Biomedical subjects
Publications and source records attributed to H Brincker.
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Thirty-five patients with advanced metastatic breast cancer refractory to prior chemotherapy were treated with vindesine given at a fixed dose as a continuous 5-day infusion of 1.5 mg/day every 4 weeks. All patients were considered evaluable, and there were four patients with partial responses for more than 3 months (11%) and 13 patients with stable disease (37%). Two of the four responders had had disease progression on other vinca alkaloids. None of the responders had proven doxorubicin resistance. Side-effects included myelosuppression, neurotoxicity, nausea, stomatitis and fever, but these were seldom dose-limiting. The results--together with the results of other single-agent studies of vindesine summarized in the paper--indicate that the drug is an active agent in advanced breast cancer. However, the optimum way of administering vindesine and its inclusion in first-line therapy needs further study.
Since Jan. 1, 1976 practically all new cases of germ cell tumours of the testis in Denmark have been included in the Danish Testicular Carcinoma Study (DATECA), permitting detailed registration of data concerning histology and stage at the time of diagnosis. The incidence of carcinoma of the testis in Denmark continues to be high with a crude rate of 8 to 9/100 000 males per year. During the past 5 years the size of the primary tumours has decreased. Parallel to this, the rate of metastatic spread has decreased for seminoma, while no such change has been observed for non-seminomatous tumours. Data are presented on histology and stage for 1058 consecutive patients.
Since Jan. 1, 1976, nearly all new cases of testicular germ cell tumours have been included in the Danish Testicular Carcinoma Study (DATECA), and have been monitored by the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). During the first five years, 1058 patients participated in the investigation, but only 603 of these patients were followed by preoperative as well as postoperative marker determinations in serum. The overall prevalence of marker positivity, i.e. elevated preoperative values for AFP and/or HCG, was 8 per cent for seminoma patients and 60 per cent for non-seminoma patients. Elevated levels of serum AFP and HCG were correlated to the presence of endodermal sinus tumour and choriocarcinoma elements, respectively, in the primary tumour. The presence of increased marker concentration in serum was correlated stage (higher percentage in higher stages) and to prognosis (marker negative patients had a better prognosis than marker positive patients). Marker production by seminoma patients seems to indicate a poor prognosis, especially for HCG producing seminomas.
Aclarubicin (ACR) was administered in a prospective cooperative phase II trial to 44 patients with possibly refractory acute nonlymphocytic leukemia who were previously treated with daunorubicin and cytarabine. Induction treatment consisted of 80 mg/m2 of ACR iv daily for 3 days, followed by 80 mg/m2 iv daily for 2 days in patients not obtaining a complete remission (CR) after 2-4 weeks. CR was observed in eight patients (18%) and partial remission was observed in six (14%). On monthly maintenance chemotherapy with ACR and cytarabine, the duration of CRs varied between 10 and 58 weeks. Achievement of remission was not related to age, presence or absence of Auer bodies, cytogenetic characteristics, or previous response to daunorubicin and cytarabine. Side effects were nausea and vomiting observed in 86% and diarrhea in 34% of the patients, whereas mucositis and alopecia were uncommon. Disturbances of cardiac function arousing suspicion of acute ACR toxicity were observed in seven patients. No case of chronic cardiotoxicity was observed, despite the fact that 20 patients received ACR doses greater than 400 mg/m2, with seven of the 20 having had a previous daunorubicin dose greater than 400 mg/m2. As CR was obtained in four of 14 patients with primary therapy-resistant leukemia and in two of 16 patients with relapse and no response to re-treatment with daunorubicin and cytarabine, ACR does not seem to show clinical cross-resistance to daunorubicin. Evaluation of ACR in first-line chemotherapy of acute nonlymphocytic leukemia appears justified.
The role of antiestrogen treatment in high risk postmenopausal patients with primary breast cancer is currently evaluated in a nationwide, prospective randomized trial conducted by the Danish Breast Cancer Cooperative Group. The primary treatment is total mastectomy and radiotherapy. As of February 1, 1982, 720 women were randomized to treatment with tamoxifen (30 mg daily for 1 year) and 691 women were randomized to no further therapy. Life-table analysis after 36 months shows a difference in recurrence rates of 9% (p = 0.19) in favor of the tamoxifen-treated patients. The material has been analyzed with respect to established prognostic factors such as age, degree of anaplasia, tumor size, and number of positive nodes. The rates of recurrent disease are lower in all subsets of patients treated with tamoxifen, but are only statistically significant in patients 50-59 years of age or with 4 or more positive lymph nodes. Regardless of treatment, ER negative patients have a 23% higher recurrence rate than ER positive patients after 18 months of analysis (p = 0.0033); this represents an approximate doubling of risk, and is independent of age, degree of anaplasia, tumor size, or lymph node status. With regard to PgR status, there is 11% higher recurrence rate in the PgR negative than in the PgR positive patients (p = 0.097).
