Frank Lawton

Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials

Results using the same drug in phase II studies of treatment in ovarian cancer vary widely. An analysis of five phase II studies with a total of 93 patients was carried out to determine whether factors other than the efficacy of the drug affect response. The drugs for the phase II studies were chosen on the basis of in vitro activity or previous activity in humans. Univariate analysis showed that several factors were of significance in predicting response. The most significant was interval from the end of previous treatment to entry into a phase II study. Others were the original presenting stage of the patient, the second line treatment given and the best previous response to therapy. In multivariate analysis, however, only two factors were shown to be of importance which were interval and the FIGO stage of the patient. Using these two variables the discriminant analysis predicted 89% of those who did not respond and 75% of those who did, with an overall correct prediction of 85%. The importance of interval is emphasised by the observation that the response rate for those patients who progressed on treatment or who relapsed within 3-6 months of primary therapy had a response rate of less than 10%. Future phase II studies should probably exclude patients in this category, since the chance of their responding is very low.

Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears.

OBJECTIVE--To determine the efficacy and morbidity of fine loop diathermy excision of the cervical transformation zone as applied to the management of outpatients with abnormal cervical smears. DESIGN--Prospective programme trial with six month follow up. SETTING--Two hospital based colposcopy clinics. PATIENTS--616 Patients aged 16-60 with abnormal cervical smears. INTERVENTIONS--After colposcopic and cytological assessment excision of the cervical transformation zone by fine loop diathermy under local anaesthesia in the outpatient department. MAIN OUTCOME MEASURES--Time to complete the treatment, immediate morbidity in terms of discomfort and bleeding, and cytological and colposcopic findings at six months. RESULTS--Treatment was completed in a mean of 3.47 minutes (SD 1.99). Immediate morbidity was minimal, and histological specimens were adequate in over 90% of cases. Almost two thirds of patients were treated at their first visit to the clinic. 58 Patients (9.4%) failed to attend for follow up at six months and one had had a hysterectomy. Of the 557 patients who attended for colposcopic and cytological follow up at six months, 506 (91%) were normal cytologically and 19 (3.4%) had histologically confirmed persistence of cervical intraepithelial neoplasia. The overall confirmed failure rate of the technique was 4.4%. CONCLUSION--Loop diathermy excision is an effective treatment with low morbidity and is an appropriate modality for patients with abnormal cervical smears.

Failure of second-look laparotomy to influence survival in epithelial ovarian cancer.

The survival benefit of second-look laparotomy after completion of primary chemotherapy in patients with epithelial ovarian cancer has been assessed in a prospective randomised trial of 166 patients. Patients were randomised into three groups. All were initially treated with cisplatin (100 mg/m2 x 5) after primary laparotomy. Group A (n = 53) was scheduled to have a second-look laparotomy, followed by cyclical oral chlorambucil. Group B (n = 56) was scheduled to have a second-look laparotomy, followed by total abdominal and pelvic irradiation, and group C (n = 57) received oral chlorambucil as for group A but had no second-look operation. With a median follow up of 46 months (range 21-64), no differences in survival were noted between the three groups. The median survival for group A was 21 months (95% CI 11-31 months), for group B 15 months (11-19), and for group C 17 months (8-26). Thus second-look laparotomy after completion of first-line single-agent cisplatin chemotherapy did not confer any survival benefit on patients with epithelial ovarian cancer.

Prevention of post‐cone biopsy cervical stenosis using a temporary cervical stent

Summary. Stenosis of the residual cervix is not an infrequent complication of cone biopsy which may result in subfertility, problems with adequate follow‐up and dysmenorrhoea. In an attempt to minimize this complication a temporary indwelling cervical support stent has been developed. This is sutured into the exposed cone bed immediately after cutting the cone specimen and removed 2 weeks later. A pilot study using this device in 33 cold knife conizations has been performed. There were no primary or secondary haemorrhages and no post‐conization pelvic infections. At follow‐up, 6 months after cone biopsy two patients (6%) had clinical cervical stenosis, and one patient (3%) complained of dysmenorrhoea (although the cervix was not stenosed). The cervical transformation zone was fully visible in 21/33 patients (64%) (95% CI48 to 80) and follow‐up smears contained endocervical cells in 20/33 patients (61%) (95% CI 44 to 78). These results compare very favourably with historical controls from the same unit and suggest that cone biopsy support stents should now be assessed in a prospective randomized trial.

