Biomedical subjects
Publications and source records attributed to M E Gore.
A patient with a residual mature solid ovarian teratoma, which underwent malignant transformation to an adenocarcinoma 10 years after previous successful treatment, is presented. This case history illustrates that patients with residual mature disease require long term follow-up.
High-dose chemotherapy with autologous bone marrow transplantation is used in the treatment of relapsed or high-risk Hodgkin's disease. As prospective randomised studies have proved difficult to accrue to, current recommendations are based on the reports of large series of prospectively collected data. We have looked at the outcome of 89 patients treated in this way at a single institution and have developed an index to predict outcome. Of 89 patients, with a median age of 29 years (range 15-51 years), eight patients were in first complete remission/partial remission (CR/PR), 17 in second or later CR, 37 were responding relapses, 13 resistant relapses, 11 primary refractory and three untested relapses. Combinations of melphalan, BCNU and etoposide were given in all cases except in ten patients who received melphalan alone. The median follow-up was 43 months (range 6-77 months). A total of 24 patients were in CR at the time of autologous bone marrow transplantation (ABMT), 33 achieved CR with ABMT, 16 PR, to give a response rate to ABMT of 49/65 = 74% (95% CI 60-83%) with a CR rate of 51% (CI 36-62%). In a Cox's multivariate analysis the most important factors in predicting outcome after ABMT were response to treatment before entry, number of previous treatments and previous chemosensitivity. Using these factors we devised a prognostic index which reliably selects a group of patients (65%) with at least a 70% chance of being progression free from 1 year onwards. Patients who have never achieved a CR and have received three or more chemotherapy regimens do not benefit from high-dose chemotherapy as used in this study.
We have examined the efficacy, toxicity and host immunological response of two different dose schedules of interleukin 2 (IL-2) given subcutaneously, daily for 3 months in patients with renal cell carcinoma (RCC) or metastatic melanoma (MM). We also examined the effect of adding the immune modulator levamisole to the two different schedules of IL-2. Thirty-nine patients were entered into two sequential phase I/II studies. Eighteen patients entered study 1 and were randomised to receive IL-2, 3 x 10(6) IU m-2 day-1, subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Twenty-one patients entered study 2 and were randomised to receive 5.4 x 10(6) IU m-2 day-1 subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Blood was taken for peripheral blood lymphocyte (PBL) phenotype analysis, and measurement of IL-2, soluble IL-2 receptor (sIL-2R) and neopterin concentration. Two patients with metastatic melanoma, one in each study, responded (11.8%); both received IL-2 alone. Observations of immunological parameters showed that treatment with subcutaneous IL-2 resulted in a significant rise in the percentage of PBLs bearing CD25, CD3/HLA-DR, CD56 and levels of IL-2 receptor and neopterin. The total white blood cell count (WBC) and total lymphocyte count rose significantly on day 18 compared with pretreatment levels. The addition of levamisole to either IL-2 schedule resulted in no significant changes in any immunological parameters. This study illustrates that prolonged subcutaneous IL-2 can be given safely in the outpatient setting. There was no evidence that levamisole acts as an immunomodulator in this study.
Imiquimod is an orally active interferon inducer with anti-tumour activity in experimental animals. In this study the tolerability, toxicity and biological effects of daily oral imiquimod administration were investigated in 21 patients with refractory cancer. Patients were treated with doses of 25 mg, 50 mg, 100 mg or 200 mg on a projected 112 day course. Only three patients completed the course, all at the 50 mg dose. Treatment toxicities were dose related and mainly comprised flu-like symptoms, nausea and lymphopenia. Of the 21 patients, five received dose reductions and in five treatment was discontinued because of treatment-related toxicity. The biological activity of imiquimod was confirmed by significant and sustained rises in peripheral blood mononuclear cell (PBMC) 2-5A synthetase (2-5AS) levels at all doses. At 100 mg and 200 mg these occurred within the first 24 h of administration. Levels of neopterin and beta 2-microglobulin (beta 2M) were also significantly elevated when assessed after three weeks' treatment. Interferon production was not demonstrated within the first 24 h of the initial dose but, following repeated doses, ten of the patients developed detectable serum interferon concentrations with a maximum value of 5600 IU ml-1 recorded. Administration of imiquimod did not have any significant effect on serum levels of tumour necrosis factor (TNF) or interleukin 1 (IL-1), nor did it lead to development of detectable levels of antibodies to interferon. One mixed clinical response was observed after 4 weeks' treatment at 100 mg in a patient with renal cell cancer. Daily administration of imiquimod causes activation of the interferon production system but at higher doses results in unacceptable toxicity. Further investigation of imiquimod as an interferon-inducing agent in cancer patients is suggested at either the lower dose levels or employing alternative dosing schedules.
