Adjuvant capecitabine in combination with docetaxel
and cyclophosphamide plus epirubicin for breast cancer:
an open-label, randomised controlled trial

Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Riikka Huovinen, Arja Jukkola-Vuorinen, Minna Tanner, Raija Asola, Riitta Kokko, Johan Ahlgren, Päivi Auvinen, Akseli Hemminki, Outi Paija, Leena Helle, Lauri Nuortio, Kenneth Villman, Greger Nilsson, Sirpa-Liisa Lahtela, Kaisa Lehtiö, Marjo Pajunen, Paula Poikonen, Paul Nyandoto, Vesa Kataja, Petri Bono, Mika Leinonen, Henrik Lindman, on behalf of the FinXX Study Investigators Summary
Background Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer
Published Online
typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of November 10, 2009
capecitabine into such a regimen enhances outcome.
See Online/Refl ection and
Methods In this open-label trial, we randomly assigned (centrally by computer; stratifi ed by node status, HER2 status, Reaction
and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of DOI:10.1016/S1470-
capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine 2045(09)70340-7
group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fl uorouracil Department of Oncology,
(control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done Helsinki University Central
after 3 years’ median follow-up. Effi

cacy analyses were by modifi ed intention to treat. The study is registered with Hospital, Helsinki, Finland, number NCT00114816.
Prof A Hemminki MD, S-L Lahtela MD, K Lehtiö MD, Findings Two patients in each group were excluded from effi
cacy analyses because of withdrawal of consent or P Poikonen MD, P Bono MD);
Department of Oncology,
distant metastases. After a median follow-up of 35 months (IQR 25∙5–43∙6), recurrence-free survival at 3 years was Tampere University Hospital,
better with the capecitabine regimen than with control (93% vs 89%; hazard ratio 0∙66, 95% CI 0∙47–0∙94; p=0∙020). Tampere, Finland
The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and (Prof P-L Kellokumpu-Lehtinen MD,
hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 M Tanner MD); Department of
Oncology, Turku University
neutropenia (368/375 [98%] vs 325/378 [86%]) and febrile neutropenia (65/741 [9%] vs 33/742 [4%]). More patients Central Hospital, Turku, Finland
discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). (R Huovinen MD, O Paija MD);
Four patients in the capecitabine group and two in the control group died from potentially treatment-related Department of Oncology and

Radiotherapy, Oulu University
Hospital, Oulu, Finland

(A Jukkola-Vuorinen MD);
Interpretation The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with Satakunta Central Hospital,
a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse Pori, Finland
(R Asola MD);
eff ects.
Kanta-Häme Central Hospital,
Hämeenlinna, Finland

(R Kokko MD); Gävle Hospital,
Funding Roche, Sanofi -Aventis, AstraZeneca, Cancer Society of Finland.
Gävle, Sweden (J Ahlgren MD);
Department of Oncology,
Administration of docetaxel, paclitaxel, or cyclophos- Kuopio University Hospital,
Kuopio, Finland (P Auvinen MD,
Adjuvant chemotherapy consisting of an alkylating agent, phamide boosts the concentration in tumour tissue of V Kataja MD); Kotka Central
an anthracycline, and a taxane is typically administered thymidine phosphorylase in xenograft models, suggesting Hospital, Kotka, Finland
for early breast cancer, although the regimens used can that these agents might act in a synergistic manner with (L Helle MD); North Karelia
vary considerably.1–3 Results from a few large randomised
capecitabine.8–10 In women treated with docetaxel, or Central Hospital, Joensuu,
Finland (L Nuortio MD); Örebro
trials and a meta-analysis suggest that addition of a doxorubicin or epirubicin given with cyclophosphamide University Hospital, Örebro,
taxane to adjuvant regimens containing an anthracycline
before surgery for breast cancer, thymidine phosphorylase Sweden (K Villman MD);
improves disease-free and overall survival.4–6 Despite was greatly stimulated in both tumour and stromal cells.11 Uppsala University Hospital,
such advances in chemotherapy, many women diagnosed
Women with advanced breast cancer treated with an Uppsala, Sweden
(H Lindman MD, G Nilsson MD);
with early breast cancer still eventually succumb to the anthracycline had augmented survival when randomised Jyväskylä Central Hospital,
to receive docetaxel plus capecitabine compared with those Jyväskylä, Finland
Capecitabine is an oral prodrug of fl uorouracil, which assigned to docetaxel alone.12 (M Pajunen MD); Päijät-Häme
has been used in the treatment of advanced breast cancer Since thymidine phosphorylase production in cancer Central Hospital, Lahti, Finland
(P Nyandoto MD); and
for a few decades. After absorption, it is metabolised in the tissue is important for capecitabine activity, in the current 4Pharma, Turku, Finland
