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The treatment of cancer can have a negative influence on bone metabolism. This can result in the development of early osteoporosis or the aggravation of existing osteoporosis, with an increased risk of fractures. Depending on the duration and type of cancer therapy, prophylactic or therapeutic measures against osteoporosis may become necessary. The risk of osteoporosis may be assessed by screening with osteodensitometry, among other methods. Effective treatment is possible, for example with bisphosphonates.

To compare the need for blood transfusions between two groups of patients treated with cisplatin-containing chemotherapy. One of these groups received epoetin alpha therapy.Prospective with an historical control group.From April 1998 to December 1999, 44 patients who were being treated with cisplatin and gemcitabine were also administered epoetin alpha (10,000 U subcutaneously, thrice weekly) from the onset of anaemia. The need for red blood cell transfusions in this group was compared to a historical control group of 46 patients treated with the same combination chemotherapy regimen from November 1995 to July 1997.In the historical control group, each patient received an average of 1.6 red blood cell transfusions as compared to 0.7 in the epoetin alpha group (a 58% reduction). The average number of units of red blood cells transfused per patient was 3.6 for the control group and 1.8 for the epoetin alpha group (a 50% reduction). In the epoetin alpha group, none of the patients received more than 2 transfusions whereas in the control group, 10 patients (22%) received 3 or more transfusions. In two patients, epoetin therapy had to be stopped due to the occurrence of hypertension.Epoetin alpha reduced the need for red blood cell transfusions during cisplatin-containing chemotherapy. Its toxic effect was minimal.

Objective. To determine the clinical effect of adjuvant active specific immunotherapy (ASI) with tumour cells and BCG after radical surgery in stage II and stage III colon cancer patients. Design. Prospective randomized controlled clinical trial. Method. In the period 1987-1996, 254 patients were randomly assigned postoperatively in the Free University Hospital in Amsterdam and in II participating hospitals in the Netherlands to receive either ASI or no adjuvant therapy. ASI consisted of 4 intradermal vaccinations with 107 irradiated autologous turnout cells. Treatment started 4-5 weeks after operation with 3 vaccinations, at one-week intervals followed by the fourth vaccination 6 months after operation. The first two vaccinations also contained 107 BCG organisms. Patients were followed for time to recurrence, recurrence-free and overall survival. Analysis was done on the basis of randomization. Results. At 5.8 year median follow-up a significant improvement (p = 0.016; relative risk reduction: 43% (SD: 18)) in the recurrence-free interval in all patients given ASI was seen; there were 44 recurrences in the control group and 27 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significant improvement in recurrence-free interval (p = 0.013) and a 57% (SD: 23) relative reduction in risk of recurrences. This was accompanied by a significant improvement in recurrence-free survival (p = 0.043; 42% relative risk reduction (SD: 21)) and an improvement of disease-specific survival (p = 0.061). Apart from transient ulcers at the first two vaccination sites and fever/chills after vaccination no adverse events were observed. Conclusion. ASI had a significant clinical benefit in colon cancer patients with stage II disease. ASI caused minimal adverse reactions and should be considered as a treatment for these patients.

Objective. To determine the clinical effect of adjuvant active specific immunotherapy (ASI) with tumour cells and BCG after radical surgery in stage II and stage III colon cancer patients. Design. Prospective randomized controlled clinical trial. Method. In the period 1987-1996, 254 patients were randomly assigned postoperatively in the Free University Hospital in Amsterdam and in II participating hospitals in the Netherlands to receive either ASI or no adjuvant therapy. ASI consisted of 4 intradermal vaccinations with 107 irradiated autologous turnout cells. Treatment started 4-5 weeks after operation with 3 vaccinations, at one-week intervals followed by the fourth vaccination 6 months after operation. The first two vaccinations also contained 107 BCG organisms. Patients were followed for time to recurrence, recurrence-free and overall survival. Analysis was done on the basis of randomization. Results. At 5.8 year median follow-up a significant improvement (p = 0.016; relative risk reduction: 43% (SD: 18)) in the recurrence-free interval in all patients given ASI was seen; there were 44 recurrences in the control group and 27 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significant improvement in recurrence-free interval (p = 0.013) and a 57% (SD: 23) relative reduction in risk of recurrences. This was accompanied by a significant improvement in recurrence-free survival (p = 0.043; 42% relative risk reduction (SD: 21)) and an improvement of disease-specific survival (p = 0.061). Apart from transient ulcers at the first two vaccination sites and fever/chills after vaccination no adverse events were observed. Conclusion. ASI had a significant clinical benefit in colon cancer patients with stage II disease. ASI caused minimal adverse reactions and should be considered as a treatment for these patients.

