Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.

BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer.

Anastrozole ('Arimidex') blocks oestrogen synthesis both peripherally and within the breast in postmenopausal women with large operable breast cancer.

The effect of anastrozole on peripheral and tumour aromatase activity and oestrogen levels in postmenopausal patients with oestrogen receptor-rich breast tumours was investigated. Twenty-six patients were randomly allocated to treatment with anastrozole 1 mg (n=13) or 10 mg (n=13), once daily. Before and after 12 weeks' treatment, patients were infused with 3H-Delta4 androstenedione (20 MBq) and 14C-oestrone (E1) (1 MBq) for 18 h. Oestrogens were purified from excised tumours and plasma samples taken after each infusion. Peripheral and tumour aromatase activity and tumour E1 uptake were calculated from levels of 3H and 14C in purified E1 fractions from tumour and plasma. Endogenous tumour oestrogens were measured by radioimmunoassay. Twenty-three patients were available for analysis (1 mg group, n=12; 10 mg group, n=11). Following treatment, anastrozole (1 and 10 mg) markedly inhibited peripheral aromatase in all patients (the difference between pre- and on-treatment values being highly significant P<0.0001). In situ aromatase activity was also profoundly decreased by anastrozole treatment in 16 of 19 tumours (the difference with treatment also being highly significant P=0.0009). Most tumours were able to concentrate E1 beyond levels in the circulation; anastrozole treatment had no consistent effect on uptake of E1. Endogenous tumour levels of both E1 and oestradiol (E2) were significantly reduced with therapy (P=0.028 for E1 and P=0.0019 for E2). Anastrozole (1 and 10 mg daily) effectively suppresses aromatase activity, and subsequently oestrogen levels, within the breast tissue of postmenopausal women with large or locally advanced, operable, oestrogen receptor-rich breast cancers.

Effect of neoadjuvant treatment with anastrozole on tumour histology in postmenopausal women with large operable breast cancer.

Anastrozole is an orally active, non-steroidal aromatase inhibitor which appears effective as neoadjuvant treatment of breast cancer. Histological changes have been evaluated in biopsies from large, oestrogen-receptor rich, operable breast tumours in postmenopausal women following 12 weeks of neoadjuvant anastrozole treatment (1 mg (n=12) or 10 mg (n=11)). Of the 23 patients, 18 had a clinical response following treatment. Compared with pre-treatment biopsies anastrozole-treated specimens displayed decreased cellularity and/or increased fibrosis in 15 tumours; changes in gland formation, nuclear pleomorphism, or mitoses, in 12 cases; and a reduction in Mib1 score in all tumours. Marked changes in apoptotic scores were seen following treatment but the direction of effect was inconsistent. In all 17 tumours which were positive for progesterone receptors before therapy, treatment was associated with reduced staining for progesterone receptors. There was no consistent effect of treatment on oestrogen-receptor expression. It is concluded that neoadjuvant anastrozole treatment in this patient group has marked effects on tumour histopathology but these do not always correlate with clinical response.

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.

BACKGROUND: In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years. METHODS: Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy was by intention to treat. FINDINGS: 9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33.3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Disease-free survival at 3 years was 89.4% on anastrozole and 87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96], p=0.013). Results with the combination were not significantly different from those with tamoxifen alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0.02), vaginal bleeding and discharge (p<0.0001 for both), cerebrovascular events (p=0.0006), venous thromboembolic events (p=0.0006), and hot flushes (p<0.0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0.0001 for both). INTERPRETATION: Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma.

BACKGROUND: Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. METHODS: The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. RESULTS: At a median duration of follow-up of 18.2 months, anastrozole was at least equivalent to tamoxifen in terms of median TTP (8.5 and 7.0 months, respectively; estimated hazard ratio [tamoxifen relative to anastrozole], 1.13 [lower 95% confidence level, 1.00]). In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. Anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. CONCLUSIONS: In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.

Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m(2) was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P<.001). Time to progression in the brain was longer in the combined-modality group (P=.005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P=.087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.

Prognostic value of DNA cytometry in 281 premenopausal patients with lymph node negative breast carcinoma randomized in a control trial: multivariate analysis with Ki-67 index, mitotic count, and microvessel density.

