Cerebral metastasis and other cerebral events in women with ovarian cancer.

AIM: To determine the incidence, imaging findings and prognostic significance of cerebral metastases and other cerebral events in women with ovarian cancer. METHOD: A 5-year retrospective review of all women with ovarian cancer who had cranial imaging was undertaken at two major gynaecological oncology centers. RESULTS: Of 1222 women under clinical review, 78 underwent cranial imaging and 13 (1.1%) had cerebral metastasis. Computed tomography (CT) was diagnostic of parenchymal disease in 12 and magnetic resonance imaging (MRI) showed leptomeningeal disease in two. The women were aged between 23 and 73 years and all had stage III or IV disease at presentation. Cerebral metastasis occurred at 6-60 months from initial diagnosis, with death occurring predominantly within 12 months, but with five survivors at 4-45 months. Of the remaining 65 women, 10 had cerebrovascular disease and three had unrelated lesions. CONCLUSION: Cerebral metastasis remains a rare event in women with ovarian cancer but may be an isolated late event associated with survival beyond a year after neurosurgery and chemotherapy. CT should be the first investigation as the incidence of cerebrovascular disease is similar to that of metastatic disease.

Palliative care activity in a medical oncology unit: the implications for oncology training.

There has been a nationwide reorganization of cancer services since publication of the Calman-Hine report, which encourages the integration of high-quality palliative care into all areas of cancer provision. Details of the daily clinical care activity for medical oncology inpatients are not collected routinely. A prospective survey of activity was carried out in a large teaching hospital, in order to ascertain the extent to which palliative care is exercised in a medical oncology unit, alongside other aspects of care provision. Almost a quarter (23%) of the admissions were for palliative care, either alone or in combination with another aspect of care. Palliative care activity accounted for 34% (169 bed-days) of daily activity, compared with 32% (163 bed-days) for the administration of chemotherapy. A high proportion of patients receive palliative care on medical oncology wards, consideration therefore needs to be given to the place of formal training in palliative medicine for oncology trainees.

Questions of training--choice or force?

Three contrasting views are presented in three short papers: that a short period of oncology training should be mandatory for trainees in palliative medicine; that many disciplines are important in palliative medicine and training programmes should be tailored to the needs of individuals while recognizing that there will always need to be close cooperation between oncology and palliative medicine; and that a short period of training in palliative medicine should be mandatory for those wishing to pursue a career in oncology.

Prognosis in low grade non-Hodgkin's lymphoma: relevance of the number of sites involved, absolute lymphocyte count and serum immunoglobulin level.

Eighty-eight patients with low grade non-Hodgkin's lymphoma were followed for a median period of 63 months. Sixty-eight per cent of the group were centrocytic/centroblastic B cell lymphomas by the updated Kiel classification. Fifty-one (58 per cent) of the patients were stage IV by the Ann Arbor classification. In 18 of these patients the bone marrow was the only site of extranodal involvement. Univariate survival analysis showed that the sum of involved sites was more discriminatory than Ann Arbor stage. Analysis by site of involvement showed that the liver and other intraabdominal sites were associated with worse survival than involvement of peripheral lymph nodes. Bone marrow and spleen involvement were not significantly associated with short survival. Increasing age at presentation was strongly associated with shorter survival and was also inversely correlated with serum albumin. Both low absolute lymphocyte count (< 1.0 x 10(9)/l), low serum IgG level (< 10 g/l) and low total immunoglobulins on presentation were significantly associated with short survival. Multivariate analysis showed that age, serum albumin and number of involved sites gave the best survival prediction. The sum of involved sites, immunoglobulin level and absolute lymphocyte count may be useful objective markers of prognosis in low-grade non-Hodgkin's lymphoma.

Ploidy, proliferative activity, cluster differentiation antigen expression and clinical remission in high-grade non-Hodgkin's lymphoma.

Using a large range of monoclonal antibodies to specific cluster differentiation antigens the phenotypes of a series of high-grade non-Hodgkin's lymphomas of B- and T-cell type were investigated. Cell ploidy and proliferative fraction were assessed by fluorescent staining of DNA and flow cytometry and data on the incidence of complete clinical remission were obtained. With the exception of some lymphoblastic lymphomas, high-grade B-cell lymphomas normally expressed the pan B-cell antigens CD19 and CD22 but only immunoblastic lymphomas consistently expressed the pan B marker CD20. Variable, generally weak expression of CD21 was observed whilst CD23 expression was most prevalent in rapidly proliferative cases and in Burkitt's and centroblastic lymphomas. A rapidly proliferative, multilobated B-cell lymphoma displayed phenotypic properties intermediate between centroblastic and immunoblastic lymphomas. The T-cell lymphomas generally showed low proliferative activity and expression of CD4 prevailed over CD8. Most cases also showed CD2 and CD5 positivity with some also showing CD3 and CD7 expression. Patients with rapidly proliferative diploid or DNA aneuploid tumours obtained complete remission more readily than patients with lowly proliferative diploid tumours. An excess of early deaths occurred among T-cell cases.

Cluster differentiation antigen expression, proliferative activity and clinical stage in centroblastic centrocytic lymphomas.

