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Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen
original article
Annals of Oncology 17: 1205–1212, 2006 doi:10.1093/annonc/mdl135 Published online 9 June 2006
Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen
Hospital Universitario San Carlos, Madrid, Spain; 2H. Clı´nico Universitario de Valencia, Valencia, Spain; 3Corporacio´n Sanitaria Parc Taulı´, Sabadell, Spain; Instituto Valenciano de Oncologı´a, Valencia, Spain; 5Centro Oncolo´gico de Galicia, La Corun˜a, Spain; 6H. General Universitario de Alicante, Alicante, Spain; 7 H. General Universitario de Elche, Elche, Spain; 8Klinik und Poliklinik Gyna¨kologie, Halle, Germany; 9C.H. Universitario Juan Canalejo, La Corun˜a, Spain; 10 PIVOTAL, Madrid, Spain; 11HORE, Barcelona, Spain; 12H. Universitario Miguel Servet, Zaragoza, Spain; 13H. Clı´nico Universitario Lozano Blesa, Zaragoza, Spain; 14 H. De Basurto, Bilbao, Spain; 15H. Universitario Virgen del Rocı´o, Sevilla, Spain; 16Wielkopolskie Centrum Onkologii, Poznan, Poland; 17H. de Terrassa, Terrasa, Spain; 18H. Universitario Marque´s de Valdecilla, Santander, Spain; 19H. Clinic i Provincial, Barcelona, Spain; 20C. H. Xeral-Calde, Lugo, Spain 4
Received 25 January 2006; revised 6 April 2006; accepted 5 May 2006
Background: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). Patients and methods: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). Results: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2–4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P < 0.03). Conclusions: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment. Key words: adjuvant chemotherapy, docetaxel, TAC, G-CSF, filgrastim, lenograstim, operable breast cancer
introduction Several randomised clinical trials and a comprehensive metaanalysis by the Early Breast Cancer Trialists’ Collaborative *Correspondence to: Dr M. Martin, Servicio de Oncologia Medica, Hospital Universitario San Carlos, Spain. Tel: +34-91-3303546; Fax: +34-91-5436223; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
Group (EBCCTG) has demonstrated that postsurgical CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy significantly decreases the risk of recurrence and death in operable breast cancer patients [1]. In the late 1970s and the 1980s, anthracycline-containing combinations (FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; FEC, 5fluorouracil, epirubicin, cyclophosphamide; AC, doxorubicin,
original article
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M. Martı´n1*, A. Lluch2, M. A. Seguı´3, A. Ruiz4, M. Ramos5, E. Adrover6, A´. Rodrı´guez-Lescure7, R. Grosse8, L. Calvo9, C. Fernandez-Chaco´n10, M. Roset11, A. Anto´n12, D. Isla13, P. Martı´nez del Prado14, L. Iglesias15, J. Zaluski16, A. Arcusa17, J. M. Lo´pez-Vega18, M. Mun˜oz19 & J. R. Mel20
original article
patients and methods selection of patients Women between 18 and 71 years of age, who had undergone appropriate primary surgery for unilateral operable breast carcinoma (either mastectomy or tumorectomy/lumpectomy with free margins, plus axillary lymphadenectomy including at least 10 axillary lymph nodes) were considered eligible for inclusion in the trial. Patients without axillary involvement but with at least one high-risk criteria according to St Gallen 1998 (grade II/III, tumours >2 cm, age <35 or hormone-receptor-negative tumours) were eligible for the trial. Exclusion criteria were: any T4 or M1 disease; previous history of cancer; abnormal renal, liver or medular function; abnormal cardiac ejection function; other serious illness or medical conditions, including cardiac disease (i.e. myocardial infarction, cardiac insufficiency or uncontrolled arrhythmia/hypertension) and unstable diabetes mellitus. The study was conducted in accordance with GCP/IHC rules, in compliance with local regulations and with approval of the ethics
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committees of the participating centres and the Spanish Health authorities (approval number 99/115). All patients provided written informed consent prior to the beginning specific protocol procedures. All relevant data were submitted to source verification by GEICAM monitors.
study design This was a phase III, open-label, randomised study conducted at 49 centres in Spain, two centres in Poland and four centres in Germany comparing TAC with FAC as postsurgical adjuvant chemotherapy in women with high-risk, node-negative breast cancer. All eligible patients were registered at GEICAM headquarters by facsimile transmission using a purpose-specific form, which included the most relevant inclusion criteria. The GEICAM study data manager verified that all eligibility criteria were met. After stratification according to institution and menopausal status, patients were randomised to FAC or TAC. Chemotherapy regimens were: (i) FAC: 5-fluorouracil 500 mg/m2 intravenously (i.v.) day 1, doxorubicin 50 mg/m2 i.v. day 1, cyclophosphamide 500 mg/m2 i.v. day 1, every 3 weeks for six cycles; (ii) TAC: docetaxel 75 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, cyclophosphamide 500 mg/m2 i.v. day 1, every 3 weeks for six cycles. Patients on TAC received premedication with dexamethasone (six doses of 8 mg p.o., starting the night before chemotherapy and ending the evening of the day after chemotherapy) in order to prevent fluid retention. Antiemetic treatment with corticoids and selective 5-HT3 receptor antagonist drugs were recommended for both arms. Primary prophylactic antibiotic therapy (ciprofloxacin 500 mg b.i.d. on days 5–14 of each cycle) was mandatory during the first chemotherapy course and subsequent cycles for patients treated with TAC. Primary prophylactic administration of G-CSF was not permitted in the original protocol. Initially, G-CSF was only allowed for cases of febrile neutropenia, infection and delayed recovery of absolute neutrophil count on day 21. After the first episode of febrile neutropenia, G-CSF was mandatory in subsequent courses in those patients. For patients with any grade of myelosuppression on day 21, the addition of G-CSF was permitted, chemotherapy treatment was delayed until recovery (‡1500 ANC) and the entire scheduled dose was administered. In July 2000, after 237 patients were enrolled (121 FAC; 116 TAC), the incidence of neutropenic fever events was reported to be nearly 25% in the TAC arm. Therefore, the protocol was amended to require PPG for the subsequent patients in the TAC arm to prevent neutropenic-related adverse events. Patients included in the TAC arm prior to the study amendment are defined as TAC-pre, while those recieving TAC after the study amendment were identified as TAC-post. No clinical or therapeutic amendments were made to the FAC procedures. Subjects in the FAC arm were not given prophylactic antibiotics but received them in addition to G-CSF for all cycles following the first episode of febrile neutropenia. The G-CSF regimen consisted of rHuG-CSF 1 vial of lenograstim (263 lg/day ) or r-metHuG-CSF 1 vial of filgastrim (300 lg/day) subcutaneously, administered on days 4–10 after chemotherapy.
evaluation of toxicity and HRQoL A complete blood cell count was mandatory on days 7–10 and 20–21 of each cycle, to ascertain the neutrophil nadir count and neutrophil recovery. Other laboratory toxicities were evaluated on days 20–21 of each cycle. Clinical toxicity was carefully evaluated on day 21. Toxicity was graded using the NCI-CTC version 1.0. The protocol definition of neutropenic fever was fever ‡38.1C with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalisation in the same cycle. The incidence of neutropenic fever defined according to NCI-CTC criteria (fever ‡38.5C with grade 4 neutropenia) was also recorded and analysed.