liver and in cancerous tissue. The fi nal step of conversion study (the Finland capecitabine trial [FinXX]), we (M Leinonen MSc)to fl uorouracil is catalysed by thymidine phosphorylase, administered capecitabine with agents that might which is present in high amounts in breast tumours.7 enhance activity of this enzyme in tumours. Capecitabine Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
was given for a total of 18 weeks to provide prolonged Randomisation and masking
exposure, which might facilitate eradication of cancer We randomly assigned patients (centrally and with cells with a slow cell-proliferation rate. Here, we report computer-assisted masking), in a 1:1 ratio, to receive cacy analysis of either a capecitabine-containing chemotherapy regimen (capecitabine group) or a control schedule. A physicist
otherwise uninvolved in the study generated the randomisation code (M Tenhunen, Department of Patients
Oncology, Helsinki University Central Hospital). We did We undertook a randomised, controlled, open-label, randomisation with permutated blocks: block size (two, phase 3 trial in 15 Finnish hospitals and fi ve Swedish four, or six) varied at random. We stratifi ed women at hospitals. We deemed women eligible for the study if they random allocation according to the number of axillary had histologically confi rmed invasive breast cancer at lymph nodes that contained cancer (≤3 vs >3), HER2 medium-to-high risk of recurrence, defi ned as either: status (negative vs positive; ascertained by either regional node-positive disease (isolated tumour-cell immunohistochemistry or in-situ hybridisation), and clusters <0∙2 mm in diameter were not judged a centre. A trained study nurse communicated the metastasis); or node-negative disease with primary tumour randomisation result to study sites by fax.
diameter greater than 20 mm and negative progesterone
receptor assay (usually classifi ed as staining of <10% of Procedures
cancer cells).13,14 Other eligibility criteria included: age Patients allocated to the capecitabine group received
18–65 years; WHO performance score 0 or 1 (on a scale of
capecitabine (900 mg/m² twice a day, days 1–15) plus 0–5, with a score of 5 indicating death); interval of 12 weeks docetaxel (60 mg/m² as a 1-h intravenous infusion on or fewer between surgery and randomisation; and normal day 1 of every 3-week cycle), followed by cyclophosphamide renal, cardiac, and hepatic function (serum alanine (600 mg/m² on day 1), epirubicin (75 mg/m² on day 1), aminotransferase ≤1∙5× upper limit of normal; alkaline and capecitabine (900 mg/m² twice a day, days 1–15, every phosphatase ≤2∙5× upper limit of normal; bilirubin ≤1∙0× 3 weeks). Those assigned control received docetaxel upper limit of normal). Main exclusion criteria were: (80 mg/m² as a 1-h intravenous infusion on day 1 of every presence of distant metastases; node-negative mucinous, 3-week cycle) followed by cyclophosphamide (600 mg/m²), papillary, medullary, or tubular disease; clinically epirubicin (75 mg/m²), and fl uorouracil (600 mg/m²), all signifi cant cardiac disease; and previous neoadjuvant administered on day 1 of every 3-week cycle. In the chemotherapy. capecitabine group, the fi rst capecitabine dose of every For the trial protocol see
The trial protocol was approved by independent ethics cycle was given in the evening of day 1 and the last dose committees and by the medical authorities. All patients was administered on the morning of day 15, followed by provided written informed consent. Study safety was a 7-day rest period. monitored by an independent data safety monitoring We gave patients oral corticosteroids at standard doses at the time of docetaxel infusions. We permitted haemopoietic growth factor support for symptomatic neutropenia but did not allow prophylactic use. We 1500 enrolled and underwent randomisation administered treatment for six cycles (three cycles of each regimen) in both groups, unless individuals had disease recurrence or intolerable toxic eff ects. Patients received locoregional radiotherapy according to the institution’s practice after completion of chemotherapy. Those with steroid hormone receptor-positive disease received adjuvant endocrine therapy for 5 years. We gave tamoxifen (20 mg/day) to individuals deemed premenopausal before the start of chemotherapy, whereas 751 included in intention-to-treat population 745 included in intention-to-treat population postmenopausal women received anastrozole (1 mg/day). 744 included in safety population (received 741 included in safety population (received Hormonal therapy was initiated within 2 months of We implemented a dose-modifi cation scheme in the event of grade 2–4 non-haematological toxic eff ects (graded according to the National Cancer Institute’s common terminology criteria for adverse events, version 3.0). If a patient had a grade 2 event, we interrupted treatment and resumed it at the same dose once the toxic eff ect had resolved. If they developed a Figure 1: Trial profi le
