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Summary Background We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8–12·7). Methods In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. Findings Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5–81·0) in the no axillary dissection group, compared with 74·9% (70·5–79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65–1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. Interpretation The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8–12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. Funding International Breast Cancer Study Group.

Pour developper et faciliter la prise en charge globale et contextuelle des patients, le service d’oncologie ambulatoire de l’EHC-Morges s’est dote d’un instrument de mesure de la complexite: INTERMED. La situation du patient et ses ressources sont evaluees par une interview. L’analyse de 277 entretiens sur quatre ans montre qu’INTERMED permet d’offrir un espace privilegie d’expression, de reperer les besoins susceptibles d’etre passes sous silence et de favoriser la communication de maniere holistique.

Summary Background: The DNA repair protein O 6 -alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m 2 , divided over two days. Fotemustine 100 mg/m 2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m 2 (200 mg/m 2 /d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

Background: CYP2D6 is genetically highly polymorphic and several studies support that patients classified as poor-or intermediate-metabolizers achieve less or no benefit from tamoxifen treatment probably because they have lower levels of endoxifen. Genotyping is currently the major method used in studies and in clinical practice. However the ability of genotyping to predict plasma levels of endoxifen is uncertain for an individual patient. We assessed prospectively CYP2D6 activity by genotyping, phenotyping and the measurement of tamoxifen and its metabolites. Methods: Patients were genotyped for CYP2D6 (*1, *3, *4, *5, *6 and *XN) polymorphism. The CYP2D6 phenotype was determined by the dextromethorphan test. Plasma was collected at 2 time points after at least 4 months of treatment with tamoxifen 20 mg daily: tamoxifen, 4-hydroxytamoxifen, N-demethyltamoxifen and endoxifen were measured with high performance liquid chromatography coupled to triple stage tandem mass spectrometry. Linear regression analyses were performed on log transformed concentrations of tamoxifen, its metabolites, and the ratios 4- hydroxytamoxifen/tamoxifen, endoxifen/N-demethyltamoxifen versus the different genotype groups (UM, EM, IM, PM) and the dextromethorphan/dextrorphan ratio. Results: The data of 26 patients are currently available. Geometric mean plasma concentrations (coefficient of variation %) of tamoxifen, N-desmethyltamoxifen, 4-OH-tamoxifen and endoxifen were 377 nmol/L (39%), 482 nmol/L (36%), 5.9 nmol/L (52%) and 60.7 nmol/L (94%), respectively. Genetic variation in CYP2D6 was significantly correlated with endoxifen, 4-hydroxytamoxifen and the ratios of 4-hydroxytamoxifen/tamoxifen and endoxifen/N-demethyltamoxifen: determination coefficients (R-squared) of 44% (P=0.0002), 30% (P=0.0038), 57% (P= Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-09.

It is desirable to identify the most effective sequence of endocrine therapies for the treatment of postmenopausal women with advanced, hormone-responsive breast cancer. In a retrospective analysis of two large, randomized, comparative Phase III trials in this patient population, the Tamoxifen or 'Arimidex' Randomized Group Efficacy and Tolerability (TARGET) trial and the North American trial, we ascertained that tumors responding to anastrozole as first-line therapy may subsequently respond to tamoxifen as second-line therapy. In a double-blind cross-over trial, the SAKK 21/95 sub-trial (including patients from the Swiss centres in the TARGET trial), we further investigated the clinical impact of anastrozole followed by tamoxifen compared with that of tamoxifen followed by anastrozole. Patients with locally advanced or metastatic breast cancer who had continued on randomized treatment until objective disease progression and were still considered suitable for endocrine therapy, could continue on blinded therapy crossing-over to the alternative treatment. They were assessed for time to progression (TTP) from treatment randomization, TTP after crossing-over treatments, time from randomization to progression after crossing-over treatments and overall survival. Median TTP from randomization for patients receiving first-line treatment with anastrozole (n = 31) and tamoxifen (n = 29) was 11.3 and 8.3 months, respectively, p = 0.75. Median TTP from treatment cross-over was 6.7 months for tamoxifen after progression on anastrozole (n = 19) and 5.7 months for anastrozole after progression on tamoxifen (n = 18), while median time from randomization to second progression was 28.2 and 19.5 months, respectively. Overall survival from randomization for the anastrozole-tamoxifen sequence and the tamoxifen-anastrozole sequence was 69.7 versus 59.3 months, respectively, p = 0.10. The relative risk of death was higher for the tamoxifen followed by anastrozole sequence (1.63; 95% confidence interval [CI] 0.89-2.98). Tamoxifen is an effective second-line therapy after anastrozole. Our data, together with the better tolerability profile of anastrozole compared with tamoxifen, support the use of anastrozole as first-line therapy for advanced breast cancer in postmenopausal women with hormone receptor-positive tumors. Treatment with tamoxifen may still be useful upon subsequent progression.

