Long-term survival in 463 women treated with platinum analogs for advanced epithelial carcinoma of the ovary: life expectancy compared to women of an age-matched normal population.

The objective was to assess the long-term survival (5-15 years) in 463 women, with stages IIb-IV epithelial carcinoma of the ovary and to compare their survival with that of a normal population matched for age and sex. Statistical analysis of 463 women, with stages IIb-IV epithelial cancer of the ovary, who were participants in two consecutive North Thames Ovary Group randomized trials, which took place between 1985 and 1994, was performed. The median follow-up period was 10.5 years. The women were treated with debulking surgery, where possible, and adjuvant platinum chemotherapy. One of the randomized groups in the first North Thames trial also received total abdominal radiotherapy. Survival rates at 5, 10, and 15 years were assessed. Prognostic factors for long-term survival were determined using a mathematical model to separate early effects from late effects. The ratio of observed to expected deaths compared to the normal population was calculated. Overall survival at 5 years was 21% (95% confidence intervals 17.5-25%), at 10 years was 13.5% (95% confidence intervals 10.5-17%), and at 15 years was 12% (95% confidence intervals 9-16%). The important prognostic factors for long-term survival were disease-free or minimal residual disease (a single remaining deposit <2 cm) at initial surgery with tumor grade 1 and good performance status. Compared with the normal population (1995 data), the ratio of observed to expected deaths after start of chemotherapy at 5 years was 14.1 (P < 0.001 Fisher's exact test), at 9-10 years 4.9 (P = 0.0033, Fisher's exact test), while in the 11- to 15-year period it had dropped to 2.75 (P = 0.090, Fisher's exact test), which was not significantly different. Patients with advanced cancer of the ovary, who survive 11 years or longer, have a life expectancy which is very similar to that of a normal population of women of the same age. Women with advanced ovarian cancer have an improved chance of long-term survival following treatment if they present with minimal residual disease after primary surgical debulking, grade 1 tumors, and good performance status.

Outcome of epithelial ovarian cancer in women under 40 years of age treated with platinum-based chemotherapy.

We retrospectively investigated the outcome of ovarian cancer in women aged less than 40 years treated in three randomised phase III studies of platinum-based chemotherapy. 624 patients had invasive epithelial ovarian cancer. A Cox proportional hazard model was used to study prognostic variables. 29 women (5%) were under 40 years of age. Stage, histological grade and amount of residual disease were significantly worse in women aged > or = 40 years. Median follow-up was 66.7 months. At 5 years 65% of women below 40 years of age were alive compared with 20% of older women (95% confidence interval (CI) of the difference 27.1-63.0). The progression-free interval was 59% versus 16% (95% CI 24.3-60.8). No patient under 40 years of age relapsed after 18 months. Age > or = 40 years was a poor prognostic variable, particularly for serous tumours, the commonest subtype in younger women (hazard ratio (HR): 3.33). Other prognostic factors were Eastern Cooperative Oncology Group (ECOG) performance status (HR: 1.25), presence of residual disease (HR: 1.43), histological grade (HR: 1.36) and International Federation of Gynaecology and Obstetrics (FIGO) stage (HR: 1.47). These results suggest that there are biological differences in the behaviour of serous carcinoma of the ovary in women of reproductive age compared with older women.

Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis.

Ovarian cancer has an overall five-year survival of around 30% in spite of complete remissions being obtained after optimal surgery and platinum-based chemotherapy. Previous studies have indicated a survival advantage for patients treated with radiolabelled monoclonal antibodies (radioimmunotherapy). We report here on the survival of patients who received single-dose intraperitoneal radioimmunotherapy after having achieved complete remission with standard management. Twenty-five patients with epithelial ovarian cancer, stages Ic-IV, received adjuvant intraperitoneal radioimmunotherapy following completion of conventional chemotherapy. On achieving complete remission they receive once 25 mg of HMFG1 labelled with 18 mCi/m2. Controls for cases were sought from the database of the North Thames ovary group (NTOG). Controls were selected on the basis of stage, histological grade and type, and age of patient at diagnosis. Kaplan-Meier survival plots were constructed for cases and controls and subjected to statistical analysis with the log-rank test. Additionally, using a database of 84 NTOG patients known to be disease-free at the end of chemotherapy, estimated survival curves were constructed using Cox's proportional hazards regression model. Close matches were found for 20 of the 25 patients. Median survival has not been reached at a median follow-up of 59 months for cases and 27 months for controls. Survival at five years is 80% for cases and 55% for controls (p=0.0035). The Cox model estimates long-term (10-year) survival of 70% for patients who received radioimmunotherapy, compared to 32% for those that did not (p=0.003). All patients developed serological evidence of human anti-mouse antibody (HAMA). This study shows a likely survival benefit for patients with ovarian cancer who receive intraperitoneal radioimmuno-therapy in the adjuvant setting.

