X-ACT Trial Research Articles

Capecitabine (cape)-associated hand-foot skin reaction (HFS) as a clinical predictor of improved survival in patients (pts) with colorectal cancer.

3541 Background: HFS is frequently observed during treatment with cape. Post hoc analyses of the X-ACT trial suggested that HFS may be associated with improved prognosis in cape recipients in stage III colon cancer. In the present analysis we evaluated the potential association of HFS and survival in pts with metastatic colorectal cancer and locally advanced rectal cancer. Methods: Pts receiving cape within AIO KRK-0104 and Mannheim rectal cancer trials were analyzed. HFS was graded according to NCI-CTC. Time to first occurrence of HFS was described per cycle and HFS developing during cycles 1 and 2 was defined as “early HFS”. Baseline characteristics in the groups of pts with or without HFS were compared using standard tests. Toxicities observed in both groups were compared with Fisher’s exact test. Progression-free (PFS) or disease-free (DFS) and overall survival (OS) data from both trials were pooled and the HFS group was compared to the non-HFS using Kaplan-Meier analysis. Results: A total of 374 pts are included, of whom 29.3% developed HFS. Of these, 70.9% had “early HFS”. Baseline characteristics were comparable between the HFS and the non-HFS groups concerning age, gender, ECOG status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFS. The percentage of all-grade hematological toxicities did not differ between both groups. Contrarily, patients in the HFS group had a significantly higher rate of all grade (but not grade 3-4) diarrhea, stomatitis/mucositis and fatigue (p<0.01 resp.). Moreover, pts in the HFS group had improved PFS/DFS (29.0 vs. 11.4 months; p=0.015, HR 0.69) and OS (75.8 vs. 41.0 months; p=0.001, HR=0.56). Within the HFS group the PFS/DFS and OS were comparable between pts in the “early” and the “late HFS” groups. Conclusions: This analysis provides further evidence for the association of HFS and survival in patients with colorectal cancer. Baseline characteristics and the time of occurrence of HFS had no impact on survival. Patients developing HFS had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with hematological toxicity was noticed.

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy

This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS). The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients. Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.

Training cognition: Parallels with physical fitness?

In their article on memory training, McDaniel and Bugg (2012) rst criticize the idea that any type of memory training will genralize to all other types; the notion that memorizing poems or peeches from plays will improve a person’s memory for names or umbers, for example. We strongly agree with this criticism. Cogitive processes resemble physical skills in many respects, and few eople would expect that hours of tennis practice would improve heir golf game, or even that putting practice would improve drivng off the tee. Memory is not one monolithic faculty. The authors f the target article then go on to advocate training methods that mphasize more specific aspects of memory performance, such s prospective memory, retrieval and recollection. We agree that his would be extremely valuable, but are somewhat skeptical that ell attested methods exist at present (see Reichman, Fiocco, & ose, 2010 for a recent review). Training strategies, with practice t applying relevant strategies to real-life problems, appears tohold ut more promise for older adults, although again the present evience is sparse. We await with interest the results of the authors’ XACT trial. We certainly hope and expect that findings from laboratory tudies of memory can be applied successfully to training regimes or older adults. McDaniel and Bugg suggest that the principles f spacing, variation and interleaving practice with various tasks nd strategiesmay be helpful. Although they tend to lump strategy

Adjuvant capecitabine treatment for stage III colon cancer in Japanese patients (KSCC0803).

571 Background: Capecitabine was approved in Japan in 2007 for the adjuvant treatment of stage III colon cancer based on Japanese clinical trial data in advanced and recurrent colorectal and breast cancers as well as data from the Phase III X-ACT trial. For the current study, we aimed to clarify compliance and tolerability of adjuvant treatment with capecitabine in Japanese patients. The study was entered in the UMIN clinical trial registry (UMIN000001444) by the Kyushu Study Group of Clinical Cancer (KSCC). Ethical approval was granted by the institutional review board of each hospital involved. Methods: Based on completion rates from the X-ACT trial we enrolled 97 patients with R0 stage III colon cancer who had histologically confirmed disease and had undergone curative resection (3D2 lymph node dissection). Patients were given oral capecitabine therapy (2,500 mg/m2/day; days 1–14 q3w; eight cycles) within 8 weeks of surgery. The proportion of patients completing eight cycles of treatment per protocol was the primary endpoint, and adverse event (AE) rate was analyzed as a secondary endpoint. Results: Treatment completion in the total patient population was 66.0% (64/97 patients; 95% CI: 55.7–75.3%) and in the per protocol population (PPP) was 70.3% (64/91; 95% CI: 59.8–79.5%). AEs leading to treatment discontinuation included hand-foot syndrome (HFS; n=7), hematotoxicity (n=5) and increased hepatic activity (n=4). Grade 3/4 AEs of note included HFS (22.7%), neutropenia (7.2%), diarrhea (2.1%), and increased bilirubin (0.0%). Of note, any treatment delay &gt;3 weeks in the current trial was considered a withdrawal. In the X-ACT trial, delays of any duration were permitted. Using the X-ACT criteria the completion rate for the PPP in this study was 80.2%, comparable to the figure reported in X-ACT. Conclusions: Our results confirm those of previous global phase III studies and show that capecitabine is well tolerated in both global and Japanese-only populations, with similar high completion rates in both. [Table: see text]

