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The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

„Innovation“ bedeutet wortlich „Neuerung“ oder „Erneuerung“. Die gynakologische Onkologie durfte in den letzten Jahren nicht nur Zeuge, sondern v. a. Motor einer Vielzahl von Innovationen sein, die von der Primarpravention, wie der Humanen-Papillomvirus(HPV)-Vakzinierung, bis hin zu bislang ungeahnten Langzeitremissionen durch die zielgerichtete Therapie des metastasierten Mammakarzinom reicht. Solche Entwicklungen kritisch zu begleiten und aktiv mitzugestalten, ist einer der besten Garanten fur die erfolgreiche Positionierung und Zukunftssicherung des Faches. In diesem Beitrag werden exemplarisch 4 Beispiele genannt, die demonstrieren sollen, dass die Gynakologie in der Lage ist, Neuerungen des medizinischen Fortschritts aktiv zu gestalten und international Akzente zu setzen, aber auch durch die notwendige kritische Auseinandersetzung mit den neuen Methoden bislang erzielte Therapieergebnisse nicht in Gefahr zu bringen. Gerade in der interdisziplinaren Zusammenarbeit liegt eine wesentliche Chance fur die Gynakologie, eine fuhrende Rolle als Innovationsmotor einzunehmen.

Der Kongress und die Konsensuskonferenz wurden von uber 4000 Teilnehmerinnen und Teilnehmern besucht. Dies entspricht einer Zunahme von uber 1000 Personen gegenuber der letzten Konferenz von 2003. Die meisten Teilnehmer kamen erneut aus Deutschland. Eine bedeutende Zunahme besteht aus Landern in Osteuropa und Asien. Die Konferenz hatte 2 Highlights, namlich die Prasentation der ersten Resultate der BIG-1-98-Studie – Letrozol als adjuvante endokrine Therapie bei postmenopausalen Frauen mit hormonabhangigem Brustkrebs – und das an den Kongress anschliessende Konsensusmeeting.

The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the adequacy of tumor margins defined as 'no ink on invasive tumor or DCIS' and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Summary Background: Up to 75% of ovarian cancers are diagnosed in advanced, incurable stage. Only one fifth of these patients survives 5 years despi

The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and 'triple-negative' disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints., SCOPUS: ar.j, info:eu-repo/semantics/published

Summary Background: 20% of lung cancers are small-cell lung carcinomas. In spite of high radio- and chemosensitivity, the prognosis mostly remains b

Summary Background: Primary thyroid carcinoma in an adult teratoma of ovarian origin is observed very rarely. Material and Methods: We report a patient

Endocrine therapy for hormone-sensitive breast cancer is a well-established treatment option, both in adjuvant and palliative settings. For patients undergoing chronic hemodialysis, only scant pharmacokinetic data have been published for tamoxifen, and no data have been published for anastrozole. We therefore measured plasma levels of tamoxifen, its major metabolite, N-desmethyl tamoxifen, and anastrozole in a breast cancer patient undergoing chronic hemodialysis. Clinical tolerability was good. The blood levels for tamoxifen, N-desmethyl tamoxifen and anastrozole were within the expected therapeutic ranges. From this study, we can conclude that endocrine therapy for breast cancer with tamoxifen or anastrozole seems feasible and safe for patients undergoing chronic hemodialysis.

More than 4,000 participants attended the congress and the consensus conference 2005, an increase of more than 1,000 participants. The conference had 2 highlights. (1) The presentation of the first results of the study BIG 1-98 -- letrozole as adjuvant, endocrine therapy in postmenopausal women with hormone-sensitive breast cancer -- showed a relative risk reduction in the disease-free survival of 19% when compared to tamoxifen. (2) The consensus conference adopted 2 new relevant developments: endocrine responsiveness as criterion for both chemotherapy and endocrine therapy. The newly introduced electronic voting system allowed the audience to observe the forming of the panelists' opinions on more than 100 predefined questions.

Anastrozole ('Arimidex') is indicated for the treatment of advanced breast cancer in postmenopausal women. Combined analysis of two international randomised, double-blind trials (n=1021) showed that in patients with hormone receptor-positive tumours, first-line treatment with anastrozole significantly prolonged the time to progression (TTP) compared with tamoxifen (median TTP: 10.7 versus 6.4 months, respectively; P=0.022). Second-line tamoxifen following anastrozole, or vice versa, in this trial population was unblinded. The treatments were crossed over and then efficacy was assessed using a questionnaire. Of 511 patients randomised to anastrozole, 137 (26.8%) received second-line tamoxifen. Questionnaire data were available for 119 patients; 58 (48.7%) gained clinical benefit (CB=complete+partial response (CR+PR)+(stable disease (SD) >/=24 weeks)), while 12 (10.1%) had an objective response (OR=CR+PR). Of 510 patients randomised to tamoxifen, 134 (26.3%) received second-line anastrozole. Questionnaire data from 95 patients showed that 54 (56.8%) gained CB and 7 of the patients gaining CB (7.4%) had an OR. Previous studies showed anastrozole is effective after first-line tamoxifen. These data show that the sequential administration of first-line anastrozole followed by tamoxifen provides effective use of these drugs in the treatment of postmenopausal women with advanced breast cancer.

