Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma.

The aim was to evaluate the activity of cisplatin and vinorelbine in previously untreated, inoperable patients having histologically verified malignant pleural mesothelioma (MPM), normal organ function, and performance status 0-2. Treatment was vinorelbine 25 mg m(-2) i.v. weekly and cisplatin 100 mg m(-2) i.v. every 4 weeks with hydration and standard prophylactic antiemetic treatment. Patients gave written informed consent. Characteristics of 54 consecutive patients were: males 85%, epithelial subtype 74%, IMIG stages III and IV 35 and 46%, performance status 0, 1, and 2, 26, 69, and 6%, and median age 63 years (31-78 years). CTC grade 3 or 4 toxicity occurred with respect to leukocytopenia (48% of patients, grade 4 in 13%), nausea (13%), neurotoxicity (11%), nephrotoxicity (4%), and other toxicities (9%). There were no toxic deaths. The median number of cycles was four. The fraction of patients alive at 1-, 2-, and 3-years were 61, 31, and 4%, respectively, and median survival and median time to progression were 16.8 months (0.5 to 46.4 +months) and 7.2 months (1.6 to 40.6 + months). There were two CRs and 14 PRs (response rate 29.6%). Cisplatin and intravenous vinorelbine is a highly active regimen in MPM with a response rate and survival comparable to the most active regimens so far reported.

Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group.

PURPOSE: To evaluate if the timing of chest irradiation with respect to chemotherapy would influence survival and local and distant control in patients with limited-stage small-cell lung cancer (LSCLC). PATIENTS AND METHODS: From 1981 to 1989, 199 consecutive patients with LSCLC were randomly allocated to receive initial chest irradiation (ICI; n = 99) or late chest irradiation (LCI; n = 100) given 18 weeks delayed. Both groups received the same nine cycles of combination chemotherapy: three cycles of cisplatin and etoposide and six cycles of cyclophosphamide, doxorubicin, and vincristine. In the first part of the study, prophylactic cranial irradiation (PCI) was only given to patients randomized to ICI, but after inclusion of 42 patients in the LCI arm, the protocol was changed, so that all patients received PCI independent of the timing of the chest irradiation (CI). A total of 157 patients received PCI with a radiation dose of 25 Gy in 11 fractions. RESULTS: The timing of radiotherapy had no significant effect on the 2-year overall survival rate (20% after ICI v 19% after LCI, P = .4) or the 2-year in-field recurrence rate (72% after ICI v 68% after LCI, P = .2). Median survival durations were 10.5 (ICI) and 12.0 (LCI) months. Similarly, no difference in the 2-year incidence of CNS recurrences was found between the 2 arms in patients who received PCI (19% after ICI v 13% after LCI, P = .24). Bone marrow toxicity was acceptable, as 15% developed World Health Organization (WHO) grade 4 leukocytopenia and 4% grade 4 thrombocytopenia. Grade 4 leukocytopenia was more pronounced in the ICI group. There was no difference in the frequency and severity of other toxicities between the 2 groups. CONCLUSION: Timing of CI did not significantly influence the incidence of in-field recurrences, CNS recurrences, or overall survival.

Prophylactic cranial irradiation in limited stage small cell lung cancer: survival benefit in patients with favourable characteristics.

The value of prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) remains controversial. As part of a randomised study investigating the timing of chest irradiation (CI) with respect to combination chemotherapy, the effect of PCI was evaluated. Between 1981 and 1989, patients were randomised to initial chest irradiation ICI (99 patients) or 18 weeks delayed late chest irradiation LCI (100 patients). PCI was given to 157 patients. In the beginning, only ICI patients received PCI, but in October 1984 the strategy was changed so that all patients received PCI. Thus, the patients who did not receive PCI were randomly allocated. The PCI dose was 33 Gy/11 fractions (45 patients) and 25 Gy/11 fractions (112 patients). The 2-year CNS-recurrence rate (+/- standard error) was significantly lower in patients who received PCI, 16.3 +/- 4.1%, than in those who did not, 55.1 +/- 12.4% (p = 0.01). In contrast, the 2-year cause-specific survival was not significantly different, 24.9 +/- 3.6% and 16.9 +/- 6.2% (p = 0.31). The 2-year progression-free rates with or without PCI were 18.5 +/- 3.3% and 11.4 +/- 5.4%, respectively (p = 0.58). To test the hypothesis that a benefit from PCI would mainly be expected among the patients with the best prognosis, a multivariate regression analysis of prognostic factors was undertaken. Based on weight loss, performance status, serum sodium and age, the third of the patients with the best prognosis were identified. In that group of patients, the survival advantage from PCI was statistically significant, 35.5 +/- 7.2% versus 14.1 +/- 8.0%, P = 0.029. These results are currently being tested in a Danish multicentre trial where patients with a good prognosis are randomised either to receive PCI or not to receive PCI.

