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.

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.

Pretreatment leukaemia cell drug resistance is correlated to clinical outcome in acute myeloid leukaemia.

In 85 adult patients diagnosed with acute myeloid leukaemia (AML) and treated at the same institution during a 5-yr period, the clinical significance of in vitro cellular drug resistance to the anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as the nucleoside analogue cytarabine (Ara-C) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. In 59 patients of whom 40 were treated by the combination of Acla and Ara-C we found that leukaemia cell drug resistance towards Acla was higher (by a factor 2.80) in patients who failed to enter complete remission (CR) after the first cycle of induction chemotherapy as compared to patients who entered complete remission. The relationship was significant in univariate as well as multivariate analysis (p=0.02 and 0.03, respectively). By contrast, no in vitro single drug resistance values were consistently correlated to other parameters of clinical outcome (overall CR rate, overall survival (OS), or continuous complete remission (CCR)), whereas the combined Acla and Ara-C drug resistance profile (Acla/Ara-C DRP) was of prognostic significance to overall survival of all 85 patients (p=0.004) as well as to the CCR of 39 complete responders (p=0.04). These findings remained statistically significant in multivariate analyses correcting for other variables influencing clinical outcome including patient age, leukocyte count, karyotype, FAB-subtype, and presence/absence of secondary AML. We conclude that the in vitro drug resistance of leukaemia cells at time of disease presentation appears to be independent of prognostic significance to short- and long-term clinical outcome in AML.

[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.

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.

MDR1 gene expression and drug resistance of AML cells.

We investigated the cellular drug resistance to aclarubicin (Acla), cytosine arabinoside (Ara-C), daunorubicin (Dau), doxorubicin (Dox), etoposide (Etop) and mitoxantrone (Mitox) using the MTT assay at time of disease presentation in 93 cases of acute myeloid leukaemia (AML). In 31 cases we concomitantly investigated MDR1 (multiple drug resistance 1 gene) expression (semi-quantitative competitive RT-PCR) of the leukaemic cells. Drug resistance towards Dau, Dox and Etop was correlated to the MDR1 expression of the AML cells (P<0.05) with high MDR1 expression being associated with high drug resistance towards these drugs. Although the data did not allow firm conclusions to be drawn on the correlation between MDR1 expression and drug resistance towards Ara-C and Mitox, the drug resistance towards Acla clearly was not correlated to, or dependent on, the MDR1 expression level of the AML blast cells. In addition, when examining the cross-activities among the six drugs distinct patterns emerged. Thus, high to very high degrees of cross-activity were found to exist between Dau, Dox, Etop and Mitox, whereas Ara-C had moderate cross-activity with the other drugs except Acla, which showed absent to moderate cross-activity with the other drugs. We conclude that MDR1 gene expression is of significance for cellular drug resistance towards specific (MDR1-related) drugs in AML, whereas it is not of significance regarding drug resistance towards other drugs, which is the case with the anthracycline Acla. We suggest that in the place of other more or less complicated ways to circumvent MDR1-mediated drug resistance, Acla may be used to replace Dau, Dox and other MDR1-related drugs if proven as potent as the drug it is to substitute.

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.

[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.

Myeloid progenitors in remission bone marrow in patients with malignant blood diseases: clues for slow hematopoietic regeneration after ABMT?

Slow hematopoietic recovery is a well-known feature in patients undergoing autologous bone marrow transplantation (ABMT), and here we demonstrate that compared with patients with other malignant blood diseases, the thrombocytopenia in acute myeloid leukemia (AML) patients stands out, with the median time to recovery of > 50 x 10(9) platelets being 101 days for AML patients and 22-37 days for other patient groups. We have consequently evaluated the content and fate of myeloid progenitor cells (BFU-E, CFU-GM, and CFU-GEMM) in bone marrow preparations from cancer patients in an attempt to uncover factors of importance for their slow hematopoietic recovery after ABMT using three experimental setups. First, we analyzed progenitors in marrow samples from 36 patients [18 AML, 5 acute lymphoblastic leukemia (ALL), and 13 non-Hodgkin's lymphoma (NHL)] exposed to multiple doses of severely myelotoxic cytoreductive regimens and observed that AML patients had suppressed numbers of CFU-GEMM and BFU-E (80% that of normal volunteers) but increased levels of CFU-GM. In contrast, the decrease in ALL patients was more pronounced (50% that of normal volunteers) and demonstrable for all progenitors. NHL patients exhibited normal progenitor frequencies of CFU-GM and CFU-GEMM, whereas their BFU-E counts were found to be increased nearly two-fold. Second, we followed the fate of progenitors through the laboratory manipulations of marrow grafts and found no evidence for selective losses in terms of disease (7 AML, 5 NHL, 1 ALL, and 2 testicular germ cell tumor patients) and progenitor type. Third, we retrospectively evaluated the cell yields of grafts from 121 cases [39 AML, 20 ALL, 22 NHL, 9 Burkitt's lymphoma (BL), 18 Hodgkin's disease (HD), and 13 testicular germ cell tumors] and found those of heavily treated AML, HD, and germinal tumors most affected, with a clear negative correlation in AML patients between age on the one hand and mononuclear cell yield and CFU-GM content on the other. We conclude that the amount of previous chemotherapy and age of patients appear to be among the determining factors on the number of myeloid progenitor cells in cancer patients and that thresholds for acceptability of grafts should take these variables into account.