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.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.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 ofor = 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.In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.

In a phase II trial, 43 patients with hormone-refractory prostate cancer were treated with gemcitabine at a dose of 1,200 mg/m2 over 2 hours (later decreased to 1,000 mg/m2 due to hematological toxicity) on days 1, 8 and 15 of a 28 day cycle.Inclusion criteria were proven tumor progression after hormonal treatment and increased PSA levels, a WHO PSor = 2, adequate bone marrow reserve, liver and renal function and ageor =, 80 years. Response criteria were based on PSA levels (CR: normalization of PSA, PR:50% decrease). Quality of life (QL) was assessed with the EORTC QLQ-C30 on day 1 of each treatment cycle and on day 8 of the first cycle (range of scales 0-100). Physician-rated pain intensity and use of pain medication were assessed at the same timepoints.Hematological toxicity of gemcitabine led to a dose-reduction in 48% of all cycles. Three of forty-three patients (RR = 7%) showed a PSA response: one CR and three PR with time to treatment failure of 8.7, 6.6 andor = 9.3 months. Seven patients (16%) had stable disease (NC) for a median duration of 7.1 months (range 6.1-11.7 months). There was one case with objective regression of lymph node metastases. Patients reported a considerably impaired health status/QL (n = 41, median = 50) and severe fatigue (n = 41, median = 55.6) at baseline, with no change under treatment. Pain (QLQ-C30) was also severe at baseline (N=41, median=50) but was improved at the end of cycles 1 (n = 33, median change = -16.7, P = 0.0002), 2 (n = 19, median change = -33.3, P = 0.0006), 3 (n = 14, median change = -16.7, P = 0.06) and 4 (n = 9, median change = -33.3, P = 0.04). Patient-rated pain and use of analgesics as combined endpoint yielded palliation for at least 8 weeks in 14 patients (32%). Nine of these patients showed at least stable disease (CR/PR or NC by PSA level), five indicated a benefit in spite of progressive disease.Gemcitabine in the dose and schedule indicated above has a significant beneficial impact on pain in patients with hormone-refractory prostatic carcinoma despite its limited activity in terms of PSA response and considerable, especially hematological, toxicity.

The proper time to commence adjuvant chemotherapy after primary surgery for breast cancer is unknown. An analysis of the International (Ludwig) Breast Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested that early initiation of adjuvant chemotherapy might improve outcome for premenopausal, node-positive patients whose tumors did not express any estrogen receptor (ER).We investigated the relationship between early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788 premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The disease-free survival for 599 patients (84 with ER-absent tumors) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for 1,189 patients (142 with ER-absent tumors) who started chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years.Among patients with ER-absent tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group (226 patients; hazard ratio [HR], 0. 49; 95% confidence interval [CI], 0.33 to 0.72; P =.0003). This difference remained statistically significant in a Cox multiple regression analysis controlling for study group, number of positive nodes, tumor size, age, vessel invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P =.019). Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P =.40).In premenopausal patients with ER-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. Further confirmatory studies are required before any widespread modification of current clinical practice. In premenopausal patients with tumors expressing some ER, gains from early initiation are unlikely to be clinically significant.

The Swiss Group for Clinical Cancer Research (SAKK) compared efficacy and toxicity of formestane (250 mg intramuscularly (i.m.) every 2 weeks) versus megestrol acetate (MGA; 160 mg orally daily) as second-line treatment in postmenopausal patients with advanced breast cancer and disease progression while on tamoxifen treatment in a randomised trial (Thürlimann B, Castiglione M, Hsu Schmitz SF, et al. Eur J Cancer 1997, 33, 1017-1024). Quality of life (QL) was evaluated as a secondary endpoint (n = 177). Overall, 83% (669/805) of expected QL forms were received, 88% (155/177) at baseline, 88% (402/457) on study treatment, and 65% (112/171) at treatment failure. Patients with no impairment in performance status reported better physical well-being (P = 0.0001), mood (P = 0.0007) and coping (P = 0.03), and less tiredness (P = 0.0001) and appetite/sense of taste disturbance (P = 0.0001) at baseline. After adjustment for baseline, there was no statistically significant difference in QL by treatment. Baseline QL was strongly predictive for QL under treatment but not for time to treatment failure. In conclusion, the question of whether oestrogen deprivation (e.g. formestane) or addition of progesterone (MGA) has a more beneficial impact on QL needs further investigation. The subjective experience of second-line endocrine treatment varies considerably as a consequence of the large variation in the individual course of the disease and has to be judged on an individual basis.

