patient characteristics are listed in Table 1. Fourteen patients entered the first phase of the study. Five patients were not evaluable for response because of grade 4 haematological toxicity and patient refusal to continue treatment early after the first cycle because of severe grade 3 diarrhoea. The median number of cycles was 2 (range 1–6).
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In the second part of the study which started in February 2000, 33 patients were treated with the lower dosage. All the patients were evaluable for toxicity, whereas two patients were not evaluable for response, one because only one cycle of treatment was administered and the other due to early death which was judged to be not related to the treatment.
treatment duration
A total of 34 cycles were administered in the first part with a median of two cycles (range 1–6) per patient, whereas in the second part 132 cycles were administered with a median of three cycles (range 1–11) per patient. The median delivered dose of IDA was 210 mg (range 105–630 mg) and 315 mg (range 105–1165 mg) respectively. Fourteen patients experienced treatment delays during the study: 13 because of haematological toxicity and one for a non-haematological adverse event.
toxicity
All 47 patients who received at least one treatment cycle were assessable for toxicity. The data are summarised in Table 2. One patient with extensive liver metastases developed grade 4 neutropenia and diarrhoea and subsequently died. In the second part of the study, one patient had grade 3 and one patient had grade 4 neutropenia respectively (6%). All other toxicities were grade 1 or 2, in particular, alopecia and cardiotoxicity > grade 1 never occurred. Due to close cardiac monitoring, one patient had a 10% decrease in the LVEF, while an asymptomatic myocardial infarction was detected in a second patient who remained asymptomatic but with a deterioration of her LVEF (43%) who subsequently died due to disease progression. Neither patient required treatment.
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activity
The overall activity data are summarized in Table 3. Only one out of nine evaluable patients in the first part of the study had an objective response. This low response rate was probably due to the very low median number of cycles administered (i.e. 2 with a range from 1 to 6).
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Of the remaining 31 evaluable patients in the second part of the study, seven achieved a partial response, bringing the objective response rate to 22% (95% CI, 9.6%–41.1%). Of the remaining patients, 11 had stable disease (33%), three of which lasted at least 6 months (median 8 months). The median time to progression was 3 months. The median survival time was 17 months. The time to progression and the overall survival curves are illustrated in Figures 1 and 2 respectively.
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pharmacokinetic and pharmacodynamic correlations
IDA Ctrough and IDOL Ctrough were determined in 35 patients enrolled at the main institution. A total of 117 cycles of 21 days of chemotherapy were analysed for IDA and IDOL plasma levels. Twelve patients (34%) received a mean dosage of 7.5 mg/day of IDA, while 23 patients (66%) were treated with 5 mg/day of IDA. For both dose regimens, the IDA Ctrough and IDOL Ctrough levels evaluated on days 7, 14 and 21 are reported in Figure 3. At the mean daily dose of 7.5 mg/day, the IDA Ctrough levels were 0.52 ± 0.18 ng/ml, 0.60 ± 0.23 ng/ml and 0.47 ± 0.16 ng/ml after 7, 14 and 21 days of treatment respectively. The IDOL Ctrough level was about 10 fold higher than that of IDA Ctrough : 4.60 ± 1.36 ng/ml, 5.32 ± 1.87 ng/ml and 4.56 ± 1.61 ng/ml after 7, 14 and 21 days respectively. In the group of patients receiving 5.0 mg/day, IDA Ctrough was 0.34 ± 0.19 ng/ml, 0.37 ± 0.19 ng/ml and 0.32 ± 0.14 ng/ml after 7, 14 and 21 days respectively, significantly lower (P < 0.01) than the group of patients receiving 7.5 mg/day (Figure 3). The IDOL Ctrough level was 4.09 ± 1.81 ng/ml, 4.45 ± 2.02 ng/ml and 4.26 ± 1.90 ng/ml after 7, 14 and 21 days respectively. No significant difference (by paired test) was observed in both IDA and IDOL levels between day 7, day 14 and day 21 in the patients treated with 5 mg/day. Conversely, in those treated with the mean daily dose of 7.5 mg, we observed a slight increase in the IDA Ctrough or IDOL Ctrough level on day 14 compared to day 7 or day 21 (Figure 4).