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cyclophosphamide; and others) were tested in prospective, randomised, adjuvant trials and were demonstrated to be slightly but significantly superior to CMF-like regimens [2]. More recently, a randomised phase III trial by the Breast Cancer International Research Group (BCIRG 001) has shown that the combination of docetaxel, doxorubicin, and cyclophosphamide (the TAC regimen) is superior to FAC as adjuvant chemotherapy for node-positive operable breast cancer [3], reducing the risk of recurrence by 28% and the risk of death by 30%, and can be considered one of the new standards of care for these patients [4]. In this study, secondary prophylaxis with G-CSF (administration after the first cycle with neutropenic fever) in the TAC arm was mandatory, but primary prophylaxis with G-CSF (from the first cycle on, PPG) was not allowed. Unfortunately, TAC was clearly more toxic than FAC, not only with respect to neutropenic fever events (24.7% versus 2.5%, P = 0.001) [3], but also with respect to many extrahaematological side-effects, like asthenia, stomatitis, diarrhoea, myalgia and others. The health related quality of life (HRQoL) of patients treated with TAC was also inferior to that of those treated with FAC during the treatment period, although it returns to baseline values after the end of chemotherapy [3]. In 1998, the Spanish Breast Cancer Research Group (GEICAM, Grupo Espan˜ol de Investigacio´n en Ca´ncer de Mama) began the study GEICAM 9805, a phase III trial comparing the TAC regimen with FAC as adjuvant chemotherapy for high-risk, node-negative breast cancer (St Gallen criteria, 1988) [5]. In the initial protocol of this study, which had a design similar to that of BCIRG 001, PPG was not allowed. However, after the entry of 237 patients, the incidence of neutropenic fever events in the TAC arm became a relevant concern. Therefore, a protocol amendment was introduced in July 2000 and all subsequent TAC-treated patients received PPG during each cycle. The main objective of the GEICAM 9805 trial was to compare disease-free survival of patients treated with TAC and FAC. Secondary objectives were to compare overall survival, HRQoL and toxicity. We report here the differences in toxicities and HRQoL between patients treated with FAC, TAC without PPG and TAC with PPG.
Annals of Oncology
original article
Annals of Oncology
results baseline characteristics During the study recruitment period (July 1999 to December 2001) 1059 female patients were randomised to receive TAC (539) or FAC (520). The trial profile (Figure 1) shows that 1047 of the 1059 patients included in the study and randomised (98.9%) were evaluable for study purposes (528 TAC patients and 519 FAC patients). Of the remaining 12 patients, nine were never treated and three were major treatment protocol violations. Table 1 shows the baseline characteristics of the three groups studied in this publication. Study groups were homogeneous at baseline in terms of EORTC-QLQ30 and BR23 scores. Since there were no statistically significant differences between patients treated with FAC before and after protocol amendment, the characteristics of both groups are shown together. description of G-CSF use and chemotherapy In the TAC-post group, 362 patients received filgrastim as PPG and the remaining 52 received lenograstim. The baseline characteristics and outcomes of patients who received filgrastim and lenogastrim were not statistically different (data not shown). Therefore, the results of both groups are shown together.
Figure 1. Trial profile. #, Consent withdrawal after randomisation. *, Major protocol violations: one patient was randomised to FAC and received TAC on cycle 1 and FAC on cycles 2–6; one patient was randomised to TAC and received TAF (taxotere, adryamicin, 5-fluorouracil) by mistake on cycle 1. No other cycles administered; one patient was randomised to TAC and received TAF on cycles 1–6.
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HRQoL was self-administered to patients during the 14 days prior to randomisation (baseline), at six prospective time points corresponding to chemotherapy cycles, with the time window (TW) related to each chemotherapy cycle defined as the period between the day following the first chemotherapy dose of the corresponding cycle and the day of the first dose of the following cycle (TW1–TW6), and then at 44, 68 and 120 weeks of the study (TW7–TW9). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ–C30) [6] and the breast cancer-specific quality-of-life questionnaire module (QLQ–BR23) [7, 8] were used. The EORTC QLQ–C30 is an international, validated HRQoL questionnaire with robust psychometric properties [6] and consists of five scales (physical, role, emotional, cognitive and social), six single–item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties), three symptom scales (fatigue, nausea and vomiting, and pain) and an overall health-status scale. The QLQ–BR23 module consists of 23 items covering symptoms and side-effects related to different treatment modalities, body image, sexuality, and future perspective, which defines four functional domains or scales (body image, future perspective, sexual enjoyment and sexual functioning) and four symptom domains or scales (arm, breast, hair loss and systematic therapy). In both questionnaires, raw scores range from 0 to 100 and a high score represents a high level of functioning or HRQoL, excluding single–item scales in which high scores represent a high level of symptoms. A difference of 10 points on the scale over baseline value was classified as the minimum clinically meaningful change in both questionnaires [9].
original article
Annals of Oncology
In the TAC-pre group 81 patients (71.1%) had G-CSF (secondary prophylaxis) in 338 cycles. In the FAC group, the respective figures were 54 patients (10.4%) and 184 cycles. Table 2 shows the compliance with treatment. The percentage of patients treated with TAC who completed six cycles of therapy increased from 90.4% without PPG prophylaxis to 95.7% with G-CSF (P = 0.0194). In spite of this, the median dose intensities of docetaxel, doxorubicin and cyclophosphamide were not significantly different in TAC-pre and TAC-post patients.
safety data The toxicities and therapeutic interventions related to myelosuppression in the three groups are shown in Table 3. The
TAC-pre Randomised patients 116 Evaluable patients 114 Age, median (range) 50 (23–74) Karnofsky PS at baseline, 100 (80–100) median (range) Baseline Global Health 66.67 Status Score (median) Menopausal status n (%) Premenopausal 66 (57.9%) Postmenopausal 48 (42.1%)
TAC-post
FAC
423 520 414 519 50 (24–74) 49 (23–73) 100 (80–100) 100 (90–100) 66.67
224 (54.1%) 190 (45.9%)
66.67
285 (54.9%) 234 (45.1%)
Table 2. Compliance with chemotherapy TAC-pre Treated patients 114 Patients completing six cycles of 103 (90.4) therapy, n (%) No. of cycles administered Total 655 Median 6 No. (%) of cycles without 609 (93) dose delay/reductiona Dose intensity of drugs (median, mg) 5-fluorouracil – Docetaxel 24.57 Doxorubicin 16.49 Cyclophosphamide 165.19 Cumulative dose of drugs (median, mg) 5-fluorouracil – Docetaxel 445.23 Doxorubicin 298.54 Cyclophosphamide 2988 a
TAC-post
FAC
414 519 396 (95.7) 505 (97.3)
2439 6 2315 (95)
3078 6 2816 (91.5)
– 24.58 16.48 164.97
162.91 – 16.29 163.00
– 448.34 299.43 2995.20
2998.15 – 299.71 2998.37
Cycle length >21 + 3 days; only the first cycle with a dose reduction was counted unless a further dose reduction occurred in a subsequent cycle.
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health related quality of life In general, any chemotherapy treatment deteriorated all HRQoL domains during the treatment period, which was more marked with TAC than with FAC, but this effect completely reversed by week 44. In terms of Global Health Status (GHS) of the EORTC QLQ-C30, statistical significant differences were detected between TAC-pre and FAC (P < 0.01) and TAC-post and FAC (P < 0.05) (Figure 3). The difference between TAC-pre and TAC-post did not reach statistical significance, although there was a trend towards better scores with TAC-post. In order to define further the clinical significance of these differences, Figure 4 shows the percentage of patients with a clinically significant reduction on GHS HRQoL score (10 or more points over baseline) at time windows 3, 6, 7 and 8 (after cycles 3 and 6, and 6- and 12-month follow-ups) After cycle 3, the percentage of patients with a clinically significant GHS decrease was not statistically different between TAC-pre and TAC-post (55% versus 52%),
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Table 1. Number of randomised and evaluable patients and baseline characteristics of the evaluable patients
percentage of patients who had febrile neutropenia according to protocol definition (fever ‡38.1C with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalisation in the same cycle) in one or more cycles was 24.6% and 6.5% in TAC-pre and TAC-post groups, respectively (P = 0.0001). According to the NCI-CTC definition of neutropenic fever, the respective figures were 27.2% and 7.5% (P = 0.0001). Figure 2 shows the distribution of the first episodes of neutropenic fever by cycle in the three arms. In the TAC-pre group, the higher percentage of cycles with neutropenic fever was observed in the first cycle of therapy (12.3% of total number of first cycles). The percentage of patients with grade 2–4 anaemia was higher in the TAC-pre group than in the TAC-post group (47.4 versus 27.5%, P < 0.0001). Similarly, the percentage of patients with grade 2–4 anaemia was higher in the TAC-post group than in the FAC (27.5 versus 7.5%, P < 0.0001). More patients in the TAC-pre group than in the TAC-post group required red cell transfusions (7 versus 2%, P < 0.0102). The difference in red cell transfusion requirements between patients in the TACpost and FAC groups was not statistically significant. Interestingly, there was a correlation between the percentage of patients with anaemia grade 2 or greater and the presence of at least one episode of neutropenic fever, in all the three arms (Table 4). For instance, the odds ratio for anaemia grade 2 or greater in patients with versus no neutropenic fever were 3.072 (P = 0.0124, TAC-pre) and 6.06 (P < 0.0001, TAC-post). The incidence of clinically relevant extrahematological toxicities (grade 2–4) that occurred in more than 1% of patients in any group are presented in Table 5. The TAC-post regimen yielded a statistically significant reduction in the incidence of asthenia (P = 0.0025), anorexia (P = 0.001), myalgia (P = 0.0193), nail disorders (P = 0.0012) and stomatitis (P = 0.0101), compared with TAC-pre. No other statistically significant toxicity differences were seen between the two groups. In spite of this improvement, TAC-post patients still had more asthenia, myalgia, diarrhoea and arthralgia (but not anorexia, dysgeusia, nail disorders and stomatitis) than patients treated with FAC. No toxic deaths (septic or non-septic) occurred in this study.
