Japanese Journal of Clinical Oncology Advance Access originally published online on June 1, 2009
Japanese Journal of Clinical Oncology 2009 39(8):478-483; doi:10.1093/jjco/hyp050
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© The Author (2009). Published by Oxford University Press. All rights reserved
Feasibility Study of Docetaxel with Cyclophosphamide as Adjuvant Chemotherapy for Japanese Breast Cancer Patients
1 Department of Breast Oncology, National Hospital Organization Shikoku Cancer Center, Ehime
2 Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Okayama, Japan
For reprints and all correspondence: Naruto Taira, Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, 2-5-1 Shikata, Okayama 700-8558, Japan. E-mail: ntaira{at}md.okayama-u.ac.jp
Received March 17, 2009; accepted April 25, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Objective: The 7-year follow-up of the US oncology 9735 trial demonstrated the superiority of TC [docetaxel (DTX)/cyclophosphamide (CPA)] to doxorubicin/CPA therapy. To introduce TC therapy in Japan, the verification of the safety and tolerability is essential. We performed a collaborative prospective safety study with Okayama University to introduce TC therapy.
Methods: The subjects were 53 patients aged from 33 to 67 years at intermediate risk based on the St Gallen risk classification who underwent radical surgery for primary breast cancer between August 2007 and December 2008. As post-operative adjuvant chemotherapy, four cycles of TC (DTX 75 mg/m2 + CPA 600 mg/m2) were administered at 3-week intervals. Adverse events were evaluated based on National Cancer Institute—Common Terminology Criteria for Adverse Events ver. 3.0. The safety and completion rate were evaluated as the primary and secondary endpoints, respectively.
Results: Regarding hematological toxicity, Grade (G) 4 neutropenia occurred in 71.7% and G3 in 26.4%. G3–4 leukopenia developed in 32.1% and 56.6%, respectively, G4 anemia in 1.9% and G1–2 anemia in 26.4%. Regarding non-hematological toxicity, systemic malaise, skin eruption, edema, myalgia, arthralgia and nausea were noted in most patients. The completion rate was 94.3%, dose reduction was necessary in 7.5% and granulocyte colony-stimulating factor (G-CSF) support was required in 17.0%. On comparison between patients aged 65 years or older and younger than 65 years, the completion rate, dose reduction and incidence of febrile neutropenia (FN) were higher in the elderly patients. G-CSF support was more often needed in this subgroup.
Conclusions: TC therapy is tolerable for Japanese patients, but attention should be paid to the development of FN and neutropenia. The completion rate was lower in the elderly patients, showing that tolerability was not necessarily favorable.
Key Words: breast cancer • docetaxel • cyclophosphamide • adjuvant therapy • safety
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The standard regimen most widely adopted for post-operative adjuvant chemotherapy for breast cancer is combination chemotherapy with drugs including anthracycline. Taxanes are also key drugs of post-operative adjuvant chemotherapy for breast cancer, and the efficacy of taxanes administered in addition to anthracycline regimens has been demonstrated by many randomized control trials (RCTs) (3). The US oncology 9735 trial (USON9735) was the first RCT in which anthracycline and taxane were directly compared as post-operative adjuvant chemotherapies for breast cancer, and the analytical results of a 7-year median follow-up have been reported (1,2). AC [doxorubicin 60 mg/m2 i.v. on day 1; cyclophosphamide (CPA) 600 mg/m2 i.v. on day 1; every 21 days x 4 cycles] and TC [docetaxel (DTX) 75 mg/m2 i.v. on day 1; CPA 600 mg/m2 i.v. on day 1; every 21 days x 4 cycles] were compared as post-operative adjuvant chemotherapies for Stages I, II and III resectable invasive breast cancer. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The lymph node metastasis positivity rate was 50% in the patients, and 16% of the patients were 65 years of age or older. DFS was 81% in the TC group and 75% in the AC group (P = 0.033), and OS was 87% in the former and 82% in the latter (P = 0.032), showing that TC therapy was significantly superior regarding the two parameters. Concerning the safety profile, the incidence of febrile neutropenia (FN) was slightly higher in the TC than in the AC group, but long-term bone marrow toxicity and cardiotoxicity were low, showing that the therapy was feasible. It was also reported that the tolerability of elderly patients at 65 years of age or older was favorable, showing the superiority of TC therapy. Based on these, the standard post-operative adjuvant chemotherapy for early-stage breast cancer may change from the current regimens including anthracyclines to taxane-based regimens without anthracycline.