Recent studies have demonstrated that rodent tumour cells engineered to secrete a variety of cytokines, or to express foreign antigens, MHC molecules or co-stimulatory molecules, are rejected by syngeneic animals. These observations have led to the initiation of a number of clinical trials using genetically modified tumour cells, to attempt to stimulate a patient anti-tumour immune response. In this study, a protocol has been developed to test in vitro the specific cytotoxic anti-tumour response generated from melanoma patient lymphocytes. The results showed that IL-12 in combination with IL-2 enhanced the autologous anti-melanoma CTL response, whereas B7.1 antigen expression on tumour cells did not increase anti-melanoma CTL generation. This method could be used to design more appropriate genetically modified tumour vaccines.
PURPOSE: The aim of this study was to investigate the independent significance of prognostic factors in stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Between 1980 and 1994, all patients with stage I EOC (borderline tumors excluded) following surgical resection were entered onto this study. No patient received adjuvant therapy and patients were monitored as follows: years 1 to 2-physical examination and serum CA125 every 3 months and computed tomographic (CT) scan every 6 months; years 3 to 5-physical examination and serum CA125 every 6 months and CT scan yearly; years 5 to 10-annual physical examination and serum CA125, with CT scan if clinically indicated. RESULTS: A total of 194 patients entered the study. The median patient age was 54 years (range, 15 to 83), and the median follow-up duration 54 months (range, 7 to 157). Five-year survival rates were as follows: stage IA, 93.7%; stage IB, 92%; and stage IC, 84%. Multivariate analysis using Cox's regression identified grade (P < .001), presence of ascites (P = .05), and surface tumor (P < .01) as independent poor prognostic factors. International Federation of Gynecology and Obstetrics (FIGO) substage did not appear to have independent prognostic significance. Intraoperative capsule rupture was not found to be prognostically significant. The impact of pre-operative rupture remains unclear. CONCLUSION: This is an important series, as no patient received adjuvant therapy, and represents the natural history of surgically resected stage I EOC.
BACKGROUND: Treatment of patients with metastatic melanoma with either dacarbazine or recombinant interleukin-2 (rIL-2) resulted in a response rate of approximately 15%. This study investigates the possible synergism of this chemoimmunotherapy combination. METHODS: Fifty-seven patients with metastatic malignant melanoma received 135 treatment cycles. Treatment consisted of dacarbazine (Days 1-5) at 250 mg/m2 by a 30-minute slow infusion, and interleukin-2 by constant intravenous infusion (Days 21-25 and 28-32) at 18 x 10(6) IU/m2/24 hours. After this treatment cycle, a 1-week rest was scheduled, and in the absence of undue toxicity or tumor progression, patients received a second cycle as described. Maximum treatment consisted of two induction and four maintenance cycles. In a subgroup of patients, immunoparameters were analyzed to identify prognostic factors. Standard supportive care was given. RESULTS: Common toxicities included fever, hypotension, nausea/vomiting, anemia, leukopenia, thrombocytopenia, an increase in serum lactic dehydrogenase levels and diarrhea. The objective response rate was 15.8% (one complete response and eight partial responses). In 14 patients, the disease stabilized. For patients who had an objective response, median response duration was 13.9 months (6.3-39.0+), and median survival was 19.0 months (6.3-39.0+); overall survival was 9.3 months (0.8-39.0+). Immunomonitoring did not reveal any relevant prognostic factors for overall response. CONCLUSIONS: Sequential treatment with dacarbazine and rIL-2 is feasible and produces long-lasting responses in a minority of patients.