second grade 2 event, or their fi rst grade 3 event, we Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
stopped chemotherapy and, after resolution to grade 0–1, Capecitabine group
Control group
resumed it at 80% of the starting dose. If a third grade 2 event arose, we continued treatment at 60% of the starting dose. For a fourth grade 2 event, the regimen was discontinued. If an individual had a second grade 3 event or any grade 4 toxic eff ect, we usually stopped treatment. If the investigator attributed an adverse event to one drug, then only that agent was dose-reduced. We decreased the doses of all drugs by 20% for febrile neutropenia or grade 3–4 neutropenia with infection. When scheduled treatment was discontinued for toxic eff ects, we replaced agents as follows: capecitabine and docetaxel by cyclophosphamide, epirubicin, and cape- citabine, or cyclophosphamide, epirubicin, and fl uoro- uracil; single-agent docetaxel by cyclophosphamide, epirubicin, and capecitabine by cyclophosphamide, epirub- We regarded staging examinations (chest CT or radiography; bone scan; and abdominal CT, MRI, or ultrasound) as mandatory at screening for patients with four or more positive axillary nodes,15,16 but these procedures were undertaken at the discretion of the investigator for all other patients. We did laboratory tests (blood-cell count and serum chemistry) within the 3 days preceding the planned start of every chemotherapy cycle. We recorded all events arising during study treatment or within 28 days of the last dose of chemotherapy. We scheduled follow-up of study participants for a minimum The primary endpoint was recurrence-free survival, defi ned as the time between randomisation and date of diagnosis of invasive breast cancer recurrence, or death if the patient died before cancer recurrence. Secondary endpoints were overall survival, defi ned as the time from randomisation to death, and treatment safety. Statistical analysis
We estimated the recruitment period to be 3·5 years. We amended the protocol on Nov 23, 2007, to include an interim analysis to assess treatment safety and early cacy. We expected that recurrence-free survival would rise from 83·0% to 88·5% (hazard ratio 0·65) after median follow-up of 5 years. Based on this assumption, a total of 205 events and 1500 patients were needed to Data are median (range) or number (%). *Menstrual periods within 6 months achieve 80% power, assuming a 3% annual dropout rate, before starting chemotherapy. †Tumours with postsurgical features defi ned as in when α=0·028 (two-sided). To maintain a signifi cance the 2002 International Union Against Cancer’s TNM Classifi cation of Malignant Tumours, 6th edn. level of 5%, we set the signifi cance level in interim and fi nal analyses at 0·028.17 The interim analysis had 80% Table 1: Baseline characteristics for all patients
power to detect an improvement from 89·0% to 93·5% (HR 0·58) after median follow-up of 3 years in axillary nodes [≤3 or >3], oestrogen receptor status [positive 1500 patients (α=0·028, two-sided testing) and when or negative], and HER2 status) were defi ned in the about 120 recurrences had happened. We calculated statistical plan for the interim analysis (approved before sample sizes with nQuery Advisor version 6.0.
the analysis was undertaken on Nov 6, 2008), but not in the cacy analyses by modifi ed intention to treat. original study protocol. The safety population included all Exploratory subgroup analyses (by centre, [number of patients who received at least one dose of any study drugs. Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
We analysed frequency tables with Fisher’s exact test or the Capecitabine group
Control group
Hazard ratio
χ² test, and we compared age and weight distributions with the t test. To compare survival between groups, we used the Kaplan-Meier life-table method and an unadjusted Cox proportional-hazards model; we implemented the log-rank test to confi rm the robustness of the analysis. We undertook subgroup analyses by inclusion in the Cox model of treatment group, the subgroup variable, and their interaction. All p values are two-sided and not adjusted for Data are number of events (%). *Calculated with unadjusted Cox proportional-hazards model. †Suicide and depression; multiple testing. We did statistical analyses with SAS suicide and intoxication; unknown; unknown (breast cancer unlikely); pulmonary embolus; septicaemia, colitis, and version 8.2 for Windows. This study is registered with multiorgan failure; acute myocardial infarction; alcohol intoxication; cardiac and pulmonary failure. ‡Pulmonary, number NCT00114816.
embolus (n=2); septicaemia; septic shock; amyotrophic lateral sclerosis; subdural haemorrhage.