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Patients who experienced a higher grade of haematological toxicity (G3 and G4) had higher levels of IDA Ctrough and IDOL Ctrough. The grade of neutropenic toxicity in relationship to the IDA Ctrough and IDOL Ctrough levels is shown in Figures 4a and b respectively. Patients who developed G3–G4 neutropenia had a mean ± SD IDA and IDOL Ctrough levels of 0.60 ± 0.20 ng/ml and 6.69 ± 2.09 ng/ml respectively, whereas in patients developing
G2 neutropenia, the mean IDA Ctrough and IDOL/IDA ratio were 0.35 ± 0.14 ng/ml (P < 0.00001 by t-test) and 3.91 ± 1.30 ng/ml (P < 0.000001 by t-test) respectively. A significant association between drug plasma levels and toxicity were also observed by comparing IDA Ctrough or IDOL Ctrough levels on days 7, 14 or 21 (data not shown). Finally, no significant association was observed between the plasma levels of IDA or IDOL and tumor response. |
discussion |
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Our study was conducted with the rationale of giving the older woman the chance to be treated with an anthracycline, trying to find a schedule of an oral drug able to simulate a continuous infusion in order to minimize the risk of toxic effects, in particular cardiotoxicity, but also mucositis and alopecia. Previous studies [16
, 17] have shown that the administration of doxorubicin at lower weekly doses, or by slow intravenous infusion, considerably reduces the incidence and severity of cardiomyopathy. However, more recent data [18] in childhood leukaemia showed that this approach failed to offer a cardioprotective advantage over bolus infusion, leaving this issue an open question. Newer less cardiotoxic agents such as epirubicin and idarubicin have been studied, and more recently the pegylated liposomal doxorubicin became available.
In a recent study by Liu et al., oral chemotherapy was found to be preferred by about 90% of patients [19]. In the current study, we evaluated IDA as first or second-line therapy in elderly patients with metastatic breast cancer. This study represented an enormous effort to join clinical and pharmacokinetical data that usually lack in studies involving the elderly patient population. It is unique in this effort, and even if it failed to improve clinical outcome, it stimulates discussion on some important points. It also confirms the difficulty to perform clinical studies in the elderly population as recently reaffirmed [20].
A total of 47 patients were treated with oral IDA in the two subsequent parts of the study. The first 14 patients treated at the higher dose level (7.5 mg/day) had unacceptable toxicity. At the lower dose level (5 mg/day), the toxicity was markedly decreased, the most common adverse events being diarrhoea, stomatitis and nausea of mild or moderate intensity. Alopecia > grade 1 was never noted and cardiotoxicity was also never encountered. Overall, the tolerability profile of the second part of the study was excellent, allowing an increase in the duration of the treatment resulting in a better clinical benefit.
Many studies have demonstrated that oral IDA is an active drug against advanced breast cancer. The majority of the studies with the oral formulation utilised 15 mg/m2 on days 1–3 q 3 weeks with response rates ranging from 0% to 36%; the selection of patients was the main factor affecting response [21–33].
Oral IDA may be useful in the palliative treatment of advanced breast cancer patients with poor venous access and may also be especially appropriate for older patients [34]. Experimental and clinical evidence shows that the activity of many antitumour compounds depends on the administration modality [35–36].
Data from the present study indicate that IDA Ctrough and IDOL Ctrough levels at the time points investigated during the course of the chemotherapy were not significantly different, indicating that once steady state is reached, it remains constant during the entire cycle of chemotherapy. A significant association was observed between higher IDA or IDOL plasma levels and a higher grade of haematological toxicity. A simple time point determination of IDA Ctrough and IDOL Ctrough on day 7 of IDA intake was able to predict the toxic effect of treatment, suggesting that it is useful to plan drug monitoring in further clinical trials utilising chronic oral IDA administration. IDA Ctrough and IDOL Ctrough levels were superimposable on those determined in the previous phase I study [10]. Thus, the schedule we adopted leads tumour cells to be exposed to a constant drug level, similar to that during a continuous intravenous infusion.
