[Prophylactic alkalization of the urine during cytostatic tumor treatment with the oxazaphosphorine derivatives, cyclophosphamide and ifosfamide]. / Prophylaktische Alkalisierung des Harns bei zytostatischer Tumorbehandlung mit en Oxazaphosphorin-Derivaten Cyclophosphamide und Ifosfamid.

The so-called cystitis due to cyclophosphamide (Cytoxan) is caused by direct contact of the mucosa with alkylating metabolites in acid urine. These alkylating metabolites can be inactivated by instillation of cysteine into the urinary bladder. The cytostatically active metabolites of ifosfamide (Holoxan), a derivative of oxazaphosphorine, are eliminated by the kidneys as well. Their special toxicity is much higher than the toxicity of Cytoxan. The alkylating metabolites of ifosfamide cause urological complications essentially in supravesical areas (tubulopyelo-ureteritis). Some clinical trials demonstrate that increase of diuresis and alkalinization of urine by orally administered Uralyt-U are able to decrease concentration and aggressiveness of those metabolites.

Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results.

A randomized study in 20 patients with cancer was carried out to test the clinical efficacy of sodium-2-mercaptoethane sulfonate (ASTA D-7093; mesnum) as an agent to prevent urotoxic side effects (in particular, hemorrhagic cystitis) during cytostatic therapy with the oxazaphosphorines cyclophosphamide and ifosfamide. Eleven patients received mesnum iv and nine patients received a standard prophylaxis. The frequency of microhematuria was significantly lower in the patients receiving mesnum. A slight microhematuria was observed in one patient. With the standard prophylaxis, all nine patients receiving single-agent therapy with ifosfamide or cyclophosphamide had hematuria and three of these had macrohematuria. According to the available results, a daily mesnum dose of 60% (wt/wt) of the ifosfamide or cyclophosphamide dose is recommended. This dose should be divided into three equal fractions. The first administration should be given concurrently with the cytostatic agent and the subsequent two administrations at 4 and 8 hours after administration of the cytostatic agent. Significantly higher doses of mesnum (eg, 133% of the cyclophosphamide or ifosfamide doses) lead to gastrointestinal disorders, which are easily reversible.

First impressions of I.V. C. parvum in patients with solid tumours.

6 patients with solid tumours (4 malignant melanomas, one fibrosarcoma, one osteogenic sarcoma) received i.v. C. parvum alone or in combination therapy (radiotherapy, Levamisole and/or vitamin A). The single doses of C. parvum ranged from 5.0-7.5 mg/m2; No. of doses ranged from 1-8; interval between doses ranged from 2-140 days. 2 patients with malignant melanoma had no measurable disease, one of them (stage I) still has no evidence of disease. The patient with fibrosarcoma appeared to have a minor decrease in size of some of the lung metastases for a short time (ca 4 weeks), but soon progressed as well as the other 4 patients. Except for the one patients still having no evidence of disease the other 5 are dead of disease. Survival time did not appear to correlate either with systemic reaction to C. parvum or with No. of doses of C. parvum. The one minor response was observed in a patient receiving a total of 8 doses; but response was seen already after 3 doses, and progression occurred after 6 doses. So this change of lung metastases might have been unrelated to this therapy. Summarizing, there was no evident anti-tumour effect observed after i.v. C. parvum in these patients with solid tumours.

Results obtained with fractionated ifosfamide massive-dose treatment in generalized malignant tumours.

In 409 sufferers from various malignant tumours, we used the cytostatic Ifosfamide (ASTAZ4942) in fractionated doses. The total i.v. dose averaging 300 mg/kg bodyweight, was either spread over 5 consecutive days (5 X 60 mg/kg i.v.) or over 10 consecutive days (10 X 30 mg/kg). At the same time, most patients were irradiated, the radiation dose usually being only one tenth the antitumour dose. Infections and electrolyte imbalance were first treated before Ifosfamide therapy was instituted. Cases of advanced cerebral sclerosis, thrombopenia below 75,000/cmm, cerebral metastases, impaired renal function and inadequate cooperation of the patient were excluded from the studies. To prevent and control side effects, various premedications and adjuvants are required: Antiemetics, prevention of cystitis and infections, cardiovascular agents etc. Corticosteroids are contraindicated. Out of 360 assessable patients 101 had a full remission, 150 a partial remission, 79 were failures; 30 cases were not evaluated. Good results were seen especially in ovarian carcinoma, mammary carcinoma and microcellular bronchial carcinoma. Particularly striking is the drug's effectiveness in testicular tumours including teratomas, osteosarcomas, chondrosarcomas and myosarcomas as well as in some adenocarcinomas of the gastro-intestinal tract, particularly pancreatic carcinoma. In lymphoreticular tumours and haemoblastoses, its potency is less pronounced. The side effects of Ifosfamide are the same as those of other alkylating agents. They are reversible and can usually be controlled or even avoided by adequate preventive measures. In the order of incidence we observed: Alopecia, leukopenia, fall in haemoglobin, cystitis, intercurrent infections, nausea and vomiting as well as cerebral disorders. Since haemorrhagic cystitis considerably interferes with Ifosfamide treatment, its prevention is of essential importance. Because of possible complications and specific premedication and adjuvant measures for their control, this type of treatment should for the present only be carried out by oncologists or special cancer centres.

[Results of the synchronization therapy with vincristine and cyclophosphamide in lymphogranulomatosis, reticulum cell sarcoma and lymphosarcoma. A phase II study (author's transl)]. / Ergebnisse der Synchronisationstherapie mit Vincristin und Cyclophosphamid bei Lymphogranulomatose, Retikulumzell- und Lymphosarkom. Eine Phase-II-Studie

The effectiveness of synchronization therapy was tested on 88 patients who had already undergone some form of treatment for lymphogranulomatosis (stage III B and IV), generalized reticulum cell sarcoma or lymphosarcoma. This therapeutical concept is based on a partial synchronic increase in tumor cells induced by noncytocidal doses of vincristine, followed by cytostatic or cytocidal treatment with cyclophosphamide during DNA synthesis of the partially synchronized tumor cells. The therapeutic plan is similar to a single-agent therapy. In lymphogranulomatosis, complete remission could be achieved in 14 out of 19 cases (stage III B) and in 9 out of 24 cases (stage IV). The mean remission period during an orally administered cytostatic maintenance therapy was 15 1/2 months. The highest rate of remission was found in the mixed cell type of granulomas (23 out of 24 patients). In the non-Hodgkin's lymphomas, complete remission was achieved in 13 out of 30 cases (lymphosarcoma) and in 19 out of 15 cases (reticulum cell sarcoma). The mean remission period for orally administered cytostatic maintenance therapy was 16 months for lymphosarcoma and 11 1/2 months for reticulum cell sarcoma. These therapeutic results are comparable to those achieved by very effective schemes of combination chemotherapy but the toxic side-effects of synchronization therapy are considerably lower.