There are racial differences in the effects and adverse effects of chemotherapy. The standard regimens to administer many therapeutic drugs for breast cancer employed in Western countries are also applicable for Japanese, but the recommended doses of some drugs established by Phase II dose-setting studies conducted in Japan are lower than those in Western countries. The standard dose of DTX for every 3-week administration in monotherapy is 100 mg/m2 in Western countries, but 70 mg/m2 in Japan. Moreover, there is no safety data concerning the combination of DTX and CPA in Japan. To introduce the TC regimen (75/600) adopted in the USON9735 into Japan, the confirmation of its safety in Japanese is essential. Based on this background, we performed a study to confirm the safety of the TC regimen (75/600) of the USON9735.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Of patients who underwent radical surgery for primary breast cancer at the Shikoku Cancer Center and Okayama University Hospital, those who met the following inclusion criteria were selected: an age between 20 and 70 years, and a risk category of intermediate or higher employing the 10th St Gallen risk classification assessed based on the clinical background and post-operative pathological diagnosis, i.e. hormone receptor-negative cases, lymph node metastasis-positive cases and lymph node metastasis-negative cases, hormone receptor-positive cases meeting one of the following conditions: a 2 cm or greater diameter of tissue invasion, histological grade of 2–3, 35 years of age or younger, the presence of severe vascular invasion and HER2-positivity. Estrogen (ER) and progesterone receptors were assessed by immunostaining, and a positive cell rate of 10% or higher was regarded as positive. HER2 was assessed by the Hercep test, and scores of 0 and 1+ were regarded as negative, and 3+ as positive. In cases graded 2+, the HER2/neu amplification rate was determined, and a 2.2 or higher rate was regarded as positive. Other inclusion criteria were the absence of distant metastasis and severe complications with a performance status of 0 or 1 and sufficient bone marrow, liver and renal functions. Written informed consent was obtained from all patients. Patients with pre-operative chemotherapy, a past medical history of drug allergy which may interfere with the therapy, inflammatory and bilateral breast cancers, double cancer and a past medical history of psychiatric diseases were excluded.
In the administration, after pre-treatment with 8 mg dexamethasone and 5-hydroxytryptamine (HT)3 receptor blockade, 75 mg/m2 DTX was administered by drip infusion for 60 min, followed by the administration of 600 mg/m2 CPA for 30 min on day 1. From 12 h later, oral dexamethasone 4 mg was administrated twice daily for 2 days. These were administered every 21 days four times (four cycles). Blood testing was performed on the day of administration in each cycle to decide on the next administration. The criteria for initiating administration were as follows, and administration was postponed until all items recovered: WBC 
3000/mm2, neutrophil count 1500/mm2, neuropathy 
Grade (G) 2, edema G2, liver dysfunction G1 and renal dysfunction G1. When these did not recover for 21 days from the scheduled administration day, the protocol was discontinued. When the following adverse reactions were noted in the previous cycle, the first dose reduction was performed based on the dose reduction criteria: (i) G3 or severer non-hematological toxicity, (ii) G4 or severer hematological toxicity excluding leukopenia and neutropenia and (iii) G4 leukopenia and neutropenia persisting for 7 days or longer. The level of first dose reduction was as follows: DTX, 60 mg/m2 and CPA, 500 mg/m2. When these adverse reactions were present after the dose reduction, the protocol was discontinued. Regarding supportive therapy, preventive antibiotic administration was prohibited, but administration for FN decided on by the attending physician was accepted. The preventive administration of granulocyte colony-stimulating factor (G-CSF) was also prohibited based on the ASCO 2006 guidelines, but according to the decision by the attending physician, the following administration criteria were accepted: (i) fever (38°C) development with a neutrophil count of <1000/mm2 or a neutrophil count of 500/mm2 after the completion of drug administration, (ii) when an identical chemotherapy is employed after meeting the condition (i), the subsequent administration starts when the neutrophil count reaches 1000/mm2.