original article
Annals of Oncology
Table 3. Myelosuppression-related toxicities and therapeutic interventions
Patients with grade 2–4 anaemia (%) Patients with red cell transfusions (%) Patients with febrile neutropenia (as per protocol) (%) Patients with febrile neutropenia (NCI-CTC definition) (%) Cycles with febrile neutropenia (%) Patients with infections (%)
TAC-pre
TAC-post
FAC
P valuea (TAC-pre versus TAC-post)
P valuea (TAC-post versus FAC)
47.4 7 24.6 27.2 5.3 31.6
27.5 2 6.5 7.5 1.2 21.7
7.5 0.8 2.3 3.1 0.4 24.3
<0.0001 <0.0102 0.0001 0.0001 <0.0001 0.0291
<0.0001 NS 0.0014 <0.0001 0.0004 NS
a
Chi-square test. NS, P > 0.05.
12.5
FAC
% OF CYCLES
7.5 5.0 2.5 0.0 1
2
3
4
5
6
CYCLE Figure 2. Time of occurrence of first episode of febrile neutropenia defined as per protocol (percentage over total number of cycles). Table 4. Correlation between anaemia (grade 2 or greater) and febrile neutropenia (FN) as per protocol
TAC-pre Patients Patients TAC-post Patients Patients FAC Patients Patients
Patients with anaemia
Patients without anaemia
P value
with FN without FN
68% 41%
32% 59%
with FN without FN
67% 25%
33% 75%
<0.001
with FN without FN
26% 1%
74% 99%
<0.0001
0.0124
but after cycle 6, the difference reached a statistical significance in favour of TAC-post patients (64% versus 46%, P < 0.03). More TAC-post than FAC patients had significant GCS decline after cycle 3 (52% versus 41%, P < 0.02), but the difference was not statistically significant after cycle 6 (46% versus 40%) or any subsequent follow-up.
discussion Our report shows the toxicity of the regimens FAC and TAC with and without primary prophylactic G-CSF (PPG). The
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TAC-pre TAC-post
10.0
addition of PPG to TAC significantly reduced the toxicity associated with this regimen, although TAC plus PPG is still more toxic than FAC. Although not coming from a randomised study, the results of the comparison between TAC and TAC plus PPG are reliable since patient characteristics and treatment were homogeneous during the study (all patients were treated according to the same protocol), primary prophylactic G-CSF being the only relevant independent variable. The use of G-CSF from the first cycle onwards (PPG) reduced the incidence of febrile neutropenia in patients treated with TAC. The reduction was clinically relevant both in terms of percentage of patients who had one or more episodes of febrile neutropenia (24% versus 6.5%) and in terms of percentage of cycles with febrile neutropenia (5.3% versus 1.2%). Guidelines on the use of colony-stimulating factors recommend that they be used in the first cycle of chemotherapy with chemotherapy regimens that are associated with an incidence of febrile neutropenia of 40% [10]. However, more recent economic models suggest that the cost of filgrastim can be offset when the risk of febrile neutropenia is 20%–25% [11], similar to the incidence of TAC-induced febrile neutropenia in our study and in previous studies [3]. Vogel et al. [12] have even advocated the use of colony-stimulating factors for single-agent docetaxel, a drug that produces febrile neutropenia in less than 20% of patients. These authors demonstrated in a double-blind, randomised, placebo-controlled trial that primary prophylaxis with pegfilgrastim reduces the incidence of docetaxel-associated febrile neutropenia from 17% to 1% (P < 0.001). With the relative decrease in the cost of colonystimulating factors (with respect to the increasing cost of hospitalisation and novel antibiotics), we think that the reduction seen in our study justifies the systematic use of PPG in all patients who are initiating TAC treatment. Avoiding neutropenic fever events, and the associated risk of life-threatening infections, is of particular importance in the adjuvant setting, where many patients can be already cured by local treatment itself. Although the mortality of neutropenic fever is very low today, some toxic deaths due to neutropenic sepsis in breast cancer patients treated with doxorubicin plus docetaxel have recently been reported [13]. PPG improved the compliance with TAC. The percentage of patients who completed six cycles of therapy increased from 90.4% without PPG to 95.7% with it (P = 0.0194). In spite of this, the median dose intensities of docetaxel, doxorubicin
original article
Annals of Oncology
Table 5. Grade 2 or greater toxicities occurring in more than 1% of patients in any group (in percentages) TAC-post
FAC
P value (TAC-pre versus TAC-post)
P value (TAC-post versus FAC)
64.0 11.4 14.9 7.9 7.0 7.9 5.3 35.1 21.1 42.1 7.0 27.2 6.1 10.5 3.5 7.0 4.4
48.1 3.6 7.7 3.1 3.6 1.4 4.10 23.2 14.7 36.7 6.0 30.9 2.9 10.4 2.7 8.2 3.1
33.3 2.9 1.2 2.3 3.1 1.3 3.9 24.5 5.2 38.9 2.5 34.1 2.1 8.7 3.7 1.5 0.6
0.0025 0.001 0.0193 0.0335 NS 0.0012 NS 0.0101 NS NS NS NS NS NS NS NS NS
<0.0001 NS <0.0001 NS NS NS S NS <0.0001 NS 0.0067 NS NS NS NS <0.0001 0.0027
NS, P > 0.05.
Figure 3. Observed means of EORTC QLQ-C30 scores at baseline, during treatment and follow-up period comparing TAC-pre, TAC-post and FAC patients. EORTC QLQ-C30: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.
and cyclophosphamide were not significantly different in TAC-pre and TAC-post patients, probably because G-CSF was administered to 71% of patients in the TAC-pre group as secondary prophylaxis after the first episode of
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febrile neutropenia, allowing a delivery of full doses of chemotherapy. One surprising finding of our study was the reduction of grade 2 to 4 anaemia and transfusional requirements associated
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Asthenia Anorexia Myalgia Dysgeusia Abdominal pain Nail disorder Conjunctivitis Stomatitis Diarrhoea Nausea Pain Vomiting Dyspepsia Neuroconstipation Neuromood Arthralgia Oedema
TAC-pre
original article
Annals of Oncology
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Figure 4. Percentage of patients with more than 10 point decrease in Global Health Status score over baseline. Chi-square test. NS, not significant.
asthenia cytokine release anorexia
anaemia TAC neutropenia
infection
stomatitis
nail changes Figure 5. Suggested pathogenic pathways of TAC-induced toxicity. TAC would induce neutropenia, anaemia, stomatitis and nail changes by a direct mechanism (direct toxicity on bone marrow, mucous membranes, muscles and skin annexes). In addition, profound neutropenia leads to infections and cytokine release. Infections are responsible for an increase in the intensity of anaemia, asthenia, stomatitis and nail changes. The cytokine release increases the intensity of asthenia and are the main cause (together with anaemia) of anorexia. The addition of G-CSF could improve toxicity by reducing the imputs at selected sites (vertical arrows).
adjuvant TAC, pegfilgrastim and dabepoietin is currently ongoing in Spain. In conclusion, our study shows that PPG reduces the incidence of neutropenic fever and other clinically relevant events (grade 2 or greater anaemia, asthenia, anorexia, myalgia, nail disorders and stomatitis) associated with TAC chemotherapy. PPG also moderately improves the HRQoL of patients treated with TAC. The results of this study support the routine use of PPG in all breast cancer patients treated with adjuvant TAC chemotherapy.