Young patients with breast cancer (BC) are often concerned about treatment-induced infertility and express maternity desire. Conception after BC does not seem to affect outcome, but information in estrogen-receptor positive (ER+) disease is not definitive. From September 2012-March 2013, 212 evaluable patients with ER+ early BC,37 years at diagnosis, from 5 regions (Europe/US/Canada/Middle-East/Australia) answered a survey about fertility concerns, maternity desire and interest in a study of endocrine therapy (ET) interruption to allow pregnancy. Overall, 37% of respondents were interested in the study; younger patients (≤30 years) reported higher interest (57%). Motivation in younger patients treated30 months was higher (83%) than in older women (14%), interest was independent of age in patients treated for ≤30 months. A prospective study in this patient population seems relevant and feasible. The International-Breast-Cancer-Study-Group (IBCSG), within the Breast-International-Group (BIG) - North-American-Breast-Cancer-Groups (NABCG) collaboration, is launching a study (POSITIVE) addressing ET interruption to allow pregnancy.

In small-cell lung carcinoma (SCLC) tumour cell contamination of leukaphereses is unknown. The present study was performed to define appropriate markers for reverse transcriptase polymerase chain reaction (RT-PCR), then to assess the contamination rate of leukaphereses and corresponding bone marrow samples. Immunocytochemistry (ICC) and RT-PCR methods were also compared. Among the 33 patients included, analyses were performed in 16 who had multiple leukaphereses and 17 who had only bone marrow. Leukapheresis products and bone marrow were analysed by ICC using several specific monoclonal antibodies against neural-cell adhesion molecule (N-CAM), epithelial glycoprotein (EGP-40) and cytokeratins (CK). Samples were also analyzed by RT-PCR for expression for N-CAM, synaptophysin, neuron-specific enolase, chromogranin, cytokeratin-18/-19, CEA, EGP-40, apomucin type 1 (MUC-1) and human endothelial cell-specific molecule (ESM-1). Using ICC staining, contaminating tumour cells were detected in 34% of leukaphereses (27% in patients with limited disease and 43% in those with extensive disease). N-CAM was the most reliable marker for detection of contamination. For RT-PCR, CK-19 and CEA were the only appropriate markers. Positive signal rate in leukaphereses increased to 78% (89% for patients with limited disease and 67% for extensive disease). In bone marrow, both techniques were in agreement whereas in leukaphereses, RT-PCR was better than ICC. A high rate of tumour cell contamination was demonstrated not only in bone marrow but also in leukaphereses from SCLC patients. The most appropriate technique was RT-PCR mainly in patients with limited disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Bcl-2 and bcl-xL function as suppressors of programmed cell death. The expression of bcl-2 protein in vivo is associated with long-lived hematopoietic cells such as mature lymphocytes and early myeloid progenitors. Bcl-xL, a homologue of bcl-2, is also expressed in lymphocytes and thymocytes. In contrast, the bcl-2-related proteins (bax, bad, and bak) act by promoting apoptotic cell death as shown from their expression in hematopoietic cell lines. We analyzed the expression of bcl-2 and bcl-x proteins in hematopoietic precursors obtained from various cell sources in adult mobilized peripheral blood collected from 13 patients with solid tumors, 8 adult bone marrow, and 12 umbilical cord blood. The analysis was based on the expression of the proliferation and activation specific antigens, CD38 and class II (HLA-DR). Similarly, we analyzed the expression of bcl-2-related proteins bcl-xL, bax, bad, and bak before and during ex-vivo expansion. Hematopoietic precursors expressing strongly the CD34 antigen (CD34s+) and lacking CD38 or HLA-DR expression were analyzed by using three-color immunofluorescence staining. The majority of CD34+ cells expressed bcl-2 and unexpectedly showed a bimodal distribution of low and high expression. More cells that lacked or expressed low density CD38 expressed low bcl-2 than the more differentiated counterparts (those with high density CD38). Immaturity (ie, little or no HLA-DR) is associated with the expression of low bcl-2 compared with HLA-DR+. However, HLA-DR−/low population contained a lower number of cells expressing low bcl-2 (30% to 40%) than CD38−/low in comparable samples. The hematopoietic precursors with bcl-2low and bcl-2high formed a homogeneous population of undifferentiated lymphoid-like cells having a similar forward scatter. These cells expressed strongly the bcl-xL protein (>95%) but were bax low (4% to 12%), bad low (0% to 0.8%), and bak low (0% to 3%). The expression of apoptosis specific protein (ASP) was also low (3.4% ± 3.1%) as was Annexin V. In addition, the CD34+/CD38−showed low cell cycle activity ( © 1998 by The American Society of Hematology.

Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy.

Prognosis of breast cancer women has been dramatically improved by the adjuvant therapies. As the vast majority of patients are cured, the importance of long-term quality of life is growing. The question of the maternity is an essential concern for the young women who have to receive chemotherapy or several years of endocrine therapy. This problem is often underestimated and may lead to emotional distress, depression or anxiety. A regional multidisciplinary working group was set up in order to offer optimal information about fertility and cancer as to propose specific therapeutic reproduction options, when applicable. Specificity of the young patients' breast cancer, the treatment approaches and their impact on fertility are discussed in this paper.

61 autologous transplantations for haematological malignancies have been performed with peripheral blood stem cells in 60 patients. 26 grafts were performed for non-Hodgkin's lymphoma (18 patients were transplanted in first remission, 8 patients after progression or relapse), 13 for multiple myeloma, 7 for Hodgkin's disease and 10 for acute myeloid leukaemia. One patient died from thrombosis of the portal vein. 38 patients were in complete remission 29 months (extremes: 14-44) after transplantation. 21 of 60 patients progressed or relapsed after transplantation, and 14 died. No death was attributed to graft failure, infection or haemorrhage. In conclusion, transplantation with peripheral blood stem cells is well tolerated, has a low toxicity rate, and can be used safely for patients with haematological malignancies.

PURPOSE: To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells (PBPCs) administered in a multicenter setting to patients with small-cell lung cancer. PATIENTS AND METHODS: Sixty-nine patients (limited disease, n = 30; extensive disease, n = 39) treated at 15 European centers were scheduled to receive three courses of high-dose chemotherapy with ifosfamide 10 g/m2, carboplatin 1200 mg/m2, and etoposide 1200 mg/m2 (ICE) divided over 4 days at 28-day intervals. PBPCs were harvested before treatment and mobilized with epirubicin 150 mg/m2 administered via an intravenous bolus divided over 2 days and filgrastim 5 μg/kg/d administered subcutaneously. RESULTS: The performed leukaphereses (one to five per patient) yielded a median of 16.6 × 106/kg (range, 1.0 to 96.6 × 106/kg) CD34+ cells, which was sufficient for three reinfusions. Fifty patients (72%) completed the treatment according to schedule. Nine patients completed two courses, and six patients completed one course of treatment. The increase in dose-intensity was 290% that of a standard ICE regimen. The median duration of myelosuppression was similar between courses, namely 4 days (range, 1 to 12 days) for leukocytes less than 0.5 × 109/L and 4 days (range, 0 to 22 days) for thrombocytes less than 20 × 109/L. Febrile neutropenia developed in 66% of courses, severe diarrhea in 14%, mucositis in 10%, and nausea and vomiting in 21% of courses. There were six cases of toxic death (9%), most of which occurred in the first year of accrual and thus were attributable to the learning curve. The antitumor effect of the regimen was reflected in an 86% remission rate (95% confidence interval [CI], 74% to 93%), with 51% of patients achieving a complete response (95% CI, 38% to 63%). Median overall survival was 18 months for patients with limited disease and 11 months for patients with extensive disease. CONCLUSION: This multiple sequential high-dose ICE regimen could be safely administered on a multicenter basis to patients with small-cell lung cancer. The dose-intensity could be increased to 290% that of standard ICE regimen. The benefit of this approach is currently being tested in a randomized trial that aims to double the long-term rate of survival for patients with small-cell lung cancer.