The primary endpoint was set as the safety. The types and grades of adverse reactions were identified following the National Cancer Institute (NCI)—Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0, and the incidences of G3 or severer adverse reactions were evaluated. The secondary endpoint was set as the protocol treatment completion rate. During the protocol treatment period, the body weight and temperature were measured, and blood testing was performed to investigate adverse reactions once a week at the outpatient clinic. Expecting of the number of patients in our institutions for a year who correspond to inclusion criteria, the target number of enrollments was set to 50. This study was approved by the Institutional Review Board.
The standard treatment arm in the USON9735 was AC (60/600), and the tolerability against this regimen has been reported and widely adopted in Japan. The dose of TC superior to AC shown by this trial should be accepted from a dose density viewpoint. Although a dose-setting study is necessary for the safety confirmation of translational combination therapy, the initial dose was set to TC (75/600). To ensure the safety of patients, an early stopping rule was established, in which enrollment was suspended after five early cases were enrolled until the completion of the protocol treatment in all five cases, and adverse reactions were evaluated. When the following adverse reactions were noted in two or more of the five cases, the study protocol was reviewed: (i) G3 or severer edema, (ii) G3 or severer peripheral neuropathy, (iii) FN, (iv) other G4 hematological toxicity and (iv) discontinuation of the protocol treatment due to an adverse reaction. The adverse event profiles of the five cases were submitted to the Effect/Safety Evaluation Committee to examine the feasibility of study continuation.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Enrollment was initiated in May 2007, and the five early cases were enrolled by July 2007. The protocol treatment was completed in four of the five cases, clearing the early stopping rule. Continuation of the study without protocol revision was approved by the Effect/Safety Evaluation Committee. Enrollment was re-started in September 2007, 53 were registered by October 2008 and the protocol treatment of the 53 cases was completed by January 2009. Adverse events could be adequately assessed in all patients.
The clinicopathological background factors of the patients are shown in Table 1. The median age was 54 years (33–67 years) and five patients (9.4%) were 65 years of age or older. Thirty-eight cases (71.7%) were ER-positive, 12 (22.6%) were HER2-positive, the mean tumor size was 1.94 cm (0.7–11.5 cm), and 22 cases (41.5%) were lymph node metastasis-positive, with a mean number of lymph node metastases of 1.4 (1–3).
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The protocol treatment was completed in 50 of the 53 cases, with a completion rate of 94.3%. The protocol was discontinued in three due to fatigue, skin eruption, G4 leukopenia and neutropenia based on the judgment by the attending physician or patient's request. One was a 62-year-old female in whom G4 leukopenia and neutropenia occurred after the first cycle, and the dose was reduced following the dose reduction criteria in the second cycle, but her attending physician decided on discontinuation due to G4 hematological toxicity. The second case was a 67-year-old female in whom G4 leukopenia and neutropenia and G2 fatigue developed following the first cycle, and the treatment was discontinued based on the patient's request. The third case was a 61-year-old female in whom G4 leukopenia and neutropenia and G3 systemic skin eruption developed following the first cycle, and her attending physician decided on the discontinuation. Dose reduction conflicting with the dose reduction criteria was necessary in four cases (7.5%).