A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study.

BACKGROUND: There is no clear data on the optimum number of courses of platinum chemotherapy required for treating advanced ovarian cancer. A prospective randomised trial was performed to compare five with eight courses of either carboplatin 400 mg/m2 or cisplatin 75 mg/m2 given four-weekly to patients with stage IC-IV ovarian cancer. PATIENTS AND METHODS: 225 patients were entered into the study and 233 were eligible for randomisation: 118 to five courses and 115 to eight courses. In each randomisation, half the patients received carboplatin and half received cisplatin. RESULTS: The mean number of courses received on the five arm was 4.74 and on the eight arm, 6.42, an increase of 35%. The median survival for all patients was 24 months with the median survival for the 156 patients with stage 3 disease being 21 months. No difference was detected in survival (P = 0.53) or time to progression from initial surgery (P = 0.29) between the two arms of the trial. False-negative calculations based on a multivariate analysis show that the trial currently has 95% power for excluding a difference of 10% in favour of the eight course arm at three years. CONCLUSION: There is insufficient evidence at the present time to justify more than five courses of first-line single agent platinum chemotherapy in the management of advanced ovarian cancer.

Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125.

PURPOSE: A phase II study was performed of oral altretamine in 71 patients with ovarian carcinoma who entered clinical complete remission with CA125 levels less than 35 U/mL after initial or second-line chemotherapy, and relapsed more than 6 months later. Response was compared between standard and CA125-based criteria. PATIENTS AND METHODS: Altretamine 260 mg/m2 was given in divided doses daily for 14 days per month. Response was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 45 of 66 eligible patients. Response was assessed according to precise CA125 criteria in 51 patients based on either a confirmed > or = 50% or > or = 75% decrease in CA125 levels. RESULTS: A combination of domperidone, dexamethasona, and chlorpromazine at night controlled toxicity in most patients, which was mainly nausea (National Cancer Institute criteria grade 2 or 3 in 27), vomiting (grade 2 or 3 in 19, grade 4 in one), and tiredness (grade 2 or 3 in 15). Responses (complete plus partial) were seen in 18 (40%; 95% confidence interval [CI], 25.4% to 54.6%) of those evaluated according to EORTC criteria and in 20 (39%; 95% CI, 25.5% to 52.9%) of those evaluated according to CA125 level. The overall response rate was 26 of 57 (45.6%) and was related to treatment-free interval: 6 to 12 months, 35%; 12 to 24 months, 52%; and greater than 24 months, 67%. The medium duration of response was 8 months. CONCLUSION: Oral altretamine is a useful agent in patients-who relapse after previously responsive ovarian cancer. Response evaluation by a strict CA125 definition gave a similar estimate of the efficacy of altretamine as EORTC criteria.

Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125.

PURPOSE: To produce definitions based on serial CA 125 levels to measure response of ovarian carcinoma in patients receiving first-line chemotherapy. PATIENTS AND METHODS: Definitions were derived from analysis of 277 patients in North Thames Ovary Trial 3. Patient data were then incorporated into a computer program and tested against 254 patients in North Thames Ovary Trial 4 and 458 patients in Gynecologic Oncology Group (GOG) protocol 97. For optimum detection of response, three response definitions have been combined into a computer program. The precise definitions use mathematic logic and take account of factors such as intervening samples. Response to a specific treatment has occurred if after two samples there has been a 50% decrease, confirmed by a fourth sample (50% response), or a serial decrease over three samples of greater than 75% (75% response). The final sample has to be at least 28 days after the previous sample. RESULTS: Six hundred twenty of 989 patients were considered assessable for response according to CA 125 level. Only two patients (0.3%) had a CA 125 response at the time of clinical progression. The CA 125 response rate was 62% and 54% in the North Thames trials. In the GOG trial, it was 66% in all 317 patients assessable for CA 125 and 67% in 221 patients whose CA 125 level was not measurable according to GOG criteria, compared with a GOG-defined response rate of 62%. The sensitivity for detecting GOG-defined response was at least 68%. CONCLUSION: Definitions based on a 50% or 75% decrease of CA 125 levels have been shown reliably to define partial response of ovarian cancer in patients receiving first-line chemotherapy. These definitions should be used in addition to or instead of standard response criteria.

Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study.

BACKGROUND: Many studies have shown that CA 125 levels frequently rise prior to clinical evidence of progression of ovarian cancer. For clinical trials an accepted definition of progression according to CA 125 is required. We therefore determined what change in CA 125 level was the most accurate predictor of relapse in patients on follow up after therapy for ovarian cancer. PATIENTS AND METHODS: Serial CA 125 levels were studied from 255 patients entering the North Thames Ovary Trial of 5 versus 8 courses of chemotherapy. An initial analysis was made 2 months after closure of the trial, a more detailed analysis was made after 81 confirmed relapses among evaluable patients and a final analysis was made one year later with longer follow-up. RESULTS: On the basis of the results from the interim analyses and the cut-off level of 22-35 U/ml used by different laboratories, 30 U/ml was chosen as the upper limit of normal. In the final analysis a doubling of CA 125 from the upper limit of normal was defined as progression. Using this method sensitivity was 85.9%, specificity 91.3%, positive predictive value 94.8%, and negative predictive value was 77.8%. Insisting on a confirmatory elevated CA 125 level reduced the false positive rate to < 2% with a sensitivity of 83.9%. The median lead-time prior to clinical progression was 63 days. CONCLUSION: A confirmed rise of serum CA 125 level to more than twice the upper limit of normal during follow up after first line chemotherapy accurately predicts tumour relapse.

Surgical clips in planning the electron boost in breast cancer: a qualitative and quantitative evaluation.

PURPOSE: To evaluate, qualitatively and quantitatively, the role of surgical clips in planning the tumor bed electron boost in patients undergoing breast conserving surgery and radiotherapy. METHODS AND MATERIALS: In 50 patients, the excision cavity boundaries were marked by clips at surgery. The electron boost field was first planned using clinical information, aiming to achieve a margin of 2 cm, and its accuracy evaluated by screening the surgical clips and, if necessary, adjusting the field to encompass all clips with 2 cm margins. Orthogonal radiographs were take with solder wire delineating the clinical and screened fields and the scar. Hypothetical clinical and radiological fields, with 1 and 3 cm margins, were reconstructed on the radiographs. RESULTS: The clinical field was inadequate in 34 patients (68%). The precision of each clinical setup was quantified by two indices. The Normal Tissue Index defined the percentage of the clinical field comprised of tissue, beyond the tumor bed, not at high risk of local recurrence, and gave an estimate of potential spring of normal tissue: median 14.6% (range 0-83.0), 17 out of 50 > 25%; median 13% (range 0-70.7), 12 out of 50 > 25%; median 9.7% (range 0-59.8), 10 out of 50 > 25%, for 1, 2, and 3 cm margins, respectively. The Geographical Miss Index defined the percentage of the radiologically defined field, at high risk of local recurrence, not predicted by the clinical field, and gave an estimate of the extent of geographical miss: median 32.9% (range 0-83.5), 28 out of 50 > 25%; median 26.1% (range 0-69.8%), 26 out of 50 > 25%; median 18.6% (range 0-60.3), 20 out of 50 > 25%, for 1, 2, and 3 cm margins, respectively. The median distance from the scar midpoint to the furthest clip was 3.8 (range 1.2-8.1) cm. The median maximal clip depth was 3.1 (range 1.4-5.2) cm. CONCLUSION: (a) Electron boost field planning by clinical landmarks alone was inaccurate in 68% of cases. (b) Quantitative measures, based on margins of 1, 2, and 3 cm, revealed that in 20-34% of patients more than one-quarter of the clinical field covered tissue at low risk of local recurrence, and in 40-56% of patients less than three-quarters of the final radiological field was predicted clinically. (c) The relative positions of the scar and clips may be widely disparate. (d) Clip depth measurements reveal a significant risk of underdosing at depth.

Palliation of obstructive nephropathy due to malignancy.

