The Effect of Exemestane on the Lipidemic Profile of Postmenopausal Early Breast Cancer Patients: Preliminary Results of the TEAM Greek Sub-study

Summary Introduction. Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion sub-protocol to the TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal women with early breast cancer in the adjuvant setting to that of tamoxifen. Patients and methods. In this open-label, randomized, parallel group study, 176 postmenopausal patients with estrogen and/or progesterone receptor positive early breast cancer were randomized to either adjuvant exemestane (25 mg/day; n = 90) or tamoxifen (20 mg/day; n = 86). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglycerides (TRG) were performed at baseline and every 3 months for the first 12 months. Results. Serum triglyceride levels were consistently increased above baseline throughout the study in the tamoxifen arm, while there was a trend towards reduction in the exemestane arm. There was also an overall trend for tamoxifen to decrease the levels of LDL throughout the study period. Exemestane did not demonstrate any other significant change in HDL levels; however, there was a consistent trend for a reduction in total cholesterol in both treatment arms. The atherogenic risk determined by the TC:HDL ratio remained stable in both arms throughout the treatment period. Conclusions. Exemestane appears to have a neutral effect on total cholesterol and HDL levels. Unlike tamoxifen’s positive effect on LDL levels, exemestane does not significantly alter LDL levels. Tamoxifen on the other hand increases triglyceride levels, while exemestane results in a beneficial reduction in TRG levels. These data offer additional information with regard to the safety and tolerability of exemestane in postmenopausal breast cancer patients and support further investigation of its potential usefulness in the adjuvant setting.     

Extended adjuvant hormonal therapy with exemestane has no detrimental effect on the lipid profile of postmenopausal breast cancer patients: final results of the ATENA lipid substudy

Introduction

Extended adjuvant endocrine therapy for breast cancer with aromatase inhibitors may potentially alter the lipid profile of postmenopausal patients and thus increase the risk of developing cardiovascular disease. In this study, a subprotocol of the ATENA (Adjuvant post-Tamoxifen Exemestane versus Nothing Applied) trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal patients with operable breast cancer, in the adjuvant setting, with that of observation alone after completion of 5 to 7 years of primary treatment with tamoxifen.

Methods

In this open-label, randomized, parallel-group study, 411 postmenopausal patients with operable breast cancer, who had been treated with tamoxifen for 5 to 7 years, were randomized to either 5 additional years of exemestane (25 mg/day; n = 211) or observation only (n = 200). Assessments of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total serum triglycerides (TRG) were performed at baseline and then during each follow-up visit, performed at either 6 or 12 months, according to the center's clinical practice, until completing 24 months in the study.

Results

TC and LDL levels increased significantly across time for both arms; TC increase was more pronounced for the observation arm, and that was sustained up to 24 months. HDL levels decreased significantly across time for the exemestane arm, whereas no significant change was detected across time for the observation arm. Triglyceride levels decreased significantly across time on both arms, with no difference detected in changes from baseline between the exemestane and the observation arms.

Conclusions

Exemestane lacks the beneficial effect of tamoxifen on lipids; however, sequential adjuvant treatment with exemestane in postmenopausal breast cancer patients after cessation of 5 to 7 years of tamoxifen does not appear to alter the lipid profile significantly compared with that of an observational arm.

Trial Registration

ClinicalTrials.gov ID: NCT00810706.     

The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, 'Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.     

Lipid concentrations in postmenopausal women on letrozole after 5?years of tamoxifen: an NCIC CTG MA.17 sub-study

To evaluate changes in serum lipid parameters (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]), in postmenopausal women receiving letrozole after tamoxifen therapy. MA.17L is a sub-study of MA.17, a double-blind, placebo-controlled trial of extended adjuvant letrozole. Eligible postmenopausal women were non-hyperlipidemic and not on lipid-lowering drugs. This analysis considers the 183 patients on the letrozole arm. Lipid parameters evaluated at baseline, 6?months, 12?months, and yearly thereafter until completion of 5?years of letrozole. The median duration of letrozole treatment was 5.0?years with a range from 0.03 to 6.05?years. After 5?year tamoxifen, patients on letrozole experienced significant increases from baseline in total cholesterol, LDL cholesterol, and Lp(a) at all study time points but no statistically significant changes in triglycerides. Specifically, a statistically significant increase was found at 60?months in total cholesterol [mean percentage change from baseline (PC) 5.27; p?=?0.003], HDL cholesterol (mean PC 6.75; p?=?0.003), LDL cholesterol (mean PC 10.02; p?=?0.001), Lp(a) (mean PC 105.95; p?<?0.0001). 103 (56?%) women in the study had clinically significantly elevated levels of Lp(a) (106?% above baseline) after 5?years of therapy. The results were similar after excluding the 21?% of patients who had ever received anti-lipid treatment. Significant increases in total cholesterol, HDL cholesterol, LDL cholesterol, and, most notably, Lp(a) in postmenopausal women were observed following 5?years of adjuvant letrozole treatment and after 5?years of tamoxifen therapy and such patients should have monitoring of their lipid levels in clinical practice.     