Table 2: Breast cancer recurrence and survival in the modifi ed intention-to-treat population
Role of the funding source
The study was designed by HJ in collaboration with
A Recurrence-free survival
members of the Finnish Breast Cancer Group. The study protocol was written by the authors and Roche. The sponsors had no access to the study database. The corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. Results
Between Jan 27, 2004, and May 29, 2007, 1500 patients
were recruited from 15 Finnish centres (n=1199) and fi ve
Swedish centres (n=301). Four women were excluded from the modifi ed intention-to-treat population (two withdrew informed consent before they received study treatments, two had overt distant metastases at the time of study entry; fi gure 1). Baseline characteristics were balanced between groups (table 1). 90% of patients had node-positive cancer, and 19% had HER2-positive disease. Number at risk
The study protocol was amended in May, 2005, to allow administration of adjuvant trastuzumab for HER2-positive disease. Subsequently, 96 (13%) of 753 patients assigned B Overall survival
to the capecitabine group and 83 (11%) of 747 allocated control were given trastuzumab. Respectively, 56 (7%) and 50 (7%) women received single-agent trastuzumab after discontinuation of chemotherapy for up to 12 months, 24 (3%) and 21 (3%) received trastuzumab concomitantly with docetaxel only, and 16 (2%) and 12 (2%) received trastuzumab concomitantly with docetaxel plus single-agent trastuzumab for up to 12 months after chemotherapy. Adjuvant endocrine therapy was given to 592 (79%) and 575 (77%) patients after completion of chemotherapy in the capecitabine and the control groups, respectively. Tamoxifen, anastrozole, and other hormonal treatments were administered, respectively, to 325 (43%), 316 (42%), and 29 (4%) patients assigned to the capecitabine group, and to 287 (38%), 328 (44%), and 27 (4%) women At the time of data lock (Aug 31, 2008), median follow-up was 35 months (IQR 25·5–43·6). 134 events (deaths, Number at risk
distant or local relapses) had happened, 54 (7%) in the capecitabine group and 80 (11%) in the control group, which triggered the interim analysis. The hazard ratio for Figure 2: Kaplan-Meier estimates of 3-year recurrence-free and overall survival in the modifi ed
intention-to-treat population

recurrence-free survival favoured the capecitabine- Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
Capecitabine group
Control group
Hazard ratio (log scale)
Hazard ratio (95% CI)
WHO performance status
Positive axillary nodes
Oestrogen receptor status
HER2 status
Figure 3: Forest plot of exploratory subgroup analyses for recurrence-free survival
containing regimen (0·66, 95% CI 0·47–0·94; p=0·020; Capecitabine group
Control group
table 2; fi gure 2). In the capecitabine group, three women (capecitabine/ (N=744)
developed invasive contralateral breast cancer and six had other cancers, compared with two and eight patients, respectively, in the control group. The proportions of women developing these cancers were similar (1·2% vs 1·3%, respectively). Disease-free survival (which includes invasive contralateral breast cancers and second cancers) was longer in the capecitabine group than in the control group (0·68, 0·49–0·94; p=0·020). When patients treated with trastuzumab were excluded from the main analysis, the hazard ratio for recurrence-free survival still favoured the capecitabine-containing regimen (0·64, 0·44–0·91; In exploratory subgroup analyses, recurrence-free survival was better in the capecitabine group than in the control group, with the exception of patients with HER2-positive disease (fi gure 3). In this analysis, the interaction between treatment and HER2 status was signifi cant (p=0·0049), whereas interactions between treatment and the other subgroups shown in fi gure 3 The safety profi les of the two regimens diff ered. Patients who received capecitabine had more occurrences of grade 3 or 4 hand-foot syndrome, diarrhoea, nail changes, and stomatitis than did those in the control group, whereas neutropenia, febrile neutropenia, infection with neutropenia, amenorrhoea, and myalgia were more Data are number of patients (%). NA=not applicable. *p values calculated with Fisher’s exact test for diff erences between treatment groups with grade 3 or 4 adverse events. †Grade 3 or 4 adverse events are listed if they were frequent in the control group (table 3). Four patients in reported in 1% or more of all patients. ‡From nadir counts; counts did not need to be measured in all study centres. the capecitabine group died during chemotherapy from §Includes premenopausal and postmenopausal patients. possibly treatment-related causes (septic colitis; suicide; Table 3: Adverse events in safety population
myocardial infarction; unknown cause [suspected cardiac arrhythmia]) and two died in the control group (pulmonary arterial embolism; septicaemia).