OBJECTIVE: To conduct a prospective study of patients with malignant obstructive uropathy treated actively by percutaneous nephrostomy and J-J ureteric stents. PATIENTS AND METHODS: Forty-two patients (27 men, 15 women, median age 62 years, range 29-83) with obstructive nephropathy secondary to malignancy underwent urinary diversion followed, where appropriate, by active treatment of the underlying cancer. RESULTS: The median survival of all patients was 133 (range 7-712) days. Seventeen patients (40%) survived for > 6 months and five (12%) for < 1 month. Patients who had received no prior therapy and for whom further therapeutic options were available were more likely to benefit from urinary diversion. In nine patients (21%) nephrostomy insertion failed to relieve renal failure. In 20 patients (48%) obstructive nephropathy recurred. The procedure was complicated by urinary tract or nephrostomy site infection in 16 patients, by septicaemia in six patients, by percutaneous urine leak in 13 patients and by pelvi-calyceal perforation in two patients, but not by haemorrhage or death. The median percentage of the patients' remaining life which was spent in hospital was 23.6% (range 2.2-100). CONCLUSIONS: Patients likely to benefit from nephrostomy were those for whom there were therapeutic options available for the treatment of their malignancy. Prolonged survival is possible in obstructive nephropathy secondary to malignancy, which should no longer be cited as an absolute contra-indication to urinary diversion. Patients unlikely to benefit from urinary diversion can also be identified and they should not routinely undergo this intervention.

Proliferating cell nuclear antigen (PCNA) immunostaining--a prognostic factor in ovarian cancer?

The measurement of tumour cell proliferation is becoming increasingly recognised in defining prognostic groups. Proliferating cell nuclear antigen (PCNA) immunolocalisation can be used as an index of cell proliferation and may define the extent of departure from normal growth control. The monoclonal antibody PC10 stains PCNA in archival paraffin-embedded tissue. This study investigates its potential as a prognostic marker in early and advanced ovarian cancer. A three-stage immunoperoxidase technique was developed to detect the monoclonal antibody PC10. Archival paraffin-embedded tissue from 19 stage I ovarian tumours (13 malignant and six borderline) and 79 advanced (stage IIb-IV) ovarian tumours (patients entered into the Third North-West Thames Ovarian Cancer Trial) was immunostained with PC10. PC10 immunostaining was performed successfully in 91.8% of cases. The PC10 labelling index (PC10 LI) ranged from 1.5% to 88% with a mean value of 47.4%. Stage I borderline tumours had significantly lower PCNA labelling indexes than stage I malignant tumours (P < 0.048). In advanced disease there was an inverse correlation between PC10 and overall survival, and in those patients who underwent good debulking surgery (37 patients with disease < 2 cm diameter) a low PC10 value (< 36.5%) correlated with improved survival (log-rank trend test for survival, chi 2 = 5.75, P = 0.017). PCNA immunostaining defines a good prognostic subgroup in adequately debulked patients with ovarian cancer.

Prostaglandin-induced cervical dilatation prior to intracavitary radiotherapy for carcinoma of the cervix: a pilot study.

The efficacy of 1 mg 16,16-dimethyl-trans-Delta2 prostaglandin E1 (Gemeprost) pessaries in achieving cervical dilatation prior to intracavitary brachytherapy was investigated in 16 post-menopausal women with cervical carcinoma. All had received external beam pelvic radiotherapy in the preceding 6 weeks. Four patients were nulliparous and 12 multiparous (mean parity 1.9). FIGO stages were IB (2), IIA (4), IIB (5), IIIA (1), IIIB (3), IVB (1). The cervical os was assessed before pessary insertion and again at the time of intracavitary insertion. The os was closed in 100% (16/16) of patients before and open in 75% (12/16) of patients after pessary insertion. The maximum size of Hegar dilator passed without mechanical dila-tation was recorded. Mean cervical dilatation was 4.25 H (5.5 H in those with a clinical response). The 12 responding patients had rapid and uncomplicated procedures with no need for additional mechanical dilatation. Both patients in whom attempted mechanical dilatation failed had had previous conization of the cervix. The following mild side-effects were reported: abdominal cramps (43.8%), headache (12.5%) and fever (6.3%). These data support the use of Gemeprost pessaries to achieve cervical dilatation in post-menopausal women undergoing intracavitary brachy-therapy following external beam radiotherapy.

Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer.