The transplantation of mobilized progenitor cells after high-dose chemotherapy shortens haemopoietic engraftment. CD34 cell subsets were examined in 20 consecutive mobilized progenitor cell collections obtained from patients with solid tumours that had not been previously treated. The analysis of CD34 cells was based on the expression of intracellular antigens, surface antigens including CD38, and cell size using multi-dimensional flow cytometry. We also correlated the numbers of stem cell subsets reinfused to haemopoietic recovery. The majority of CD34+ cells expressed CD13 and CD33. A significant proportion was cytoplasmic myeloperoxidase (cMPO) positive. CD34+ MPO+ cells increased significantly in late collections. MPO expression was related to cell size. Cells expressing CD13 also increased in late collections in parallel to CFU-GM count. Small subpopulations of CD34+ CD38+ were committed to B cells, T cells and erythroid cell lineages. A small population expressing the megakaryocytic antigen had a small size and were predominantly CD38-. A minor subpopulation expressed stem cells antigens. These were significantly higher in late collections (CD34+ Thy-1+ and CD34+ CD33-). After mobilization, patients received three cycles of intensive chemotherapy followed by reinfusion of mobilized progenitors (5.45 x 10(6)/kg CD34+ cells, range 3.4-11.88). The numbers of reinfused CD34 cells or the individual subsets did not influence recovery of leucocytes (9 d) or platelets (9 d). In conclusion, the numbers of stem cells and their subsets differed between collections and, in unpretreated patients receiving intensive chemotherapy, there was no delayed engraftment when sufficient numbers of stem cells were reinfused. The recovery period was short and not correlated to any stem cell subsets.

Recently, genetic analyses in high risk families with several members suffering of breast and/or ovarian carcinoma led to the discovery of two genes, called BRCA1 and BRCA2, clearly responsible for hereditary predisposition of breast carcinoma. Another gene, p53, was also shown to be involved in hereditary predisposition of breast and other tumors in the setting of Li-Fraumeni syndrome. It is very important that women at risk could be seen by a specialized team for genetic counselling and explanation of advances and limits of molecular genetics. Such a team should be multidisciplinary in order to cover genetic, oncological, social, psychological and economical aspects of hereditary cancer predisposition. Prevention interventions and early detection methods are still investigational and definitely need to be performed in the setting of protocols in order to better evaluate their long term efficacy.

Background: Retrospective studies assessing the impact of tamoxifen (Tam) metabolism and its active metabolite, endoxifen, on the efficacy of the treatment produced conflicting results. The prospective CYPTAM-BRUT 2 trial is ongoing1. In the present study we assessed if the level of Tam metabolites could be improved by doubling tamoxifen dose in breast cancer patients (pts) with any CYP2D6 genotype, poor (PM), intermediate (IM) and also extensive metabolizer (EM). Patients and methods: This multicenter, prospective, open-label trial included pts treated with Tam for ≥ 4 months. CYP2D6 activity was determined centrally by genotyping and phenotyping (dextromethorphan test). Liquid chromatography-tandem-mass spectrometry was used to measure Tam, N-desmethyltamoxifen (N-DMT), 4-hydroxytamoxifen (4-HT) and endoxifen twice at baseline (Tam 20 mg qd), then at days 30, 90 and 120 after having increased the dose to 20 mg bid. Endoxifen increase and the differences between genotype/phenotype subgroups were analyzed by ANOVA. Results: 76 pts were analyzed. Steady-state concentrations for Tam and its metabolites were reached in 30 days after doubling the dose. A range of 1.6 to 1.8 fold increase was observed. Geometric mean plasma concentrations in ng/ml (CV%) were: at baseline and day 30 respectively 134 (48) and 246 (46) for tamoxifen (p < 0.0001); 246 (53) and 413 (48) for N-DMT (p < 0.0001); 2.3 (44) and 3.7 (51) for 4HT (p < 0.0001); 18.7 (89) and 31.1 (92) for endoxifen (p = 0.005). The level of endoxifen increased 1.4 to 1.7 folds in all genotype subgroups with geometric mean plasma concentrations in ng/ml (CV%): 6.9 (36) to 9.7 (24) in PMs (p = 0.7); 14.2 (69) to 20.7 (76) in IMs (p < 0.0001); and 22.6 (76) to 38.7 (85) in EMs (p < 0.0001). Similar results were obtained while considering phenotype subgroups. Genotypes and phenotypes explained less than 30% of the variability in endoxifen levels. The occurrence of hot flashes and night sweating were followed prospectively. Endoxifen levels did not predict an increase in HF/NS events' overall occurrence (OR = 1.01, CI95% 0.78–1.31 for HF and 1.01, CI95% 0.79–1.29 for NS). Twelve pts received CYP2D6 inhibitors. Nine pts did not complete the planned 4 months with tamoxifen 20 mg bid. The main reasons were mood disorders, hot flashes, headache and nausea. Self-reported treatment compliance assessed by monthly anonymous questionnaire was ≥ 95%, except 80–95% in 4 pts. Conclusions: This is the first trial reporting the impact of the increase of tamoxifen dose in all CYP2D6 genotypes, including EMs. Dose escalation of tamoxifen increased significantly the plasma level of endoxifen by similar ratio in all genotype subgroups. Because of a huge inter-individual variability genotyping and phenotyping are not adequate surrogate markers of endoxifen level. Very low endoxifen levels are observed even in pts classified as EM. Future trials aiming to improve the plasma level of endoxifen should consider direct measurement of the metabolite in plasma and adjust tamoxifen dose according to the initial level of the metabolite independently of the genotype. Reference 1. A. Dieudonné, Journal of Clinical Oncology, 2011; vol 29, No 15, suppl (May 20, 2011): TPS 140 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-05.