treatment was most frequent in the capecitabine group All six planned cycles of chemotherapy were (178 [24%] vs 23 [3%] assigned control; p<0·0001). Of administered to 566 (75%) individuals assigned the those allocated to the capecitabine group, 98 (13%) capecitabine-containing regimen compared with discontinued during docetaxel and capecitabine cycles 718 (96%) allocated control. Discontinuation of scheduled and a further 80 (11%) during cyclophosphamide, Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
epirubicin, and capecitabine cycles. In the control group, The control arm in our study represents a regimen 16 (2%) individuals discontinued during docetaxel frequently used in Finland and Sweden, which is not monotherapy and seven (1%) stopped during cyclo- dissimilar to the types of regimen administered in phosphamide, epirubicin, and fl uorouracil. Adverse many other countries.8,23,24 Docetaxel 80 mg/m² is a events were the most usual reason for treatment lower dose than the 100 mg/m2 regarded as standard in discontinuation in both groups. some regions. We selected the dose of 80 mg/m² for 58 (8%) and 139 (19%) patients assigned to the two reasons: (1) on the basis of toxic eff ects recorded capecitabine and control groups, respectively, had the with docetaxel 100 mg/m² in the FinHer trial, leading docetaxel dose reduced because of toxic eff ects. 319 (43%) to protocol modifi cation;25 and (2) because no diff erence women took less than the scheduled starting dose of in time-to-progression or survival was recorded between capecitabine on one or more occasions owing to toxic starting doses of 75 mg/m² and 100 mg/m² in the eff ects or for other reasons. Including replaced cycles, intention-to-treat population of a randomised trial of most patients (1461 [98%]) received a total of six cycles.
docetaxel as second-line therapy for advanced breast cancer.26 Adjuvant docetaxel administered at either Discussion
80 mg/m² or 100 mg/m² at 3-week intervals before Our fi ndings showed enhanced recurrence-free survival three cycles of fl for patients who received a regimen containing capecita- cyclophosphamide for early breast cancer might show bine in addition to docetaxel, epirubicin, and cyclo- similar survival.27 The docetaxel dose of 60 mg/m² phosphamide compared with women who received administered in the capecitabine group is fairly low, but docetaxel, epirubicin, cyclophosphamide, and fl uorouracil. this amount was eff ective in combination with other Overall survival data from FinXX are not yet mature, but agents and rarely needed to be reduced. we noted the hazard ratio for overall survival was similar to that for recurrence-free survival. Single-agent capecitabine capecitabine is given at a dose of 900 mg/m² instead of has been compared with combination chemotherapy in 1250 mg/m² twice a day in combination with docetaxel,12 the adjuvant treatment of elderly patients with breast and these data are consistent with analyses of cancer,18 but to our knowledge, FinXX is the fi rst adjuvant capecitabine dose-reduction in metastatic disease.28 The trial to report effi cacy of capecitabine in combination with hypothesis that an even lower capecitabine dose could other agents for treatment of early breast cancer.
