Mitoxantrone, a recent anthracenedione derivative, is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leucopenia) was observed in 4 patients only after 35 and 40 mg/m2 i.p. Pharmacokinetic analysis using high performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to plasma was 1109. The peritoneal clearance rate was 680 ml/min and the mean disappearance half life was 13.1 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase I study we recommend phase II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.

Adult↗

PubMed1987

Poly(I).poly(C), a potential drug carrier for the antitumor agent mitoxantrone: in vitro drug binding study.

Coupling of mitoxantrone, a new antitumor agent, to a macromolecular carrier system may improve the drug's selectivity of action and pharmacokinetic properties. We have studied in vitro binding of mitoxantrone to poly(I).poly(C), a macromolecular, double-stranded homoribopolymer, by equilibrium dialysis and high-performance liquid chromatography (HPLC). Results showed high binding affinity for mitoxantrone to poly(I).poly(C) (Kd = 1.05 X 10(-6) M), the calculated number of mitoxantrone-binding sites is 60 per molecule poly(I).poly(C). In view of the good tolerance in clinical studies, poly(I).poly(C) may thus be a useful drug carrier for mitoxantrone. A mitoxantrone:poly(I).poly(C) ratio of 1:30 (w/w) is recommended for therapeutic studies.

Binding Sites↗

PubMed1987

Phase-I study of intraperitoneal mitoxantrone--clinical and pharmacokinetic evaluation.

Mitoxantrone, a recent anthracenedione derivative is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue-binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leukopenia) was observed in 4 patients only after 35 mg/m2 and 40 mg/m2 i.p. Pharmacokinetic analysis using high-performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to serum was 1,108. The peritoneal clearance ranged from 2 ml/min to 9,617 ml/min and the disappearance half-life from 0.6-28.9 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase-I study we recommend phase-II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.

Drug Evaluation↗

PubMed1987

Coupling of mitoxantrone to poly(I).poly(C) reduces absorption after intraperitoneal administration.

Coupling of mitoxantrone (M), an intercalating cytostatic, to macromolecular polynucleotides may reduce side effects after direct intraperitoneal chemotherapy by interfering with systemic absorption of M. We have administered free M (30 mg/m2) or M mixed with poly(I).poly(C) (90 mg/m2) intraperitoneally to 5 patients with peritoneal carcinosis (cross-over study): peak plasma levels (HPLC assay) were 62 +/- 12 versus 28 +/- 4 ng/ml (p less than 0.0025), AUC0-24h were 583 +/- 126 versus 481 +/- 57 ng X h/ml (p less than 0.025). Coupling of M to poly(I).poly(C) seems to reduce M absorption after intraperitoneal administration.

Absorption↗

PubMed1987

[Depressed skull fractures in children].

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Brain Injuries↗

PubMed1986

[Adjuvant chemotherapy in patients with radical resection of stomach cancer: 5-year results of a prospective randomized study].

102 patients with operable gastric carcinoma were randomly allocated to untreated control, polychemotherapy, chemoimmunotherapy. At a median follow-up of 5 years, chemotherapy did not improve the overall survival rate. However, in certain subgroups, patients with lymphnode metastases and intestinal tumor type showed a significant survival benefit when treated with adjuvant chemotherapy. Furthermore, we found the site of first recurrence very closely related to the type of tumor histology. Regardless of the positive effect of chemotherapy in retrospective subset-analysis, we do not generally recommend the use of polychemotherapy in operable gastric carcinoma.

Aged↗

PubMed1986

[An elastic obturator with a valve for the prosthetic treatment of maxillary resection defects].

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Denture Design↗

PubMed1985

Prospective randomized clinical trial: protoadjuvant chemotherapy vs. protoadjuvant radiotherapy in breast cancer stages T3/4, N+/-, M0.

