Cyclophosphamide, epirubicin and cisplatin (CEP) versus epirubicin plus cisplatin (EP) in stage Ic-IV ovarian cancer: a randomized phase III trial of the Gynecologic Oncology Group of the Comprehensive Cancer Center Limburg.

Cisplatin is the most important drug in the treatment of advanced ovarian cancer. The role of anthracyclines is controversial. We compared a combination of epirubicin plus cisplatin (EP) with a regimen of cyclophosphamide, epirubicin and cisplatin (CEP). Patients with stage Ic-IV ovarian cancer were randomized to receive either epirubicin 100 mg/m2 plus cisplatin 75 mg/m2 q 4 weeks or cyclophosphamide 500 mg/m2 plus epirubicin 75 mg/m2 plus cisplatin 50 mg/m2 q 4 weeks, which we considered the reference treatment based on our previous experience. Patients were initially debulked, followed by six cycles of chemotherapy, or in case primary debulking was insufficient or considered inappropriate, secondary debulking was attempted in selected cases after sufficient chemotherapy-induced regression. Optimal debulking was defined as residual lesions < or = 2 cm. A total of 210 patients (191 eligible) were randomized. Results did not show significant differences in all major endpoints (pathologically documented complete response and survival). The median survival for all patients was 34 months, for patients with stage III 26 months, for patients with stage IV 20 months and it has not been reached for patients with stage Ic-II. As no significant differences between an equitoxic regimen of EP and CEP were detected, it might be more useful to look again at the anthracyclines as part of combination chemotherapy instead of the alkylating agents.

Efficacy of carboplatin plus primary prophylactic filgrastim (granulocyte colony stimulating factor) in relapsed ovarian cancer: a study of the Gynecologic Oncology Group of the Comprehensive Cancer Center Limburg.

A total of 34 patients with advanced ovarian cancer, who relapsed 1-72 months after at least one first-line cisplatin-based chemotherapy protocol, were treated with carboplatin, 350 mg/m2 q 4 weeks, with the adjunct of primary prophylactic granulocyte colony stimulating factor (G-CSF; filgrastim), 300 or 480 microg daily, days 5-9. Over 90% of the anticipated dose of carboplatin could be administered. Partial response, defined as a decline in CA-125 of 50% or more on two consecutive samples, occurred in 42%, while 15% of patients achieved a complete response (no clinical signs of disease with normalization of CA-125). Survival from start of carboplatin treatment was 23 months. Myelosuppression was the most important toxicity with 35% of patients experiencing grade 4 thrombocytopenia of short duration. Grade 4 leucopenia occurred in only one patient. It is concluded that single-agent carboplatin, with the adjunct of prophylactic G-CSF, can be administered with adequate dose intensity, and is an effective and acceptable palliative treatment for patients with relapse after first-line cisplatin-based chemotherapy.

Rising case fatality of bacteriologically proven pulmonary tuberculosis in The Netherlands.

Analysis of registration cards from the Tuberculosis Control Program (TCP) showed a four-fold increase in case fatality of bacteriologically proven pulmonary tuberculosis in Dutch patients in the period 1973-1984. Registered data of 125 deceased patients whose primary cause of death was pulmonary tuberculosis were analyzed. Increased case fatality predominantly occurred in the elderly. Elderly patients presented often with other, less specific, complaints than coughing, but had a shorter combined patient's and doctor's delay than younger patients. The elderly were more often treated with 3 tuberculostatic drugs (INH, pyrazinamide, rifampin). Bacterial resistance was found in only 2%. Probably the most important factor concerning the raised case fatality in the elderly is the decline in immune response, due to ageing of the Dutch population. An effective response to tuberculostatic drugs needs a reasonably intact immune response. Declining immunity of the elderly group will increase incidence and mortality of pulmonary tuberculosis in this group.

Chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide as an adjunct to surgery in stage Ic-II epithelial ovarian carcinoma. Gynecologic Oncology Group of the Comprehensive Cancer Center.

Twenty-five patients with stage Ic-II ovarian cancer (8 stage Ic and 17 stage IIb-c) were treated with total tumor removal followed by six cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin (CAP-1) i.v. on day 1, every 4 weeks. Of 18 patients in whom a second look was performed, 16 (89%) achieved a pathologically documented complete response and 2 had positive peritoneal washings at second look. Seven patients did not undergo second-look laparotomy. All had no clinical evidence of disease. One patient with stage Ic relapsed and died after 40 months. Nine patients with stage II relapsed, and 8 died after a median of 25 months (range, 18-58 months). The overall relapse rate in all patients was therefore 40% (95% confidence interval: 21-61%). Median follow-up of all patients is 5 years (range, 40-85 months). The 5-year survival of patients with early-stage ovarian cancer treated with cisplatin-based chemotherapy appears to be at least as good as reported with the use of postoperative irradiation or intraperitoneal radioactive phosphate. Optimal treatment of these patients remains to be further defined.

The prognostic value of morphometrical features and cellular DNA content in cis-platin treated late ovarian cancer patients.