This study evaluates the morphological and phenotypic changes that occur in squamous cell carcinoma of the head and neck when local infusions of interleukin-2 (IL-2) are given. Twelve patients were treated with a range of doses of IL-2 (3 x 10(3) to 3 x 10(6) international units/day) by continuous intra-arterial infusion for 10 days. Biopsies of the tumour were taken pre- and 48 h post-therapy, snap-frozen, cut, and examined histologically and immunocytochemically. Local infusions of IL-2 increase the numbers of antigen-presenting Langerhans cells (CD1a-positive) and infiltrating lymphocytes, predominantly of the CD3 and CD4 (T-helper) phenotypes. Locally infused IL-2 results in the expression of MHC (major histocompatibility complex) class II antigens on the surface of the tumour cells, capillary and post-capillary endothelial cells, and peri-tumoural macrophages. Intratumoural NK (natural killer) cells and CD8-positive (T-cytotoxic) infiltrating lymphocytes were not increased by this therapy and CD25 (IL-2 receptor) was only increased in those patients treated at the lower dose levels. The system of intra-arterial cytokine infusion into head and neck tumours developed in this study is a useful model to examine the biological effects of cytokines, since in vivo they are mainly produced and act locally. Furthermore, the infused tumours are easily accessible to biopsy. The results from studies such as this may influence the design of tumour-targeted cytokine gene therapy programmes.
The aim of this study was to assess the clinical evidence for platinum-Taxol non-cross-resistance in patients with epithelial ovarian cancer. Unlike other studies, only patients who had demonstrably progressive disease on platinum therapy were analysed. Patients received 135-200 mg m-2 of Taxol over 3 or 24 h and all patients were assessed for response by computerised axial tomography. The overall response rate was 22.2% (8/36 patients, 95% CI 10-39%). Only patients who received > or = 175 mg m-2 of Taxol responded (26.7%; 8/30 patients, 95% CI 12-46%). No complete responses were seen and the duration of response was short, median 7 months (range 5-9+). Response was associated with a short treatment-free interval (P = 0.02); only those who were treated immediately after they had progressed on their previous platinum therapy responded. Response duration was associated with a good performance status (P < 0.05). Platinum and Taxol are non-cross-resistant in a proportion of patients and therefore patients who are resistant to platinum compounds may benefit from Taxol although the duration of any response is short. These data support current strategies that involve combining Taxol with platinum compounds as first-line therapy in advanced epithelial ovarian cancer.
The purpose of our study was to investigate the efficacy and toxicity of paclitaxel in patients with relapsed or refractory epithelial ovarian cancer in the context of a large multicentre study performed in the UK and Eire. Patients with previously treated epithelial carcinoma of the ovary or fallopian tube who fulfilled the eligibility criteria were entered in the study. Eligibility criteria included: measurable or evaluable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; up to three prior chemotherapy regimens, one of which had to contain a platinum agent; adequate haematological, renal and hepatic function; and no significant cardiac history. Patients received either 175 mg m-2 or 135 mg m-2 paclitaxel. The lower dose was administered to patients who had received more than two prior chemotherapy regimens. Paclitaxel was given by i.v. infusion over 3 h every 21 days. Response was assessed at three-cycle intervals or earlier if required. A total of 155 patients were registered for the study in the UK of whom 140 were eligible for response and toxicity evaluation, and 12 patients were assessed for toxicity only. Hair loss was the most frequently reported toxicity, with 74% (119/152) of patients reporting grade 3 alopecia. The most frequently reported serious toxicity was neutropenia, with 49% (74/152) of patients experiencing neutropenia grade 3 or 4. The response rate was 16% [two complete responders (CR), 20 partial responders (PR)], the median duration of response was 275 days and median survival was 244 days. Paclitaxel is active in relapsed and platinum-resistant epithelial ovarian cancer. It is well tolerated and can be given in an out-patient setting. The UK and Eire experience is very similar to that of US investigators in this group of patients. Further work is required to assess the optimal use of the drug in both first- and second-line therapy.