Patients selected for neo-adjuvant therapy in this trial suffered from breast cancer stages T3/4, N0/+, M0. Selected patients were stratified and assigned to either pre- and post-operative chemotherapy (tamoxifen, fluorouracil, vincristine, methotrexate, cyclophosphamide, mitoxantrone) or radiotherapy by randomization. This interim report deals with side-effects and response rates of pre-operative therapy only. For this subgroup from 41 centres, 67 patients have so far been accepted for protocol treatment. 36 received peri-operative chemotherapy and 31 perioperative radiotherapy. We have completed reports of 66 pre-operative chemotherapeutic cycles pointing out only low side-effects in spite of a combination consisting of 5 different cytotoxic agents plus hormonal therapy. It is remarkable that 79% had no hair loss and 74% no gastrointestinal side-effects; in the chemotherapy-group 24 patients so far have been operated. Response rates were as follows: 1 (4%) complete remission, 9 (38%) partial remission, 7 (29%) minor response, 2 (8%) no response and 2 (8%) progression. In 2 patients response could not be determined. In the perioperative radiotherapy-group 10 patients have been operated with similar response rates. It is interesting to note, that both therapies influenced receptor values in different ways: Chemotherapy decreased receptor values, whereas radiotherapy insignificantly increased them. The purpose of this study is to establish a rational base for post-operative cytotoxic treatment of patients as only patients who objectively respond to preoperative treatment are likely to benefit from postoperative drug administration. The study is open for enrollment until a total of 200 patients is reached.

Adult↗

PubMed1985

Effect of adjuvant chemo- or immunotherapy on the prognosis of colorectal cancer operated for cure.

After radical surgery for colorectal cancer, 178 patients with a Dukes' B or C tumour were randomly assigned to one of three groups: A, controls (n = 62); B, chemotherapy (n = 59); C, immunotherapy (n = 57). Randomization criteria (age, sex, Dukes' stage, localization of tumour, operative procedure) were evenly distributed throughout the groups. After a median observation time of 30 months, statistical analyses were performed: survival and probability to be free of recurrence was described by Kaplan-Meier estimates of the survival function; for comparison of these survival functions, Breslow's test was used. Overall analyses show no benefit in the treatment group compared to controls. Separate analyses by Dukes' stages showed that in patients with Dukes' C tumours the probability of survival 40 months after surgery was 72 per cent in group C, 51 per cent in group B, and 33 per cent in group A. The differences between groups C and A, and B and A were statistically significant (P less than 0.02 and P less than 0.03 respectively). For a Dukes' C tumour the probability to be free of distant metastases at 30 months after surgery was 80 per cent in group B, 68 per cent in group C and 52 per cent in group A. Also for a Dukes' C tumour the probability to be free of liver metastases at 21 months after surgery was 83 per cent in group B, 81 per cent in group C, and 54 per cent in group A (significant differences: B-A and C-A P less than 0.04 for both). There was no influence on the estimated incidence of local recurrences for stage Dukes' C. Patients with a Dukes' B tumour did not benefit from either of the adjuvant therapy schemes.

Adjuvants, Immunologic↗

PubMed1985

Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study.

Mitoxantrone (Novantrone; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors. One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m2 i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22-39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks. Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174-256 mg/m2. Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.

Adult↗

PubMed1985

[Results of the first Austrian multicenter ovarian cancer study: prospective randomized comparison of sequential chemotherapy (adriamycin/cisplatin--vincristine/cyclophosphamide--methotrexate) with 2 standard protocols (adriamycin/cyclophosphamide or adriamycin/cisplatin) in stage III and IV patients].

From June 1980 to December 1982 164 patients with ovarian cancer stage III and IV were randomized into the three-legged Austrian Ovarian Cancer Study. A new polychemotherapy, known as the "changing-scheme" (adriamycin/cisplatinum--vincristine/cyclophosphamide--high dose methotrexate), developed in Vienna, was compared with adriamycin/cyclophosphamide and adriamycin/cisplatinum. The risk factors were stratified by means of special computer-assisted randomization. The first study evaluation in 1982 showed a significant advantage for the changing-scheme with regard to recurrence-free interval and survival (Mantel test: p less than 0.01, Breslow test: p less than 0.03). No difference was found between the combinations of adriamycin/cyclophosphamide and adriamycin/cisplatinum. At the second study evaluation in June 1984 the differences previously observed were no longe present to the same significant extent. The changing-scheme continued to be superior for the subgroups of patients with highly differentiated tumors, without ascites, with larger postoperative tumor burden and with liver metastases. The use of this therapy is be recommended for women with advanced ovarian cancer, especially in consideration of the much lower toxicity caused by the less frequent cisplatinum administrations as compared to the adriamycin/cisplatinum combination.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1985

Simultaneous and sequential determinations of steroid hormone receptors in human breast cancer. Influence of intervening therapy.