BACKGROUND: The intracavitary route for the administration of monoclonal antibodies is used in a variety of locally spreading cancers. The authors have been treating patients with ovarian cancer in Phase I and II studies assessing toxicity and response to improved radioimmunoconjugates. METHODS: Nineteen patients, 34-65 years of age, were treated with a new radioimmunoconjugate, 90Y-CITC-DTPA-HMFG1, instilled in the peritoneal cavity after second-look laparoscopy. Activity was increased in a stepwise fashion. RESULTS: Following the intraperitoneal administration of 90Y-CITC-DTPA-HMFG1, levels of the radioimmunoconjugate in the blood increased, reaching a peak of about 30% of injected activity at around 54 hours posttreatment. Approximately 18% of the radiolabel was excreted in the urine within 96 hours. Bone-marrow toxicity was the dose-limiting factor. Grade III platelet and granulocyte toxicity was observed at 19.3 mCi/m2. A type III immunologic response was observed in a number of patients. CONCLUSIONS: A dose of 18.5 mCi/m2 for subsequent treatments is recommended, based on a linear correlation of activity dose-to-body surface area. The clinical profile of a mild to moderate hypersensitivity syndrome is presented and hypotheses regarding its etiology are suggested.

Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody.

Fifty-two patients with epithelial ovarian cancer were treated with yttrium-90-labelled monoclonal antibody HMFG1 administered intraperitoneally following conventional surgery and chemotherapy as part of an extended phase I-II trial. The treatment was well tolerated and the only significant toxicity observed was reversible myelosuppression as previously described. Following conventional surgery and chemotherapy, 21 out of the 52 patients had no evidence of residual disease and were regarded as receiving treatment in an adjuvant setting. To date, two of these patients have died of their disease (follow-up 3-62 months, median follow-up 35 months). This extended phase I-II study suggests that patients with advanced ovarian cancer who achieve a complete remission following conventional therapy may benefit from further treatment with intraperitoneal radioactive monoclonal antibody.

A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group study.

PURPOSE: To determine in a randomized trial of advanced ovarian carcinoma whether consolidation therapy with whole-abdominal radiotherapy (RT) after chemotherapy improves survival and disease-free survival compared with the continued chemotherapy. PATIENTS AND METHODS: Two hundred fifty-four patients with advanced epithelial ovarian cancer (stages IIB to IV) were entered onto a study of five monthly courses of 400 mg/m2 of carboplatin. One hundred seventeen patients with residual disease of 2 cm or less at second-look laparotomy or laparoscopy were then randomized to receive consolidation therapy, either five further courses of carboplatin at the same dosage or whole-abdominal RT (24 Gy). There was no control arm. RESULTS: Chemotherapy was well tolerated and was usually administered on an outpatient basis. Myelosuppression that was sufficient to delay chemotherapy occurred in only 3% of 1,418 courses analyzed. The main toxicity of carboplatin was nausea and vomiting, but this was easier to control than that with cisplatin. Although RT was well tolerated in the majority of the 58 patients, one patient who had been found to have multiple adhesions at second-look surgery developed fecal fistulae post-RT that resulted in the patient's death from peritonitis. Median survival for the whole group from date of surgery was 25 months. No statistical difference was found in either survival or disease-free survival between those patients who received consolidation chemotherapy and those who were treated with abdominal RT. Prognostic factors used to assess survival were stage, histology, amount of residual disease after primary surgery, and presence of tumor at second-look surgery. CONCLUSION: There seems to be no significant advantage for consolidation whole-abdominal RT compared with the continuation of the same chemotherapy in the management of advanced epithelial carcinoma of the ovary, even when no macroscopic residual disease is apparent at second-look surgery.

Solitary cerebral metastases from gynaecological malignancy: the case for radical therapy.

Three cases of solitary cerebral metastases from gynaecological malignancy are reported. Each was treated with surgical resection followed by radical radiotherapy resulting in prolonged disease-free survival. The reasons for the increasing incidence of cerebral metastases in these malignancies is discussed, the case for radical treatment made and the literature reviewed.

Savings obtained by CA-125 measurements during therapy for ovarian carcinoma. The North Thames Ovary Group.

The value of serial CA-125 measurements for predicting progression of ovarian carcinoma during therapy was calculated in 71 patients. The optimal algorithm that defined disease progression by CA-125 levels was either two values above 100 U/ml which had decreased by less than 50% over a minimum of 56 days, or a rise of 25% between successive samples plus a confirmatory sample. Of 13 patients with progressive disease according to the CA-125 criteria, 12 developed clinical evidence of progression within 12 months; predictions were false positive in 1, true negative in 50 and false negative in 8. Retrospective analysis showed that therapy and investigations costing 7979 pounds could have been avoided, if CA-125 assays costing 5470 pounds had been acted upon. The efficacy of the CA-125 algorithm is being independently verified to confirm that monthly CA-125 measurements whilst on treatment combine cost-effectiveness with a decrease in unpleasant interventions.