Synergistic and antagonistic effects of myeloid growth factors on in vitro cellular killing by cytotoxic drugs.

The effect of stimulating acute myeloid leukemia blast cells with a combination of growth factors (G-CSF, GM-CSF, and IL-3) on cellular resistance to the antileukemia drugs Ara-C, daunorubicin, aclarubicin, and mitoxantrone was studied. For assessment of in vitro cellular drug resistance the MTT assay was employed. Stimulated cells showed enhanced sensitivity to Ara-C (p < 0.02), whereas a significant increase in cellular drug resistance to daunorubicin (p < 0.02) was observed. Variable and statistically non-significant changes in drug resistance to aclarubicin and mitoxantrone was induced by stimulation of the blast cells. We conclude on the basis of these observations that myeloid growth factors should be used with caution in combination with daunorubicin in AML treatment until further confirmatory evidence has been presented by other investigators.

Relevance of in vitro leukaemia cell survival to short- and long term clinical outcome in AML.

In ninety-three cases of newly diagnosed acute myeloid leukaemia (AML) we investigated the importance to short- and long term clinical outcome of the in vitro short term leukaemia cell survival as measured by a 4-day MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)-assay. In 67 patients treated by intravenous remission induction therapy we found that patients who after the first induction cycle or after induction therapy overall achieved a complete remission (CR) had leukaemia cells with significantly lower in vitro cell survival ability than cells of non-responders (p = 0.02 and 0.06, respectively). These relations remained statistically significant in subsequent multivariate analyses. Likewise, a favourable effect of low in vitro leukaemia cell survival on overall survival of the patients was detected in the (largest) subgroup of adult patients treated uniformly by the same remission induction regimen as well as in all patients. However, in the 44 patients, who achieved CR, the in vitro leukaemia cell survival did not show significance to remission duration or time to first relapse. Furthermore, the leukaemia cell survival (MTT-assay) did not to correlate with the Bcl-2 expression level (quantitative flow cytometry) of the leukaemia cells (r = 0.18, n = 34, p = 0.32). In addition, in a cell line model employing the growth factor dependent MO7 human AML cell line, growth factor withdrawal was associated with rapid onset of cellular apoptosis as evaluated by morphology, occurrence of a subG1 peak in DNA histograms, and loss of cellular activity in the MTT-assay. In contrast, a more moderate decline in Bcl-2 expression and gradual loss of ability to exclude the trypan blue dye was seen in the leukaemia cells in response to growth factor withdrawal. We conclude, that the MTT-assay provides a simple and sensitive method for measuring in vitro cell survival. The differences in leukaemia cell survival seen in AML may well be clinically relevant and may help to provide a better understanding of clinical drug resistance.

Principles and indications of endocrine treatment of advanced breast cancer.

The numerous trials that have been conducted in advanced breast cancer in premenopausal and postmenopausal women have increased the empiric basis for systemic cytotoxic and endocrine treatment. The treatment results have improved but are still very unsatisfactory, and with all the drugs now at our disposal many questions are still unanswered. For instant this applies to the optimal composition and scheduling of endocrine treatment, cytotoxic treatment, and combinations of these two treatments. During recent years the results of experimental studies have expanded our knowledge of the biology of breast cancer. Future clinical trials should be designed to test and use this information gained from basic research with the aim of improving the rational basis of treatment and obtaining better treatment results in advanced breast cancer.

PIP: This paper summarizes the available data on the efficacy of endocrine and cytotoxic therapy for breast cancer in pre- and postmenopausal women. Various studies which were conducted suggested that regardless of hormone receptor status, premenopausal women should receive combined endocrine and cytotoxic therapy. However, it is now believed that future trials should take into account hormone receport status. For ER+ tumors, the standard initial treatment should be ovariectomy and later tamoxifen and chemotherapy could be added. A table, included in this brief review, summarizes treatment strategy for premenopausal women. If ER status is unknown treatment should include ovariectomy and combination chemotherapy; if ER+, ovariectomy along with tamoxifen and chemotherapy if indicated; and if ER-, then only combination chemotherapy. To a great extent, antiestrogens have been substituted in the treatment of breast cancer in postmenopausal women. Estrogens have been administered most widely and induce up to a 30% response; trials with antiestrogens have obtained similar results and thus tamoxifen is being used widely. Also it appears that the effect of treatment is related to the presence of estrogen receptors in the tumor tissue and thus 50-70% of ER+ tumors will respond to estrogens or antiestrogens. Tamoxifen apears to have a lower frequency and milder degree of side effects. Multi-drug therapy has now superseded single drug treatment in the last 5-10 years. If ER status in postmenopausal patients is unknown, the 1st treatment should be chemotherapy for women under age 60-70 and endocrine therapy for the 2nd treatment. In women older than 60-70, the preferred 1st choice therapy should be endocrine. For premenopausal women, those with ER+ tumors, endocrine therapy with tamoxifen should be the therapy of choice; in those with ER- tumors, chemotherapy should be the lst treatment.