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with the use of PPG. Since G-CSF does not stimulate the erythroid progenitors, an indirect mechanism (i.e. reduction of infections and cytokine release, a well known cause of anemia [14]) could be the reason behind this finding. In support of this hypothesis, we found a clear correlation between anaemia and neutropenic fever in all the three arms. Thus, reducing neutropenic fever events and infections with PPG may be an indirect way of preventing anaemia in TAC-treated patients. Still more surprising was the reduction seen in some extrahaematological side-effects of TAC. PPG was associated with a statistically significant reduction in the incidence of clinically relevant (i.e. grade 2 or greater) asthenia, anorexia, myalgia, nail disorders and stomatitis compared with secondary prophylactic G-CSF in patients treated with TAC. The mechanism underlying this protective effect is unknown. We speculate that the protection against clinical and subclinical infections associated with PPG could explain the reduction in the incidence of nail changes and stomatitis, disorders in which an infectious component is often involved. Other authors have also found a reduction in the severity of chemotherapy-induced stomatitis with the use of G-CSF [15]. The reduced incidence of clinically relevant asthenia and anorexia could be related to the lower incidence of anaemia in the TAC-post group, which could also be related to the reduction of infection. An alternative or complementary explanation could be the reduction of the release of cytokines associated with the reduction of infections. Cytokines are known to be mediators of both asthenia and anorexia and are released during infections [16]. Figure 4 summarises the hypothetic pathogenic pathways of TAC-induced toxicities. The results of the present study show a HRQoL deterioration in patients during the chemotherapy treatment period that improves once chemotherapy is completed. The deterioration of HRQoL during treatment is obviously due to adverse events associated with chemotherapy and is clearly less marked in the FAC group than in both TAC groups, in which the side-effects are more frequent and severe. The addition of PPG to TAC resulted in a reduction of anaemia and, as in other studies [17, 18], this can explain the moderate improvement in HRQoL we have described. Although the improvement of Global Health Status score of TAC-post patients did not reach a statistically significant value compared with TAC-pre patients, the percentage of patients with a clinically relevant impairment in HRQoL (reduction of 10 or more points over baseline value) over time was lower with PPG, particularly in the second half of chemotherapy treatment. Further improvements on QoL of patients treated with TAC are, therefore, necessary. A recent report by von Minckwitz et al. [19] showed that pegfilgrastim (administered on day 2 of each cycle) is superior to filgrastim or lenogastrim (administered on days 5–10 of each cycle) in the prevention of TAC-induced neutropenic fever. Interestingly, in this study pelfisgastrim also reduced the incidence of grade 3–4 stomatitis and diarrhoea compared with daily conventional G-CSF. On the other hand, 27.5% of TAC-treated patients still have grade 2 or greater anaemia in spite of PPG. Reducing this toxicity by means of erythropoietin could translate into an improvement of QoL [20]. A prospective study of QoL in patients treated with
original article acknowledgements
references 1. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 30–942. 2. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–1717. 3. Martin M, Pienkowski T, Mackey J et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005; 352: 2302–2313.
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4. Perez E. TAC—A new standard in adjuvant therapy for breast cancer? N Engl J Med 2005; 352: 2346–2348. 5. Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90: 1601–1608. 6. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Tretament of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376. 7. Sprangers MA, Groenvold M, Arraras JI et al. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol 1996; 14: 2756–2768. 8. Goodwin PJ, Black JT, Bordeleau LJ et al. Health-related quality-of-life measurement in randomized clinical trials in breast cancer—taking stock. J Natl Cancer Inst 2003; 5:263–281. 9. Osoba D, Rodrigues G, Myles J et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998; 16: 139–144. 10. Ozer H, Armitage JO, Bennet CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines—American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000; 18: 3558–3585. 11. Lyman GH, Kuderer N, Green J et al. The economics of febrile neutropenia: Implications for the use of colony-stimulating factors. Eur J Cancer 1998; 34: 1857–1864. 12. Vogel CL, Wojtukiewicz MZ, Carroll RR et al. First and subsequent cycle use of pelfisgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 2005; 23: 1178–1184. 13. Brain EGC, Bachelot T, Serin D et al. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. JAMA 2005; 293: 2367–2371. 14. Schnall SF, Berliner N, Duffy TP et al. Approach to the adult and child with anemia. In Hoffman R, Benz EJ Jr, Shattil SJ et al (eds): Hematology. Basic Principles and Practice. New York, NY: Churchill Livingstone 2000; 367–382. 15. Gabrilove JL, Jakubowski A, Scher H et al. Effect of granulocyte colonystimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of urothelium. N Engl J Med 1988; 318: 1414–1422. 16. Aggarwal BB, Puri RJ (eds). Human Cytokines: Their Role in Disease and Therapy. Cambridge: Blackwell Science 1995. 17. Holzner B, Kemmler G, Greil R et al. The impact of hemoglobin levels on fatigue and quality of life in cancer patients. Ann Oncol 2002; 3: 965–3973. 18. Lind M, Vernon C, Crickshank D et al. The level of hemoglobin in anaemic cancer patients correlates positively with quality of life. Br J Cancer 2002; 86: 1243–1249. 19. von Minckwitz G, Blohmer J, Loehr A et al. Pegfilgastrim alone or with ciproflaxin significantly reduces febrile neutropenia and hospitalization vs G-CSF alone in breast cancer patients receiving neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC). Eur J Cancer 2006; 4 (Suppl 2): 151–152. 20. Gabrilove J. Overview: Erythropoiesis, anemia and the impact of erythropoietin. Sem Hematol 2000; 37 (Suppl 4): 1–3.
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The authors thank the 1059 patients who agreed to participate in this trial and to the following additional investigators who contributed to patient enrolment in this study: B. Muna´rriz (H. Universitario La Fe, Valencia ), C. Llorca (H. General de Elda, Elda), P. Koralewski (Regional Rydygiera Specialistic H., Krako´w), E. Alba (C.H. Virgen de la Victoria, Ma´laga), C. Jara (Fundacio´n Hospitalaria de Alcorco´n, Alcorco´n), J. Floria´n (H. De Barbastro, Barbastro), C. Oberhoff (Universita¨tsfrauenklinik, Essen), C. Crespo (H. Ramo´n y Cajal, Madrid), A. Pelegrı´ (H. Universitario San Juan de Reus, Reus), M. Margelı´ (H. Universitario Germans Trias i Pujol, Badalona), V. Alberola (H. Arnau de Vilanova, Valencia), J. L. Garcı´a-Puche (H. Universitario Clı´nico San Cecilio, Granada), A. Go´mez (H. Clı´nico Universitario de Salamanca, Salamanca), A. Oltra (H. Virgen de los Lirios, Alcoy), I. A´lvarez (H. De Donostia, San Sebastia´n), J. Castellanos (C.H. Xeral-Cı´es, Vigo), A. Garcı´a-Palomo (C.H. de Leo´n, Leo´n), A. Modollel (Clı´nica Coracha´n, Barcelona), E. Aranda (H. Universitario Reina Sofı´a, Co´rdoba), R. M. Franquesa (H. General de Vic, Vic), A. Murias (C.H. Materno-Insular, Las Palmas de Gran Canaria), P. Aramburo (H. Ruber Internacional, Madrid), M. Mun˜oz (H. General Virgen de la Luz, Cuenca), S. Morales (H. Universitario Arnau de Vilanova, Le´rida), M. Stamm (St. Marien-Krh, Siegen), A. Ferna´ndez (C.H. Universitario de Albacete, Albacete), J. Garcı´a-Mata (C.H. de Orense, Orense), M. Constenla (C.H. de Pontevedra, Pontevedra), A. Lorenzo (H. Universitario de Puerto Real, Puerto Real), A. Velasco (H. Universitario de la Princesa, Madrid), A. Arizcun (H. General Rı´o Carrio´n, Palencia), J. M. Baena (H. Universitario Puerta del Mar, Ca´diz), L. de Paz (C.H. Arquitecto Marcide, El Ferrol), J. M. Cuevas (H. De La Ribera, Alcira), M. Ferna´ndez (C.H. de Jae´n, Jae´n), F. Melcher (Klinikum Mannheim, Mannheim), M. Navalo´n (H. Provincial de Zamora, Zamora). Miguel Martin received a speaker’s honoraria from SanofiAventis, Novartis, Pfizer, Roche and Bristol-Myers Squibb. The study was presented at ASCO.
