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.

Use of CA-125 to predict survival of patients with ovarian carcinoma. North Thames Cooperative Group.

The prognostic value of serum CA-125 measurements was assessed in 54 patients with advanced ovarian adenocarcinoma. All patients received a minimum of two courses of carboplatin as part of the North Thames Cooperative Group trial. With a minimum follow-up of 6 months, 37 patients (69%) have clinical evidence of progressive disease and 28 have died. The absolute prechemotherapy level of CA-125 was of no value in predicting which patients would develop progressive disease. However, the change in CA-125 levels from before chemotherapy to 1 month later, after one course of carboplatin, could be used to divide patients into different prognostic groups. The best discrimination was found by dividing the patients into those who showed a greater than sevenfold decrease in CA-125 levels and those who showed a smaller change. Eight of 14 (58%) patients with a greater than sevenfold decrease in CA-125 levels remain disease-free compared with three of 36 (9%) patients with a lesser fall (P = .0005). The change in CA-125 levels during the first month of chemotherapy may indicate which patients should be offered alternative or symptomatic therapy and which should continue with the currently available toxic chemotherapy.

Intraperitoneal yttrium-90-labeled monoclonal antibody in ovarian cancer.

From March 1987 to March 1988, a phase I to II study was carried out in 25 patients with ovarian cancer. They received escalating doses of intraperitoneally (IP) administered yttrium-90 (Y-90)-labeled monoclonal antibody, HMFG1, against a tumor cell-surface antigen. Myelosuppression prevented an escalation of the administered Y-90 activity above 25 mCi. Y-90-labeled antibody was absorbed from the peritoneal cavity into the circulation. Maximum blood Y-90 activity was observed 40 hours after the IP injection with a mean of 21% of the injected activity (range, 14.2% to 26.4%) in the circulation. The radiation dose the bone marrow received from circulating Y-90-labeled antibody (the blood radiation dose) was calculated by applying the Medical Internal Radiation Dose (MIRD) formulation to the measured Y-90 activity in patients blood. Myelosuppression occurred following calculated blood radiation doses to bone marrow of only 10 to 30 cGy. The excessive myelosuppression following such modest radiation doses from circulating Y-90-labeled antibody could be explained by the uptake of Y-90 by bone. In an attempt to reduce bone absorption of Y-90, seven patients received an intravenous (IV) infusion of EDTA (Sinclair Pharmaceuticals Ltd, Godalming, United Kingdom). This increased the urinary excretion of Y-90 from a mean of 11.1% to 32.3% of the injected activity (P = .0001). Fourteen patients had assessable tumor at laparoscopy. Tumor regression was observed in one patient, and palliation of ascites in a further patient.

Antibody-guided irradiation of advanced ovarian cancer with intraperitoneally administered radiolabeled monoclonal antibodies.

Twenty-four patients with persistent epithelial ovarian cancer after chemotherapy with or without external beam irradiation, were treated with intraperitoneally administered 131I-labeled monoclonal antibodies HMFG1, HMFG2, AUA1, H17E2, directed against tumor-associated antigens. Acute side effects were mild abdominal pain, pyrexia, diarrhea, and moderate reversible pancytopenia. One patient developed a subphrenic abscess requiring surgical drainage. Eight patients with large volume disease, ie, greater than 2 cm tumor diameter, did not respond to antibody-guided irradiation and died of progressive disease within 9 months of treatment. Sixteen patients had small-volume (less than 2 cm) disease at the time of treatment with radiolabeled antibody. Seven patients failed to respond, and of nine initial responders, four patients remain alive and free from disease 6 months to 3 years from treatment. Analysis of the data on relapse indicated that doses greater than 140 mCi were more effective than lower doses. We conclude that the intraperitoneal administration of 140 mCi or more of 131I-labeled tumor-associated monoclonal antibodies represents a new and potentially effective form of therapy for patients with small-volume stage III 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.

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.

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.

Intraperitoneal radioimmunotherapy for ovarian cancer: pharmacokinetics, toxicity, and efficacy of I-131 labeled monoclonal antibodies.

Thirty-six patients with ovarian cancer were treated with intraperitoneal I-131 labeled monoclonal antibodies to tumor associated antigens. The activity of I-131 administered was increased from 20 mCi to 158 mCi and the pharmacokinetics and toxicity evaluated. Five patients who had developed HAMA (Human Antimouse Antibodies) were retreated, and the pharmacokinetics and toxicity of the first and second treatment compared. Patients receiving their first therapy (HAMA negative), had a maximum of 25% (range 19.8-39.8%) of the injected activity in their circulation. This was accompanied by severe marrow suppression at I-131 activities over 120 mCi. The 5 HAMA positive patients had only 5% injected activity in the systemic circulation (range 3.8-6%), with rapid urinary excretion and neglible marrow suppression. In 31 patients with assessable disease there were no responses in 8 patients with gross disease (nodules greater than 2 cms), partial responses in 2 out of 15 patients with nodules less than 2 cms, and complete responses in 3 out of 6 patients with microscopic disease. The non specific radiation dose to the peritoneal cavity was estimated to be less than 500 cGy by lithium fluoride TLD, and could not be expected to account for the responses seen.

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.

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.

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.

The treatment of difficult cutaneous basal and squamous cell carcinomata with electrons.

The use of electron beam therapy with energies up to 10 MeV in the treatment of basal and squamous cell carcinomata of the skin is described. The results of treatment of 15 cases are presented with photographs of six cases. Excellent clinical and cosmetic results have been obtained. Electron therapy has been found to be simple and convenient, avoiding the necessity for the use of radium moulds in a number of cases and thus avoiding radiation exposure of staff.

A device for interstitial therapy of low pelvic tumours--the Hammersmith perineal hedgehog.

The freehand production of accurate volume or multiplane implants for interstitial therapy is difficult. The size of tumour that may be treated in this fashion is therefore limited. A solution to this problem is to use a perspex template to guide the implant and maintain its configuration during treatment. We describe our experience using such a template (the Syed-Neblett template) in treating pelvic tumours. The device has been adapted for use with the iridium wire available in the UK. Two new templates have been designed which are more versatile for treating tumours in this area. Ten patients have been treated and with appropriate analgesia, antibiotic cover and nursing care the implant was well tolerated.

Treating the vaginal vault in carcinoma of the endometrium using the Buchler afterloading system.

The advent of high-dose-rate afterloading intracavitary radiotherapy has implications for both staff safety and the possibility of convenient, outpatient-based treatment for the patient. We have carried out a retrospective analysis of its use with high-activity iridium 192 and the Buchler machine to treat the vaginal valut in patients with adenocarcinoma of the endometrium, most of whom also received external-beam radiotherapy to the pelvis. We have compared the survival, complication and local control rates with a comparable group of historical controls treated with low-dose-rate intracavitary caesium ovoids. Complication rates, which included vaginal stenosis not volunteered by the patient, were 16% (95% confidence intervals 6-26%) in the study group and 28% (95% confidence intervals 17-41%) in the control group, with no serious complications requiring surgery. The actuarial survival was 92% at 5 years in the study group, and 94% at 5 years in the control group. Local control was 94% at 5 years in the control group and 98% at 5 years in the study group. The authors suggest that the use of high-dose-rate intracavitary radiotherapy, with the Buchler afterloading system, for vaginal vault irradiation in carcinoma of the endometrium is a convenient, safe and quick method, which does not necessitate admission or sedation of the patient. In addition it provides complete radiation protection for staff.

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.