After total mastectomy and partial axillary dissection, 805 premenopausal women with stage II breast cancer were randomized to receive postoperative radiotherapy (RT) alone, RT + cyclophosphamide (C) for 12 monthly cycles, or RT + cyclophosphamide/methotrexate/5-fluorouracil (CMF) for 12 monthly cycles. At 3 years actuarial relapse-free survival for RT + C and RT + CMF was significantly better than for RT alone (p = 0.0009 and 0.0001, respectively). There was no significant difference in relapse-free survival between RT + C and RT + CMF. C resulted in more pronounced haematologic toxicity and a higher frequency of amenorrhoea and of alopecia than CMF, while CMF resulted in more pronounced nausea and stomatitis than C. In the preliminary results, C alone may be as effective as CMF in prolonging relapse-free survival in premenopausal women with stage II breast cancer.
The DATECA Project was started in January 1976 and includes all patients with testicular cancer in Denmark. During the first 6 years, 1246 patients entered the joint protocol for histology, staging, management, and clinical use of tumor markers. Only 746 DATECA patients fulfilled the claims for being ideally monitored with preoperative as well as postoperative serologic marker determinations. The overall prevalence of marker positivity, that is, elevated preoperative values of alpha-fetoprotein (AFP) and/or human chorionic gonadotrophin (HCG) was 8% for patients with seminoma and 63% for patients with nonseminomatous disease. The prevalence of increased marker concentration in serum was correlated to stage (higher prevalence in higher stages) and to prognosis (marker-negative patients had a better prognosis than did marker-positive patients). An increased concentration of AFP or HCG was correlated with the presence of a primary endodermal sinus tumor and choriocarcinoma component, respectively.
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Due to recent developments in clinical haematology, 98.8% of all 1980 cases of leukaemia reported to the Danish Cancer Registry during the 4-year period 1973-76 could be subclassified into the 4 main types of leukaemia. Thus, it has been possible to characterize each of these types more accurately than before regarding age- and sex-specific incidence rates, relative frequency, male/female ratio, and median age at diagnosis. Chronic lymphatic leukaemia constituted 38% and chronic myeloid leukaemia 15% of the cases. These figures are larger and smaller, respectively, than these previously reported. The median age of all cases combined was 67 years, and the median age in cases of acute non-lymphocytic leukaemia was 64 years with 59% of the latter patients more than 60 years of age. In childhood myeloid leukaemia, an early incidence peak, not previously described, was observed before the age of 2 years. Analysis of Danish leukaemia incidence rates from 1943 and onwards shows no increase over 3 decades in patients less than 75 years of age. Thus, the observed increase in incidence from 5866-9942/100 000 during the period studied is limited to the very oldest age groups and is probably due to improved diagnostic efforts.
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In a longitudinal study, several immunologic in vitro tests were performed on peripheral lymphocytes in four patients with immunoblastic lymphadenopathy during sequential therapy with Levamisole and polychemotherapy. The percentage of T cells tended to fall with increasing disease activity, while the percentage of B cells remained almost constant. Blast transformation tests showed that both the T-cell and B-cell responses are defective and that improvement in disease status is correlated closely with an improvement of the blast transformation response. Levamisole treatment improved the blast transformation response but did not produce clinical remission in contrast to polychemotherapy, which produced clinical remission as well as improvement of the blast transformation response. No conclusions about the pathogenesis of this disease could be made in the present study. No proof was found of a primary defective T-cell function (including T-suppressor activity) although the available methods did not preclude this possibility completely.
In a prospective, nationwide, decentralized breast cancer project conducted by The Danish Breast Cancer Cooperative Group (DBCG) the recurrence rate within the first year after surgery was analysed in relation to tumor anaplasia. One thousand forty-eight patients met the requirements of eligibility, i.e. tumor size less than or equal to 5 cm with negative axillary nodes, and no skin or deep invasion. The recurrence rates in tumors with anaplasia Grades I, II, and III were 4, 9, and 14%, respectively (p = 0.001). Therefore, it seems possible, prospectively, among otherwise prognostically favorable patients, to select a group with high risk of recurrence which might benefit from adjuvant systemic therapy.
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In a multi-centre study in which data from all Danish Hodgkin patients have been registered since 1971, all patients in supradiaphragmatic stages I or II, as confirmed by staging laparotomy, were randomized to either radiotherapy (RT) to supra- and infradiaphragmatic lymph node regions (total nodal irradiation, TNI), or RT to a mantle field followed by 6 cycles of MOPP combination chemotherapy (RT+CT). Interim results up to July 1979, when 237 patients had entered the study, showed a treatment failure rate of 19/117 in the TNI group and 4/120 in the RT+CT group (P less than 0.05). 19 of the 23 relapsing patients were under the age of 40, and 14 in the TNI group and 3 in the RT+CT group belonged to stage II. 13 patients had nodular sclerosis, 9 had mixed cellularity and 1 had lymphocytic predominance histology. 12 of 19 relapsing patients in the TNI group had hilar or mediastinal involvement as against 51 of the 117 patients in the entire group. Most of the TNI failures could be retreated, and as yet there is no difference in the overall survival.
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