On hematological toxicity evaluation following the NCI-CTCAE, G3–4 leukopenia developed in 47 (88.7%), G3–4 neutropenia in 52 (98.1%) and FN in 15 (28.3%). G-CSF was administered to nine (17.0%). G4 anemia occurred in one (1.9%) (Table 2).
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Regarding non-hematological toxicity, hair loss occurred in most patients, and G2 or milder fatigue in 42 (79.2%). Edema occurred in 13 (24.5%), but all were G1, and could be resolved by diuretic treatment. G2 or milder arthralgia and myalgia occurred in 20 (37.8%) and 21 (39.7%), respectively. Peripheral neuropathy developed in 12 (22.7%), but the severity was G2 or milder (Table 3).
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As another non-hematological toxicity, skin eruption accompanied by pruritus appeared at a high incidence. In one case (1.9%), systemic skin eruption developed and was graded G3.
As subgroup analysis by age, the patients were divided into those aged 65 years or older and those younger than 65 years, as in the USON9735. Dose reduction was necessary in 2 of 48 patients younger than 65 years (4.2%), and 2 of 5 patients aged 65 years or older (40%). All patients in the younger group completed the protocol treatment, whereas only two of the five patients (40%) completed the treatment in the elderly group, with higher dose reduction rate, decreasing the completion rate. FN developed in 11 (22.9%) in the younger group and 4 (80%) in the elderly group, showing that the incidence of FN was also higher, and G-CSF support was more often needed in the elderly patients (Table 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Although the importance of systemic drug therapy to improve the prognosis of breast cancer is widely recognized, combination chemotherapy including anthracycline has been employed as the standard post-operative adjuvant chemotherapy after initial cyclophosphamide, methotrexate, 5-FU therapy (4–6). Many clinical studies have since been performed, and the efficacy of additional taxane administration for lymph node metastasis-positive and -negative high-risk cases was demonstrated, which attracted attention to taxanes for post-operative adjuvant therapy (7,8). Although the efficacy of anthracyclines was established, the development of cardiotoxicity and myelodysplasia as late adverse effects was often problematic. An increase in the incidence of cardiotoxicity to 4–18% in a cumulative dose-dependent manner has been reported (9). Three fatal cases due to heart disease and osteomyelodysplasia syndrome were also reported in the USON9735, for which the involvement of adriamycin could not be ruled out because of the administration of the AC arm alone (1). As HER2 and Topo II
gene aberrations attract attention as anthracycline efficacy predicting factors, the individualized administration of anthracycline in consideration of these predictive factors may also progress in the future (10,11). In addition, a recurrence-inhibitory effect of trastuzumab in HER2-overexpressing patients has been demonstrated, and the frequency of combining trastuzumab with cytotoxic drugs or consecutive administration has increased, with which the usefulness of taxanes with lower-level cardiotoxic adverse effects has been increasing (12,13). As the superiority of TC to AC therapy was demonstrated in the USON9735 (1,2), taxane regimens not including anthracycline may become a major trend in the future, and this trend may not be ignored in Japan. Regarding the safety, although the 9735 trial reported favorable tolerability (1), it is well known that there exists ethnic or racial difference in pharmacokinetics and pharmacodynamics. These have been attributed to the distinctions in the genetics, physiological and pathological factors. Moreover, these differences are also known to be influenced by several extrinsic factors such as socioeconomic backgrounds, culture, diet and environments (14,15). Therefore, the verification of tolerability and adverse effects is an important clinical task to introduce TC therapy into Japan. This is the first report on the safety of TC therapy in Japanese patients.
