Carcinogenicity of antineoplastic agents in man.

Review of the literature shows that: Anticancer drugs are in all probability mostly also carcinogenic. Alkylating agents such as melphalan, chlorambucil and cyclophosphamide seem to lead to the highest rate of second malignancies. Second malignancies after antitumour drugs are mostly acute leukaemias. Conditions which could influence the carcinogenicity of an antitumour drug are (a) its carcinogenic potency; (b) long-term administration; (c) the total dose used and (d) long-term survival of the patient. Irradiation and chemotherapy seem to have the greatest carcinogenic potential, e.g. in malignant lymphomas. The role of immunosuppression as a co-carcinogenic factor is difficult to estimate. Although transplant patients on anticancer drugs for immunosuppression have a higher risk of reticulosarcomas, but not of solid tumours, there is no evidence to suppose that in general immunosuppression and carcinogenicity are directly related. There is no reason to abandon intensive chemotherapy regimes if they lead to significant therapeutic results on the grounds of possible carcinogenicity of these drugs.

Epirubicin and ifosfamide in metastatic breast cancer.

In a randomized, phase II trial, we evaluated the effectiveness of continued chemotherapy with epirubicin/ ifosfamide versus unmaintained treatment interruption in advanced metastatic breast cancer. Three hundred fifty-seven patients were enrolled and 331 were evaluable for response. Complete response was achieved in 25 patients (8%) and partial response in 121 patients (37%). Pretreatment status correlated significantly with response (complete and partial response). While 54% of unpretreated patients responded, only 42% of the patients responded who had been pretreated with adjuvant chemotherapy and 33% who had been pretreated in the metastatic stage of disease; 69 patients (21%) had disease progression. Of 11 patients pretreated in both the adjuvant and metastatic setting, only two responded. Toxicity of treatment was mild, with leukopenia being the treatment-limiting factor. Thrombocyte levels were not altered significantly by treatment. Thus, there seems to be room for dose escalation using granulocyte colony-stimulating factor. There was no considerable cardiotoxicity, central nervous system toxicity, or cystitis observed. The low rate of cardiotoxicity appeared to be related to dose fractionation of epirubicin. After randomization of patients to treatment interruption versus continuation of chemotherapy, a longer relapse-free survival was observed for patients who continued chemotherapy (mean relapse-free survival, 2+ months); however, this did not translate into prolonged survival. The cumulative scores of toxicity and quality of life parameters showed increasing superiority for treatment interruption. Therefore, a strategy of treatment until maximum response and subsequent treatment interruption seems to be superior to treatment continuation.

[The present state of chemotherapy of gastric cancer (author's transl)]. / Zur derzeitigen Situation der chemotherapeutischen Behandlung des Magenkrebses

The therapeutic results in stomach cancer are still very poor. Especially in advanced stages of the disease, cytostatic treatment is of little value. The most promising drugs available at present are 5-fluoroaracil or its analogues, Mitomycin C, and Chromomycin A3. Proper combinations of cytostatics are expected to become more therapeutic tools. Further chances of improving therapeutic results are seen in the combination of surgery with irradiation and chemotherapy. Such efforts should include individualization of the therapy with regard to factors of the tumor-host relationships influencing the prognosis, and utilization of tumor-biological data.

[Aminoglutethimide in metastasizing carcinoma of the breast resistant to hormonal and cytostatic treatment (author's transl)]. / Aminoglutethimid bei hormon- und zytostatikaresistentem metastasierendem Mammakarzinom.

Aminoglutethimide (Elipten), at a dosage between 250 and 1500 mg/d by mouth, was administered in a clinical phase II study to 17 patients with metastasizing carcinoma of the breast resistant to hormones and cytostatic drugs. Results of this treatment were available for 14 patients. Nine women were given the drug alone, eight in combination with cytostatic drugs. In 11 women the drug significantly decreased pain within 3-14 days. Used alone aminoglutethimide produced objective regression of the metastases in two women, two further instances of regression occurred when the drug was combined with cytostatic agents. Five women developed urticarial rash, while six had somnolence and nausea or lethargy. Aminoglutethimide is suitable for symptomatic treatment of metastasizing treatment-resistant carcinoma of the breast, either alone or in combination with cytostatic drugs.

[Cancer chemotherapy of inoperable bronchial carcinomas (author's transl)]. / Die Chemotherapie des inoperablen Bronchuskarzinoms

The nowadays' therapeutic results in bronchogenic cancer are rather poor. However, chemotherapy-promises some improvements in remission rates and survival. These results are achievable as well as by mono and by polychemotherapy. The current clinical studies are aimed at optimal application regimes of the drugs beeing at hand. Cyclophosphamide, Methotrexate and Adriamycin are the most effective drugs for montherapy. Alkylants and Methotrexate are especially effective in the oat cell carcinomas. Many cases seem to be more benefited by polychemotherapy than by monotherapy. However, a randomized clinical trial is presented which shows that a montherapy with Adriamycin gave the same results as polychemotherapy. In the case of bronchogenic carcinoma a simultaneously given polychemotherapy is more effective than a sequentially given one. Novel approaches aiming at further improvement of therapeutic results should more consider individual tumour-biological parameters of the tumour-host relationships and possbilities of pharmacological influences upon hemostasis, tumour vascularisation and immunological defense system.