BACKGROUND: The clinical relevance of DNA image cytometry (ICM) and flow cytometry (FCM) remains under investigation in breast carcinoma. The objective of the current work was to study the prognostic value of DNA ICM and FCM in a series of patients randomized in a control trial. A multivariate analysis has been performed including other factors still under investigation such as Ki-67 index, mitotic count, microvessel density, and P53 and Bcl-2 expression. METHODS: Two hundred and eighty-one patients were randomized in the European Organization for Research and Treatment of Cancer 10854 trial comparing surgery followed by one course of perioperative chemotherapy versus surgery alone. Tumor parameters studied were pT, multicentricity, tumor grading according to modified Scarff-Bloom-Richardson, estrogen receptors, mitotic count per 1.7 mm(2), MIB-1, and BCL-2 scores, microvessel density, and p53 expression. ICM DNA parameters studied from paraffin embedded specimens, were DNA ploidy, proliferative index, 2c deviation index, malignancy grade, and Auer-Baldetorp typing. FCM DNA parameters analyzed on the same samples were ploidy and S-phase fraction statistics. The influence of tumor parameters, and DNA parameters on overall survival (OS), disease free survival (DFS), and metastasis-free survival (MFS) was evaluated using the Cox model. Median follow-up was 82 months. RESULTS: For OS, the prognostic parameters retained were pathologic tumor size (pT) and mitotic index (MI). Overall survival was 94% and 68% for tumors pT1/MI less than 10 and pT2-3 MI greater than or equal to 10, respectively. For DFS, age, multicentricity, and grading according to modified Scarff and Bloom were predicting factors with the same relative risk. Disease free survival was 96%, 78% and 68% respectively, when 1, 2, or 3 of those factors were present. For MFS, the only retained predicting factor was MI. MFS was 97% and 73% when MI was less than 10 and MI was greater than or equal to 10, respectively. CONCLUSIONS: Evaluation of proliferative compartment was the most important predicting factor for OS and MFS in the current series of premenopausal lymph node negative patients with breast invasive carcinoma. When working on paraffin embedded tissue, the best way of assessing it was MI count. ICM DNA analysis results were not selected in multivariate analysis. DNA analysis by FCM should be considered as an unsuitable technique when working on paraffin embedded tissue.

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

OBJECTIVE: The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA: A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS: Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS: Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS: Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.

PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a Phase II study of the EORTC Gynaecological Cancer Cooperative Group.

Dysgerminoma accounts for 1% of all ovarian cancers and for 50% of all ovarian germ cell malignancies. Low stage patients (50%) can be cured with local treatment. The aim of this trial was to study the objective tumour response rate and toxicity of PVB (cisplatin, vinblastine, bleomycin) chemotherapy in patients with pure advanced or recurrent dysgerminoma. Eighteen eligible patients with advanced dysgerminoma were entered into this study. Three patients had local bulky recurrence only; all the others also had metastatic disease. The median age at entry was 27 years (range 1348). Seventeen patients had had prior surgery and one had undergone prior radiotherapy. The WHO performance status was 0 in 12 patients, 1 in three patients, and 2 in three patients. The treatment consisted of: intravenous or intramuscular bleomycin 30 mg on days 2, 9 and 16, intravenous vinblastine 0.15 mg/kg on days 1 and 2, and intravenous cisplatin 20 mg/m2 on days 1-5. This regimen was given at 3-week intervals for a total of four cycles. Twelve patients obtained a complete response (66%), five a partial response (28%), and one could not be evaluated because radiotherapy was administered immediately after chemotherapy. After a median follow-up of 76 months (range 4-132), 14 (78%) patients were alive and well. Two died of disease progression, one of neutropenic septicaemia and one of lung fibrosis. No unusual toxicity was reported. Alopecia, as well as nausea and vomiting, were common. Leucopenia (78%), thrombocytopenia (17%) and infection (11%) were the other severe (grade 3-4) side effects. The PVB chemotherapy regimen is highly effective in patients with advanced ovarian dysgerminoma. However, the BEP (bleomycin, etoposide, cisplatin) regimen, which is equally as potent and less toxic, is preferred.

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group, the Gruppo Interdisciplinare Valutazione Interventi in Oncologia, and the Japanese Foundation for Cancer Research.

BACKGROUND: There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS: 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS: 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION: PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Evaluation of clinical efficacy of new medical treatments in advanced colorectal cancer. Results of a workshop organized by the EORTC GITCCG. European Organization for Research and Treatment of Cancer. Gastrointestinal Tract Cancer Cooperative Group.

During the last few years several factors have contributed to an increasing change in the medical treatment of advanced colorectal cancer. Among them are the more general acceptance of the impact of chemotherapy on quality of life and survival in first as well as in second-line treatment, the introduction of new drugs and the definition of novel endpoints which can roughly be defined as "patient benefit". For this reason the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) felt it was appropriate to organize a workshop with experts from different countries and national groups to discuss in depth several aspects concerning the treatment of patients with advanced colorectal cancer.

Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: To compare two cisplatin based chemotherapy schedules in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 332 patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day 1 either in combination with teniposide 100 mg/m2 on days 1, 3, and 5 (arm A) or paclitaxel 175 mg/m2 by 3-hour infusion on day 1 (arm B); cycles were repeated every 3 weeks. RESULTS: Fifteen patients were ineligible; patient characteristics were well balanced between the two arms: 71% were male, 71% had less than 5% weight loss, 89% had a World Health Organization (WHO) performance status of 0 to 1, 51% had adenocarcinoma, and 61% had stage IV disease. Hematologic toxicity was significantly more severe in arm A (leukopenia, neutropenia, and thrombocytopenia grade 3 or 4: 66% v 19%, 83% v 55%, 36% v 2% in arms A and B, respectively), which resulted in more febrile neutropenia (27% v 3% in arms A and B, respectively), dose reductions, and treatment delays. There were a total of nine toxic deaths, six due to neutropenic sepsis: five in arm A and one in arm B. In contrast, arthralgia/myalgia (grade 2 or 3, 4% v 17%), peripheral neurotoxicity (grade 2 or 3, 6% v 29%), and hypersensitivity reactions (1% v 7%, all grades) were significantly more frequent in arm B. The frequency and severity of other toxicities were comparable between the two arms. Responses were one complete and 44 partial on arm A (28%) and two complete and 61 partial (41%) on arm B (P = .018). There was no significant difference in survival, with median and 1-year survivals 9.9 versus 9.7 months and 41% versus 43%, respectively in arm A and B. Progression-free survival was 4.9 and 5.4 months in arm A and B, respectively. Selected centers participated in a quality-of-life (QoL) assessment, which was performed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and LC-13 administered at baseline and every 6 weeks thereafter. Arm B achieved a better score at week 6 for emotional, cognitive and social functioning, global health status, fatigue, and appetite loss, which was lost at 12 weeks. In conclusion, arm B appears superior to arm A with regard to response rate, side effects, and QoL. CONCLUSION: Although survival was not improved, arm B offers a better palliation for advanced NSCLC patients than arm A.

Response of recurrent glioblastoma and anaplastic astrocytoma to dibromodulcitol, BCNU and procarbazine--a phase-II study.

Twenty six (17 males) patients with glioblastoma (GBL), median age 55 years, median Karnofsky Index (KI) 70/100, and 11 patients (9 males) with anaplastic astrocytoma (AA), median age 56 years, median KI 70/100 were treated at recurrence with dibromodulcitol (DBD) 1400 mg/m2 on day 1, BCNU 150 mg/m2 on day 2, and procarbazine (PCZ) 150 mg/day on days 1 to 15. The course was repeated every 4 weeks, but was delayed or decreased by 25% according to hematological toxicity. Response to treatment was evaluated by the criteria of MacDonald et al. (J Clin Oncol 1990; 8: 1277-1280). All GBL-patients were followed until death. One patient with complete response (CR) survived one year, and 2 patients with partial response (PR) survived 1 and 3 years. Ten patients who stabilized (SD) survived 7.5 months, and 13 patients who progressed under chemotherapy had a median survival of 3.5 months. In AA-group 3 patients were alive at the time of the analyses. Six patients: 1 CR and 5 PR survived 6 to 40+ months. Two patients with SD survived 4 and 14 months. Three patients with progressive disease had a mean survived of less than 3 months. The response rate of 55% in AA was significantly higher (p = 0.011) than the 12% response rate seen in GBL. We conclude that the regimen tested appears particularly promising in AA. The results in GBL are comparable to those obtained with a single nitrosourea, despite an increased but reversible toxicity.

Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study.

BACKGROUND AND PURPOSE: To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer. PATIENTS AND METHODS: The patients had brain metastases of small cell lung cancer without any sign of tumour outside the brain and were treated with 10 x 3.0 Gy WBRT. Response and neurological functions were evaluated after 6, 18 and 36 weeks. RESULTS: Twenty of 22 eligible patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% (95% CI 28-72%). Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function. CONCLUSION: WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short.

Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial.

PURPOSE: The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS: Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION: This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer.