Recent studies have described the generation of a mAb, designated DF3-P, which reacts with underglycosylated precursors of the DF3/MUC1 mucin-like glycoprotein. The present work demonstrates that the epitope recognized by mAb DF3-P is expressed by cell lines derived from human epithelial ovarian carcinomas and not a teratocarcinoma. Indirect immunofluorescence assays of single-cell suspensions support expression of the DF3-P epitope on the surface of ovarian carcinomas. Immunofluorescence studies on chamber slides further demonstrate that the mAb DF3-P-reactive cells are present in clusters. We also demonstrate that 125I-labeled mAb DF3-P selectively localizes to human ovarian carcinoma xenografts in athymic mice. The percentage of injected 125I dose/g tissue ranged between 10 and 17% for implanted CAOV-3 and OVCAR-3 tumors. Finally, the results of immunoperoxidase staining studies demonstrate that the DF3-P epitope is detectable in formalin-fixed sections of ovarian tumors and that mAb DF3-P exhibits little if any reactivity with normal surrounding tissues. Selective expression of the DF3-P epitope may be useful as a target for radioimaging or immunotherapeutic approaches to ovarian cancer.

During the last years, high-dose chemotherapy with autologous hematological rescue has been increasingly used not only in the treatment of patients with relapsing lymphoma but also in ovarian and breast carcinoma. In this manuscript we present results in patients with high-risk primary breast cancer, and in those with metastatic tumors. When high-dose chemotherapy is given in the adjuvant setting for women presenting withor = 10 metastatic axillary nodes, results are very promising since 72% of the patients are alive without evidence of disease more than 3 years after operation. In patients with inflammatory breast carcinoma, high-dose chemotherapy induces 80% of complete remissions. Considering patients with metastatic disease, high-dose, chemotherapy increases the complete remission rate and duration of response. In several studies, survival exceeding 5 years without relapse is seen in 10 to 15% of the patients. Toxic death rate globally is 10% and is decreasing progressively since the first studies. However, in order to really determine the value of high-dose chemotherapy with autologous hematological support, randomized trials will be needed, comparing this new approach to conventional treatment. Such studies are already going on in the USA and in Europe and results are awaited with great interest.

Several articles covering treatment of mammary carcinoma in situ and invading mammary cancer have been published recently. This article delivers a short description of the clinical picture and the treatment of a noninvasive tumor as well as of the mainly conservative primary treatment of invasive carcinoma in common use since 20 years. Systemic adjuvant treatment is discussed in the context of results from a meta-analysis publishes two years ago in 'Lancet'. Finally, various directives for the execution of an adjuvant treatment are given that are offered today outside of a study protocol.

e19599 Background: Infertility secondary to adjuvant chemotherapy is a major problem in young women with breast cancer. We developed a multidisciplinary-multicenter network, the “RRCF”, aiming to o...