[Foundations of modern chemotherapy of malignant tumors]. / Grundlagen der modernen Chemotherapie maligner Tumoren

Position of tumour chemotherapy among tumour treatment. Cytostatics as a systemic active means of tumour management. Adjuvant application of chemotherapy in the postoperative period. Achievements of nowadays chemotherapy in some tumours. Rules of chemotherapy action on tumours, tumour biological considerations. Cytokinetic aspects of tumour chemotherapy. Critics on partial synchronization. Specialties of the chemotherapy in the field of head and neck tumours. Some dosage recommendations for a few drugs to be systematically or locally administered. Possibilities for potentiating of cytostatic action--by using the oncobiogram, anticoagulation or defibrination and immunostimulation, respectively. Clinical evaluation of cytostatic effectivity applying the method of randomized clinically controlled study.

[General aspects of cytostatic therapy of hemoblastoses]. / Allgemeine Aspekte der zytostatischen Therapie der HAmoblastosen

In haemoblastoses the chemotherapy is able to achieve remissions and prolongations of the survival time. The combined or polychemotherapy, respectively, is here comparatively more effective than the monotherapy. In haemoblastoses the concept of the maximal destruction of tumours (induction therapy) could be realised by means of consolidation and maintenance therapy. The prediction of the therapy effects by inclusion of different host parameters (morphology, immune state, age, sensibility test) may only approximately be done. In the induction and maintenance of the remission the supportive therapeutic measures play an essential role. By the development of selective cytostatic drugs and further utilisation of the results of molecular-biological experiments further ameliorations of the therapeutic situation are to be awaited.

[Thoughts about the present state of tumour chemotherapy (author's transl)]. / Ubersicht. Zum derzeitigen Stand der Tumorchemotherapie (Mit einer Auswertung des IX. Internationalen Chemotherapie-kongresses in London vom 13.-18. Juli 1975)

There are some impacts in tumour chemotherapy being worth-while to be discussed. Considering the information received during the Ninth International Congress of Chemotherapy, held in 1975, the author tries to evaluate the present state of clinical tumour chemotherapy from clinical point of view. The modern oncological clinician (oncologist) has to be faced with a lot of new facts, e.g. use of quantitative differences between normal and tumour cells for individualization of therapy, timing of cancer drug administration, new drugs for cancer treatment, mutual inhibition or potentiation of drug's effects, immunotherapy and possible adverse effects of clinically available drugs.

[Long-term treatment with "Anovlar" of inbred mice affected with breast cancer]. / Langzeitbehandlung mit "Anovlar" bei Mammakarzinom-belasteten Inzuchtmäusen.

PIP: Inbred mice were treated for 305 days with Anovlar. Throughout the observation under continuous hormonal treatment there was neither an increase in spontaneous mammary tumour rate nor any reduction in tumour taking time. Mortality was higher in the hormone-treated animals, obviously because they badly tolerated the treatment at the beginning of the experiment. If further studies do not reveal a cocarcinogenity of the hormonal preparations or show a cancriprophylactical action, they might be well recommended as anticarcinogenic drugs for women.^ieng

[Androgen therapy of incurable breast neoplasms. Controlled clinical study: nandrolone-testololactone-drostanolone]. / Zur Androgentherapie des inkurablen Mammakarzinoms Kontrollierter klinischer Versuch: Nandrolon-Testololakton-Drostanolon.

In 91 patients with advanced breast cancer testololactone, drostanolone, and nandrolone were compared in a controlled clinical trial. Remissions were registered after 4 weeks and after another 12 week period; during this second interval the patients received an additional treatment with cyclophosphamide. There was no difference in the effectivity between the three drugs. Remission rate was in average after 4 weeks 24% and after 16 weeks 46%.

Comparison of testosterone decanoate, drostanolone and testololactone in disseminated breast cancer--a randomized clinical study.

It can be said that a single hormone therapy with testosterone decanoate, drostanolone, and testosterone gave similar rates of objective responses in metastatic breast cancer. The presented randomized study has been done to prove whether an additional chemotherapy to hormone applications would further improve therapeutic results. During an observation period of 10 to 16 weeks testosterone decanoate and testolactone in combination with cyclophosphamide have more benefitial effects on the patients than drostanolone plus cyclophosphamide. The combination therapy augmented the rate of objective responses from 22-25 percent to 46-55 percent.

Comparative studies on the behaviour of the plasmatic clotting system and platelet function in surgically treated cancer patients.

By measuring 18 functional parameters of blood coagulation the dynamic pattern of pre- and postoperative blood coagulation was studied in a total of 43 patients with primarily operable solid tumours. The results were compared with those obtained in patients having benign diseases in the same anatomical regions. Results were discussed preferably from the tumourbiological point of view. Changes of blood coagulation occuring in operated cancer patients with benign diseases. Compensatory processes operating in the haemostatic system provide a well balanced coagulation even in cancer patients. Patients with gastric cancer having low adenine nucleotide levels in platelets had a significantly higher risk to die postoperatively than those with normal levels. This indicates metabolic disorder on cellular levels than haemostatic dysfunctions.