Review of completed and ongoing trials of capecitabine-based adjuvant therapy in patients with early-stage colon cancer.

495 Background: Capecitabine is an established alternative to 5-FU in gastrointestinal cancers. In metastatic colorectal cancer, capecitabine is non-inferior to 5-FU and capecitabine + oxaliplatin (XELOX) is non-inferior to FOLFOX4. Capecitabine is also an effective adjuvant treatment for early-stage colon cancer. Here we review the evidence available from completed studies of adjuvant capecitabine and describe ongoing trials in this setting. Methods: The X-ACT trial included 1,987 patients (pts) with resected stage III disease receiving either capecitabine (n=1,004) or bolus 5-FU/LV (n=983). NO16968 included 1,886 pts with resected stage III disease receiving either XELOX (n=944) or 5-FU/LV (n=942). The primary efficacy endpoint of both trials was DFS. Other large phase III trials of capecitabine in high-risk stage II/stage III pts include AVANT (XELOX + bevacizumab vs. FOLFOX4 ± bevacizumab), QUASAR2 (capecitabine vs. capecitabine + bevacizumab), SCOT (capecitabine or 5-FU/LV + oxaliplatin 12w vs. 24w), and a Japanese study of single-agent capecitabine. Results: In X- ACT, capecitabine was at least equivalent to 5-FU/LV in terms of DFS (HR=0.88; 95% CI, 0.77–1.01) and OS (HR=0.86; 95% CI, 0.74–1.01). In a preplanned multivariate analysis, capecitabine led to significantly superior DFS (p=0.02) and OS (p=0.02) vs. bolus 5-FU/LV [Twelves et al. WCGIC 2010]. In NO16968, DFS was significantly superior for XELOX vs. 5-FU/LV (HR=0.80; 95% CI, 0.69–0.93; p=0.0045) [Haller et al. ECCO-ESMO 2009]. There was a trend towards improvement in OS with XELOX (HR=0.87; 95% CI, 0.72–1.05; p=0.1486); follow-up is ongoing. Capecitabine-based therapy had an acceptable safety profile in both trials [Twelves et al. NEJM 2005; Schmoll et al. JCO 2007]. Data have yet to be reported from the AVANT, QUASAR2, SCOT and Japanese trials, although results from these trials in over 15,000 pts are awaited with interest. Conclusions: Adjuvant capecitabine is non-inferior to 5-FU/LV when given as monotherapy and superior to 5-FU/LV when given in combination with oxaliplatin. Capecitabine should be considered as a standard component of adjuvant treatment regimens for pts with stage III disease. [Table: see text]

Cost-Effectiveness Analysis of Capecitabine Compared with Bolus 5-Fluorouracil/l-Leucovorin for the Adjuvant Treatment of Colon Cancer in Japan

A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective. Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses. In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product. This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6–8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand–foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.

