Determining clinically important differences in health-related quality of life in older patients with cancer undergoing chemotherapy or surgery.

PURPOSE: Using the EORTC Global Health Status (GHS) scale, we aimed to determine minimal clinically important differences (MCID) in health-related quality of life (HRQOL) changes for older cancer patients with a geriatric risk profile, as defined by the geriatric 8 (G8) health screening tool, undergoing treatment. Simultaneously, we assessed baseline patient characteristics prognostic for HRQOL changes. METHODS: Our analysis included 1424 (G8 ≤ 14) older patients with cancer scheduled to receive chemotherapy (n = 683) or surgery (n = 741). Anchor-based methods, linking the GHS score to clinical indicators, were used to determine MCID between baseline and follow-up at 3 months. A threshold of 0.2 standard deviation (SD) was used to exclude MCID estimates too small for interpretation. Logistic regressions analysed baseline patient characteristics prognostic for HRQOL changes. RESULTS: The 15-item Geriatric Depression Scale (GDS15), Visual Analogue Scale (VAS) for Fatigue and ECOG Performance Status (PS) were selected as clinical anchors. In the surgery group, MCID estimates for improvement and deterioration were ECOG PS (5*, 11*), GDS15 (5*, 2) and VAS Fatigue (3, 9*). In the chemotherapy group, MCID estimates for improvement and deterioration were ECOG PS (8*, 7*), GDS15 (5, 4) and VAS Fatigue (5, 5*). Estimates with * were > 0.2 SD threshold. Patients experiencing pain or malnutrition (surgery group) or fatigue (chemotherapy group) at baseline showed a significantly stable or improved HRQOL (p < 0.05) after their treatment. CONCLUSION: The reported MCID for improvement and deterioration depended on the anchor used and treatment received. The estimates can be used to evaluate significant changes in HRQOL and to determine sample sizes in clinical trials.

Adherence to geriatric assessment-based recommendations in older patients with cancer: a multicenter prospective cohort study in Belgium.

Background: In the general older population, geriatric assessment (GA)-guided treatment plans can improve overall survival, quality of life and functional status (FS). In GA-related research in geriatric oncology, studies mainly focused on geriatric screening and GA but not on geriatric recommendations, interventions and follow-up. The aim of this study was to investigate the adherence to geriatric recommendations and subsequent actions undertaken in older patients with cancer. Patient and methods: A prospective Belgian multicenter (N = 22) cohort study included patients ≥70 years with a malignant tumor upon oncologic treatment decision. Patients with an abnormal result on the geriatric screening (G8 ≤14/17) underwent GA. Geriatric recommendations were formulated based on GA results. At follow-up the adherence to geriatric recommendations was documented including a description of actions undertaken. Results: From November 2012 till February 2015, G8 screening was carried out in 8451 patients, of which 5838 patients had an abnormal result. Geriatric recommendations data were available for 5631 patients. Geriatric recommendations were made for 4459 patients. Geriatric interventions data were available for 4167 patients. A total of 12 384 geriatric recommendations were made. At least one different geriatric recommendation was implemented in 2874 patients. A dietician, social worker and geriatrician intervened most frequently for problems detected on the nutritional, social and functional domain. A total of 7569 actions were undertaken for a total of 5725 geriatric interventions, most frequently nutritional support and supplements, extended home care and psychological support. Conclusions: This large-scale Belgian study focuses on the adherence to geriatric recommendations and subsequent actions undertaken and contributes to the optimal management of older patients with cancer. We identified the domains for which geriatric recommendations are most frequently made and adhered to, and which referrals to other health care workers and facilities are frequently applied in the multidisciplinary approach of older patients with cancer.

Postoperative complications in individuals aged 70 and over undergoing elective surgery for colorectal cancer.

