Anti-depressants and anti-convulsants for the treatment of neuropathic pain syndromes in cancer patients.

20 patients with neuropathic pain syndromes due to tumor-infiltration, who had not responded to conventional analgesics including strong opioids, received additional combination anti-convulsant and anti-depressant treatment. Pain amelioration occurred in all patients within median 46 h, and maximum effect was encountered within one week. Severe side effects were confined to three cases and were associated with carbamazepine treatment. Replacement by another type of anticonvulsants in 6 cases with either no response or intolerable side effects was successful in 5 patients, both in terms of efficacy and tolerability. One patient stopped taking AD/AC after 48 h.

Interferon alfa-2b in acute- and chronic-phase chronic myelogenous leukaemia: initial response and long-term results in 54 patients.

Fifty-four patients with Ph1-positive chronic myelogenous leukaemia (CML) (48 with chronic-phase and six acute-phase disease) were treated with interferon alfa-2b subcutaneously (s.c.). The starting dose was 4 million units (MU)/m2 body surface area daily. It was reduced in parallel with serially determined leucocyte counts, and minimal effective doses were given as maintenance after achieving remission. Haematological remissions were induced in 22 of the 48 patients (46%) with chronic-phase disease. Thirteen patients (27%) revealed partial haematological remission and another 13 no response to treatment. No complete remission could be induced, although minor or partial cytogenetic responses were seen in 16 patients (33%). Moreover, a bcr-abl reduction was detected on Southern blot analysis in two patients. In chronic-phase disease, results of treatment were influenced by elapsed time after diagnosis, extent of previous treatment and interferon dosage. No beneficial effects of interferon were detected in the six patients with acute-phase disease. Principal acute side effects were fever and flu-like symptoms at the beginning of the therapy, which usually subsided within 3-7 days. Chronic side effects, especially weakness and neuropathy, were less frequent but more severe and necessitated discontinuation of treatment in 10 patients. In summary, interferon alfa-2b seems to be an effective treatment in early chronic-phase CML. Long-term effects on the course of the disease, however, must be determined.

Etoposide, ifosfamide, and methotrexate with or without bleomycin in refractory or recurrent lymphomas.

The prognosis of patients with refractory or relapsed malignant lymphoma is poor. To improve the outcome of such patients, a therapeutic regimen of VIM +/- B (etoposide/ifosfamide plus mesna/methotrexate/ with or without bleomycin) was administered. Of 47 patients treated, 15 had relapsed following complete remission (CR) after first-line chemotherapy, 28 had failed to achieve CR with first-line therapy, and four failed to respond to multiple salvage regimens. All patients had received extensive prior chemotherapy, and 36 had received combinations containing doxorubicin. Eight patients had low-grade non-Hodgkin's lymphoma (NHL), 28 had high-grade NHL, and 11 patients had Hodgkin's disease. Overall response rate was 87%, with 45% CR and 42% partial remission (PR). Median relapse-free interval was 8 months in patients with CR and 6 months in those with PR. Of patients with CR, 43% were predicted to be without relapse at 2 years and 31% at 5 years. Median survival time for all patients treated with 14 months-22 months for those with CR and 10 months for those with PR. Probability of survival at 2 years was 30% in all patients, 50% in patients with CR, and 15% in those with PR. VIM +/- B appears to be effective against refractory or recurrent lymphoma, resulting in response in a large number of patients and long-term survival and possible cure in a small but significant number. Results indicate that VIM +/- B is particularly effective in patients with high-grade NHL who have responded suboptimally to primary therapy.

Ifosfamide, methotrexate and 5-fluorouracil for pretreated advanced breast cancer.

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.

Etoposide in patients with previously untreated non-small-cell lung cancer: a phase I study.

In a phase I study, a range of doses of etoposide (200-370 mg/m2 given i.v. daily on 3 consecutive days) were evaluated for tolerance and response as first-line treatment in 26 patients with non-small-cell lung cancer. The dose-limiting toxicity was myelosuppression, especially leukopenia. At dose levels of 350 and 370 mg/m2 etoposide per day, leukopenia of WHO grade 4 occurred in two and one of seven patients, respectively. No thrombocytopenia of this degree was observed. Myelosuppression was quickly reversible and noncumulative. Apart from alopecia, nonhematologic organ toxicities above WHO grade 2 were not seen. Toxicity analysis suggests that the recommended dose of single-agent etoposide for phase II studies in untreated patients is 330-370 mg/m2 given i.v. daily for 3 days. At the dose levels tested, 6 (23%) major responses could be induced. All responses were seen at a starting dose of greater than 300 mg/m2 per day. The median duration of response was 4 months. The median survival for all patients was 8 months and that for responding patients was 15 months.