1LB 5-year overall survival update from the X-ACT trial of capecitabine vs. 5-FU/LV as adjuvant treatment for stage-III colon cancer

1LB 5-year overall survival update from the X-ACT trial of capecitabine vs. 5-FU/LV as adjuvant treatment for stage-III colon cancer

Stage Iii Colon Cancer at Baylor University Medical Center at Dallas and the Baylor Sammons Cancer Center: Experience from 2000 to 2004

Colon cancer remains a major cause of cancer-related morbidity and mortality. In the USA, it is estimated that 106,680 new cases will be diagnosed and that 55,170 deaths will be attributed to the disease in 2006 (1). The stage of disease at the time of diagnosis is the single most important factor for predicting survival from the disease. In early stages, colon cancer is eminently curable, with expected 5-year survival rates of 90% or better. However, if the disease is more advanced at the time of diagnosis, the outlook is not nearly as favorable. In patients with advanced or metastatic disease at presentation, the chance of 5-year survival drops below 10% (2). Colon cancer is often asymptomatic or minimally symptomatic in the early stages of the illness, especially when the malignancy arises within the right side of the bowel. With appropriate screening, however, the disease can be discovered in the precancerous stage or in the earlier stages of cancer, when appropriate management offers an improved likelihood of cure. Unfortunately, studies have documented a low overall compliance with recommendations for colon cancer screening in the USA (3). Ongoing research continues to focus on understanding the obstacles to screening and improving compliance. At the time of diagnosis, clinical evaluations including physical examination and radiographic studies can determine if the colon cancer has spread beyond the regional tissues and lymph nodes. Seventy-five percent of patients are diagnosed before such spread, and in those patients surgical resection remains the mainstay of curative therapy. Analysis of the surgical specimen provides critical information regarding the pathologic stage of the cancer. In colon cancer, the stage is determined by the depth of invasion of the tumor through the bowel wall (T stage), the presence of local lymph node involvement (N stage), and the presence of distant spread or metastasis (M stage). Patients who have evidence of tumor in the local lymph nodes but no signs of additional spread are categorized as stage III. Recently, three additional substages (IIIa, IIIb, and IIIc) have been applied to this group of patients, reflecting the heterogeneity in prognosis seen among these patients (4). The role of postoperative or adjuvant chemotherapy has been clearly established in patients with surgically resected stage III colon cancer. Several large randomized trials have repeatedly demonstrated the benefits of this treatment, and in 1990 the National Institutes of Health Consensus Conference recommended adjuvant chemotherapy for all patients with stage III colon cancer (5). One of the first trials to unequivocally demonstrate the advantages of adjuvant chemotherapy for patients with stage III colon cancer was Intergroup Trial 0035 (6), which demonstrated a significant reduction in the rates of cancer recurrence as well as a significant improvement in the survival rates of patients who were randomly assigned to receive 1 year of postoperative 5-fluorouracil (5-FU)–based chemotherapy. Since that publication, several trials have reported similar findings (7–9). Newer chemotherapy agents have been studied in an effort to add to the convenience and efficacy of adjuvant therapy in patients with stage III colon cancer. Two such agents—capecitabine (10, 11) and oxaliplatin (12, 13)—were shown to be effective in stage IV colorectal cancer and were then tested in patients with stage III disease. Capecitabine, an orally administered prodrug that is converted to the active cytotoxic agent 5-FU, was studied as postoperative therapy in patients with stage III colon cancer in the X-ACT trial: 1987 patients were randomly assigned to receive 5-FU plus leucovorin administered intravenously for 6 months or capecitabine administered orally for 6 months. The two regimens were equivalent in their efficacy, with the toxicity profile and convenience of administration favoring the orally administered capecitabine (14). The combination of oxaliplatin with infusional 5-FU and leucovorin, a therapeutic regimen known as FOLFOX, was studied in patients with stage III colon cancer in the large MOSAIC trial. European investigators demonstrated a better cancer-free survival rate in patients treated with FOLFOX than in those treated with 5-FU plus leucovorin alone (15). Another trial from the National Surgical Adjuvant Breast and Bowel Project involved 2407 patients with stage II or III colon cancer who were randomly assigned to postoperative treatment with standard 5-FU and leucovorin alone or the same regimen of 5-FU and leucovorin plus oxaliplatin. Again, the patients in the oxaliplatin group experienced a better 3-year cancer-free survival rate than those assigned to treatment with 5-FU and leucovorin alone (78% vs 73%) (16). The findings of this trial have confirmed the additional benefits of oxaliplatin in the treatment of patients with stage III colon cancer.

