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Background: Circulating apoptotic proteins are increased in heart failure patients. We evaluated whether circulating soluble apoptosis-related protein levels change after anthracycline-containing chemotherapy and radiotherapy in relation to cardiac dysfunction or the applied treatment., Patients and Methods: Circulating apoptotic proteins were measured with immunoassay in 40 breast cancer patients following surgery (TO), one month (T1) and one year (T2) after epirubicin-based chemotherapy. Standard-dose (n=21) or high-dose (n=19) myeloablative chemotherapy, preceded irradiation and tamoxifen. Circulating apoptotic proteins were compared with previous cardiac evaluations., Results: Soluble tumor necrosis factor receptor 1 (+30%), 2 (+43%) and Fas (+40%) were transiently increased at T1 compared to T0, whereas Fas ligand (-64%) was transiently decreased, especially in the high-dose group. Apoptosis markers were not associated with cardiac dysfunction., Conclusion: Significant, but transient changes in soluble apoptotic protein levels were observed, particularly after high-dose chemotherapy. No relation was found between apoptosis-related proteins and cardiotoxicity.

Aim: To examine fatigue among testicular cancer patients during the first year after diagnosis., Patients and Methods: Fifteen patients treated with orchidectomy (group 1) and 37 treated with orchidectomy plus chemotherapy (group 2) were assessed within 1 month after orchidectomy, and 3 and 12 months later. Fatigue, sociodemographics, anemia, testosterone levels and trait anxiety were assessed., Results: At TI and T3, the groups reported similar levels of fatigue. Increased fatigue was found in group 2 at T2. A continuing decrease in fatigue was found in group 1. At T3, patients reported similar levels of fatigue as healthy individuals. Older age, trait anxiety and earlier levels of fatigue were predictive of fatigue, while anemia and testosterone levels were not., Conclusion: Fatigue seems not to be an enduring problem for testicular cancer patients, with treatment only having an impact on fatigue levels shortly after treatment. Highly anxious patients and those who were fatigued after orchidectomy might benefit from a multidisciplinary intervention.

Background: Plasma natriuretic peptides are increased in patients with cardiac dysfunction. N-terminal (NT-ANP) and B-type (BNP) natriuretic peptides were measured in disease-free breast cancer survivors, during long-term follow-up after epirubicin (360 mg/m2 or 450 mg/m2 cumulatively) and chest irradiation., Patients and Methods: Plasma samples for natriuretic peptide measurement were repeated after extended follow-up in 54 patients, who had participated in 2 studies evaluating cardiotoxicity., Results: From a median follow-up of 2.7 to 6.5 years, median BNP was raised almost three-fold (p<0.001). Symptomatic heart failure was now present in 2 patients. Compared to the epirubicin 360 mg/m2 group, BNP was higher (p=0.006) in the 450 mg/m2 group, with a trend (p=0.054) for higher NT-ANP., Conclusion: These findings suggest that anticancer therapy initiates an autonomically progressive process that may ultimately lead to symptomatic cardiac dysfunction, years after treatment. BNP measurement may be of value to identify patients requiring intensive cardiac follow-up.

Testicular germ cell tumours are rarely diagnosed in the elderly. In view of the high cure rate of these tumours, even in elderly patients treatment with chemotherapy and/or radiotherapy should be considered. In this report we describe two older patients with metastatic testicular seminoma. Both were treated with chemotherapy with curative intention. Described are the problems related to treatment with chemotherapy in these elderly.

Background: Dose adaptation based on pharmacokinetic parameters has been shown to decrease toxicity of some 5-fluorouracil(5-FU)-based continuous infusion regimens., Patients and Methods: In the present study the relationship between 5-FU pharmacokinetics in plasma and in saliva, and toxicity was investigated in 40 patients receiving the combination of 5-FU 425 mg/m2 and folinic acid 20 mg/m2 daily during 5 consecutive days according to the Mayo-regimen., Results: The overall non-hematological and hematological toxicity, as well as mucositis only, were not statistically significant related to the area-under-the-curve in plasma (AUCp) or in saliva (AUCs), nor to the maximum concentration measured in plasma (Cmaxp) or in saliva (Cmaxs). Although statistically significant, the correlation between the AUCp and AUCs was relatively low, implying that salivary pharmacokinetics are not accurately predictive of plasma pharmacokinetics., Conclusion: The conclusion of this study is that the application of pharmacokinetic parameters is not appropriate for identification of patients at risk for developing toxicity from treatment with 5-FU according to the Mayo-regimen.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

The additive effect of peripheral blood stem cells (PBSCs) to autologous bone marrow transplantation (ABMT) on haematopoietic reconstitution, after ablative chemotherapy in patients with locally advanced breast cancer, was evaluated. Patients were treated with induction chemotherapy, followed by ablative chemotherapy consisting of mitoxantrone and thiotepa. Group I (n = 14) received ABMT and granulocyte macrophage-colony stimulating factor (GM-CSF), group II (n = 11) received ABMT, PBSCs and granulocyte-colony stimulating factor (G- CSF). PBSCs were harvested after a low-dose cyclophosphamide (750 mg/m2), followed by G-CSF. Stem cell harvest was routinely started 12 days after cyclophosphamide. Compared to group I, group II showed a significant reduction in the median number of days for leukocytes < 0.5 x 10(9)/L 4.5 days, leukocytes < 1.0 x 10(9) / l 5.5 days, platelets < 20 x 10(9)/ l 9 days and platelets < 40 x 10(9) / l 12.5 days. The median number of transfusions of platelets fell from 11.5 to 7 and of red blood cells from 8.5 to 6. The median hospitalisation duration declined from 40.5 to 30 days, fever above 38 degrees C with 7.5 days, fever above 38.5 degrees C with 4 days and antibiotic treatment with 8.5 days in group I versus group II. Improvement of haematological recovery, duration of fever and hospitalisation was observed by the addition of PBSCs, obtained after a relatively low-dose cyclophosphamide and G-CSF and stem cell pheresis on fixed days, to autologous bone marrow and growth factor in the period after ablative chemotherapy.