The combination of cisplatin (80 mg/m2, i.v., day 1), 96-h infusion of 5-fluorouracil (5-FU) (30 mg/kg/24 h) and vindesine (3 mg/m2 days 1 and 8) was evaluated in 31 patients with histologically proven epidermoid carcinoma of the head and neck. All patients were nonpretreated and had measurable lesions. Three (10%) of the 29 evaluable patients achieved a complete response (CR) and 19 (66%) had partial response (PR) with an overall response rate (CR + PR) of 76%. The major toxicity was leukopenia. Median overall survival was 14.5 months. It is concluded that the combination of cisplatin, 96-h infusion of 5-FU, and vindesine was as effective as other regimens including 5-FU and cisplatin reported in the literature, with a similar toxicity. The low CR rate in this trial is related to the high percentage of T4 N3 disease.

CA125 is more commonly elevated in metastatic breast carcinoma patients than previously recognised and can serve as a marker to monitor disease course if CA15-3 is not elevated. However, the performance characteristics of CA125 in breast cancer are not as satisfactory as for CA15-3, which should be considered the marker of choice in patients with disseminated breast carcinoma

7064 Background: EBMT has defined in a phase II trial (JCO 1999, 3531) feasibility and activity of high-dose sequential CT for SCLC increasing 3 fold the dose-intensity and significantly the peak-dose and the total dose of CT. Methods: Randomized prospective study aiming to improve the 3-year survival from 12% in the standard (S) to 24% in the high-dose (H) arm, for a total accrual of 340 patients. Limited or extensive ≤ 2 metastatic sites, age ≤ 65 y.o., PS 0–1. Arm S/Arm H: ifosfamide 5 g/m2 d1/2.5 g/m2/d × 4; carboplatin 300 mg/m2 d1/AUC = 5/d × 4; etoposide 180 mg/m2/d. × 2/300 mg/m2/d × 4, every 28 days, for 6 cycles in Arm S. Three cycles were given in Arm H supported by PBPC collected after 2 courses of epirubicin 150 mg/m2/paclitaxel 175 mg/m2. Due to low accrual, a formal stopping rule was introduced with boundaries for early stopping in favour of a difference (O’Brien-Fleming) or of lack thereof (Pocock). The present analysis has been done with 110 deaths. Results: Since June 1997, 145 patients have been accrued (evaluable =140, S = 71, H = 69), median age 53, prognostic factors balanced. Mobilization toxicity ≥ 3: neutropenia 61%, thrombopenia 11%, anemia 7%, infection 6%, mucositis 9% and 2 toxic deaths. Toxicity ≥ 3 among 353 cycles of S and 152 of H respectively: neutropenia 26%/100%, thrombopenia 12%/100%, anemia 8%/69%, infection 1%/15%, fever 11%/72%, toxic death 1/8. Response rate of S and H: 67% (CR 32%)/77% (CR 37%) (p = 0.188). Median follow-up 4.9 years. Progression free survival 8.8 and 12 months (p = 0.737, unadjusted) and median overall survival 15 and 19.1 months (p = 0.659, unadjusted) for S and H respectively. At 3 years, 19% of the patients were alive in both arms. Conclusions: Random-ICE was designed with strong statistical power and shows no evidence that the treatment of SCLC can be improved by increasing the dose-intensity, the peak-dose or the total dose of ICE and that such intensification strategy should probably be abandoned. No significant financial relationships to disclose.

The clinical and haematological findings in 18 patients with human immunodeficiency virus (HIV) infection were correlated with the histological features of plastic embedded bone marrow biopsies. Fifteen patients presented with peripheral cytopaenia of one or several cell lines. Twelve (66%) of the 18 patients exhibited bone marrow findings including normo- to hypercellularity, myelodysplasia, lymphocytosis with or without plasmacytosis and fibrosis of the reticulin type. Seventeen patients had myelodysplastic features, 5 of the 3 haematopoietic lines, 10 of 2 lines and 2 of 1 line. Dysmegakaryocytopoiesis and dyserythropoiesis, seen in 88% and 83% of the 18 patients respectively, were the most common myelodysplastic features. Bone marrow gelatinous transformation (serous atrophy) was a conspicuous finding in 7 (38%) of the 18 patients. The constellation of histological features here described, although not pathognomonic, is highly suggestive of HIV infection. The pathogenesis of the haematological abnormalities in HIV infection is discussed.