Annals of Oncology
Annals of Oncology 17: 1205–1212, 2006 doi:10.1093/annonc/mdl135 Published online 9 June 2006
Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen
Hospital Universitario San Carlos, Madrid, Spain; 2H. Clı´nico Universitario de Valencia, Valencia, Spain; 3Corporacio´n Sanitaria Parc Taulı´, Sabadell, Spain; Instituto Valenciano de Oncologı´a, Valencia, Spain; 5Centro Oncolo´gico de Galicia, La Corun˜a, Spain; 6H. General Universitario de Alicante, Alicante, Spain; 7 H. General Universitario de Elche, Elche, Spain; 8Klinik und Poliklinik Gyna¨kologie, Halle, Germany; 9C.H. Universitario Juan Canalejo, La Corun˜a, Spain; 10 PIVOTAL, Madrid, Spain; 11HORE, Barcelona, Spain; 12H. Universitario Miguel Servet, Zaragoza, Spain; 13H. Clı´nico Universitario Lozano Blesa, Zaragoza, Spain; 14 H. De Basurto, Bilbao, Spain; 15H. Universitario Virgen del Rocı´o, Sevilla, Spain; 16Wielkopolskie Centrum Onkologii, Poznan, Poland; 17H. de Terrassa, Terrasa, Spain; 18H. Universitario Marque´s de Valdecilla, Santander, Spain; 19H. Clinic i Provincial, Barcelona, Spain; 20C. H. Xeral-Calde, Lugo, Spain 4
Received 25 January 2006; revised 6 April 2006; accepted 5 May 2006
Background: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). Patients and methods: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). Results: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2–4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P < 0.03). Conclusions: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment. Key words: adjuvant chemotherapy, docetaxel, TAC, G-CSF, filgrastim, lenograstim, operable breast cancer
introduction Several randomised clinical trials and a comprehensive metaanalysis by the Early Breast Cancer Trialists’ Collaborative *Correspondence to: Dr M. Martin, Servicio de Oncologia Medica, Hospital Universitario San Carlos, Spain. Tel: +34-91-3303546; Fax: +34-91-5436223; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
Group (EBCCTG) has demonstrated that postsurgical CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy significantly decreases the risk of recurrence and death in operable breast cancer patients [1]. In the late 1970s and the 1980s, anthracycline-containing combinations (FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; FEC, 5fluorouracil, epirubicin, cyclophosphamide; AC, doxorubicin,
original article
1
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M. Martı´n1*, A. Lluch2, M. A. Seguı´3, A. Ruiz4, M. Ramos5, E. Adrover6, A´. Rodrı´guez-Lescure7, R. Grosse8, L. Calvo9, C. Fernandez-Chaco´n10, M. Roset11, A. Anto´n12, D. Isla13, P. Martı´nez del Prado14, L. Iglesias15, J. Zaluski16, A. Arcusa17, J. M. Lo´pez-Vega18, M. Mun˜oz19 & J. R. Mel20
original article
patients and methods selection of patients Women between 18 and 71 years of age, who had undergone appropriate primary surgery for unilateral operable breast carcinoma (either mastectomy or tumorectomy/lumpectomy with free margins, plus axillary lymphadenectomy including at least 10 axillary lymph nodes) were considered eligible for inclusion in the trial. Patients without axillary involvement but with at least one high-risk criteria according to St Gallen 1998 (grade II/III, tumours >2 cm, age <35 or hormone-receptor-negative tumours) were eligible for the trial. Exclusion criteria were: any T4 or M1 disease; previous history of cancer; abnormal renal, liver or medular function; abnormal cardiac ejection function; other serious illness or medical conditions, including cardiac disease (i.e. myocardial infarction, cardiac insufficiency or uncontrolled arrhythmia/hypertension) and unstable diabetes mellitus. The study was conducted in accordance with GCP/IHC rules, in compliance with local regulations and with approval of the ethics
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committees of the participating centres and the Spanish Health authorities (approval number 99/115). All patients provided written informed consent prior to the beginning specific protocol procedures. All relevant data were submitted to source verification by GEICAM monitors.
study design This was a phase III, open-label, randomised study conducted at 49 centres in Spain, two centres in Poland and four centres in Germany comparing TAC with FAC as postsurgical adjuvant chemotherapy in women with high-risk, node-negative breast cancer. All eligible patients were registered at GEICAM headquarters by facsimile transmission using a purpose-specific form, which included the most relevant inclusion criteria. The GEICAM study data manager verified that all eligibility criteria were met. After stratification according to institution and menopausal status, patients were randomised to FAC or TAC. Chemotherapy regimens were: (i) FAC: 5-fluorouracil 500 mg/m2 intravenously (i.v.) day 1, doxorubicin 50 mg/m2 i.v. day 1, cyclophosphamide 500 mg/m2 i.v. day 1, every 3 weeks for six cycles; (ii) TAC: docetaxel 75 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, cyclophosphamide 500 mg/m2 i.v. day 1, every 3 weeks for six cycles. Patients on TAC received premedication with dexamethasone (six doses of 8 mg p.o., starting the night before chemotherapy and ending the evening of the day after chemotherapy) in order to prevent fluid retention. Antiemetic treatment with corticoids and selective 5-HT3 receptor antagonist drugs were recommended for both arms. Primary prophylactic antibiotic therapy (ciprofloxacin 500 mg b.i.d. on days 5–14 of each cycle) was mandatory during the first chemotherapy course and subsequent cycles for patients treated with TAC. Primary prophylactic administration of G-CSF was not permitted in the original protocol. Initially, G-CSF was only allowed for cases of febrile neutropenia, infection and delayed recovery of absolute neutrophil count on day 21. After the first episode of febrile neutropenia, G-CSF was mandatory in subsequent courses in those patients. For patients with any grade of myelosuppression on day 21, the addition of G-CSF was permitted, chemotherapy treatment was delayed until recovery (‡1500 ANC) and the entire scheduled dose was administered. In July 2000, after 237 patients were enrolled (121 FAC; 116 TAC), the incidence of neutropenic fever events was reported to be nearly 25% in the TAC arm. Therefore, the protocol was amended to require PPG for the subsequent patients in the TAC arm to prevent neutropenic-related adverse events. Patients included in the TAC arm prior to the study amendment are defined as TAC-pre, while those recieving TAC after the study amendment were identified as TAC-post. No clinical or therapeutic amendments were made to the FAC procedures. Subjects in the FAC arm were not given prophylactic antibiotics but received them in addition to G-CSF for all cycles following the first episode of febrile neutropenia. The G-CSF regimen consisted of rHuG-CSF 1 vial of lenograstim (263 lg/day ) or r-metHuG-CSF 1 vial of filgastrim (300 lg/day) subcutaneously, administered on days 4–10 after chemotherapy.
evaluation of toxicity and HRQoL A complete blood cell count was mandatory on days 7–10 and 20–21 of each cycle, to ascertain the neutrophil nadir count and neutrophil recovery. Other laboratory toxicities were evaluated on days 20–21 of each cycle. Clinical toxicity was carefully evaluated on day 21. Toxicity was graded using the NCI-CTC version 1.0. The protocol definition of neutropenic fever was fever ‡38.1C with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalisation in the same cycle. The incidence of neutropenic fever defined according to NCI-CTC criteria (fever ‡38.5C with grade 4 neutropenia) was also recorded and analysed.