The overall completion rate was 94.3%, similar to that (93%) in the USON9735. The protocol treatment was discontinued in three cases (5.7%). Dose reduction was necessary in 7.5%. The dose intensities of DTX and CPA were 98.5% and 98.7%, respectively. The completion rate was mostly favorable, and fewer cases required dose reduction, but hematological toxicity: G3–4 leucopenia and neutropenia occurred in almost all cases. In the USON9735, the incidence of G3–4 neutropenia was 61%, slightly lower than that in the present study, but this difference may have been due to variation in the observation interval: every 3 weeks in the 9735 trial, whereas weekly in our study to closely observe adverse effects. Since the safety of TC therapy in Japanese was confirmed by this study, observation every 3 weeks and on the administration days may be sufficient for actual clinical practice. The incidence of FN in all cases was reported to be 5% in the USON9735, but attention should be paid to the fact that the administration of prophylactic antibiotics was accepted in the USON9735. No prophylactic administration was performed in our study, and the incidence was 28.3%. FN could be controlled by oral antibiotics in most cases, but G-CSF administration was necessary in 17%. Regarding hematological toxicity in AC therapy (60/600 mg/m2), Tsutani et al. (16) reported that G3–4 neutropenia occurred in 24.3% and FN in 3.8% in Japanese. Based on these findings, the incidences of hematological toxicity and FN are apparently higher in TC than in AC therapy, to which closer attention should be paid. For actual clinical cases, prophylactic antibiotics administration may be considered. Regarding non-hematological toxicity, G2 or milder edema developed in 34% in the USON9735, whereas the grade was G1 or milder, and the incidence was only 24.5% in our study. Diuretics were administered to some cases, but most cases remitted under course observation alone. The incidences of nausea and vomiting were 35.9% and 7.5%, respectively, lower than those in the USON9735 (53% and 14%, respectively). Another non-hematological toxicity mentioned was skin eruption. The incidences of G1, G2 and G3 skin eruption were 34%, 18.9% and 1.9%, respectively, 
55% in total. Skin eruption persisted after the completion of four cycles in some cases. The establishment of effective countermeasures against skin eruption in TC therapy is necessary. Regarding DTX-induced skin eruption, although several cases have been reported, no therapy has been established, and only symptomatic therapy is available (17–19). The incidence in DTX monotherapy is reported to be 20–48%, suggesting that the combination with CPA increases the rate of development (20).
The subgroup analysis by age in the 9735 trial concluded that the incidence of adverse effects in elderly patients aged 65 years or older was not significantly different, and the tolerability of the elderly patients was favorable (1). In contrast, in our study, because of the small sample size, statistical comparison was not performed, the protocol treatment completion rate was lower in the patients aged 65 years or older than in those younger than 65 years (40% vs. 100%), the dose reduction rate was higher (40% vs. 4.2%) and the incidence of FN was higher (80% vs. 22.9%) (Table 4). Although the number of patients was small, it cannot be concluded that TC therapy is applicable for patients aged 65 years or older. Loibl et al. (21) investigated tolerability against taxane-based adjuvant therapy by age, in which the incidences of leukopenia and neutropenia increased with age, but the incidence of FN was similar. Regarding non-hematological toxicity, there was no age-related difference in the incidence of G1–2 fatigue, but the incidence of G3–4 fatigue was significantly higher in the elderly patients. Regarding skin eruption, there was no age-related difference in the incidence of G1–2, but that of G3 or severer skin eruption was significantly higher in the elderly patients (21). Although simple comparison with TC in the above reports is difficult because the regimen was different, these previous reports may support our study results regarding the feasibility of taxane-containing regimens for elderly patients. No significant difference was noted in non-hematological toxicity between the age groups, which may have been due to the small number of patients.
This study confirmed that TC therapy can be safely performed in Japanese. Regarding hematological toxicity, since FN developed at a relatively high rate (28.3%), the use of prophylactic antibiotics should be considered. Regarding non-hematological toxicity, no severe edema developed, but skin eruption accompanied by pruritus appeared in about half of the patients, for which the establishment of supportive therapy may be necessary. On profiling adverse effects by age, the incidence of hematological toxicity markedly increased in patients aged 65 years or older, decreasing the treatment completion rate. The tolerability of patients aged 65 years or older is not favorable, and administration should be carefully decided upon.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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