be appropriate is being tested in an ongoing US Our results suggest that integration of capecitabine Oncology Group trial, in which capecitabine is given at upfront with potentially synergistic chemotherapeutic a dose of 825 mg/m² concomitantly with docetaxel. agents and into several cycles might be an eff ective Retrospective analysis of one study suggests that treatment strategy. This hypothesis is supported by data docetaxel plus capecitabine might be more eff ective of randomised studies undertaken in the neoadjuvant than docetaxel alone for treatment of oestrogen receptor-setting.19,20 Inclusion of capecitabine in the taxane and positive advanced breast cancer in particular, but this idea anthracycline-containing parts of the regimen needs confi rmation.29 Chemotherapy-induced amenorrhoea distinguishes FinXX from other trials investigating is unlikely to account for the high effi incorporation of capecitabine into adjuvant regimens. combinations, because persistent amenorrhoea was less Findings of a randomised trial in the neoadjuvant frequent in women allocated to the capecitabine group setting indicated a 20% pathological complete response rate with cyclophosphamide, epirubicin, and In conclusion, risk of breast-cancer recurrence was capecitabine compared with 13% in patients receiving reduced by incorporation of capecitabine into a regimen fl uorouracil, epirubicin, and cyclophosphamide.21 containing a taxane and anthracycline. The eff ect was cacy we recorded in the capecitabine substantial and could be comparable to or greater than arm was gained at the cost of increased diarrhoea and that achieved with the introduction of taxanes to hand-foot syndrome, although febrile neutropenia was less adjuvant treatment of early breast cancer.6,30 However, frequent than with the control regimen, which is probably this possibility needs to be confi rmed in ongoing trials attributable to the reduced docetaxel dose. Two women in of adjuvant capecitabine. Integration of capecitabine the capecitabine group died from cardiac causes possibly was associated with frequent discontinuation of planned related to study treatment. Cardiotoxicity is a known eff ect chemotherapy, but most patients could tolerate all six
of the fl uoropyrimidine class of chemotherapeutic agents, scheduled cycles. Studies that focus on further refi nement
and individuals receiving fl uoropyrimidines need to be of the current chemotherapy regimen are warranted.
monitored for symptoms and signs of these cardiac eff ects, Contributors
although cardiotoxicity might be less typical with HJ, P-LK-L, AJ-V, MT, PA, PB, and HL had the idea for and designed the
capecitabine than with infused fl uorouracil.22 In our study,
study. HJ and P-LK-L did the literature search. HJ, P-LK-L, AJ-V, MT, RA, most patients who interrupted capecitabine administration RK, JA, PA, AH, OP, LH, LN, KV, GN, S-LL, KL, MP, PP, PN, VK, PB, and HL provided study materials and obtained data. HJ, P-LK-L, JA, AH, could continue treatment with other study agents and PB, and ML analysed and interpreted data. HJ, P-LK-L, OP, PB, and HL complete six cycles of chemotherapy. wrote the report. HJ, RH, and HL provided administrative support. Published online November 10, 2009 DOI:10.1016/S1470-2045(09)70307-9
Confl icts of interest
16 Myers RE, Johnston M, Pritchard K, Levine M, Oliver T, and the P-LK-L, MP, PP, and PB have received honoraria or consulting fees from Breast Cancer Disease Site Group of the Cancer Care Ontario Roche. HJ, P-LK-L, and PB have received honoraria or consulting fees Practice Guidelines Initiative. Baseline staging tests in primary from Sanofi -Aventis. MP has received a travel grant from Sanofi -Aventis. breast cancer: a practice guideline. CMAJ 2001; 164: 1439–44.
All other authors declared no confl icts of interest.
17 Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 1977; 64: 191–99.
18 Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB We thank members of the independent monitoring committee; Investigators. Adjuvant chemotherapy in older women with Chairman of the independent monitoring committee Pertti Neuvonen; early-stage breast cancer. N Engl J Med 2009; 360: 2055–65.
trial monitor Raija Husa; medical, nursing, and clerical staff at 19 von Minckwitz G, Rezai M, Loibl S, et al. Capecitabine given participating centres; and all women taking part in the FinXX trial. concomitantly or in sequence with EC→docetaxel as neoadjuvant treatment for early breast cancer: GeparQuattro—a GBG/AGO References
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Fertility of beef cattle grazing endophyte-infected tall fescue pastures

NUTRITIONAL INFLUENCES ON REPRODUCTION: EFFECTS OF ENDOPHYTE-INFECTED TALL FESCUE F. N. Schrick, J. L. Edwards, J. C. Waller, and F. M. Hopkins Department of Animal Science, The University of Tennessee, Knoxville Introduction Tall fescue, a cool-season perennial grass, is one of the most commonly grown forages for over 8.5 million cattle in the United States [Hoveland, 1993].

T h e n e w e ng l a n d j o u r na l o f m e dic i n e This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. An otherwise healthy 53-year-old woman is seen for routin

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