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cyclophosphamide; and others) were tested in prospective, randomised, adjuvant trials and were demonstrated to be slightly but significantly superior to CMF-like regimens [2]. More recently, a randomised phase III trial by the Breast Cancer International Research Group (BCIRG 001) has shown that the combination of docetaxel, doxorubicin, and cyclophosphamide (the TAC regimen) is superior to FAC as adjuvant chemotherapy for node-positive operable breast cancer [3], reducing the risk of recurrence by 28% and the risk of death by 30%, and can be considered one of the new standards of care for these patients [4]. In this study, secondary prophylaxis with G-CSF (administration after the first cycle with neutropenic fever) in the TAC arm was mandatory, but primary prophylaxis with G-CSF (from the first cycle on, PPG) was not allowed. Unfortunately, TAC was clearly more toxic than FAC, not only with respect to neutropenic fever events (24.7% versus 2.5%, P = 0.001) [3], but also with respect to many extrahaematological side-effects, like asthenia, stomatitis, diarrhoea, myalgia and others. The health related quality of life (HRQoL) of patients treated with TAC was also inferior to that of those treated with FAC during the treatment period, although it returns to baseline values after the end of chemotherapy [3]. In 1998, the Spanish Breast Cancer Research Group (GEICAM, Grupo Espan˜ol de Investigacio´n en Ca´ncer de Mama) began the study GEICAM 9805, a phase III trial comparing the TAC regimen with FAC as adjuvant chemotherapy for high-risk, node-negative breast cancer (St Gallen criteria, 1988) [5]. In the initial protocol of this study, which had a design similar to that of BCIRG 001, PPG was not allowed. However, after the entry of 237 patients, the incidence of neutropenic fever events in the TAC arm became a relevant concern. Therefore, a protocol amendment was introduced in July 2000 and all subsequent TAC-treated patients received PPG during each cycle. The main objective of the GEICAM 9805 trial was to compare disease-free survival of patients treated with TAC and FAC. Secondary objectives were to compare overall survival, HRQoL and toxicity. We report here the differences in toxicities and HRQoL between patients treated with FAC, TAC without PPG and TAC with PPG.
Annals of Oncology
original article
Annals of Oncology
results baseline characteristics During the study recruitment period (July 1999 to December 2001) 1059 female patients were randomised to receive TAC (539) or FAC (520). The trial profile (Figure 1) shows that 1047 of the 1059 patients included in the study and randomised (98.9%) were evaluable for study purposes (528 TAC patients and 519 FAC patients). Of the remaining 12 patients, nine were never treated and three were major treatment protocol violations. Table 1 shows the baseline characteristics of the three groups studied in this publication. Study groups were homogeneous at baseline in terms of EORTC-QLQ30 and BR23 scores. Since there were no statistically significant differences between patients treated with FAC before and after protocol amendment, the characteristics of both groups are shown together. description of G-CSF use and chemotherapy In the TAC-post group, 362 patients received filgrastim as PPG and the remaining 52 received lenograstim. The baseline characteristics and outcomes of patients who received filgrastim and lenogastrim were not statistically different (data not shown). Therefore, the results of both groups are shown together.
Figure 1. Trial profile. #, Consent withdrawal after randomisation. *, Major protocol violations: one patient was randomised to FAC and received TAC on cycle 1 and FAC on cycles 2–6; one patient was randomised to TAC and received TAF (taxotere, adryamicin, 5-fluorouracil) by mistake on cycle 1. No other cycles administered; one patient was randomised to TAC and received TAF on cycles 1–6.
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HRQoL was self-administered to patients during the 14 days prior to randomisation (baseline), at six prospective time points corresponding to chemotherapy cycles, with the time window (TW) related to each chemotherapy cycle defined as the period between the day following the first chemotherapy dose of the corresponding cycle and the day of the first dose of the following cycle (TW1–TW6), and then at 44, 68 and 120 weeks of the study (TW7–TW9). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ–C30) [6] and the breast cancer-specific quality-of-life questionnaire module (QLQ–BR23) [7, 8] were used. The EORTC QLQ–C30 is an international, validated HRQoL questionnaire with robust psychometric properties [6] and consists of five scales (physical, role, emotional, cognitive and social), six single–item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties), three symptom scales (fatigue, nausea and vomiting, and pain) and an overall health-status scale. The QLQ–BR23 module consists of 23 items covering symptoms and side-effects related to different treatment modalities, body image, sexuality, and future perspective, which defines four functional domains or scales (body image, future perspective, sexual enjoyment and sexual functioning) and four symptom domains or scales (arm, breast, hair loss and systematic therapy). In both questionnaires, raw scores range from 0 to 100 and a high score represents a high level of functioning or HRQoL, excluding single–item scales in which high scores represent a high level of symptoms. A difference of 10 points on the scale over baseline value was classified as the minimum clinically meaningful change in both questionnaires [9].
original article
Annals of Oncology
In the TAC-pre group 81 patients (71.1%) had G-CSF (secondary prophylaxis) in 338 cycles. In the FAC group, the respective figures were 54 patients (10.4%) and 184 cycles. Table 2 shows the compliance with treatment. The percentage of patients treated with TAC who completed six cycles of therapy increased from 90.4% without PPG prophylaxis to 95.7% with G-CSF (P = 0.0194). In spite of this, the median dose intensities of docetaxel, doxorubicin and cyclophosphamide were not significantly different in TAC-pre and TAC-post patients.
safety data The toxicities and therapeutic interventions related to myelosuppression in the three groups are shown in Table 3. The
TAC-pre Randomised patients 116 Evaluable patients 114 Age, median (range) 50 (23–74) Karnofsky PS at baseline, 100 (80–100) median (range) Baseline Global Health 66.67 Status Score (median) Menopausal status n (%) Premenopausal 66 (57.9%) Postmenopausal 48 (42.1%)
TAC-post
FAC
423 520 414 519 50 (24–74) 49 (23–73) 100 (80–100) 100 (90–100) 66.67
224 (54.1%) 190 (45.9%)
66.67
285 (54.9%) 234 (45.1%)
Table 2. Compliance with chemotherapy TAC-pre Treated patients 114 Patients completing six cycles of 103 (90.4) therapy, n (%) No. of cycles administered Total 655 Median 6 No. (%) of cycles without 609 (93) dose delay/reductiona Dose intensity of drugs (median, mg) 5-fluorouracil – Docetaxel 24.57 Doxorubicin 16.49 Cyclophosphamide 165.19 Cumulative dose of drugs (median, mg) 5-fluorouracil – Docetaxel 445.23 Doxorubicin 298.54 Cyclophosphamide 2988 a
TAC-post
FAC
414 519 396 (95.7) 505 (97.3)
2439 6 2315 (95)
3078 6 2816 (91.5)
– 24.58 16.48 164.97
162.91 – 16.29 163.00
– 448.34 299.43 2995.20
2998.15 – 299.71 2998.37
Cycle length >21 + 3 days; only the first cycle with a dose reduction was counted unless a further dose reduction occurred in a subsequent cycle.
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health related quality of life In general, any chemotherapy treatment deteriorated all HRQoL domains during the treatment period, which was more marked with TAC than with FAC, but this effect completely reversed by week 44. In terms of Global Health Status (GHS) of the EORTC QLQ-C30, statistical significant differences were detected between TAC-pre and FAC (P < 0.01) and TAC-post and FAC (P < 0.05) (Figure 3). The difference between TAC-pre and TAC-post did not reach statistical significance, although there was a trend towards better scores with TAC-post. In order to define further the clinical significance of these differences, Figure 4 shows the percentage of patients with a clinically significant reduction on GHS HRQoL score (10 or more points over baseline) at time windows 3, 6, 7 and 8 (after cycles 3 and 6, and 6- and 12-month follow-ups) After cycle 3, the percentage of patients with a clinically significant GHS decrease was not statistically different between TAC-pre and TAC-post (55% versus 52%),
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Table 1. Number of randomised and evaluable patients and baseline characteristics of the evaluable patients
percentage of patients who had febrile neutropenia according to protocol definition (fever ‡38.1C with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalisation in the same cycle) in one or more cycles was 24.6% and 6.5% in TAC-pre and TAC-post groups, respectively (P = 0.0001). According to the NCI-CTC definition of neutropenic fever, the respective figures were 27.2% and 7.5% (P = 0.0001). Figure 2 shows the distribution of the first episodes of neutropenic fever by cycle in the three arms. In the TAC-pre group, the higher percentage of cycles with neutropenic fever was observed in the first cycle of therapy (12.3% of total number of first cycles). The percentage of patients with grade 2–4 anaemia was higher in the TAC-pre group than in the TAC-post group (47.4 versus 27.5%, P < 0.0001). Similarly, the percentage of patients with grade 2–4 anaemia was higher in the TAC-post group than in the FAC (27.5 versus 7.5%, P < 0.0001). More patients in the TAC-pre group than in the TAC-post group required red cell transfusions (7 versus 2%, P < 0.0102). The difference in red cell transfusion requirements between patients in the TACpost and FAC groups was not statistically significant. Interestingly, there was a correlation between the percentage of patients with anaemia grade 2 or greater and the presence of at least one episode of neutropenic fever, in all the three arms (Table 4). For instance, the odds ratio for anaemia grade 2 or greater in patients with versus no neutropenic fever were 3.072 (P = 0.0124, TAC-pre) and 6.06 (P < 0.0001, TAC-post). The incidence of clinically relevant extrahematological toxicities (grade 2–4) that occurred in more than 1% of patients in any group are presented in Table 5. The TAC-post regimen yielded a statistically significant reduction in the incidence of asthenia (P = 0.0025), anorexia (P = 0.001), myalgia (P = 0.0193), nail disorders (P = 0.0012) and stomatitis (P = 0.0101), compared with TAC-pre. No other statistically significant toxicity differences were seen between the two groups. In spite of this improvement, TAC-post patients still had more asthenia, myalgia, diarrhoea and arthralgia (but not anorexia, dysgeusia, nail disorders and stomatitis) than patients treated with FAC. No toxic deaths (septic or non-septic) occurred in this study.