There is evidence in the literature of a relationship between dose and response to adjuvant chemotherapy for breast cancer, although published results are conflicting. We therefore retrospectively analysed the role of dose response in patients included in four adjuvant trials of the International Breast Cancer Study Group (IBCSG, formerly the Ludwig Breast Cancer Study Group (trials I, II, III and V), all using 'classical' cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). A total of 1385 node-positive patients were treated with oral cyclophosphamide, and intravenous methotrexate plus 5-fluorouracil (CMF) for at least six 4 week courses. 1350 of these were included in 6 month landmark treatment outcome analyses. A total of 1029 patients were premenopausal, 321 were postmenopausal; 800 had one to three and 550 more than three involved axillary nodes at surgery. The median follow-up ranged from 12 years for trial V to 15 years for trials I-III. Patients were grouped according to three prospectively defined dose levels based on the percentage of the protocol prescribed dose that was actually administered (level Ior = 85%, level II 65-84%, level III65%). Patients who received dose level II had a higher disease-free (P = 0.07) and overall survival (P = 0.03) than those who received a higher (level I) or lower (level III) percentage. The 10 year overall survival was 60% for dose level II, 56% for dose level I, 51% for dose level III. The results were generally consistent within trial, menopausal status, and oestrogen receptor status groups. The results within nodal groups showed a large difference among the dose levels for the group with one to three positive nodes (P = 0.02), but no difference for the group with four or more positive nodes. Our results indicate that the dose-response effect remains a crucial factor in adjuvant chemotherapy of breast cancer. Reductions larger than 35% in the dose administered of oral CMF adversely influenced the outcome of breast cancer patients and should be avoided. The better outcome of the intermediate dose group indicates the need to investigate other aspects involved in the cytotoxicity of adjuvant CMF chemotherapy.

Quality of life (QL) is used to assess treatments in clinical trials but may be influenced by other factors. We analysed the impact of biomedical, sociodemographic and cultural factors on baseline QL indicators in two International Breast Cancer Study Group trials. Patients with stage II breast cancer were randomized within 6 weeks of primary surgery to various adjuvant treatments. They were asked to assess five indicators of QL at baseline. QL forms were available for 1231 (83%) of the 1475 premenopausal and 989 (82%) of the 1212 post-menopausal patients, who were from nine countries and spoke seven languages. Culture (defined as language/country groups) had a statistically significant impact on baseline QL measures. Premenopausal patients with poor prognostic factors showed a tendency to report worse QL, with oestrogen receptor status as an independent predictor for mood (P = 0.0005). Older post-menopausal patients reported better emotional wellbeing (P = 0.002), mood (P = 0.002), and less effort to cope (P = 0.0009) compared with younger post-menopausal patients. Co-morbidity, type of surgery, treatment assignment and sociodemographic factors showed a statistically significant impact in post-menopausal patients only. Cultural and biomedical factors influenced baseline QL and should be considered when evaluating the impact of treatment on QL in international breast cancer clinical trials.

The aim of the study was to compare efficacy and tolerability of the new aromatase inhibitor formestane (Lentaron) with megestrol acetate (Megestat) (MGA) in postmenopausal patients with advanced breast cancer. 179 patients were randomised to receive either 250 mg formestane intramuscularly biweekly or MGA 160 mg orally daily. 51% of the patients had received tamoxifen as adjuvant treatment; 73% of the patients had positive and 16% unknown oestrogen receptor values. The response rate was 17% in both treatment arms (95% confidence interval 10-26% for formestane and 10-27% for MGA). Disease stabilisationor = 6 months was seen in 25% of the formestane and 22% of the MGA patients. Time to treatment failure was 120 days in the formestane arm and 111 days in the MGA arm. There was no significant difference between the treatments with regard to response rate and time to treatment failure. Overall toxicity was similar in both arms, but weight gain3 kg (P = 0.081) and severe cardiovascular toxicity (P = 0.044) were more frequently observed with MGA, e.g. deep vein thrombosis 0/90 formestane versus 5/81 MGA cases (P = 0.022). Formestane was associated with worsening of hot flushes/sleeping problems (P = 0.051) and mild leucopenia (P = 0.004). In our study, formestane and MGA showed similar antineoplastic activity as second-line hormonal treatment for advanced breast cancer. Both drugs have a specific toxicity profile. MGA was associated with significantly more severe cardiovascular toxicity and weight increase than formestane.