The effect of exemestane,anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study

BackgroundIn this Tamoxifen Exemestane Adjuvant Multinational Japan sub-study, we evaluated the time course of changes in serum lipids in postmenopausal women with hormone-sensitive early breast cancer treated with exemestane, anastrozole, or tamoxifen for postoperative adjuvant therapy.Patients and methodsA total of 154 breast cancer patients were assigned to receive exemestane, anastrozole, or tamoxifen in this randomized open-label study. Serum lipid parameters including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during 1 year of treatment.ResultsTC and LDL-C rapidly decreased in patients treated with tamoxifen at 3 months. Compared with anastrozole and exemestane patients, TC and LDL-C were significantly lower at all assessment time points in tamoxifen patients (P < 0.05). TG increased in tamoxifen patients; it was significantly higher compared with exemestane patients at all assessment time points (P < 0.05). HDL-C slightly decreased in exemestane patients; it was significantly lower compared with anastrozole patients at 3 months and 1 year (P = 0.0179 and 0.0013, respectively).ConclusionChanges of lipid profiles in Japanese postmenopausal women treated with tamoxifen were relatively favorable, while exemestane and anastrozole had no clinically significant effect on the serum lipids.     

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.     

Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids

Recent studies have shown that administering the aromatase inhibitor exemestane after 2-3 years of tamoxifen therapy significantly improves disease-free survival in postmenopausal women with primary breast cancer in comparison with standard 5-year tamoxifen treatment. Although many of the adverse effects associated with exemestane and tamoxifen have been analysed, there are no comparative data concerning body weight and body composition. The aim of this randomised study was to evaluate the longitudinal changes in body composition and lipid profiles in postmenopausal women switched from tamoxifen to exemestane. In total, 60 overweight or obese postmenopausal patients were enrolled. Their anthropometric data, body composition, including fat mass (FM) and fat-free mass (FFM), and lipid profiles, caloric intake and physical activity were assessed 1 week before randomisation, and 6 and 12 months later. In all, 55 patients (27 on tamoxifen and 28 on exemestane) completed the 1-year study period. Fat mass had significantly decreased by month 12 in the exemestane, but not in the tamoxifen group; the between-group difference was statistically significant (P<0.01). The FFM/FM ratio had significantly increased in the exemestane group, but not the tamoxifen group; the between-group difference was statistically significant (P<0.05). Triglycerides and high-density lipoprotein cholesterol significantly decreased (P<0.01; P<0.05), and low-density lipoprotein cholesterol significantly increased (P<0.01) in the exemestane group at the end of the 1-year study period. Our findings suggest that switching patients to adjuvant exemestane treatment after at least 2 years of tamoxifen therapy may be associated with an advantage over continuing adjuvant tamoxifen treatment in terms of body composition.     

Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)—a randomised controlled trial of exemestane versus continued tamoxifen after 2–3 years tamoxifen

BackgroundThe antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen.Patients and methodsSonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2–3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (≥5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation.ResultsThe analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67).ConclusionSwitching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.     

Endocrine effects of tamoxifen plus exemestane in postmenopausal women with breast cancer.

PURPOSE: In some specific circumstances, combined hormonal therapies for breast cancer seem to be more effective than single maneuvers. In two laboratory mammary cancer models, the combination of the aromatase inactivator exemestane plus tamoxifen gives a higher response rate than is found with either agent alone.To evaluate the endocrine effects of the combination of exemestane and tamoxifen, we studied 33 postmenopausal women disease-free following primary treatments for breast cancer who were taking tamoxifen for at least 3 months. DESIGN: After observation for symptoms on tamoxifen for 4 weeks, blood samples were taken and patients were begun additionally on exemestane 25 mg p.o. qd. Eight weeks later, blood samples were again taken, and exemestane was discontinued. RESULTS: A decrease in alkaline phosphatase was found with exemestane treatment (P = 0.06), whereas no change in osteocalcin level was observed. A decrease in high-density lipoprotein cholesterol level was found (P = 0.0025), whereas total cholesterol, low-density lipoprotein cholesterol and triglyceride levels showed no changes with exemestane treatment. Estradiol, estrone, and estrone sulfate levels decreased to immeasurable or very low levels with exemestane treatment (all P < 0.001). No significant changes in frequencies of common drug-associated side effects, such as vasomotor symptoms or weight change, were found. CONCLUSIONS: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted.     