Therapeutic effect of tamoxifen alone versus tamoxifen in combination wtih gestagen and oestrogen in advanced breast cancer.

PIP: 2 clinical studies of postmenopausal patients, all under 68 years old and resistant to chemotherapy, with breast cancer are reported. In Study 1, 46 patients were randomized to treatment with 10 mg of tamoxifen (TAM) 3 times daily and 55 were randomized to treatment with 10 mg of TAM 3 times daily plus 100 mg of medroxy progesterone acetate (MPA) once daily. Combined partial and complete (PR+CR) remission occurred in 20 patients (45%) with TAM vs. 14 patients (26%) with the combined TAM+MPA therapy. This difference, however, was not significant (P .02); in addition, the median duration of remission was not significantly different between the 2 therapies:6-15 months with TAM alone compared with 4-17+ months with the combined TAM+MPA treatment. 12 patients experienced side effects. Rate of response was correlated with the presence of estrogen receptor, but there were no significant differences between the 2 therapy groups. In Study 2, results of 38 randomized patients treated with 10 mg of TAM 3 times daily and 32 randomized to treatment with 10 mg of TAM 3 times daily plus 1 mg of diethylstilbestrol (DES) 3 times daily are presented. PR+CR was achieved in 16 patients (42%) with TAM alone vs. 12 patients (38%) treated with the combined TAM+DES therapy (P .08). As in Study 1, response rates were related to the presence of ER. Median duration of remission with the 2 treatments was 6+ and 5+ months, respectively. Side effects occurred in 4 patients treated with TAM alone and in 15 patients treated with TAM+DES.^ieng

Adjuvant endocrine therapy of breast cancer--a controlled clinical trial of oestrogen and anti-oestrogen: preliminary results of the Copenhagen breast cancer trials.

In an attempt to clarify the value of adjuvant endocrine therapy as an alternative to other treatment modalities, we have started two controlled, prospective, double-blind trials, the Copenhagen Breast Cancer Trials. In these studies postmenopausal women are randomised after primary local treatment to treatment with DES, tamoxifen, or placebo. Premenopausal women are similarly randomised to receive treatment with tamoxifen or placebo. Entry to the trials was closed in March 1978, when 343 patients had entered the studies. The preliminary results indicate that postmenopausal patients with ER+ tumours benefit from adjuvant treatment with tamoxifen. Adjuvant treatment with DES seems to be effective in ER- postmenopausal patients. In postmenopausal patients the ER+ tumors have a lower rate of recurrence. At present these preliminary results do not permit definite conclusions.

Therapeutic effect of tamoxifen related to estrogen receptor level.

Cytoplasmic oestrogen receptor (ER) determinations were performed in 59 postmenopausal patients with metastatic breast cancer. Fifty percent of the patients were found to be ER+. Forty patients were treated with tamoxifen (TAM) and 19 patients were treated with tamoxifen plus medroxyprogesterone acetate (MPA). The response rate of TAM-treated patients was 30% (12/40). Of the 21 ER+ patients, ten (48%) responded to therapy. The ER values of these patients were significantly higher than the ER values of nonresponders (P less than 0.01). No correlation could be found between the ER value and the duration of remission in TAM-treated patients.

PIP: In this study of 59 postmenopausal patients with metastatic breast cancer, the therapeutic effect of tamoxifen (TAM) and/or TAM plus medroxyprogesterone acetate (MPA) was investigated and its effectiveness was related to the patients estrogen receptor (ER) levels. 3 studies are discussed: 1) Study 1, in which TAM was used alone; 2) Study 2, in which TAM was tested against TAM+MPA; and 3) Study 3, in which TAM was tested against TAM+diethylstilbestrol (DES). In this unselected population of post menopausal patients with metastatic breast cancer, the overall response rate to TAM treatment was 80% (12/40). Of 21 ER positive patients, 10 (48%) responded to TAM therapy. The ER values of these patients were significantly higher than the ER values of nonresponders (P .001), but no correlation was found between the ER value and the duration of remission in TAM-treated patients. These results are from the population of Studies 1 and 2; Study 3's population was too small for significant findings to be reported.