[Chemotherapy of nonendemic Burkitt's lymphoma]. / Chemotherapie des nicht-endemischen Burkitt-Lymphoms.

14 patients (12 men, 2 women, mean age 26.3 [15-47] years) with histologically confirmed Burkitt's lymphoma were subjected between 1984 and 1989 to chemotherapy originally developed for treating lymphomas in children. Treatment consisted of medium doses of methotrexate, cyclophosphamide, teniposide, cytarabine, adriamycin and prednisone, intrathecal administration of methotrexate and if necessary prophylactic or therapeutic irradiation of the cranium. Most of the patients (64%) were in advanced stages of the disease. The rate of complete remissions was 100%. Four patients (29%) had a recurrence. Side effects were leukopenia (WHO grade III and IV) in 71%, grade III anaemia in 43% and grade III-IV thrombopenia in 29% of the patients. Considerable mucositides in 5 of the 14 patients (36%), and in one case a tumour lysis syndrome with transient renal insufficiency were other therapy-induced side effects. These results suggest that this treatment course can be successful also in non-endemic Burkitt's lymphoma in adolescents and adults.

[Cardiac side effects of 5-fluorouracil]. / Kardiale Nebenwirkungen von 5-Fluorouracil.

In four patients (a 54-year-old man and three women aged 57, 60 and 65 years, respectively) with colorectal carcinoma and no obvious cardiac abnormality anginal symptoms and ECG changes occurred during chemotherapy with 5-fluorouracil at a dose of 400 and 600 mg/m2. The ECG changes consisted of descending ST depressions with preterminally negative T waves, terminally negative T waves, ventricular extrasystoles and sinus tachycardia with intermittent atrial fibrillation. The signs first appeared between the second and fourth day of treatment; in two patients they improved with glyceryl trinitrate. A few days after 5-fluorouracil had last been administered all ECG changes had disappeared. The causes of cardiotoxicity of the drug remain unknown.

Seven variants including four new Philadelphia translocations.

This paper reports on seven atypical Philadelphia chromosome translocations in chronic myelocytic leukemia. Three of them, a t(16;22), t(17;22), and t(9;14;22) have already been observed before, while the t(X;9;11;22), t(X;22), t(3;22) and t(3;4;9;22) are newly reported.

[Tumor progression and metastasis]. / Tumorprogression und Metastasierung.

The heterogeneity of cells capable of metastasation has proved to be the greatest obstacle to successful treatment or to prevention of metastatic diseases. This variety appears to be attributable to processes of selection. Cytobiological investigations which are helpful in casting some light at selective mechanisms of metastasation may, perhaps, make substantive contributions to cancer therapy.

Mafosfamide induces less sister chromatid exchange in Ph-positive cells than in normal bone marrow.

The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.

[Sequential induction chemotherapy and radiation treatment of inoperable small cell bronchial cancer. Results of a prospective randomized study]. / Sequentielle Induktionschemotherapie und Strahlenbehandlung inoperabler kleinzelliger Bronchialkarzinome. Ergebnisse einer prospektiven randomisierten Studie.

To study the potential benefit of sequential chemotherapy in inoperable small cell lung cancer (SCLC), from 1982 to 1986 ninety-one patients with histologically proven and previously untreated SCLC (median age: 53 years; median Karnofsky status: 80%) were randomly assigned to an initial therapy with adriamycin (since 1984 epirubicin), cyclophosphamide, vincristine (ACO resp. EPICO) or etoposide/cisplatin (VP16/DDP). Treatment courses were repeated every 3 weeks for a total of less than or equal to 6 courses with a crossover after a maximum of 3 cycles of either regimen. Limited disease (LD) patients with bronchoscopical, computertomographical and (re-) mediastinoscopical complete remission (CR) randomly received either a thoracic irradiation with 40 Gy or observation only. Overall, 60 out of 85 evaluable patients achieved an objective remission. A CR was observed in 24/51 patients (47%) with limited disease, and in 8/34 patients (24%) with extensive disease. Both, ACO (EPICO) and VP16/DDP were equally effective as initial and second-line therapy. Moreover, after failure to the initial therapy an objective remission could be achieved in 13% of the patients following the alternative second line combination. In 28% of LD patients with an otherwise complete remission residual tumor was detected by (re-) mediastinoscopy. Median survival times were 14 (CR: 16) months in LD patients and 10 (CR: 15) months in ED patients. At present, median survival is significantly improved in irradiated versus non-irradiated LD patients (25 vs. 13 months, p less than 0.04). The remission rates and median survival times observed in this study are comparable to those of a historical control group treated with ACO plus radiotherapy alone.