Salubrious effect of vitamin C and vitamin E on tamoxifen-treated women in breast cancer with reference to plasma lipid and lipoprotein levels

Tamoxifen, a non-steroidal antiestrogen, has been used in the hormonal treatment for breast cancer. The hepatic estrogenic effect of tamoxifen causes severe triglyceridemia. The combined effect of tamoxifen, vitamin C and vitamin E on plasma lipid and lipoprotein is important, since, vitamin C and vitamin E encumbered the lipid abnormalities instigated by tamoxifen. Therefore supplementation of vitamin C (Celin 500 mg) and vitamin E (Evion 400 mg) for 90 days along with tamoxifen (10 mg twice a day) to postmenopausal breast cancer patients was ventured. In tamoxifen-treated patients, total cholesterol (TC), free cholesterol (FC), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol (LDL) levels were decreased and the triglycerides (TG), ester cholesterol (EC), high density lipoprotein cholesterol (HDL) and very low density lipoprotein cholesterol (VLDL) levels were increased. Combination therapy reduce all the cholesterol level and VLDL, LDL. TG levels were significantly decreased and HDL, EC levels were significantly increased. These results suggested that tamoxifen treatment is the most effective during co-administration of vitamin C and vitamin E in that they reduce the tamoxifen-induced hypertriglyceridemia.     

Are the effects of tamoxifen on the serum lipid profile modified by apolipoprotein E phenotypes?

BACKGROUND: Tamoxifen has favorable effects on the serum lipid profile. It has been suggested that the apolipoprotein (Apo) E phenotype can influence serum lipid parameters; the ApoE allele 4 (ApoE4) is associated with higher total and low-density lipoprotein (LDL) cholesterol levels. The ApoE phenotype also affects lipid responses to diets or treatment with statins. However, the effect of tamoxifen on the lipid profile in different ApoE phenotypes is unknown. PATIENTS AND METHODS: In the present study, we evaluated the effects of tamoxifen on the serum lipid profile in 11 ApoE4-positive postmenopausal women with breast cancer (phenotypes 3/4 and 4/4) compared with 33 ApoE4-negative women (phenotypes 3/2 and 3/3). Serum lipid parameters [high-density (HDL), LDL and total cholesterol, triglycerides, ApoAI, ApoB and lipoprotein (a)] were measured after an overnight fast before treatment and after 3 and 12 months. ApoE isoforms were determined by isoelectric focusing of delipidated very-low-density lipoproteins (VLDL). RESULTS: During the follow-up period, serum levels of total and LDL cholesterol and ApoB decreased significantly in both groups, but no significant differences were found. Concentrations of serum HDL cholesterol were not significantly different between both groups. However, serum ApoAI levels increased significantly in ApoE4-negative subjects (p = 0.00005), but no significant changes in ApoE4-positive women were observed. Serum triglyceride levels increased by 23.2% (p < 0.05) in ApoE4-positive patients, but they did not change significantly in ApoE4-negative patients. The LDL/HDL cholesterol ratio decreased similarly in the two groups, but the ApoAI/ApoB ratio, which may be a better predictor of cardiovascular events, significantly changed in the ApoE4-negative subjects. Finally, the median level of Lp(a) decreased by 43.4% in the ApoE4-negative patients, whereas it did not change significantly in the ApoE4-positive group. CONCLUSION: In postmenopausal Greek women with breast cancer, the levels of Lp(a) and triglycerides and the ApoAI/ApoB ratio respond more favorably to tamoxifen treatment in ApoE4-negative than in ApoE4-positive patients.     

Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.     

Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer

Background: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin(LV) are standard first-line treatments for patients with metastaticcolorectal cancer (mCRC). The aim of this multicentre, open-label,phase IIIb study was to assess the addition of oxaliplatin totwo different 5-FU regimens. Patients and methods: Patients with previously untreated mCRCwere randomised to arm A [two-weekly oxaliplatin 85 mg/m² +either continuous intravenous infusion (CIV) of 5-FU withoutLV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B(5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was plannedon progression. Results: A total of 725 patients were enrolled. After a fixedfollow-up of 2 years for each patient, 2-year survival rateswere 27.3% and 24.8% in arms A and B, respectively (hazard ratio0.93; 95% confidence interval 0.78–1.10). The additionof oxaliplatin significantly improved response rates (54.1 versus29.8%; P < 0.0001) and median progression-free survival (7.9versus 5.9 months; P < 0.0001). The most common grade 3–4toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea(arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%). Conclusions: Despite improved rates of tumour control, theseresults failed to demonstrate a survival benefit from the additionof oxaliplatin to infused 5-FU and lend further support to theuse of sequential monotherapy in some patients with mCRC. Key words: colorectal cancer, 5-fluorouracil, leucovorin, metastatic, oxaliplatin, phase III Received for publication May 12, 2008. Revision received July 16, 2008. Accepted for publication August 22, 2008.     

Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer

Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15–20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40mg toremifene or 20mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40mg toremifene and 20mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.     

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17

Background: MA.17 evaluated letrozole or placebo after 5 yearsof tamoxifen and showed significant improvement in disease-freesurvival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008].The trial was unblinded and placebo patients were offered letrozole. Patients and methods: An intent-to-treat analysis of all outcomes,before and after unblinding, on the basis of the original randomizationwas carried out. Results: In all, 5187 patients were randomly allocated to thestudy at baseline and, at unblinding, 1579 (66%) of 2383 placebopatients accepted letrozole. At median follow-up of 64 months(range 16–95), 399 recurrences or contralateral breastcancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-yearDFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95%confidence interval (CI) 0.55–0.83, P = 0.0001] and showedsuperiority for letrozole in both node-positive and -negativepatients. Corresponding 4-year distant DFS was 96.3% and 94.9%(HR 0.80, 95% CI 0.62–1.03, P = 0.082). Four-year overallsurvival was 95.1% for both groups. The annual rate of CLBCwas 0.28% for letrozole and 0.46% for placebo patients (HR 0.61,95% CI 0.39–0.97, P = 0.033). Conclusions: Patients originally randomly assigned to receiveletrozole within 3 months of stopping tamoxifen did better thanplacebo patients in DFS and CLBC, despite 66% of placebo patientstaking letrozole after unblinding. Key words: extended adjuvant therapy, intent-to-treat, letrozole Received for publication September 19, 2007. Revision received November 20, 2007. Accepted for publication November 22, 2007.     

Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study

Background: Irinotecan plus infusional 5-fluorouracil/leucovorin(FOLFIRI) is accepted as a reference treatment for the first-linetreatment of patients with metastatic colorectal cancer (MCRC).The aim of this study was to demonstrate that a regimen withoutleucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI(response rate). Patients and methods: Chemotherapy-naive patients with MCRCwere randomized to receive either irinotecan (180 mg/m² on day1) + 5-fluorouracil (5-FU) (400 mg/m² bolus and 600 mg/m² 22-hinfusion) + LV (200 mg/m² on days 1–2) (FOLFIRI) every2 weeks or irinotecan (80 mg/m²) + 5-FU (2.250 mg/m² 48-h infusion)(FUIRI) weekly. Results: In all, 346 patients were included, 173 in each arm.In the intention-to-treat analysis, the response rates for FOLFIRIand FUIRI were 57% [95% confidence interval (CI) 49% to 64%]and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statisticallysignificant differences were observed between FOLFIRI and FUIRIregarding median progression-free survival (8.3 versus 8.4 months;P = 0.4339) nor median overall survival (21.6 versus 19.2 months;log-rank test P = 0.2941). Grade 3/4 neutropenia was significantlymore frequent on FOLFIRI arm (27% versus 9%), while the proportionof diarrhea was higher on FUIRI arm (21% versus 42%). Conclusion: FUIRI represents a valid alternative without LVto the FOLFIRI regimen as MCRC first-line treatment. Key words: colorectal cancer, 5-fluorouracil, irinotecan Received for publication May 7, 2008. Revision received July 11, 2008. Accepted for publication July 14, 2008.     