In this chapter the behavior and strength of simple structures made of reinforced or prestressed concrete is investigated with the aid of stress fields. In particular, the webs and flanges of beams, simple walls, brackets, bracing beams and joints of frames are investigated. By this means, the majority of design cases are already covered.

In chapter 2 it was shown that for the dimensioning of beams basically two methods are possible. The first method, called the Integral Method, involves developing a stress field for the whole structure. In the second method, called the Sectional Method, the stress resultants are determined firstly using conventional statical methods (elastic and plastic analysis). The dimensioning is then carried out for the governing regions with the aid of equilibrium considerations in suitable sections. In the case of simple sectional forms and distributed loads design formulas have been derived (Figs. 2.36, 2.51 and 2.59).

Since in statically indeterminate structures more than one distribution of internal forces, which fulfils equilibrium is possible, further criteria are possibly necessary in design to guarantee a satisfactory structural behavior at working load. To explain this observation, the behavior of a statically indeterminate structure is considered. Elastic and plastic design methods are compared. Then the behavior at working load of an elastically designed structure is compared to that of a plastically designed structure. From these investigations criteria are obtained for the choice of suitable stress fields.

The stress-strain relations for the usual types of reinforcing steels are shown in Fig. 3.1a.

So far all numerical examples have been presented without any recourse to computer programs. In many, if not to say in most practical cases the use of hand calculations possibly supported by some auxiliary programs are completely sufficient and also economically competitive.

The aim of statical analysis is to design, calculate and erect a structure in such a way that the demands of strength, functionality and durability are fulfilled. Important parts of the design process are the dimensioning, i.e. fixing the dimensions and the reinforcement, and the detailing, i.e. the arrangement of the reinforcement, and the layout of reinforcing bars, joints and supports etc. Up to the present time empirical rules based on years of practical experience and test results have been applied for design and construction purposes. What these lack, however, is a unified theoretical basis.

In patients with metastatic breast cancer, cure is almost always an exception, irrespective of the therapy given. Thus the preservation of the quality of life or palliation in case of symptoms must be the principal goal. Only a small group of patients with their tumour showing a highly aggressive behaviour should be considered for primary chemotherapy. Aggressive tumour growth is then characterized by negative hormonal receptors, short disease-free interval and predominant visceral tumour growth. For all other patients there is not enough advantage to justify the clearly higher toxicity of a primary chemotherapy. This majority of patients with metastatic breast cancer can profit to a higher degree from hormonal treatment. Irrespective of the type of the hormonal therapy, the response rate is positively correlated with postmenopausal status, high hormonal receptor expression, al long disease-free interval, no previous adjuvant therapy and higher age. Advantages and problems of the various forms of hormonal manipulations are discussed. The recommended sequence of therapy represents only a handrail that needs to be adjusted carefully, according to the individual situation, the needs and expectations of the patient and in due knowledge of the toxicity of each hormonal substance. Combinations of different hormonal agents do not yield an additional benefit and should therefore be dropped for a sequential approach.