In 73 CAP-1 treated stage III and IV ovarian cancers, the prognostic significance of morphometric features and cellular DNA content has been evaluated in comparison with histologic type, grade of differentiation and a number of clinical characteristics. Borderline tumours were excluded from the study. Median follow-up was 44 months, median survival time 36 months. Single features associated with prognosis were (in order of decreasing significance according to single variate analysis): FIGO stage (P = 0.0002), bulky disease (P = 0.004), standard deviation and mean of nuclear area (P = 0.0006 and P = 0.01), cellular DNA content (P = 0.01), mitotic activity index (P = 0.08) and volume percentage epithelium (P = 0.13, not quite significant). Tumours with a mean nuclear area greater than 70 micron2 (which occurred in 35% of the cases) were nearly all aneuploid. Multivariate analysis showed that the statistically most significant prognostic combination of features consisted of mean nuclear area, presence or absence of bulky disease and FIGO stage (in order of decreasing importance) (Mantel-Cox = 23.07, P less than 0.00001). A low value for the multivariate function of this combination of features was associated with a poor prognosis within 24 months, a high value with a favourable outcome. Another favourable combination of features appeared to be diploid cellular DNA content and a low mitotic activity index (11 patients, one died). However, even with the prognostically most favourable combination of these features, several patients died. Of all combinations of features investigated, only two were associated with an excellent prognosis (low mitotic activity index and low volume percentage epithelium). Cancers of 7 patients (10%) displayed such features, and none of them died during the follow-up period (minimally 20 and maximally 54 months). It is concluded that morphometric and flow cytometric analysis can provide significant and objective information to predict the prognosis of cis-platin-treated advanced ovarian cancer patients.

Proposal for therapeutic approach based on prognostic factors including morphometric and flow-cytometric features in stage III-IV ovarian cancer.

In 73 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III and IV ovarian cancer the prognostic significance of morphometric and flow-cytometric features has been evaluated in comparison with more commonly used prognostic factors such as stage and tumor mass. Single features associated with prognosis were as follows: FIGO stage, bulky disease, mean and standard deviation of nuclear area, cellular DNA content, mitotic activity index, and volume percentage epithelium. Multivariate analysis showed that the most significant prognostic combination of features consisted of mean nuclear area, presence or absence of bulky disease, and FIGO stage (in sequence of decreasing importance; Mantel-Cox = 23.07, P less than 0.00001). On the basis of these factors patients with a poor prognosis can be identified. On the other hand two features were associated with an excellent prognosis namely a low mitotic index and a low-volume percentage epithelium. It is concluded that morphometric and flow-cytometric analysis in combination with clinical features can provide significant information to predict the prognosis of patients with advanced ovarian cancer treated with debulking surgery and platinum-based chemotherapy. On the basis of our data a tentative proposal for future therapeutic approaches is made.

The yield of active case-finding in persons with inactive pulmonary tuberculosis or fibrotic lesions. A 5-year study in tuberculosis clinics in Amsterdam, Rotterdam and Utrecht.

The aim of the study was to elucidate the yield of annual chest X-ray and bacteriological examination in subjects with inactive tuberculosis or fibrotic lesions. Nearly 15 000 such persons registered at the Tuberculosis Clinics (C.B.s.) in Amsterdam, Rotterdam and Utrecht were allocated at random to either the Check-up group or the Discharge group: every person had an initial chest X-ray and examination of sputum or tracheal lavage for tubercle bacilli. Those in the Check-up group were re-examined annually for 3 years, while those in the Discharge group were not, but were encouraged to come to the C.B. if they developed symptoms suggestive of tuberculosis. Every patient was invited, after 3 years, to attend for a final follow-up examination. Nearly 90% of patients in the Check-up group attended for annual examination. Twenty-eight reactivations were reported during the 3 years, 23 pulmonary and 5 non-respiratory. They occurred in 12 patients previously treated by chemotherapy (1.2 per 1000 per year), in 15 with inactive tuberculosis (1.5 per 1000 per year) and in one with a fibrotic lesion (0.3 per 1000). Tubercle bacilli were found by smear and culture in only 2 cases and by culture only in 24. In the majority of reactivations only a small number of colonies were isolated on culture and no deterioration on the X-ray was seen. In the discharge group, 917 persons reported to the C.B.s because of pulmonary symptoms; 12 reactivations were found during the 3 years: 10 of the patients had received previous chemotherapy. Only 2 patients were positive at microscopy and in the majority of culture-positive cases a small number of colonies were isolated; 5 of the 9 patients with pulmonary tuberculosis showed deterioration in the X-ray appearance. At the final re-examination in the fourth year, similar numbers of cases were found in the Check-up group (14) and Discharge group (15). However, there were less smear-positive cases in the Check-up group and less cases with X-ray deterioration. There were 69 confirmed reactivations in all. The annual rate of reactivation was 1.6 per 1000 in the Check-up group and 1.1 per 1000 in the Discharge group. It is suggested that routine annual check-ups of patients with inactive tuberculosis or fibrotic lesions should be discontinued.

[Tuberculosis in the developing countries and the work of the international Union for the control of tuberculosis (author's transl)]. / Tuberkulose in den Entwicklungsländern und die Tätigkeit der Internationalen Union zur Bekämpfung der Tuberkulose.

In the developing countries tuberculosis is one of the most common diseases. According to estimates the number of cases of infectious tuberculosis is 3-4 millions. The guidelines for the effective control of the disease in the developing countries were laid down in a report by a Spezial Committee of the W.H.O. in 1974. The emphasis is 1) on protecting young people as far as possible by BCG vaccination, 2) on the early detection and treatment of as many cases of infectious tuberculosis as possible. The diagnosis does not depend on (expensive) radiographic equipment, as it can be made simply by microscopic examination of the sputum. For treating the infection various efficacious and not too expensive drugs are available which succeed within a few weeks in reducing the process to a non-infectious stage. Sanatorium or hospital treatment is generally not necessary.