In the Netherlands, cancer will remain a significant issue in health care according to a signalling commission of the Dutch national cancer fund (Nederlandse Kankerbestrijding/Koningin Wilhelmina Fonds). If smoking would be abandoned, the incidence of lung cancer would drop dramatically. The role of food in carcinogenesis appears to be much less than was earlier believed. Chemoprevention will also have very limited influence on cancer incidence. Attempts at early diagnosis of cancer have been so far successful only in patients with breast cancer over 50 years of age and in cervical cancer. More effective therapies for cancer are urgently needed. The cost-effectiveness of adjuvant chemotherapy in breast cancer and colon cancer is unfavourable. Determination of better prognostic factors may reduce the number of patients who unnecessarily undergo this treatment. New anticancer drugs tend to be very expensive and this lays a heavy burden on health care budgets. Efficacy of new treatments needs to be compared with established ones in randomized trials before reimbursement can be granted.

Angiogenesis is the process of new vessel formation from pre-existing vasculature. In preclinical as well as clinical research it has been demonstrated that tumour growth and formation of metastases are angiogenesis dependent. High microvessel density in most tumour types is associated with a bad prognosis. A variety of angiogenic stimuli and inhibitors have been discovered and are expressed in tumours of cancer patients. In addition to specific angiogenic factors, the synthesis and breakdown of the extracellular matrix, the adherence of endothelial cells, the coagulation process and the immune system are important for tumour-induced angiogenesis. Preclinical research has demonstrated that tumour growth can be inhibited by angiogenesis inhibitors. These findings stimulated the development of angiogenesis inhibitors, which are currently under investigation in phase I, phase II and phase III studies for toxicity and efficacy. In the future angiogenesis inhibitors, like insulin therapy in diabetes, may be used to inhibit tumour growth and to induce stabilization of the disease.

Bone metastases occur frequently in cancer and are commonly associated with bone degradation due to the tumoral production of factors which stimulate the development and activation of osteoclasts. During osteolysis growth factors are released which stimulate tumour growth. Bisphosphonates inhibit osteoclastic bone resorption. Recently, in several large randomised studies of patients with multiple myeloma or bone metastases of breast cancer, long-term treatment with clodronate or pamidronate gave significant bone protection.

To assess the anti-tumour and side effects of paclitaxel in patients with ovarian carcinoma, after prior treatment with al least one platinum-containing chemotherapy regimen.Phase II study.Academic Hospital of the Free University, Amsterdam.Fourteen of 55 patients with progressive ovarian carcinoma were treated with 135 mg/m2 and 41 with 175 mg/m2 paclitaxel. 9 patients by 24-hour and 46 by 3-hour intravenous infusion.In 9/55 (16%) patients an objective tumour response was obtained, which was complete in 1 patient. In 19/55 (35%) patients the disease stabilised. The serum CA 125 level was increased in 52 patients. In 33% of the patients the course of the serum CA 125 was an indication of the tumour response. The median duration of response was 8 months (range 4.1-13.1) and the median duration of survival was 11.3 months (range 0.3-28.2). Side effects of paclitaxel treatment were hair-loss, arthralgia and myalgia and neutropenia of short duration. In 76% of patients pre-existing neurosensory symptoms increased mildly or developed de novo. The neurotoxic effect appeared reversible in most instances after discontinuation of the paclitaxel treatment.In this rather unfavourable patient population, paclitaxel induced only 16% objective response. However, more than 50% of the patients did benefit from paclitaxel treatment, as a much larger group had long lasting disease stabilisation without symptoms or had reduction of symptoms. The treatment was well tolerated by most patients.