AIM: This study aims to describe the nature, incidence, severity and outcomes of in-hospital postoperative complications (POCs) in older patients undergoing elective surgery for colorectal cancer. METHOD: Patients ≥ 70 years old were identified from a prospectively collected database (2009-2015) focusing on the implementation of geriatric screening and assessment in patients with cancer. Medical and surgical POCs were retrieved retrospectively from the medical records, and the severity of the POCs was graded by the Clavien-Dindo (CD) grading system. The following outcomes were analysed comparing patients with and without CD ≥ 2 and CD ≥ 3 POCs: length of stay (LOS), transfer to the intensive care unit, 30-day readmission rates, 30-day and 1-year mortality. RESULTS: In the 190 patients included, medical POCs (40.5%) were more frequent than surgical POCs (17.9%), and 37.9% experienced CD ≥ 2 POCs. The most common medical POCs were infections (26.8%), transient confusion or altered mental function (12.1%), cardiac arrhythmia (4.7%), and ileus/gastroparesis/prolonged recovery of transit (4.7%). The most common surgical POCs were surgical site infections (12.1%), wound dehiscence/bleeding (4.7%), anastomotic leak (3.7%) and surgical site bleeding (3.7%). The reoperation rate was 7.9%. CD ≥ 2 POCs led to 11 intensive care unit admissions and increased median postoperative LOS by 114% (P < 0.0001 for both), but did not significantly alter 30-day readmission and 30-day and 1-year mortality rates. CD ≥ 3 POCs increased LOS by 162% (P < 0.0001) and showed an increased 1-year mortality (P = 0.07). CONCLUSION: This study shows that in-hospital medical and surgical complications after surgery for colorectal cancer in patients ≥ 70 years old are frequent and that complications lead to less favourable outcomes.

Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer.

PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

A Belgian Survey on Geriatric Assessment in Oncology Focusing on Large-Scale Implementation and Related Barriers and Facilitators.

OBJECTIVES: The aim of this study is to describe a large-scale, Belgian implementation project about geriatric assessment (=GA) in daily oncology practice and to identify barriers and facilitators for implementing GA in this setting. Design / setting / participants: The principal investigator of every participating hospital (n=22) was invited to complete a newly developed questionnaire with closed- and open-ended questions. The closed-ended questions surveyed how GA was implemented. The open-ended questions identified barriers and facilitators for the implementation of GA in daily oncology practice. Descriptive statistics and conventional content analysis were performed as appropriate. RESULTS: Qualifying criteria (e.g. disease status and cancer type) for GA varied substantially between hospitals. Thirteen hospitals (59.1%) succeeded to screen more than half of eligible patients. Most hospitals reported that GA data and follow-up data had been collected in almost all screened patients. Implementing geriatric recommendations and formulating new geriatric recommendations at the time of follow-up are important opportunities for improvement. The majority of identified barriers were organizational, with high workload, lack of time or financial/staffing problems as most cited. The most cited facilitators were all related to collaboration. CONCLUSION: Interventions to improve the implementation of GA in older patients with cancer need to address a wide range of factors, with organization and collaboration as key elements. All stakeholders, seeking to improve the implementation of GA in older patients with cancer, should consider and address the identified barriers and facilitators.

Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study.

BACKGROUND: To evaluate the large-scale feasibility and usefulness of geriatric screening and assessment in clinical oncology practice by assessing the impact on the detection of unknown geriatric problems, geriatric interventions and treatment decisions. PATIENTS AND METHODS: Eligible patients who had a malignant tumour were ≥70 years old and treatment decision had to be made. Patients were screened using G8; if abnormal (score ≤14/17) followed by Comprehensive Geriatric Assessment (CGA). The assessment results were communicated to the treating physician using a predefined questionnaire to assess the topics mentioned above. RESULTS: One thousand nine hundred and sixty-seven patients were included in 10 hospitals. Of these patients, 70.7% had an abnormal G8 score warranting a CGA. Physicians were aware of the assessment results at the time of treatment decision in two-thirds of the patients (n = 1115; 61.3%). The assessment detected unknown geriatric problems in 51.2% of patients. When the physician was aware of the assessment results at the time of decision making, geriatric interventions were planned in 286 patients (25.7%) and the treatment decision was influenced in 282 patients (25.3%). CONCLUSION: Geriatric screening and assessment in older patients with cancer is feasible at large scale and has a significant impact on the detection of unknown geriatric problems, leading to geriatric interventions and adapted treatment.

A double-blind randomized phase II study on the efficacy of topical eye treatment in the prevention of docetaxel-induced dacryostenosis.

BACKGROUND: Dacryostenosis is a common side-effect of weekly docetaxel (Taxotere). We investigate the efficacy of eyedrops containing corticosteroids (CS) versus artificial tears (AT) in patients receiving weekly docetaxel in the prevention of dacryostenosis. PATIENTS AND METHODS: Twenty patients receiving weekly docetaxel were evaluated. Forty eyes were double-blind randomized: AT in one eye and CS in the other eye were administered, six times daily, throughout the docetaxel administration. Patients were assessed for tearing and stenosis at weeks 3, 6, 9 and 26. The primary end point was the incidence of dacryostenosis in each group at 9 weeks. RESULTS: At 9 weeks, punctal or canalicular stenosis was observed in 9 of 20 (45%) of the CS eyes and 9 of 20 (45%) of the AT eyes. Dacryostenosis was mild in 37 of 40 eyes (93%) and severe in 3 of 40 eyes (8%), with equal distribution in the CS and AT group. Tearing was present in 9 of 20 (45%) of the CS eyes and 8 of 20 (40%) of the AT eyes, of which two eyes without stenosis in each group. CONCLUSIONS: The incidence of dacryostenosis in patients receiving weekly docetaxel was not different for the AT- and the CS-treated eyes. The dacryostenosis was predominantly mild, not leading to surgical interventions.