Due to the limitation of the commercial formulation of IDA capsules (Zavedos Pfizer 5 mg), the first group of patients treated with alternating doses of 10 mg/day and 5 mg/day (daily dose of 7.5 mg/day) had high levels of toxicity that were reflected in the plasma drug peaks after the administration of the 10 mg dose, which our previous phase I study indicated as the maximum tolerated dose [10].
Another point to discuss is the fact that other drugs (oral or intravenous) have been studied during the last few years in trials dedicated to older women affected by metastatic breast cancer. Capecitabine was studied by Bajetta et al. [37] in 73 elderly patients, median age 73 years. This study, like ours, consisted of two parts, each with a different dosage; the second part with a lower dose showed a better compliance level and an equivalent response rate that was 34.9% (95% CI, 21% to 50.9%). In the study with the standard dose, the authors noted two cases (7%) of lethal toxicity (one patient of 80 years and another of 75), in both cases for grade 4 diarrhoea and severe dehydration. In addition, in the low-dose cohort, three patients discontinued treatment, respectively for acute myocardial infarction, heart failure or grade 4 diarrhoea. The authors concluded that the drug is safe and effective in elderly women with metastatic breast cancer. Even better results in terms of response rate were reported by Del Mastro et al. for the GIOGer group [38] with weekly paclitaxel (80 mg/m2 for 3 weeks every 28 days). Among 41 evaluable patients, they reported two complete responses and 20 partial responses for an overall response rate of 53.7% (95% CI 38.7% to 67.9%). This high response rate is probably partly due to the fact that locally advanced disease was also evaluated (stage IIIA/IIIB nine patients). In this study, a comprehensive geriatric assessment was performed in order to select the patients. Unacceptable toxicity was, however, reported in seven out of 46 evaluable patients (15.2%), including two toxic deaths for pulmonary embolism and congestive heart failure. Five cases of cardiac toxicity, one case of febrile neutropenia and one case of severe allergic reaction were also reported. In no case could the geriatric assessment have predicted the unacceptable toxicity.
More recently, a randomised trial comparing gemcitabine and epirubicin was performed in women older than 60 years as first-line chemotherapy [39]. Epirubicin proved superior to gemcitabine in all the end-points: TTP (6.1 versus 3.4 months), overall survival (19.1 versus 11.8 months) and response rate (40.3% versus 16.4%). Three possibly treatment-related deaths were reported, all in the gemcitabine arm and in patients over 70 years of age. Worthy of note is the fact that 10 patients discontinued epirubicin treatment due to cardiac events, while this was the case in only one patient in the gemcitabine arm.
Different types of toxicities may be expected with different drugs (cardiotoxicity with anthracyclines, mucosal toxicities with capecitabine, neuropathy with taxanes etc). This has to be taken into account in the decision-making process, together with the universal occurrence of toxic deaths, including those in trials dedicated to elderly patients, where particular attention is given to toxicity assessment and where patients are highly selected. Unfortunately, the predictive value of geriatric scales is very low, as demonstrated by the colleagues of the GIOGer [35]. Future studies on the elderly should probably incorporate pharmacokinetic and pharmacodynamic parameters as they could perhaps more ably explain eventual unexpected problems. A recently reported study showed, for instance, a significant pharmacokinetic interaction between capecitabine and S-warfarin (a drug frequently used by older patients), resulting in an exaggerated anticoagulant activity [40].
In conclusion, even though our results with this new oral drug schedule confirm previous data on the activity of IDA but do not demonstrate an improvement in efficacy, the opportunity to utilise the schedule should not be underestimated.
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Acknowledgements |
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The authors wish to thank Anna Maria Colussi for editing assistance.
Received for publication November 10, 2005. Revision received January 6, 2006. Accepted for publication January 9, 2006.
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References |
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