PURPOSE: Thirty percent of women with node-negative breast cancer will have a recurrence within 10 years after diagnosis. Molecular markers may identify those patients and predict whether they benefit from adjuvant therapy. The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare perioperative treatment with one course of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus no further therapy. We studied tumors from premenopausal patients with node-negative breast cancer randomized in this trial to determine whether p53 accumulation, c-erbB-2 expression, percentage of Ki-67-positive cells, estrogen receptor (ER-immunoassay [IA]), progesterone receptor (PR-IA), and angiogenesis could be used as prognostic factors and predictors of responsiveness to adjuvant chemotherapy. PATIENTS AND METHODS: Paraffin-embedded tumor specimens from 441 premenopausal women with node-negative breast cancer were collected from the larger EORTC trial. Paraffin sections from the tumors were analyzed for immunohistochemical expression of p53, c-erbB-2, Ki-67, ER, PR, and angiogenesis. RESULTS: Patients with p53-negative tumors showed a significant benefit from perioperative chemotherapy (P < .01), whereas patients who had p53-positive tumors did not (P = .80). At a median follow-up time of 49 months, univariate analyses for disease-free survival (DFS) failed to show prognostic value for p53, c-erbB-2 and angiogenesis. Both univariate and multivariate results showed Ki-67 positivity, ER-IA negativity, and a younger age to be associated with a worse prognosis. CONCLUSION: p53 accumulation was associated with a poor response to one perioperative course of FAC chemotherapy. Ki-67, ER-IA, and age are important prognostic factors in premenopausal women with node-negative breast cancer.

Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience.

PURPOSE: Identification of prognostic factors in patients with malignant pleural mesothelioma based on prospectively collected international data. PATIENTS AND METHODS: From October 1984 to October 1993, 204 eligible adult patients with malignant pleural mesothelioma were entered into five consecutive prospective European Organization for Research and Treatment of Cancer (EORTC) phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel). The Cox model was used to assess 13 factors related to biology and disease history with respect to survival. RESULTS: The median survival duration was 12.6 months from diagnosis and 8.4 months from trial entry. In the multivariate analysis, poor prognosis was associated with a poor performance status, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified into two groups: a good-prognosis group (1-year survival rate, 40%; 95% confidence interval [CI], 30% to 50%) and a poor-prognosis group (1-year survival, 12%; 95% CI, 4% to 20%). CONCLUSION: These results may help to design new clinical trials in pleural mesothelioma by selecting more homogenous groups of patients.

Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study.

PURPOSE: To evaluate the effectiveness of alternating or sequential schedules of cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and irradiation in patients with previously untreated small-cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 335 eligible patients were randomized between five courses of CDE chemotherapy followed by thoracic irradiation 50 Gy in 20 daily fractions (S) and the same total dose of chemotherapy and irradiation split into four courses of five daily fractions delivered on days 14 to 21 of the second and subsequent chemotherapy courses (A). Patients had a median age of 61 years (range, 33 to 75); 224 (66%) were male; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 311; and 254 had weight loss less than 10%. RESULTS: The overall median survival duration was 15 months, with 62% (95% confidence interval [CI], 57% to 67%) 1-year, 25% (95% CI, 20% to 30%) 2-year, and 14% (95% CI, 10% to 18%) 3-year survival rates. There was no significant difference between the arms. The median survival time was 14 months in A and 15 months in S. One-year survival was 60% in A (95% CI, 53% to 67%) and 64% in S (95% CI, 57% to 71%); 2-year survival was 26% in A (95% CI, 19% to 33%) and 23% in S (95% CI, 16% to 30%); and 3-year survival was 12% in A (95% CI, 6% to 18%) and 15% in S (95% CI, 9% to 21%). World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 90% of A and 77% of S patients (P < .001) and WHO grade 3 and 4 thrombocytopenia in 33% of A and 20% of S patients (P < .001). Rates of other acute and late toxicities were similar in both arms. Hematologic toxicity compromised treatment dose delivery; less than 50% of A patients received greater than 95% of prescribed chemotherapy and 77% their full radiation course, compared with 60% and 93% for arm S (P < .009). Local relapse was the site of first failure in 60% of all patients and 75% of these suffered an in-field relapse; no difference could be seen between the two arms. CONCLUSION: This trial failed to confirm the superiority of an alternating schedule of delivery. For this combination of chemotherapy and irradiation, hematologic toxicity compromised treatment delivery and could have contributed to the overall result. The poor rates of local control are disappointing and require intensification of the radiation therapy strategy.

Phase II study of weekly 4'-epidoxorubicin in patients with metastatic adenocarcinoma of the cervix: an EORTC Gynaecological Cancer Cooperative Group study.

In this study 22 patients with metastatic adenocarcinoma of the cervix were treated with a weekly bolus injection of 4'-epidoxorubicin at a dose of 12 mg/m2. Seventeen patients had received prior radiotherapy, all patients were chemo-naive. Toxicity was generally absent or very mild. One patient had a complete response and 2 patients had a partial response, one was an unconfirmed partial response, giving a response rate of 14%. Six patients had stable disease. The median progression-free survival and overall survival was 2.8 months and 6.1 months, respectively. In conclusion, 4'-epidoxorubicin used at this dosage and schedule has minimal activity in metastatic adenocarcinoma of the cervix.