Disappointing results after surgery alone for locally advanced adenocarcinoma of the cardia and the distal oesophagus (stage IIIB/IV) prompted us to combine surgery with neo-adjuvant chemotherapy. With a remission rate of about 70% the combination of etoposide, adriamycin and cisplatin (EAP) has been considered to be the superior treatment, but it has inherent severe toxicity. The authors conducted a phase II study of combined treatment with Carboplatin, 4-Epiadriamycin and Teniposide (CET) to ameliorate this toxicity and to evaluate the effectivity of this regimen in patients with these unresectable tumours. A regimen of 4 cycles of Carboplatin 300mg/m2, 4-Epiadriamycin 80mg/m2 and Teniposide 100mg/m2 was administered intravenously. Treatment cycles were repeated every 3 weeks in patients with initially unresectable adenocarcinoma of the gastro-oesophageal junction proven at laparotomy and/or CT scanning. Nineteen patients were studied and 17 underwent a second laparotomy in an attempt to resect the tumour radically. Eleven patients (65%) of the re-explored group achieved tumour reduction, enabling resection with curative intent. Recurrences, however occurred in 9 patients after a median of 9.5 (4-42) months. One patient died postoperatively as a result of pulmonary embolism. Only one patient remained free of disease after 42+ months. Leucopenia and thrombocytopenia of WHO grade 23 occurred in 58% and 37% of the patients, respectively. This regimen appears to be effective in patients with locally advanced adenocarcinoma of the cardia and the distal oesophagus. Although it can be used in an outpatient setting, the overall toxicity is relatively high and the results are comparable with other less toxic regimens.

Twenty-nine patients with metastatic or T4 breast cancer who were in pathologically proven complete remission after induction chemotherapy, received intensification chemotherapy with autologous bone marrow support. Twelve patients had T4 breast cancer, 17 had metastatic disease. The median age was 42 years (27-52). Intensification consisted of cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. in 24 patients, or thiotepa 800 mg/m2 i.v. and mitoxantrone 50-75 mg/m2 i.v. in 5 patients. The median observation is 7 years. Median survival is 36 months. Ten year relapse-free survival is 20%. For patients with metastatic disease median survival is 34 months, time to relapse 18 months; two patients (12%) have survived disease-free for more than 6 years. The patients with T4 cancer have a median survival of 80 months and a median time to relapse of 53 months; four patients (33%) have survived more than 5 years disease-free.

Unlabelled: The aim of the study was to define an effective regimen as induction treatment in chemotherapy naive patients with advanced breast cancer as preparation for ablative chemotherapy., Patients and Methods: Patients with locally advanced or metastatic breast cancer (AJCC stage IIIB or IV) received 5-fluorouracil, methotrexate with leucovorin rescue and prednisone, alternating with doxorubicin and vincristine for six cycles. Results One hundred and eleven patients were eligible. All patients were evaluable for toxicity and seventy were evaluable for response. Thirty patients achieved a complete remission (43%) and 24 a partial remission (34%). Hematological toxicity was acceptable, as in 7% of 602 treatment cycles patients were admitted for neutropenic fever. Patients with liver metastases had a higher incidence of leucopenic fever, 32% compared to 15% for all patients, and a 25% incidence of cerebellar neuropathy compared to 9% for all patients. Mucositis more severe than WHO grade I occurred in 8% of cycles. Nausea and vomiting were not severe and cardiac or renal toxicity did not occur. Thromboembolic events occurred in 7% of the patients., Conclusions: This induction regimen carries a 43% complete and 77% overall remission rate, which is high compared to other conventional and even escalated regimens. The toxicity profile is acceptable except for the higher incidence of leucopenic fever and the reversible 5-FU cerebellar syndrome in patients with liver metastases.

To define the activity of an individually escalated dacarbazine (DTIC) dose combined with interferon-alpha-2a (IFN), granulocyte-colony stimulating-factor (G-CSF) and ondansetron, 20 patients (pts) with metastatic melanoma were treated with DTIC, ondansetron 8 mg iv, G-CSF 300 micrograms sc and IFN 9 MU sc. Treatment was performed every 21 days to a maximum of 6 courses. DTIC dose was escalated with 250 mg/m2 in case of acceptable toxicity to 1250, 1500 and 1750 mg/m2 in (projected/realized), 14/19, 8/11 and 0/5 pts, respectively. Dose escalation prohibiting toxicities were thrombocytopenia (10 pts), leukopenia (9 pts), and nausea/vomiting (2 pts). Four partial remissions were observed, for a response rate of 20% (95% confidence interval, 6 to 44%). Duration of responses was 1, 2, 3 and 3 months. Median overall survival was 8 months.