Moira E. Stewart

A prognostic model for ovarian cancer

About 6000 women in the United Kingdom develop ovarian cancer each year and about two-thirds of the women will die from the disease. Establishing the prognosis of a woman with ovarian cancer is an important part of her evaluation and treatment. Prognostic models and indices in ovarian cancer should be developed using large databases and, ideally, with complete information on both prognostic indicators and long-term outcome. We developed a prognostic model using Cox regression and multiple imputation from 1189 primary cases of epithelial ovarian cancer (with median follow-up of 4.6 years). We found that the significant (P≤ 0.05) prognostic factors for overall survival were age at diagnosis, FIGO stage, grade of tumour, histology (mixed mesodermal, clear cell and endometrioid versus serous papillary), the presence or absence of ascites, albumin, alkaline phosphatase, performance status on the ZUBROD-ECOG-WHO scale, and debulking of the tumour. This model is consistent with other models in the ovarian cancer literature; it has better predictive ability and, after simplification and validation, could be used in clinical practice.

Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters

BACKGROUND Cognitive deficits are the hallmark of dose limiting late radiation morbidity in the CNS. Little is known about the neuropsychometric morbidity of treatment in adults with primary brain tumours. We set out to evaluate systematically the neuropsychometric function of all long-term survivors in order to document the frequency and severity of impairment and study its relationship with tumour and treatment related parameters. MATERIALS AND METHODS 30 patients surviving in clinical and radiological remission for > 4 years following irradiation were recalled for clinical examination, CT/MRI scan and neuropsychometric testing. The 14 males, 16 females, (mean age 42.5 years), represented all but one long term survivors treated with radiotherapy in the Department of Clinical Oncology between 1971 and 1990. Twenty-five patients had a histological diagnosis of glioma. Patients treated before 1987 (n = 16) received whole brain irradiation (WBI); focused irradiation (FI) has been used since (n = 14). RESULTS The two groups were similar were in age, initial tumour type and surgical treatment, but the WBI group showed more evidence of neuropsychometric impairment than the FI group with significantly lower group median scores in tests of visuospatial organisation (WAIS Block Design, P = 0.01), visual memory (Rey Complex figure, P = 0.003) and complex information processing (Trails A, P = 0.003; Trails B, P = 0.002). Pre-morbid IQ estimated from sociodemographic variables, was comparable in the 2 groups which were not significantly different in their emotional state as assessed by the HADS. On univariate analysis radiation volume (P = 0.05) and time from treatment (P = 0.02) were the main factors associated with neuropsychometric deficit. Multivariate analysis by logistic regression confirmed WBI as the only independent predictor of neuropsychometric impairment (WBI vs. FI, odds ratio = 7.1, 95% C.I. 1.2-42.3, P = 0.03). CONCLUSIONS Neuropsychometric deficits are common and can be related to time from treatment and radiation technique. Neuropsychometric testing can be a useful tool in the evaluation of different treatment strategies.

Neurological and cognitive impairment in long-term survivors of small cell lung cancer

Despite its effectiveness in reducing the rate of brain metastases, the role of prophylactic cranial irradiation (PCI) in the management of small cell lung cancer (SCLC) remains controversial because of concern about radiation-induced neurological morbidity. In order to evaluate morbidity and its impact on quality of life 64 patients surviving > or = 2 years in remission were recalled for assessment. 52 had received PCI. Most of the patients were well: 95% had performance status < or = 1 and nine out of 37 neurological examinations were abnormal. On neuropsychometric testing, only 19% of patients performed at the level expected for their age and intellectual ability on all four tests used. Fifty-four per cent of patients were impaired on two or more of the tests, suggesting a significant degree of measurable cognitive dysfunction. The number of patients who had not received PCI was insufficient for comparative analysis with the number who had, but among those treated with PCI, patients receiving 8 Gy in 1 fraction appeared less impaired than those receiving higher radiation doses in multiple fractions. The study showed that neuropsychometric testing is acceptable to patients, can be administered by non-psychologists in the clinic and is sensitive to otherwise undetected deficits of cognitive function in this patient population. Prospective evaluation of PCI should include neuropsychometric testing.