Using a panel of B-cell antibodies recognizing clusters of leucocyte differentiation antigens, immunostaining patterns of eight reactive lymph nodes and 28 centroblastic/centrocytic and centrocytic lymphomas have been studied. Centroblastic/centrocytic and centrocytic lymphomas retained many of the B-cell differentiation antigens and neoplastic follicles partially recapitulated the staining patterns observed in reactive follicles. Centrocytic lymphomas usually expressed a heavy chain mantle zone-like phenotype. Nearly one-half of follicular lymphomas showed extension of neoplastic cells into interfollicular areas as evidenced by positivity for CD10 (common acute lymphoblastic leukaemia) and/or CD9 (immature B-cell) and CD23 (B-blast cell) antigens. Cases showing interfollicular involvement also manifested considerable phenotypic heterogeneity. Light chain restriction could not be used to determine interfollicular involvement because of the presence of many non-neoplastic cells. Most follicular lymphomas retained a polyclonal mantle around at least some neoplastic follicles and in no case was a monoclonal mantle seen. Most lymphomas (16/21) were diploid when examined by flow cytometry. Diploid tumours exhibiting interfollicular lymphomatous involvement had high proliferation (S + G2) fractions and these lymph nodes were usually derived from patients with widespread disease. Tumours containing a high percentage of cells in the G0/G1 phases displayed fewer B-cell differentiation antigens than tumours with low G0/G1 fractions.

A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717.

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.

Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse.

The tissue distribution, excretion, and metabolism of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) have been investigated in the mouse. Following 100 mg/kg of 2-14C-CB3717 ip, levels of radioactivity in the brain, testes, muscle, heart, and lung equilibrated slowly with those in the plasma and were no longer significantly lower 5 hours (lung) and 12 hours (brain, testes, muscle, and heart) after administration. In contrast, concentrations of 14C in the liver and kidney were markedly higher than those in the plasma at all time points studied (1.3 hours-23 days). High-performance liquid chromatographic (HPLC) analysis of livers removed 5 hours after drug administration and kidneys excised 24 hours after treatment indicated that, at these time points, greater than 50% of the radioactivity was in the form of unchanged CB3717. Furthermore, HPLC analysis of plasma removed over the period 0.5-6 hours demonstrated that all of the 14C could be accounted for as CB3717. Although the accumulation and retention of radioactivity in the liver and kidney were also apparent following 20 and 200 mg/kg of 14C-CB3717, the effect was less marked at the lower dose, thereby suggesting dose-dependent pharmacokinetics. In excretion studies (0-48 hours), the major route of elimination was found to be via the feces, with 46% of the 14C recovered; 26% of the dose was recovered as unchanged CB3717. Radioactivity excreted in the urine accounted for 20% of the administered 14C, while CB3717 eliminated via this route represented 15% of the dose. In addition to CB3717, a metabolite was detected in the feces which comprised 8% of the dose administered. The metabolite was shown to be 4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoic acid (CB3751) by HPLC and mass spectrometry. The formation of CB3751 could be catalyzed in vitro by the contents of the cecum and prevented in vivo by antibiotic pretreatment and is therefore considered to be the result of bacterial metabolism. CB3717 binds extensively to plasma proteins (92%; concentration range, 25-250 microM). These studies have shown that CB3717 does not apparently undergo extensive host metabolism in vivo, and therefore the biological properties of this novel antimetabolite are probably a function of the parent compound. In addition, the accumulation of CB3717 in the liver and kidney may be related to the hepatotoxic and nephrotoxic effects of this drug.

Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies.

The properties are described of a mutant L1210 cell line (L1210:C15) with acquired resistance (greater than 200-fold) to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. TS was overproduced 45-fold and was accompanied by a small increase in the activity of dihydrofolate reductase (2.6-fold). Both the level of resistance and enzyme activities were maintained in drug-free medium (greater than 300 generations). Failure of N10-propargyl-5,8-dideazafolic acid to suppress the [3H]-2'-deoxyuridine incorporation into the acid-precipitable material of the resistant line supported the evidence that TS overproduction was the mechanism of resistance; consequently the L1210:C15 cells were largely cross-resistant to another (but weaker) TS inhibitor, 5,8-dideazafolic acid. Minimal cross-resistance was observed to the dihydrofolate reductase inhibitors methotrexate and 5-methyl-5,8-dideazaaminopterin (5- and 2-fold, respectively). L1210 and L1210:C15 cells were, however, equally sensitive to 5-fluorodeoxyuridine (FdUrd), an unexpected finding since a metabolite, 5-fluorodeoxyuridine monophosphate, is a potent TS inhibitor; however, this cytotoxicity against the L1210:C15 cells was antagonized by coincubation with 5 microM folinic acid although folinic acid potentiated the cytotoxicity of FdUrd to the N10-propargyl-5,8-dideazafolic acid-sensitive L1210 line. Thymidine was much less effective as a FdUrd protecting agent in the L1210:C15 when compared with the L1210 cells; however, a combination of thymidine plus hypoxanthine was without any additional effect (compared with thymidine alone) against the sensitive line but effectively protected L1210:C15 cells such that the concentration of FdUrd necessary to reduce the cell count to 50% of control at 48 h was increased greater than 11,000-fold. We propose that the elevated TS levels result in sequestration of the reduced-folate pool (as N5,10-methylene tetrahydrofolic acid) into the TS ternary complex with 5-fluoro-2'-deoxyuridine 5'-monophosphate. Despite "free" TS, the de novo synthesis of thymidylate and purines is inhibited by substrate depletion. The fact that folinic acid is able to reverse the inhibition of [3H]-2'-deoxyuridine incorporation by FdUrd into the resistant cells supports this hypothesis.

The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717).

The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100-550 mg/m2 in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40-200 microM. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t1/2 alpha = 49 +/- 9 min, t1/2 beta = 739 +/- 209 min). 27% +/- 2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6% +/- 0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid. Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m2 CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m2) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r = 0.69, P = 0.02). These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.