Randomised controlled trial of a shared care programme for newly referred cancer patients: bridging the gap between general practice and hospital.

OBJECTIVE: To determine the effect of a shared care programme on the attitudes of newly referred cancer patients towards the healthcare system and their health related quality of life and performance status, and to assess patients' reports on contacts with their general practitioner (GP). SETTING: Department of Oncology at Aarhus University Hospital and general practices. DESIGN: Randomised controlled trial in which patients completed questionnaires at three time points. The shared care programme included transfer of knowledge from the oncologist to the GP, improved communication between the parties, and active patient involvement. PARTICIPANTS: 248 consecutive cancer patients recently referred to the department. MAIN OUTCOME MEASURES: Patients' attitudes towards the healthcare services, their health related quality of life, performance status, and reports on contacts with their GPs. RESULTS: The shared care programme had a positive effect on patient evaluation of cooperation between the primary and secondary healthcare sectors. The effect was particularly significant in men and in younger patients (18-49 years) who felt they received more care from the GP and were left less in limbo. Young patients in the intervention group rated the GP's knowledge of disease and treatment significantly higher than young patients in the control group. The number of contacts with the GP was significantly higher in the intervention group. The EORTC quality of life questionnaire and performance status showed no significant differences between the two groups. CONCLUSIONS: An intersectoral shared care programme in which GPs and patients are actively involved has a positive influence on patients' attitudes towards the healthcare system. Young patients and men particularly benefit from the programme.

[Cross-sectorial cooperation regarding cancer patients in a recently started care program. Ideas and themes based on focus group interviews with general practitioners and oncologists]. / Tvaersektorielt samarbejde omkring kraeftpatienter i nystartede behandlingsforløb. Ideer og temaer udsprunget af fokusgruppeinterview med praktiserende laeger og onkologer.

This study identified ideas for an improved collaboration between general practitioners and oncologists regarding patients with cancer. A qualitative research-method with focused group interviews was chosen. The results demonstrated that both oncologists and general practitioners would like the general practitioners to take more active part in the total care programme for cancer patients. Some of the needed improvements were more detailed referral letters including description of treatment plans, information about what the patient had been told and general information about the specific cancer disease. Both parts desire bilateral information exchange and a dialogue about the distribution of tasks. Both parts are willing to collaborate but this is at present restricted due to lack of knowledge of each others' working areas and the oncologists' impression that general practitioners need more medical knowledge regarding specific aspects of cancer. A randomized intervention study using ideas from this study may clarify if it is possible to improve the collaboration and thereby the cancer patients' satisfaction with care.

[Attitudes to autopsy among critically ill patients and the general population]. / Holdninger til obduktion blandt alvorligt syge samt i befolkningen.

Attitudes towards autopsy were investigated by a questionnaire given to 60 cancer patients, 30 patients with severe cardiac disease and 132 healthy people without known disease. Eighty-five percent of the patients and 82% of the healthy people had a positive attitude towards autopsy. A majority (65-72%) found that permission should be given by the patient rather than the family. Only 6% of patients and 13% of the healthy people would refuse to give permission to autopsy, 71% and 47% would give permission and 10% and 25% would consent to autopsy under certain conditions. both groups were more reluctant to give consent to the performance of an autopsy on a relative. It is concluded that hospital routine should be changed so that patients should be asked whether they would permit an autopsy to be performed in event of their decease.

[Preventive strategies against infections in autologous bone marrow transplantation]. / Infektionsstrategi ved autolog knoglemarvstransplantation.

The routine microbial surveillance, the prophylatic antibiotic regime and the management of infections were retrospectively evaluated in 26 autologous bone marrow transplantation episodes. The surveillance specimens indicated that ciprofloxacin prophylaxis was effective in minimising gram-negative functions. The comparison between specimens taken before and during the granulocytopenic period showed a shift towards more yeast, otherwise there were no big differences. The surveillance specimen could not identify the causative organisms in case of fever. The proven infections comprised four cases of bacteriaemia and one case of gastro-enteritis. Two patients died from disseminated Aspergillus infection not diagnosed prior to death. In 11 episodes the cause of fever remained unknown. Both fungal infections were related to nearby building construction work. None of the patients with bacterial infections were in a serious clinical condition. In the future the number of routine microbial surveillance specimens will be reduced. The aim of surveillance will be to monitor the potential occurrence of fluoroquinolone resistance, and more attention will be paid to possible fungal infections. The antibacterial policy will be continued.