OBJECTIVE: To establish if the prognosis of a stage III breast carcinoma is improved by primary high-dose chemotherapy in combination with haemopoietic growth factors, followed by radical surgery and radiotherapy.DESIGN: Phase II study.SETTING: University Hospital Free University, Amsterdam.METHOD: Fifteen patients with a locally advanced breast carcinoma (stages IIIA or IIIB) were treated every three weeks with doxorubicin 90 mg/sq.m. and cyclophosphamide 1000 mg/sq.m., followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 micrograms/sq.m. from day 2 up to and including day 12. After 4-6 of these courses the treatment in principle was continued with a modified radical mastectomy, followed by radiotherapy. Median duration of follow-up was 18 months.RESULTS: All tumours were reduced by over 50%. 10/15 Patients went into clinical complete remission; in 6/9 of these, pathological examination revealed only microscopical tumour rests, in the other three the rest diameter was < or = 1 cm. The haematological toxicity was mild. Grade III-IV bone marrow suppression was followed by rapid return to normal of the numbers of neutrophil granulocytes and thrombocytes under the influence of GM-CSF. The non-haematological toxicity manifested itself with nausea and vomiting, stomatitis and mild side effects attributable to GM-CSF.CONCLUSION: It appears justified in the treatment of locally advanced breast carcinoma to start with chemotherapy. Dose escalation of efficacious chemotherapeutics resulted in a large number of complete remissions.

To establish if the prognosis of a stage III breast carcinoma is improved by primary high-dose chemotherapy in combination with haemopoietic growth factors, followed by radical surgery and radiotherapy.Phase II study.University Hospital Free University, Amsterdam.Fifteen patients with a locally advanced breast carcinoma (stages IIIA or IIIB) were treated every three weeks with doxorubicin 90 mg/sq.m. and cyclophosphamide 1000 mg/sq.m., followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 micrograms/sq.m. from day 2 up to and including day 12. After 4-6 of these courses the treatment in principle was continued with a modified radical mastectomy, followed by radiotherapy. Median duration of follow-up was 18 months.All tumours were reduced by over 50%. 10/15 Patients went into clinical complete remission; in 6/9 of these, pathological examination revealed only microscopical tumour rests, in the other three the rest diameter wasor = 1 cm. The haematological toxicity was mild. Grade III-IV bone marrow suppression was followed by rapid return to normal of the numbers of neutrophil granulocytes and thrombocytes under the influence of GM-CSF. The non-haematological toxicity manifested itself with nausea and vomiting, stomatitis and mild side effects attributable to GM-CSF.It appears justified in the treatment of locally advanced breast carcinoma to start with chemotherapy. Dose escalation of efficacious chemotherapeutics resulted in a large number of complete remissions.

Thirty-seven patients with liver metastases from colorectal cancer were treated with hepatic arterial infusion of 5-FU. Before therapy an arterial access device (Port-A-Cath) was implanted. Treatment was given on an outpatient basis with a portable infusion pump. 5-FU was administered as a continuous infusion at a dose of 1000 mg/sq.m. per day during 5 or 6 days. Cycles were repeated every three weeks. In 12 (37.5%) of the 32 evaluable patients a partial remission was achieved. Median duration of remission was 11 months and median duration of survival was 16 months. Side effects of chemotherapy were usually mild. In 11 patients thrombosis of the hepatic artery was observed, occurring after a median period of 5 months after implantation of the access device. Further study is required to improve the treatment results in this disease with its unfavourable prognosis.

A non-randomized study was carried out in the Free University Hospital, Amsterdam, to investigate the (hematologic) toxicity and antitumor response of patients with advanced breast cancer treated with intensive chemotherapy in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Of 11 patients with an inoperable or metastasized breast cancer, 5 were treated with doxorubicin 75 mg/m2 + cyclophosphamide 750 mg/m2 intravenously every 3 weeks and 6 patients with 90 and 1000 mg/m2 respectively. When in a preceding cycle a significant hematologic toxicity was observed, this patient was treated in the subsequent cycle with the same dose of chemotherapy in combination with GM-CSF 250 micrograms/m2/day from day 2-12 as a continuous infusion. Bone marrow depression was diminished in the presence of GM-CSF. This was apparent from a milder decline of the number of neutrophilic granulocytes, reduction of the neutropenic period and a more rapid recovery of the neutrophil number. A transient eosinophilia and a mild monocytosis were also observed. GM-CSF did not improve erythrocyte and thrombocyte counts. The efficacy of GM-CSF was less pronounced in the group of patients with the highest dose of chemotherapy. GM-CSF was associated with malaise, fever and a small decrease of blood pressure, which in combination with a frequently occurring anemia and the side-effects of high dose chemotherapy, resulted in a substantial toxicity. In 9/11 patients an objective tumor regression was noted. GM-CSF stimulated the recovery of granulocytes after intensive chemotherapy. Treatment of a small group of patients with advanced breast cancer with intensive chemotherapy resulted in a high antitumor response.