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

This prospective, randomized, double-blind study assessed whether the addition of dexamethasone to ondansetron leads to improved control of chemotherapy--induced emesis, both in patients undergoing their first course of highly emetogenic chemotherapy and in chemotherapy-pretreated patients refractory to standard anti-emetics.Patients were randomized to receive either 20 mg dexamethasone as an intravenous infusion or placebo plus ondansetron 8 mg 15 minutes prior to and 4 and 8 hours after the administration of chemotherapy. According to the randomisation code patients received from day 2 to day 5 either ondansetron 8 mg p.o. + placebo p.o., three times daily, or ondansetron 8 mg p.o. + dexamethasone 4 mg p.o., three times daily. Patients undergoing multiple-day treatment received intravenous study treatment on the days of chemotherapy and thereafter oral treatment as outlined above.A total of 215 patients were entered into the study. Of these, 207 were evaluable (111 previously-untreated and 96 previously-treated patients). In the chemotherapy-naive patients the combination of ondansetron plus dexamethasone was significantly superior to ondansetron plus placebo in protecting the patients completely from emesis (retching and vomiting) (81% versus 64%, p = 0.04). The mean number of vomiting episodes was significantly lower in the ondansetron-plus-dexamethasone-treated patients than in those receiving ondansetron plus placebo (0.8 versus 2.1, p = 0.03). In this group of patients there was significantly superior protection from emesis on the second day (p-value = 0.04), and a trend towards a better protection on the third and fourth days. On each day the active combination offered better protection from nausea with an approximately 20% difference in favor of ondansetron plus dexamethasone. In the group of established vomiters the combination of ondansetron plus dexamethansone was superior to ondansetron plus placebo in protecting the patients from acute emesis, with 70% versus 48% of the patients being completely protected (p = 0.03). The mean number of vomiting episodes was significantly lower in the ondansetron-plus-dexamethasone-treated-patients than in those receiving ondansetron plus placebo (0.9 versus 2.1, p = 0.02). In the ondansetron-plus-dexamethasone arm 55% of the patients had complete protection from nausea, retching and vomiting compared to 35% in the ondansetron-plus-placebo-treated group (p = 0.05). Overall 22% of the patients (20% in the ondansetron-plus-placebo and 25% in the ondansetron-plus-dexamethasone arm) experienced at least one, usually mild, adverse event. More patients in the ondansetron-plus-dexamethasone arm complained of epigastric pain or burning (8/101 versus 4/112, p-value = 0.16). The difference in patients reporting constipation (6/101 versus 0/112) was highly significant at a p-value of 0.008.The combination of dexamethasone plus ondansetron is more effective in protecting chemotherapy-naive patients undergoing their first course of highly emetogenic chemotherapy with cisplatin and chemotherapy-pretreated patients refractory to standard antiemetics from chemotherapy-induced nausea and vomiting compared to ondansetron plus placebo.

Bisphosphonates are the treatment of choice in tumor-induced hypercalcemia. Pamidronate (Aredia) is effective in this indication, but few studies have addressed the question of its dose-effect relationship. Review of the published literature suggests that a clinically relevant dose-response relationship exists in the dose range 30-60 mg; most hypercalcemic patients will achieve normocalcemia with a dose of 60 mg pamidronate or more. More recent publications have reported the emerging role of bisphosphonates in the treatment of malignant osteolytic bone disease. Several non-randomized studies have shown beneficial effects from continuous administration of clodronate or pamidronate, though the magnitude of such effects was moderate. Two dose escalation trials with pamidronate showed that regimens with a dose intensity below 20 mg/week and single doses of 30 mg or less were ineffective. One randomized, prospective study compared pamidronate 60 mg with 90 mg given intravenously every 3 weeks. Both regimens showed a significant palliative effect. Patients treated with 90 mg had a greater reduction in pain intensity compared to those receiving 60 mg. Optimal schedules for different patient populations require further investigation.

We have conducted a randomized crossover comparative trial of a single-dose course of disodium (3-amino-1-hydroxypropylidene) bisphosphonate pentahydrate (pamidronate) and plicamycin in 48 patients with a first occurrence of tumor-related hypercalcemia. All patients had hypercalcaemia-associated symptoms and serum-calcium levels (corrected for total protein) greater than or equal to 2.80 mmol/l. Pamidronate and plicamycin were given concurrently with rehydration immediately after diagnosis of hypercalcaemia was made. Both agents lowered serum calcium levels significantly within 1 week, with 88% of the evaluable patients in the pamidronate group and 45% of those in the plicamycin group achieving normocalcemia (p less than 0.01). In the patients who received pamidronate, the duration of normocalcemia was longer (p less than 0.05) and there was a significant decrease in serum creatinine (p less than 0.05). Vomiting occurred in 8 of 22 evaluable patients (36%) who received plicamycin, but in none of 25 evaluable patients who received pamidronate (P less than 0.01). Phlebitis occurred at the infusion site in more of the pamidronate-treated patients (P less than 0.05). Hypocalcemia, which occurred in 8 of 25 evaluable patients (32%) in the pamidronate group and in 1 of 22 of those (5%) in the plicamycin group, was either clinically asymptomatic or mild, except in one pamidronate-treated patient. Overall, pamidronate was found to be more effective and better tolerated than plicamycin, thereby confirming results of previous studies that showed pamidronate to be an effective, simple, and safe agent for the relief of the morbidity associated with tumor-related hypercalcemia.

In a prospective randomised trial patients receiving multiple-day chemotherapy and heparin had significantly fewer local complications at the site of venous access than patients who had chemotherapy alone. The need to move peripheral venous catheters to other sites was decreased significantly, from 36% to 6%. Prophylaxis of phlebitis with low-dose continuous heparin is safe, simple, cheap and effective. It facilitates administration of multiple-day chemotherapy for the patients, the nurses and the physicians.