Poor maternal weight gain between 28 and 32 weeks gestation may predict small-for-gestational-age infants

Summary. In a retrospective analysis of 158 women considered to have had normal, low‐risk pregnancies, 30 gave birth to infants with a birth‐weight less than the 10th centile for gestation. These 30 women had a significantly poorer mean increase in weight (0·99 kg) between 28 and 32 weeks gestation than the other 128 women (1·95 kg) who gave birth to infants with birthweights above the 10th centile for gestation. There was no statistically significant difference in booking weight, overall weight gain or other variables associated with low birthweight between the two groups of women which suggests that poor maternal weight gain specifically between 28 and 32 weeks gestation may predict small‐for‐gestational‐age infants.

Antenatal attendance and fasting of pregnant muslims during ramadan

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Problems of peritoneal access in intraperitoneal treatment and monitoring of ovarian cancer

Summary. A total of 154 peritoneal lavages was attempted through either a permanent (17) or a temporary percutaneous cannula (137) in 59 ovarian cancer patients undergoing intraperitoneal treatment or monitoring. Seven of the eight permanent catheters were removed because of complications; intraperitoneal adhesions were a major problem in this group. Overall, 137 temporary catheters were inserted (14G Venflon i. v. cannula in 119, Verres needle in 15, and a Trocath peritoneal dialysis catheter in 3 instances) but it was not possible to perform a peritoneal lavage in 42 (30%). Access to the peritoneal cavity was unsatisfactory on 29 (34%) occasions when a Venflon cannula was used, either because there was inadequate flow of lavage fluid into the peritoneal cavity or this was limited by pain. Perforation of the bowel occurred in 12 (9%) cases but there was no significant morbidity. Problems with achieving reliable peritoneal access using either permanent or temporary catheters may limit the potential advantages of the intraperitoneal route for treatment and monitoring.

Speed of response to platinum-based chemotherapy: Implications for the management of epithelial ovarian cancer

Seventy-nine patients with evaluable epithelial ovarian cancer following primary laparotomy and treated with one of three primary cis-platinum-containing regimens were studied to determine the rate at which clinical cytoreduction occurred and whether a rapid response to treatment was of prognostic significance by improving progression free interval (PFI) or survival. A rapid response to treatment improved PFI in patients treated with single agent cis-platinum (P = 0.04) and increased survival in patients treated with a sequential cis-platinum based combination regimen (P = 0.03). The rate of cytoreduction was not a significant variable, however, in a multiple regression analysis of prognostic factors. Over 75% of all clinical responses, regardless of the regimen, had begun by the completion of the third course of chemotherapy. We conclude that response to active chemotherapy is a rapid phenomenon in ovarian cancer and this has important implications in both the decision to change drug therapy and the timing of further surgical effort.

Predicting response to chemotherapy for patients with epithelial ovarian cancer using urinary polyamine excretion patterns.

Urinary polyamine (UPA) excretion patterns were measured in 39 patients with clinically evaluable epithelial ovarian cancer immediately before they were treated with a cycle of chemotherapy and 24-48 h after chemotherapy to ascertain if changes in UPA excretion patterns correlated with eventual response to treatment. Almost all of the 19 patients who responded to chemotherapy had a rise in the excretion of all UPA fractions after treatment while most patients with chemoresistant cancer showed only an increase in the excretion of the putrescine and spermine fractions. However, a two-fold increase in excretion of the spermidine fractions occurred exclusively in patients who would eventually respond to chemotherapy. This phenomenon was not seen in patients with chemoresistant cancer. If, 48 h after chemotherapy, a patient with epithelial ovarian cancer does not show at least a doubling of the urinary levels of spermidine, acetylspermidine or total polyamine excretion that chemotherapy should be stopped since it is unlikely to be effective.

Urinary polyamine excretion patterns in patients with epithelial ovarian cancer

Free and acetylated urinary putrescine, spermine and spermidine levels (UPA) and total polyamine excretion were measured by high-performance liquid chromatography in 57 patients with epithelial ovarian cancer (EOC) and 43 control patients. Mean UPA levels were higher and the number of abnormal UPAs per sample greater for cancer patients but maximum single UPA sensitivity was only 29%. No control subject had more than 2 abnormal UPA values compared with 42% of patients with EOC. Rising UPA levels reflected progressive disease in 83% of patients and fell with tumour response in 66%.