[Combination of aminoglutethimide and polychemotherapy for the treatment of predominant bone metastasis in breast cancer]. / Kombination von Aminoglutethimid und Polychemotherapie zur Behandlung von dominanter Knochenmetastasierung des Mammakarzinoms.

A clinical phase II study was performed to evaluate the therapeutic efficacy of simultaneously administered aminoglutethimide and polychemotherapy in 31 patients with predominant bone metastases of breast cancer. The majority of patients was postmenopausal and pretreated with hormones and (or) chemotherapy. In 28 evaluable patients an overall objective response rate of 61% was achieved. Patients who received aminoglutethimide and polychemotherapy containing anthracyclines as FAC- or AV-regimen showed the highest objective response rate (67%). Thus, simultaneous combination of aminoglutethimide and polychemotherapy containing anthracycline derivatives is the most effective therapeutic regimen for those patients who were either pretreated or have progressive bone metastases with confinement to bed or have concomitant visceral metastases.

[Clinical evaluation of Ftorafur (author's transl)]. / Die klinische Erprobung von Ftorafur

The new soviet antimetabolite Ftorafur (N1-2'-Furanidyl-5-Fluorouracil, FFU) has been clinically evaluated in 18 selected patients with various solid tumours. Several of them had been treated before with other drugs. FFU was given to 8 patients as a monotherapy whereas 10 patients received the drug in combination with other therapeutic measures. A total response rate of 9/18 was seen. Three out of 8 patients treated with FFU alone have responded objectively. Due to its low toxicity FFU became a clinically interesting drug which is suitable for long-lasting administration. Its therapeutic activity is similar to that of 5-Fluorouracil. FFU is especially effective in carcinomas of the breast and the gastro-intestinal tract. It can be applied locally or safely be combined with other drugs or with irradiation.

Cellular immunity in mammary cancer patients as measured by the leukocyte migration test (LMT). A follow-up study.

In 58 cases of mammary cancer treated by surgery the leukocyte migration test (LMT) has been applied to the study of cellular immunity using homogenate from autochthonous and homologous tumors as antigens. A positive test, i.e. inhibition of migration by antigen, was observed in 52 patients from 1 day up to 40 days after surgery. Six patients were negative. There was extensive immunological cross-reactivity among mammary cancer in that a positive test was also obtained with homogenate from homologous mammary tumors. Generally, antigens from other tumors did not react. The test was also negative when the leukocytes were derived from healthy persons. Sera from mammary cancer patients abrogated the inhibitory effect of tumor antigen. The disappearance of positivity about 40 days after surgery and its reappearance during the metastatic process indicates that the positive LMT is associated with progressive disease.

[Cellelectrophoretic studies of the effect of methylglyoxal-bis-guanylhydrazone on blood cells of tumour patients (author's transl)]. / Zellelektrophoretische Studie über den Effekt von Methylglyoxal-bis-guanylhydrazon auf Blutkörpe rchen von Krebspatienten

The effect of methylglyoxal-bis-guanylhydrazone has been studied on the electrophoretic mobility of blood cells of 10 unselected and untreated patients with preferably solid malignant diseases. Prior to the incubation with CH3-G the electrophoretic mobility of lymphocytes and erythrocytes showed increased and of platelets showed decreased rates which extend over a larger range than usual and for which reasons cannot be given till now. The incubation with CH3-G caused a concentration-dependent reduction of the electrophoretic mobility of all three tested types of blood cells. This can be estimated as an impairment of a function of surface membrane and confirms recently obtained results of activity of CH3-G on platelets' surface membrane.

Phase II evaluation of carboplatin in advanced esophageal carcinoma. A trial of the Phase I/II Study Group of the Association for Medical Oncology of the German Cancer Society.

Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.

Chemotherapy with tauromustine in advanced non-small cell lung cancer. A trial of the Phase II Study Group of the Association for Medical Oncology of the German Cancer Society.

Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32-70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adenocarcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is less than 20% (p less than 0.05). It is improbable that TCNU has a relevant impact on the course of inoperable NSCLC.

Tumor necrosis factor in advanced colorectal cancer: a phase II study. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

In a phase II study, the efficacy and toxicity of human recombinant tumor necrosis factor (rh TNF-alpha) were evaluated in patients with advanced colorectal carcinoma. Rh TNF-alpha was given as short term infusion at a dose of 3 x 10(5) U/m2 on three successive days. Treatment was repeated after a two week interval. The response was evaluated after four treatment cycles. In 15 patients entering the study, we found one partial response, one stable disease, 9 progressive diseases, and four patients who were not evaluable for tumor remission. There were numerous side effects of the treatment, mainly fever, chills, loss of appetite, leukopenia, and hepatotoxicity. In this regimen, rh TNF-alpha does not suggest a therapeutic advantage for treatment of advanced colorectal carcinoma.