Relation of blast cell survival and proliferation to chemotherapy resistance in AML.

We have investigated the in vitro blast cell survival (viability) and drug resistance to cytosine arabinoside (Ara-C), daunorubicin (Dau), mitoxantrone (Mitox) and aclarubicin (Acla) of fresh leukaemic blast cells from 80 patients with newly diagnosed acute myeloid leukaemia (AML) employing the semiautomated colourimetric MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)-assay. In 15 cases we concurrently investigated the relation between in vitro blast cell survival (MTT assay) and blast cell proliferation (3H-thymidine incorporation) in the presence and absence of myeloid growth factors (GFs) G-CSF, GM-CSF and IL-3 (individually and in combination). A highly significant correlation was found between blast cell survival and blast cell proliferation (r = 0.87, P < 1 x 10(-4). Furthermore, in 40 evaluable adult patients who completed intravenous induction chemotherapy and were evaluable for response to chemotherapy we found a positive correlation between in vitro blast survival (MTT assay) and response to chemotherapy with high blast survival being associated with poor response to chemotherapy (P = 0.05). Moreover, in a multivariate analysis, high blast cell survival was significantly associated with high CD13 expression and monocytic phenotype (P = 0.0003 and P = 0.02, respectively). Furthermore, we found an inverse relationship between the baseline proliferation of the blasts and the magnitude of response to the GFs (P < 0.02), indicating that cells with low baseline proliferation were more readily stimulated by growth factors. Finally, we found a significant correlation between leukaemic cell survival and cellular drug resistance towards Dau (P = 0.001) and Mitox (P = 0.03), but not towards Ara-C (P = 0.68) and Acla (P = 0.13). We conclude that high in vitro leukaemic cell survival is associated with drug resistance in vivo and in vitro, and furthermore is correlated with high blast cell proliferation and some adverse prognostic factors previously identified in AML.

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.

[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.

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.

Performance status assessment in cancer patients. An inter-observer variability study.

The ECOG Scale of Performance Status (PS) is widely used to quantify the functional status of cancer patients, and is an important factor determining prognosis in a number of malignant conditions. The PS describes the status of symptoms and functions with respect to ambulatory status and need for care. PS 0 means normal activity, PS 1 means some symptoms, but still near fully ambulatory, PS 2 means less than 50%, and PS 3 means more than 50% of daytime in bed, while PS 4 means completely bedridden. An inter-observer variability study of PS assessment has been carried out to evaluate the non-chance agreement among three oncologists rating 100 consecutive cancer patients. Total unanimity was observed in 40 cases, unanimity between two observers in 53 cases, and total disagreement in seven cases. Kappa statistics reveal the ability of the observers compared to change alone and were used to evaluate non-chance agreement. Overall Kappa was 0.44, (95% confidence limits 0.38-0.51). The Kappa for PS 0 was 0.55 (0.44-0.67), while those for PS 1, 2, 3 and four were 0.48 (0.37-0.60), 0.31 (0.19-0.42), 0.43 (0.32-0.55), and 0.33 (0.33-0.45), respectively. If one observer allocated patients to PS 0-2, then another randomly selected observed placed the patients in the same category with a probability of 0.92. For patients with PS 3-4 the probability that the same category would be chosen was 0.82. Overall, the non-chance agreement between observers was only moderate, when all ECOG Performance Status groups were considered. However, agreement with regard to allocation of patients to PS 0-2 versus 3-4 was high. This is of interest because this cut-off is often used in clinical studies.

The effect of tamoxifen on bone mineral content in premenopausal women with breast cancer.

Thirty-one of 62 consecutive premenopausal women with primary cancer of the breast completed a 1-year investigation period, receiving either 30 mg tamoxifen daily (15 patients) or placebo (16 patients). They were examined at the operation (t0) and at 3-month intervals (t1, t2, t3, and t4). Bone mineral content (BMC) was measured at operation and after 12 months. Fifty-six patients with benign tumors were included as healthy controls. All values of both cancer treatment groups and of the benign tumor group were comparable at the time of operation. BMC decreased significantly in both cancer patient groups when 12-month values were compared to the initial level (tamoxifen, -3.2%, P less than 0.001 and placebo -2.5%, P less than 0.01). However, no significant difference in BMC changes was noted between tamoxifen and placebo treatment. The serum phosphate was significantly decreased in the tamoxifen treatment group at each examination. In the placebo group, the alkaline phosphatase level increased significantly at each examination, whereas the serum magnesium fell at the 6- and 12-month examinations. All other biochemical indices of calcium metabolism were basically unchanged. It is concluded that BMC is reduced in metastatic breast cancer through osteolytic metastatic bone foci. Tamoxifen also decreases the BMC. It is, however, unclear if this effect is due to a progression of the disease in spite of the treatment or if it is caused by a direct action of tamoxifen on bone.