Tamoxifen treatment reverses the adverse effects of chemotherapy-induced ovarian failure on serum lipids

In all, 146 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, 5-year tamoxifen treatment was started after chemotherapy to those 112 patients with hormone-receptor-positive tumours while those with hormone-receptor-negative tumours received no further therapy. The serum lipid levels were followed in both groups. The levels of serum total and low-density lipoprotein (LDL) cholesterol increased significantly after chemotherapy only in patients who developed ovarian dysfunction. Total cholesterol increased +9.5% and LDL cholesterol +16.6% in patients who developed amenorrhoea (P<0.00001 and 0.00001, respectively). The cholesterol levels did not change in patients who preserved regular menstruation after chemotherapy. After 6 months of tamoxifen therapy, the total cholesterol decreased -9.7% and the LDL cholesterol -16.7% from levels after the chemotherapy, while the cholesterol concentrations remained at increased levels in the control group (P=0.001 and P<0.0001, respectively). The high-density lipoprotein cholesterol levels did not change significantly in either tamoxifen or control group. The effects of tamoxifen treatment on serum lipids after chemotherapy have not been studied before. Our current study suggests that adjuvant tamoxifen therapy reverses the adverse effects of chemotherapy-induced ovarian failure on total and LDL cholesterol and even lowers their serum levels below the baseline.     

Effect of letrozole on plasma lipids, triglycerides, and estradiol in postmenopausal women with metastatic breast cancer

Purpose.

The aromatase inhibitor letrozole effectively treats breast cancer by decreasing estrogen levels in postmenopausal women. The aim of this prospective study was to evaluate the effect of letrozole on plasma lipids, triglyceride lipase (TGL), and estradiol levels in women with metastatic breast cancer (MBC).

Materials and Methods.

Fifty-two postmenopausal women with MBC received letrozole, 2.5 mg/day. Blood samples for assessment of plasma levels of total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, TGL, and estradiol were taken at baseline and after 3, 6, and 12 months of treatment.

Results.

A nonsignificant increase was found in TC and HDL cholesterol levels after 3 months, which returned to baseline levels after 6 months (p = .794 and p = .444, respectively). LDL cholesterol increased nonsignificantly after 6 months and returned to baseline thereafter (p = .886). The mean estradiol level was suppressed from 44 pmol/l before treatment to <18 pmol/l after 6 months (p = .014). No difference was found in the estradiol suppression rate whether baseline levels were >40 or <40 pmol/l.

Conclusion.

Letrozole has a safe effect on the lipid and TGL profiles of postmenopausal women with MBC. Estradiol levels were maximally suppressed within 6 months of treatment. The increased levels of TC during treatment were reversible and returned to normal levels after 3 months.     

Adjuvant tamoxifen in primary breast cancer: Influence on plasma lipids and antithrombin III levels

The possible estrogenic effects of tamoxifen on plasma lipids and antithrombin III levels were investigated in 91 breast cancer patients. Mean values of total, HDL and LDL cholesterol, triglycerides, glucose, uric acid, and antithrombin III were evaluated in 55 patients on adjuvant tamoxifen for at least 3 months and compared with those found in 36 patients on no therapy. Total cholesterol, LDL cholesterol, and antithrombin III levels were significantly lower in treated patients (p<0.05).Our results support the hypothesis of a partial agonist action of this antiestrogen, although general clinical practice suggests that tamoxifen-related thrombotic events are rare.     

Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers

Background: Clinical trials frequently report acute myeloidleukemia (AML) as a complication of adjuvant chemotherapy forbreast cancer (BC). Patients and methods: This retrospective population-based studyinvestigated AML risk after a prior BC diagnosis and comparedthe results with women after a prior diagnosis of hematologicalmalignancies (HM), other cancers combined (OCC), and the age-matchedAustralian female population. Results: Women with a prior BC diagnosis had 2.56 times therisk of developing AML compared with the Australian female population(P < 0.001). AML risk was also elevated after prior HM andOCC diagnoses (4.73, P < 0.001, and 1.70, P < 0.001, respectively).Although the incidence of AML rose sharply with age in all cohorts,the age-specific relative risk was highest in the 30- to 49-age-groupand decreased with increasing age. AML risk increased with theduration of follow-up but there was no change of risk duringthe 23 years of this study. Conclusion: AML risk was elevated after a prior diagnosis ofBC but there was no evidence of an increasing risk of AML aftera BC diagnosis or, in any of the other cancer cohorts, duringthis era of expansion of the evidence base for more intensivetreatments. Key words: acute myeloid leukemia, all cancers, breast cancer, epidemiology, hematological malignancies Received for publication June 18, 2008. Accepted for publication June 23, 2008.