original article
Annals of Oncology
Table 3. Myelosuppression-related toxicities and therapeutic interventions
Patients with grade 2–4 anaemia (%) Patients with red cell transfusions (%) Patients with febrile neutropenia (as per protocol) (%) Patients with febrile neutropenia (NCI-CTC definition) (%) Cycles with febrile neutropenia (%) Patients with infections (%)
TAC-pre
TAC-post
FAC
P valuea (TAC-pre versus TAC-post)
P valuea (TAC-post versus FAC)
47.4 7 24.6 27.2 5.3 31.6
27.5 2 6.5 7.5 1.2 21.7
7.5 0.8 2.3 3.1 0.4 24.3
<0.0001 <0.0102 0.0001 0.0001 <0.0001 0.0291
<0.0001 NS 0.0014 <0.0001 0.0004 NS
a
Chi-square test. NS, P > 0.05.
12.5
FAC
% OF CYCLES
7.5 5.0 2.5 0.0 1
2
3
4
5
6
CYCLE Figure 2. Time of occurrence of first episode of febrile neutropenia defined as per protocol (percentage over total number of cycles). Table 4. Correlation between anaemia (grade 2 or greater) and febrile neutropenia (FN) as per protocol
TAC-pre Patients Patients TAC-post Patients Patients FAC Patients Patients
Patients with anaemia
Patients without anaemia
P value
with FN without FN
68% 41%
32% 59%
with FN without FN
67% 25%
33% 75%
<0.001
with FN without FN
26% 1%
74% 99%
<0.0001
0.0124
but after cycle 6, the difference reached a statistical significance in favour of TAC-post patients (64% versus 46%, P < 0.03). More TAC-post than FAC patients had significant GCS decline after cycle 3 (52% versus 41%, P < 0.02), but the difference was not statistically significant after cycle 6 (46% versus 40%) or any subsequent follow-up.
discussion Our report shows the toxicity of the regimens FAC and TAC with and without primary prophylactic G-CSF (PPG). The
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TAC-pre TAC-post
10.0
addition of PPG to TAC significantly reduced the toxicity associated with this regimen, although TAC plus PPG is still more toxic than FAC. Although not coming from a randomised study, the results of the comparison between TAC and TAC plus PPG are reliable since patient characteristics and treatment were homogeneous during the study (all patients were treated according to the same protocol), primary prophylactic G-CSF being the only relevant independent variable. The use of G-CSF from the first cycle onwards (PPG) reduced the incidence of febrile neutropenia in patients treated with TAC. The reduction was clinically relevant both in terms of percentage of patients who had one or more episodes of febrile neutropenia (24% versus 6.5%) and in terms of percentage of cycles with febrile neutropenia (5.3% versus 1.2%). Guidelines on the use of colony-stimulating factors recommend that they be used in the first cycle of chemotherapy with chemotherapy regimens that are associated with an incidence of febrile neutropenia of 40% [10]. However, more recent economic models suggest that the cost of filgrastim can be offset when the risk of febrile neutropenia is 20%–25% [11], similar to the incidence of TAC-induced febrile neutropenia in our study and in previous studies [3]. Vogel et al. [12] have even advocated the use of colony-stimulating factors for single-agent docetaxel, a drug that produces febrile neutropenia in less than 20% of patients. These authors demonstrated in a double-blind, randomised, placebo-controlled trial that primary prophylaxis with pegfilgrastim reduces the incidence of docetaxel-associated febrile neutropenia from 17% to 1% (P < 0.001). With the relative decrease in the cost of colonystimulating factors (with respect to the increasing cost of hospitalisation and novel antibiotics), we think that the reduction seen in our study justifies the systematic use of PPG in all patients who are initiating TAC treatment. Avoiding neutropenic fever events, and the associated risk of life-threatening infections, is of particular importance in the adjuvant setting, where many patients can be already cured by local treatment itself. Although the mortality of neutropenic fever is very low today, some toxic deaths due to neutropenic sepsis in breast cancer patients treated with doxorubicin plus docetaxel have recently been reported [13]. PPG improved the compliance with TAC. The percentage of patients who completed six cycles of therapy increased from 90.4% without PPG to 95.7% with it (P = 0.0194). In spite of this, the median dose intensities of docetaxel, doxorubicin
original article
Annals of Oncology
Table 5. Grade 2 or greater toxicities occurring in more than 1% of patients in any group (in percentages) TAC-post
FAC
P value (TAC-pre versus TAC-post)
P value (TAC-post versus FAC)
64.0 11.4 14.9 7.9 7.0 7.9 5.3 35.1 21.1 42.1 7.0 27.2 6.1 10.5 3.5 7.0 4.4
48.1 3.6 7.7 3.1 3.6 1.4 4.10 23.2 14.7 36.7 6.0 30.9 2.9 10.4 2.7 8.2 3.1
33.3 2.9 1.2 2.3 3.1 1.3 3.9 24.5 5.2 38.9 2.5 34.1 2.1 8.7 3.7 1.5 0.6
0.0025 0.001 0.0193 0.0335 NS 0.0012 NS 0.0101 NS NS NS NS NS NS NS NS NS
<0.0001 NS <0.0001 NS NS NS S NS <0.0001 NS 0.0067 NS NS NS NS <0.0001 0.0027
NS, P > 0.05.
Figure 3. Observed means of EORTC QLQ-C30 scores at baseline, during treatment and follow-up period comparing TAC-pre, TAC-post and FAC patients. EORTC QLQ-C30: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.
and cyclophosphamide were not significantly different in TAC-pre and TAC-post patients, probably because G-CSF was administered to 71% of patients in the TAC-pre group as secondary prophylaxis after the first episode of
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febrile neutropenia, allowing a delivery of full doses of chemotherapy. One surprising finding of our study was the reduction of grade 2 to 4 anaemia and transfusional requirements associated
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Asthenia Anorexia Myalgia Dysgeusia Abdominal pain Nail disorder Conjunctivitis Stomatitis Diarrhoea Nausea Pain Vomiting Dyspepsia Neuroconstipation Neuromood Arthralgia Oedema
TAC-pre
original article
Annals of Oncology
Volume 17 | No. 8 | August 2006
Figure 4. Percentage of patients with more than 10 point decrease in Global Health Status score over baseline. Chi-square test. NS, not significant.
asthenia cytokine release anorexia
anaemia TAC neutropenia
infection
stomatitis
nail changes Figure 5. Suggested pathogenic pathways of TAC-induced toxicity. TAC would induce neutropenia, anaemia, stomatitis and nail changes by a direct mechanism (direct toxicity on bone marrow, mucous membranes, muscles and skin annexes). In addition, profound neutropenia leads to infections and cytokine release. Infections are responsible for an increase in the intensity of anaemia, asthenia, stomatitis and nail changes. The cytokine release increases the intensity of asthenia and are the main cause (together with anaemia) of anorexia. The addition of G-CSF could improve toxicity by reducing the imputs at selected sites (vertical arrows).
adjuvant TAC, pegfilgrastim and dabepoietin is currently ongoing in Spain. In conclusion, our study shows that PPG reduces the incidence of neutropenic fever and other clinically relevant events (grade 2 or greater anaemia, asthenia, anorexia, myalgia, nail disorders and stomatitis) associated with TAC chemotherapy. PPG also moderately improves the HRQoL of patients treated with TAC. The results of this study support the routine use of PPG in all breast cancer patients treated with adjuvant TAC chemotherapy.
