Adjuvant chemotherapy followed by goserelin compared with either modality alone: the impact on amenorrhea, hot flashes, and quality of life in premenopausal patients--the International Breast Cancer Study Group Trial VIII

The purpose of this article is to compare quality of life (QOL) and menopausal symptoms among premenopausal patients with lymph node-negative breast cancer receiving chemotherapy, goserelin, or their sequential combination, and to investigate differential effects by age.

Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93

PURPOSE: The value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer has not been adequately assessed. PATIENTS AND METHODS: Between 1993 and 1999, International Breast Cancer Study Group Trial 13-93 enrolled 1,246 assessable premenopausal women with axillary node-positive, operable breast cancer. All patients received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for four courses followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil for three courses), which was followed by either tamoxifen (20 mg daily) for 5 years or no further treatment. The primary end point was disease-free survival (DFS). Tumors were classified as estrogen receptor (ER) -positive (n = 735, 59%) if immunohistochemical (IHC) or ligand-binding assays (LBA) were clearly positive. The ER-negative group included all other tumors (n = 511, 41%). A subset of the ER-negative group was defined as ER absent (n = 108, 9%) if IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. The median follow-up time was 7 years. RESULTS: Tamoxifen improved DFS in the ER-positive cohort (hazard ratio [HR] for tamoxifen v no tamoxifen = 0.59; 95% CI, 0.46 to 0.75; P < .0001) but not in the ER-negative cohort (HR = 1.02; 95% CI, 0.77 to 1.35; P = .89). Tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen in an unplanned exploratory analysis (HR = 2.10; 95% CI, 1.03 to 4.29; P = .04). Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen. CONCLUSION: Tamoxifen after adjuvant chemotherapy significantly improved treatment outcome in premenopausal patients with endocrine-responsive disease, but its use as adjuvant therapy for patients with ER-negative tumors is not recommended.

Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95

PURPOSE: To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes. PATIENTS AND METHODS: Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). RESULTS: After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC. CONCLUSION: There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.

Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93

Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS).

Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891

PURPOSE: This study (EORTC 30891) attempted to demonstrate equivalent overall survival in patients with localized prostate cancer not suitable for local curative treatment treated with immediate or deferred androgen ablation. PATIENTS AND METHODS: We randomly assigned 985 patients with newly diagnosed prostate cancer T0-4 N0-2 M0 to receive androgen deprivation either immediately (n = 493) or on symptomatic disease progression or occurrence of serious complications (n = 492). RESULTS: Baseline characteristics were well balanced in the two groups. Median age was 73 years (range, 52 to 81). At a median follow-up of 7.8 years, 541 of 985 patients had died, mostly of prostate cancer (n = 193) or cardiovascular disease (n = 185). The overall survival hazard ratio was 1.25 (95% CI, 1.05 to 1.48; noninferiority P > .1) favoring immediate treatment, seemingly due to fewer deaths of nonprostatic cancer causes (P = .06). The time from randomization to progression of hormone refractory disease did not differ significantly, nor did prostate-cancer specific survival. The median time to the start of deferred treatment after study entry was 7 years. In this group 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). CONCLUSION: Immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptom-free survival. This must be weighed on an individual basis against the adverse effects of life-long androgen deprivation, which may be avoided in a substantial number of patients with a deferred treatment policy.

Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial

PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.

Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy

Pericyte loss is an early pathologic feature of diabetic retinopathy, consistently present in retinae of diabetic humans and animals. Because pericyte recruitment and endothelial cell survival are controlled, in part, by the angiopoietin/Tie2 ligand/receptor system, we studied the expression of angiopoietin-2 and -1 in relation to the evolution of pericyte loss in diabetic rat retinae, using quantitative retinal morphometry, and in retinae from mice with heterozygous angiopoietin deficiency (Ang-2 LacZ knock-in mice). Finally, recombinant angiopoietin-2 was injected into eyes of nondiabetic rats, and pericyte numbers were quantitated in retinal capillaries. Angiopoietin-1 protein was present in the normal maturing retina and was upregulated 2.5-fold in diabetic retinae over 3 months of diabetes. In contrast, angiopoietin-2 protein was consistently upregulated more than 30-fold in the retinae of diabetic rats, preceding the onset of pericyte loss. Heterozygous angiopoietin-2 deficiency completely prevented diabetes-induced pericyte loss and reduced the number of acellular capillary segments. Injection of angiopoietin-2 into the eyes of normal rats induced a dose-dependent pericyte loss. These data show that upregulation of angiopoietin-2 plays a critical role in the loss of pericytes in the diabetic retina.

Pericytes and the pathogenesis of diabetic retinopathy

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.

The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer

PURPOSE: To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT). PATIENTS AND METHODS: Prognostic factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT. RESULTS: No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001). CONCLUSION: Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.

Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial

PURPOSE: Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98. PATIENTS AND METHODS: Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms). RESULTS: Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)--an excess only partially attributable to prior hypercholesterolemia--and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events. CONCLUSION: The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.