High-dose medroxyprogesterone acetate in advanced breast cancer. Clinical and pharmacokinetic study with a combined oral and intramuscular regimen.

Seventy-five patients with advanced and intensively pretreated breast cancer received high-dose medroxyprogesterone acetate (MPA) using a schedule consisting of an intramuscular (IM) loading dose (1 g MPA IM days 1 to 10) and an oral maintenance treatment (200 mg/day three times a day) thereafter. A reinduction was performed in part of the responding patients at time of early relapse (1 g MPA IM for 10 consecutive days). MPA serum levels above 100 ng/ml were achieved during induction treatment and maintained for 3 to 4 months during the oral phase of therapy before decreasing to approximately 50 ng/ml. Two complete remissions (duration, 17.2 and 62 months), 15 partial remissions (median duration, 7 months), and 21 cases of disease stabilization (median duration, 5.5 months) were achieved. The median survival time was significantly longer for responders (19.9 months) than nonresponders (4.8 months). Although a higher proportion of postmenopausal patients responded, the remission duration in premenopausal women was remarkably long. Favorable sites of response were soft tissue, lymph nodes, and bone lesions. Reinduction treatment yielded a second response (two partial remissions, three no change) in five of six patients indicating that high-dose conditions were necessary to maintain response. This schedule allows to restrict higher doses of MPA on a long-term basis to responding patients.

A PvuII polymorphism of the bcr region in patients with hematopoietic disorders and their families.

The BCR gene on chromosome 22 has received increasing attention because of its involvement in the Philadelphia (Ph') translocation. For most restriction enzymes, this locus has been found to be nonpolymorphic. Two alleles have only been found when Taql-digested DNA is hybridized to a 5' bcr-specific probe. We describe another two-allele polymorphism detected by the same probe in PvuII-digested DNA. The polymorphism is characterized by an additional PvuII site in the bcr region: this causes the appearance of an additional band of about 2.3 kb or 2.5 kb besides a 4.8-kb fragment in hybridizations with the 5' bcr or a 3' bcr probe. The incidence of the second allele is very low. It has only been found in some patients with hematopoietic malignancies and in a group of volunteers having a leukemia patient in their families.

Ifosfamide, methotrexate, and 5-fluorouracil in advanced pretreated breast cancer.

Thirty-five patients with a median age of 55 years (range, 28 to 68 years) and a median Karnofsky status of 80% (range, 40% to 100%) were treated with ifosfamide (1.5 g/m2 plus mesna), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) intravenously (IV) days 1 and 8 at intervals of 4 weeks. Thirty-four patients had received previous chemotherapy, including anthracyclines in 28 patients. All patients were evaluable for response. A partial remission was achieved in six patients (17%), stable disease in 13 patients (37%), and 16 patients (46%) were unresponsive. Median time to progression was 7 months (range, 4 to 13 months) for partial responders, and 4 months for patients with stable disease. Median survival was 9 months for all patients, 13 months for partial responders, 16 months for no change, and 3 months for progressive disease. Toxicity was tolerable, with myelotoxicity being a dose-limiting factor, mainly in heavily pretreated patients. No treatment-related death occurred. In conclusion, this combination is effective and well tolerated. Ifosfamide is suggested for further evaluation in advanced breast cancer.

Sequential combination chemotherapy (CABOPP/VIM) for the treatment of high-grade malignant non-Hodgkin lymphoma.

In 42 patients with high-grade malignant non-Hodgkin lymphomas, a new treatment program was used in an attempt to improve results without increasing toxicity. Two effective but relatively well tolerated and non-cross resistant drug combinations were given sequentially according to the response of disease. Therapy was started with a combination consisting of cyclophosphamide, doxorubicin, bleomycin, vincristine, procarbazine and prednisone (CABOPP). In patients with complete remission after a maximum of 4 cycles of CABOPP, this regimen was continued for a total of 6 cycles. In patients with progressive disease or with only a partial remission after 4 cycles of CABOPP, therapy was switched to a combination consisting of etoposide, ifosfamide and methotrexate (VIM). Complete remission (CR) was achieved in 86% of patients. Sixty-nine percent achieved CR with CA-BOPP alone and 17% after changing to VIM. The CR rate was 100% in patients with stage I or II and 78% in those with stage III or IV of disease. The projected survival at 2 years is 66%. Fifty-six percent of patients with CR are predicted to have continued CR at 2 years. Thus, CABOPP/VIM appears to be an effective and well tolerated program for the treatment of aggressive lymphomas. The value of this program, however, can only be established comparing it with other newly developed protocols in randomized studies.