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with the use of PPG. Since G-CSF does not stimulate the erythroid progenitors, an indirect mechanism (i.e. reduction of infections and cytokine release, a well known cause of anemia [14]) could be the reason behind this finding. In support of this hypothesis, we found a clear correlation between anaemia and neutropenic fever in all the three arms. Thus, reducing neutropenic fever events and infections with PPG may be an indirect way of preventing anaemia in TAC-treated patients. Still more surprising was the reduction seen in some extrahaematological side-effects of TAC. PPG was associated with a statistically significant reduction in the incidence of clinically relevant (i.e. grade 2 or greater) asthenia, anorexia, myalgia, nail disorders and stomatitis compared with secondary prophylactic G-CSF in patients treated with TAC. The mechanism underlying this protective effect is unknown. We speculate that the protection against clinical and subclinical infections associated with PPG could explain the reduction in the incidence of nail changes and stomatitis, disorders in which an infectious component is often involved. Other authors have also found a reduction in the severity of chemotherapy-induced stomatitis with the use of G-CSF [15]. The reduced incidence of clinically relevant asthenia and anorexia could be related to the lower incidence of anaemia in the TAC-post group, which could also be related to the reduction of infection. An alternative or complementary explanation could be the reduction of the release of cytokines associated with the reduction of infections. Cytokines are known to be mediators of both asthenia and anorexia and are released during infections [16]. Figure 4 summarises the hypothetic pathogenic pathways of TAC-induced toxicities. The results of the present study show a HRQoL deterioration in patients during the chemotherapy treatment period that improves once chemotherapy is completed. The deterioration of HRQoL during treatment is obviously due to adverse events associated with chemotherapy and is clearly less marked in the FAC group than in both TAC groups, in which the side-effects are more frequent and severe. The addition of PPG to TAC resulted in a reduction of anaemia and, as in other studies [17, 18], this can explain the moderate improvement in HRQoL we have described. Although the improvement of Global Health Status score of TAC-post patients did not reach a statistically significant value compared with TAC-pre patients, the percentage of patients with a clinically relevant impairment in HRQoL (reduction of 10 or more points over baseline value) over time was lower with PPG, particularly in the second half of chemotherapy treatment. Further improvements on QoL of patients treated with TAC are, therefore, necessary. A recent report by von Minckwitz et al. [19] showed that pegfilgrastim (administered on day 2 of each cycle) is superior to filgrastim or lenogastrim (administered on days 5–10 of each cycle) in the prevention of TAC-induced neutropenic fever. Interestingly, in this study pelfisgastrim also reduced the incidence of grade 3–4 stomatitis and diarrhoea compared with daily conventional G-CSF. On the other hand, 27.5% of TAC-treated patients still have grade 2 or greater anaemia in spite of PPG. Reducing this toxicity by means of erythropoietin could translate into an improvement of QoL [20]. A prospective study of QoL in patients treated with
original article acknowledgements
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4. Perez E. TAC—A new standard in adjuvant therapy for breast cancer? N Engl J Med 2005; 352: 2346–2348. 5. Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90: 1601–1608. 6. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Tretament of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376. 7. Sprangers MA, Groenvold M, Arraras JI et al. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol 1996; 14: 2756–2768. 8. Goodwin PJ, Black JT, Bordeleau LJ et al. Health-related quality-of-life measurement in randomized clinical trials in breast cancer—taking stock. J Natl Cancer Inst 2003; 5:263–281. 9. Osoba D, Rodrigues G, Myles J et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998; 16: 139–144. 10. Ozer H, Armitage JO, Bennet CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines—American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000; 18: 3558–3585. 11. Lyman GH, Kuderer N, Green J et al. The economics of febrile neutropenia: Implications for the use of colony-stimulating factors. Eur J Cancer 1998; 34: 1857–1864. 12. Vogel CL, Wojtukiewicz MZ, Carroll RR et al. First and subsequent cycle use of pelfisgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 2005; 23: 1178–1184. 13. Brain EGC, Bachelot T, Serin D et al. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. JAMA 2005; 293: 2367–2371. 14. Schnall SF, Berliner N, Duffy TP et al. Approach to the adult and child with anemia. In Hoffman R, Benz EJ Jr, Shattil SJ et al (eds): Hematology. Basic Principles and Practice. New York, NY: Churchill Livingstone 2000; 367–382. 15. Gabrilove JL, Jakubowski A, Scher H et al. Effect of granulocyte colonystimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of urothelium. N Engl J Med 1988; 318: 1414–1422. 16. Aggarwal BB, Puri RJ (eds). Human Cytokines: Their Role in Disease and Therapy. Cambridge: Blackwell Science 1995. 17. Holzner B, Kemmler G, Greil R et al. The impact of hemoglobin levels on fatigue and quality of life in cancer patients. Ann Oncol 2002; 3: 965–3973. 18. Lind M, Vernon C, Crickshank D et al. The level of hemoglobin in anaemic cancer patients correlates positively with quality of life. Br J Cancer 2002; 86: 1243–1249. 19. von Minckwitz G, Blohmer J, Loehr A et al. Pegfilgastrim alone or with ciproflaxin significantly reduces febrile neutropenia and hospitalization vs G-CSF alone in breast cancer patients receiving neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC). Eur J Cancer 2006; 4 (Suppl 2): 151–152. 20. Gabrilove J. Overview: Erythropoiesis, anemia and the impact of erythropoietin. Sem Hematol 2000; 37 (Suppl 4): 1–3.
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The authors thank the 1059 patients who agreed to participate in this trial and to the following additional investigators who contributed to patient enrolment in this study: B. Muna´rriz (H. Universitario La Fe, Valencia ), C. Llorca (H. General de Elda, Elda), P. Koralewski (Regional Rydygiera Specialistic H., Krako´w), E. Alba (C.H. Virgen de la Victoria, Ma´laga), C. Jara (Fundacio´n Hospitalaria de Alcorco´n, Alcorco´n), J. Floria´n (H. De Barbastro, Barbastro), C. Oberhoff (Universita¨tsfrauenklinik, Essen), C. Crespo (H. Ramo´n y Cajal, Madrid), A. Pelegrı´ (H. Universitario San Juan de Reus, Reus), M. Margelı´ (H. Universitario Germans Trias i Pujol, Badalona), V. Alberola (H. Arnau de Vilanova, Valencia), J. L. Garcı´a-Puche (H. Universitario Clı´nico San Cecilio, Granada), A. Go´mez (H. Clı´nico Universitario de Salamanca, Salamanca), A. Oltra (H. Virgen de los Lirios, Alcoy), I. A´lvarez (H. De Donostia, San Sebastia´n), J. Castellanos (C.H. Xeral-Cı´es, Vigo), A. Garcı´a-Palomo (C.H. de Leo´n, Leo´n), A. Modollel (Clı´nica Coracha´n, Barcelona), E. Aranda (H. Universitario Reina Sofı´a, Co´rdoba), R. M. Franquesa (H. General de Vic, Vic), A. Murias (C.H. Materno-Insular, Las Palmas de Gran Canaria), P. Aramburo (H. Ruber Internacional, Madrid), M. Mun˜oz (H. General Virgen de la Luz, Cuenca), S. Morales (H. Universitario Arnau de Vilanova, Le´rida), M. Stamm (St. Marien-Krh, Siegen), A. Ferna´ndez (C.H. Universitario de Albacete, Albacete), J. Garcı´a-Mata (C.H. de Orense, Orense), M. Constenla (C.H. de Pontevedra, Pontevedra), A. Lorenzo (H. Universitario de Puerto Real, Puerto Real), A. Velasco (H. Universitario de la Princesa, Madrid), A. Arizcun (H. General Rı´o Carrio´n, Palencia), J. M. Baena (H. Universitario Puerta del Mar, Ca´diz), L. de Paz (C.H. Arquitecto Marcide, El Ferrol), J. M. Cuevas (H. De La Ribera, Alcira), M. Ferna´ndez (C.H. de Jae´n, Jae´n), F. Melcher (Klinikum Mannheim, Mannheim), M. Navalo´n (H. Provincial de Zamora, Zamora). Miguel Martin received a speaker’s honoraria from SanofiAventis, Novartis, Pfizer, Roche and Bristol-Myers Squibb. The study was presented at ASCO.
Annals of Oncology