Estrogen (ER), progesterone (PgR), and androgen (AR) receptors were measured in two simultaneous or subsequent specimens taken each from 259 patients with breast cancer. We studied in 182 patients results from receptor assays, either from one tumor or from the primary tumor, and a lymph node metastasis, and in 77 sequential biopsies with or without intervening therapy. All assays were performed in a single laboratory, considering 10 fmol/mg cytosol protein bound ligand as receptor positive. The concordance rate in simultaneous ER assays was 85%; however, we found a considerable high discordance rate for PgR in primary tumor and lymph node metastasis (25%). The overall discordance rate in sequential biopsies for ER was 38% and for PgR 25%. This discordance rate was primarily dependent on the receptor quality of the first assay (ER+: 50%, ER-: 24%, PgR+: 68%, PgR-: 9%). Considering only the ER+ and PgR+ cases, we found the greatest discordance rate in the patients having endocrine treatment following the first biopsy (55% and 84%, respectively). We conclude that the receptor status of one tumor biopsy is highly representative for other tumor or lymph node biopsies. Because of the high discordance rate of primarily receptor + cases in subsequent recurrences, the receptor quality of these lesions should be analyzed whenever possible.

Biopsy↗

PubMed1984

[Surgical therapy of breast cancer: to operate radically or to preserve the breast?].

Surgical treatment, i.e. partial resection (R) versus modified radical mastectomy (M) in lymph node negative T1/2 patients and M versus the classical Halsted procedure (RM) in lymph node positive cases, as well as adjuvant treatment forms, namely chemotherapy (B) and chemoimmunotherapy (C) versus a control group treated by surgery only (A) have been evaluated in 241 patients with breast cancer follow up over a median observation time of 48 months. Whereas M showed significantly better results than R, no difference was detected between M and RM. The incidence of recurrence in the R group did not appear to be markedly reduced by cytotoxic treatment. In the same way, the data from a retrospective study on non-randomized patients treated by breast resection, showed a relatively high local recurrence rate (23.6%) at a median observation level of 10 years. Considering the various forms of surgical treatment for operable breast cancer by analysing the data from retrospective studies and prospective randomized trials from the literature as well as our own results, the only recommendation for the standard treatment of patients with primary operable breast cancer should be nothing less than modified radical mastectomy. Breast-conserving treatment forms should be tested only within the framework of controlled clinical trials.

Breast Neoplasms↗

PubMed1984

[Cytostatic therapy in metastatic breast cancer].

Although no breast cancer patient can be cured after metastases have been found, the fact that survival is prolonged and the symptoms and signs of advanced disease can be relieved, often impressively, by the administration of cytostatic chemotherapy justifies their implementation. Chemotherapy is only one aspect of a comprehensive treatment modality in this controversial field and has to be strictly reviewed in the light of indications and contraindications in every single patient. Step-by-step development over the past twenty years has proven the clear-cut advantages of polychemotherapy over a single-drug regimen. Adriamycin, the parent drug of the large group of anthracyclines has proved to be a highly efficacious substance in the treatment of metastatic breast cancer. Chronic administration of this compound is associated with the development of dose-dependent cardiotoxicity. This side effect is the most important limiting factor for the unrestricted use of this drug. Over the past years several anthracycline analogues have been developed which appear to be as effective against metastatic breast cancer as the parent compound. Moreover, there is some slight evidence that these drugs show less cardiotoxic activity than adriamycin. However, on objective review of the common treatment schedules in current use or under trial at present, it must be concluded that not one fully satisfies the ideal criteria of a safe and practicable procedure which does not stress the patient and is universally effective.

Anthraquinones↗