Clinicopathological features of inflammatory versus noninflammatory locally advanced nonmetastatic breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. It is mainly a clinical diagnosis. The aim of this study was to compare IBC to clinically diagnosed noninflammatory locally advanced nonmetastatic breast cancer, also called cLABC. MATERIAL AND METHODS: One hundred and eight patients were studied: 49 with IBC and 59 with cLABC. The following features were analyzed: age at diagnosis, body mass index (BMI), axillary lymph node status (cN), estrogen receptor status (ER), progesterone receptor status (PR), HER2 status, histological tumor grade and subtype. Short-term disease-free (DFS) and overall survival (OS) were also assessed in both groups. RESULTS: Compared with cLABC, IBC was less often PR positive (41.7 vs. 66.1%, p = 0.01) and showed a trend to be more often HER2 positive (34.7 vs. 19.3%, p = 0.07). The 3-year DFS was 63 and 77%, respectively, for IBC and cLABC (p = 0.01); these figures were 83 and 85% for OS (p = 0.17). No significant differences in age at diagnosis, ER, cN, BMI, histological tumor grade or subtype were demonstrated. CONCLUSION: Compared to cLABC, IBC are more frequently PR negative, have a worse DFS, and have a tendency to be more often HER2 positive. These data reinforce the idea of IBC being a distinct biological entity compared to noninflammatory breast cancer.

Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.

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.

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.

BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.

BACKGROUND: Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce. PATIENTS AND METHODS: This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer. RESULTS: At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05). CONCLUSIONS: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.

HER-2 and topo-isomerase IIalpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide.

BACKGROUND: The predictive role of HER-2 in node-positive breast cancer patients receiving CMF or an anthracycline-based adjuvant therapy remains unclear. In addition, topo-isomerase II alpha (topo IIalpha), as the cellular target of anthracyclines, might have value as a predictive marker. PATIENTS AND METHODS: Four hundred eighty-one archival primary tumor samples were collected among 777 patients entered into a multicenter phase III trial comparing classical CMF with epirubicin cyclophosphamide (HEC) as adjuvant therapy of node-positive breast cancer. HER-2 was evaluated by immunohistochemistry (IHC) using different antibodies (Abs). Topo IIalpha was evaluated by IHC using the Ab KiS 1. In each subgroup of patients identified by HER-2 and topo IIalpha, adjusted hazard ratios for event-free survival (EFS) and the corresponding 95% confidence intervals have been calculated for the different study comparisons. An interaction test has been performed to investigate the role of HER-2 and topo IIalpha as predictive markers. RESULTS: When HER-2 was evaluated by CB-11 and 4D5 mAbs, the EFS adjusted hazard ratios (HR) for the main study comparison HEC vs. CMF were: HER-2 positive: 0.33 (95% confidence interval (95% CI): 0.09 1.27, P = 0.08), HER-2 negative: 1.16 (95%, CI: 0.71-1.90, P = 0.56); the P-value for the interaction test was 0.10. When HER-2 was evaluated by TAB-250 + pAbl Abs, the adjusted HR for the same comparison were: HER-2 positive: 1.06 (95% CI: 0.45-2.52, P = 0.90), HER-2 negative: 0.99 (95% CI: 0.58-1.68, P = 0.97); the P-value for the interaction test was 0.84. With regard to topo IIalpha, the adjusted HR for the EFS comparison HEC vs. CMF were: topo IIalpha positive: 0.66 (95% CI: 0.32-1.36, P = 0.25), topo IIalpha negative: 1.26 (95% CI: 0.63-2.50, P = 0.51); the P-value for the interaction test was 0.13. CONCLUSIONS: This study suggests that in node-positive breast cancer patients randomly treated with CMF or an epirubicin-based regimen, the predictive value of HER-2 may vary according to the Abs used in the immunohistochemistry assay. In addition, the study supports the concept that topo IIalpha might be involved in the determination of tumor responsiveness to an anthracycline-based adjuvant therapy.

Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial.

The authors updated their report on a randomized trial initiated in 1982 comparing, in early breast cancer, high-dose IM Medroxyprogesterone acetate (HD-MPA) adjuvant hormonotherapy during 6 months with no hormonotherapy; node-positive patients also received 6 courses of IV CMF (day 1, day 8; q.4 weeks). 246 node-negative (NN) and 270 node-positive (NP) patients had been followed for a median duration of 13 years. Previous results were confirmed in this analysis on mature data. In NN patients, relapse-free survival (RFS) was improved in the adjuvant hormonotherapy arm, regardless of age while overall survival (OAS) was also increased in younger (less then 50 years) patients. In the whole group of NP patients, no difference was seen regarding RFS or OAS. However, an age-dependant opposite effect was observed: younger patients (< 50) experienced a worse and significant outcome of relapse-free and overall survivals when receiving adjuvant HD-MPA while older patients (> or = 50) enjoyed a significant improvement of their relapse-free survival. For both NN and NP patients, differences in overall survivals observed in older women with a shorter follow-up, were no longer detected.

Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.

PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.

High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment.

This phase II, multicentre, open-label, clinical trial evaluated antitumoral efficacy, tolerability and endocrine effects following 25 mg of treatment with oral exemestane given daily to postmenopausal women with metastatic breast cancer. Eligibility criteria included oestrogen and/or progesterone positivity or a prior response to hormonal therapy if receptor status was unknown; prior failure to tamoxifen therapy; and progressive disease. Patients were divided into three strata: patients who did not respond to tamoxifen or progressed after disease stabilisation (SD) for less than 6 months (stratum 1); patients who, after an initial response or SD lasting at least 6 months, experienced disease progression whilst on tamoxifen (stratum 2); patients with recurrent metastatic disease during or within 12 months of discontinuing adjuvant tamoxifen (stratum 3). Of the 137 patients who received exemestane, 4 experienced a complete response (CR) and 28 a partial response (PR), for an overall response rate of 23%. Another 33 patients had SD for > or = 24 weeks, resulting in an overall success rate of 47%. The median time to objective response was 16.1 weeks (95% confidence interval (CI) 9.9-24.1). The median response duration was 69.4 weeks, the median duration of overall success 59.1 weeks, the median time to progression (TTP) 25.1 weeks and the median time to treatment failure (TTF) 24 weeks. Response to previous hormonal therapy had little effect on the results, except that there was a trend toward a higher overall success rate in patients who did not respond to previous hormonal therapy. After 8 weeks of therapy, serum levels of oestradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were suppressed to 15.2%, 9.7% and 10.7% of baseline, respectively. The most common adverse events of drug-related or indeterminate cause were hot flushes (14%), dizziness (9%), nausea (8%) and increased sweating (5%). Exemestane had a favourable effect on performance status and tumour-related signs and symptoms, both of which improved or stabilised in approximately 67% and 68% of patients respectively. Exemestane is a unique therapy that is highly active and well tolerated as a new treatment for women with metastatic breast cancer.

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control.

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion.

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.

Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study.

Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.

Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial.

PURPOSE: We compared prospectively the antitumor efficacy of two combination chemotherapy regimens with two different dose levels of epirubicin as first-line treatment for advanced breast cancer. PATIENTS AND METHODS: One hundred forty-one fully assessable patients were randomized to receive either our intensified schedule (group A, n = 71) of epirubicin 50 mg/m2 on days 1 and 8 (every 3 weeks), or a non-intensified program (group B, n = 70) in which epirubicin was only administered on day 1. Both groups also received fluorouracil (5 FU) and cyclophosphamide 500 mg/m2 on day 1 of each course. RESULTS: A statistically significant difference in response rate was observed (69% in group A v 41% in group B, P < .001) for both locally advanced (LA) and recurrent metastatic (RM) disease. Response duration (22 v 14 months, P < .01) and time to progression (TTP; 19 v 8 months, P < .02) were also significantly improved. Overall survival was similar in both groups. However, univariate and/or multivariate analyses showed a meaningful relationship between type of treatment allocated, dose-intensity (DI) of epirubicin, and response rate, as well as between TTP and survival. Ultimately, TTP and survival were also influenced by further treatment modalities, namely, hormonotherapy and chemotherapy. CONCLUSION: This study validates prospectively the concept of a dose-response relationship for an anthracycline-based chemotherapy in previously untreated advanced breast cancer.