Economic evaluation of adjuvant chemotherapy in Stage III (SIII) colon cancer: Capecitabine versus 5FU/LV

6046 Background: Adjuvant chemotherapy for SIII colon cancer is an accepted standard of care. Oral Capecitabine (C) has been shown to be at least equivalent and possibly superior to 5FU/LV (F) with a superior relapse free survival (RFS). This new option is associated with a higher drug cost. An economic analysis was undertaken to compare these two alternatives. Methods: A cost minimisation analysis was performed in Canadian $ ($) using C and F given as per the X-ACT (X) trial. The direct costs including chemotherapy drug acquisition, supportive medications, laboratory investigation and health resources utilisation were examined based in Nova Scotia. Indirect costs included travel and opportunity cost based on the average provincial wage and participation rates. Complete drug delivery was assumed. A direct payer perspective was used. A cost-effectiveness (CE) model was also constructed to estimate the required lower risk of cancer recurrence for C to be cost effective compared to F at a commonly used CE threshold. The Markov model developed used a hypothetical cohort of 1,000 patients with SIII colon cancer and projected costs and outcomes over 5 years (discounted 3% and in $2,005). All recurrences were modeled to death. Recurrence rates, median survival with recurrent disease, costs and utility scores were derived from the literature. Estimates of background mortality without recurrence were obtained from Canadian Life Tables. Sensitivity analysis (SA) was performed using a range of recurrence risk hazard ratios (HR) including that reported in the X trial. Results: Compared to F, C is associated with higher direct costs, principally reflecting the higher drug cost (difference: $5,589/patient) but less resources utilisation cost (difference: - $1,804/patient). The total indirect costs favour C (difference: - $2,464/patient). For C to be potentially CE compared to 5FU/LV, a ≥ 9% lower relative recurrence risk (HR = 0.91) with C would be required. At the reported RFS HR 0.86, the CE of C relative to F is $15,844 per disease free survival years gained and $22,097 per quality adjusted life years gained. Conclusions: C has more direct costs but has indirect cost savings. It has the potential to be cost effective as seen in the SA and is a CE alternative to F at the HR for RFS reported in the X trial. No significant financial relationships to disclose.

Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

Oral capecitabine (Xeloda®) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.

The X-ACT trial: lessons learned

The X-ACT trial: lessons learned

Analysis of post-study chemotherapy in patients (pts) enrolled in the X-ACT phase III trial of capecitabine (X) vs. bolus 5-FU/LV as adjuvant therapy for Dukes’ C colon cancer: No differences in treatment arms that could influence survival outcome

3586 Background: The X-ACT trial evaluated adjuvant X vs. 5-FU/LV in colon cancer. Between Nov98 and Nov01, 1987 pts with resected Dukes’ C colon carcinoma were randomized to receive either oral X ...

Capecitabine (X) is resource saving compared with i.v. bolus 5-FU/LV in adjuvant chemotherapy for Dukes' C colon cancer patients: Medical resource utilization (MRU) data from a large phase III trial (X-ACT)

3578 Background: Treatment resource use has important implications for the total costs of therapy and quality of life / clinical outcomes. Treatment convenience impacts patient satisfaction and compliance. The X-ACT trial aimed to replace intravenous (i.v.) 5-FU/LV with oral X, an effective 1st line treatment in metastatic colorectal cancer. Methods: MRU was measured in the trial, which compared 6 months of twice-daily oral X 1,250mg/m2 d1–14 every 3 weeks (n=993) with i.v. 5-FU/LV (n=974; Mayo Clinic regimen). Information was collected on visits for study drug administration, hospital use, visits to providers and medication for adverse events (AEs). Hospitalizations linked to specific AEs were designated by the investigator as being study treatment-related or not. Results: Patients on 5-FU/LV typically made 30 visits to the clinic for treatment administration, while X patients made 8 visits, one at the beginning of each cycle. Treatment-related hospitalizations were lower (91 vs 100) in the X arm but the total number of associated days hospitalized was nearly identical (961 vs 959). On average, all patients made approximately 1 additional visit to general practitioners or specialists during the treatment period. In terms of medications to treat adverse events, patients on 5-FU/LV required more days of therapy for higher cost drugs such as anti-diarrheals, analgesics, and anti-fungals; patients on X used more low-cost vitamins and emollients. Conclusions: Adjuvant chemotherapy with oral X yields substantial savings in MRU due to the avoidance of administration costs of i.v. therapy. The indirect cost savings in terms of the value of patient time are substantial. Other potential cost factors, including hospital use, ambulatory encounters, and other medications, did not differ significantly between the regimens. If this trial meets its primary endpoint of equivalence in disease-free survival, X is likely to be cost-effective from a societal perspective compared with the Mayo Clinic regimen in the adjuvant treatment of Dukes' C colon cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche Roche

Future treatment options with capecitabine in solid tumours

The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.