Endometrioid epithelial ovarian cancer : 20 years of prospectively collected data from a single center.

Clinicopathological features and outcome of women with endometrioid and serous ovarian adenocarcinoma were compared.

Prognosis at presentation of small cell carcinoma of the lung

Prognostic factors in 411 patients with small cell lung carcinoma have been retrospectively analysed. Univariate analysis of continuous variables showed that prognosis was worse with deteriorating performance status, extensive disease, positive bone scan, increasing age, elevated total white cell count, alkaline phosphatase, lactate dehydrogenase, and decreased serum chloride and albumin. Low serum sodium was less clearly associated with poor survival. Cox multivariate regression showed that performance status, disease extent, age and raised lactate dehydrogenase and white cell count were independent prognostic factors. When disease extent was excluded from analysis, performance status, age, total white cell count, lowered serum chloride and raised lactate dehydrogenase were significant independent prognostic variables.

Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology.

SummaryIn a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r=0.924) over the full range of doses studied (4–36 mg/m2) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1±7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of >18 mg/m2 and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m2. No response were seen in this patient population.

The late results of consolidation treatment following induction chemotherapy for small cell lung cancer

Abstract 33 106 (32%) patients with limited disease (LD) small cell lung cancer (SCLC) achieved a bronchoscopically confirmed complete response (CR) following 4 courses of induction chemotherapy. These patients were offered ‘late intensification’ with high dose melphalan (HDM) (140 mg/m 2 ) and autologous bone marrow support. LDCR patients were advised also to receive radiotherapy to the primary site and prophylactic cranial irradiation (PCI). After a minimum follow-up of 3 years, the LDCR patients who received HDM ( n =13) have had a median disease-free survival (DFS) of 15 months and a median overall survival (OS) of 16 months, compared with a DFS of 9 months ( P =0.06) and OS of 11 months ( P =0.23) for patients who did not receive late intensification ( n =20). Chest radiotherapy and PCI reduced the frequency of recurrence at these sites. Only patients who had received both chest radiotherapy and PCI were disease-free at 18 months. In this non-randomised study it is not possible to state with certainty the contribution of consolidation treatment in SCLC. Nevertheless, in patients with chemosensitive limited disease, late intensification chemotherapy, chest radiotherapy and PCI all appear to have a positive effect on DFS.

A phase II trial of mitomycin C and 5-fluorouracil as second-line therapy in advanced breast cancer

SummaryFifty five patients who had relapsed or progressed from chemotherapy for advanced disease were treated with mitomycin C and 5-FU on a 6 weekly regimen. After a median of 2 cycles of therapy the overall response rate was 12% with no complete responses. Significant leucopenia but no thrombocytopenia was seen and despite the low overall response rate the regimen was tolerable and did produce responses in patients primarily resistant to Adriamycin combination chemotherapy. Low overall activity indicates the need for more effective second line treatment.

Treatment of advanced breast cancer with the aromatase inhibitor 4-hydroxyandrostenedione: a phase II trial

Abstract 50 postmenopausal women with advanced breast cancer were treated with 4-hydroxy-androstenedione (4-OHA) by intramuscular injection of 500 mg given every 2 weeks for 24 weeks unless progression of disease or intolerable side-effects precluded further treatment. All patients had received prior chemotherapy or hormone therapy and 16 patients had responded to their most recent treatment. 46 patients were evaluable for efficacy; 1 died of progressive disease within 3 weeks and 3 were withdrawn for unrelated medical conditions and were ineligible for assessment. All 50 patients were evaluated for toxicity; systemic symptoms were uncommon but 10 patients reported buttock discomfort. Of the 46 patients assessable for response, 7 (15%) had a partial response and 12 (26%) stable disease with 27 (59%) showing disease progression. The median duration of response was 85 weeks (range 32–219 weeks) and the median time to progression was 12 weeks (range 2–219 weeks).

A phase I and pharmacology study of GR63178A, a water-soluble analogue of mitoquidone

SummaryGR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). the drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.