BACKGROUND: Many of the characteristics of patients with familial epithelial ovarian cancer (EOC) are not yet well defined. This report describes some of the characteristics of patients with EOC in particular response rates to chemotherapy and 5-year survival, and compares them with matched controls with sporadic EOC. PATIENTS AND METHODS: There were 28 cases of familial epithelial ovarian cancer (EOC) presenting to the Royal Marsden Hospital from January 1983 to September 1993. The incidence of familial EOC over this time period was 2.2% (28/1268). For each case of familial EOC, 3 controls were selected and matched for age, FIGO stage, volume of residual disease after initial surgery and type of chemotherapy; the matched controls were compared to the familial EOC cases for differences in histological subtype, response to chemotherapy and 5-year survival. There was a statistically significant difference in histological subtype, 83% of patients with familial EOC had serous cystadenocarcinoma compared to 49% in the matched control group (p = 0.0025) providing evidence that familial EOC has a genetic basis. However there were no differences in median age or FIGO stage between patients with familial EOC and the sporadic cases and no difference in overall response to chemotherapy or 5-year survival. CONCLUSIONS: Our results imply that familial and sporadic EOC are biologically very similar and therefore molecular studies on the pathogenesis of and cellular mechanisms involved in EOC may have an important impact on therapeutic strategies for the much commoner sporadic form of the disease. In addition, our data suggest that all patients should be closely questioned with regard to family history not just those who present at a young age.
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BACKGROUND: Carcinosarcomas (also known as malignant mixed mullerian tumours) are rare malignant neoplasms that histologically contain both epithelial and stromal components. METHODS AND MATERIALS: All cases of carcinosarcoma of the ovary presenting to the Royal Marsden Hospital from January 1975 to August 1993 were retrospectively analysed and the histological sections reviewed. RESULTS: There were 37 cases of carcinosarcoma of the ovary representing 1.12% of the ovarian neoplasms seen at this institution. The median age of presentation was 65 years (range 26-85 years) and 70% of patients had advanced disease (FIGO stage III and IV). Clinical features at presentation were similar to those encountered in patients with epithelial ovarian cancer. The overall median survival was 247 days with 40% 1-year survival and 6% 5-year survival for all stages. Early FIGO stage was the only independent prognostic factor for survival. Histology (homologous/heterologous subtypes; grade, type or percentage of the epithelial component) had no significant impact on survival. Adjuvant radiotherapy may have a role and single agent platinum compounds are active, giving a response rate of 35%. CONCLUSIONS: The management of this tumour is difficult and randomised trials are needed to accrue sufficient patient numbers to demonstrate optimal therapy.
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Selection of specific appropriate drugs has been facilitated by a series of randomised clinical trials confirmed by overview analysis. Hitherto these issues have dominated the debate over optimal chemotherapy management of advanced ovarian cancer. The impact of true dose escalation therapy is yet to be evaluated but appears to be worthy of examination in demonstrably chemosensitive disease.
The histological and immunocytochemical appearances of skin with altered pigmentation from two patients receiving chemoimmunotherapy for melanoma were examined. In both patients, there was a clinical response to treatment coincident with depigmentation of skin and hair. Skin biopsies showed extensive infiltration with CD8+ and CD4+ lymphocytes rather than CD57+ in the depigmented areas suggestive of a specific MHC-related cytotoxic T-cell activity against melanocytes. In keeping with this, MHCII expression was markedly up-regulated. These observations suggest the development of a simultaneous anti-tumour and anti-melanocyte immune response stimulated by chemoimmunotherapy, possibly against the same or similar antigens.
OBJECTIVE: To review the clinical features of women with ovarian cancer on whom minimal access surgery has been performed and to determine guidelines for the safe use of minimal access surgery for adnexal masses. DESIGN: Postal survey of members of the British Gynaecological Cancer Society (BGCS) and retrospective case review. RESULTS: BGCS consultants used ultrasound scanning (70%) and serum CA-125 estimations (53%) prior to adnexal mass surgery. The membership felt that adnexal masses with solid elements, diameter greater than 8 cm, multi-ocular or bilateral cysts or increased blood flow on Doppler scanning should not be operated on by minimal access surgery. A positive family history was also considered to be a contraindication. A total of 29 cases of ovarian cancer were identified on whom MAS had been performed. The incidence of cases was 4.1% of referrals to a tertiary referral centre (the Royal Marsden Hospital). The median age of patients was 37 years (range 20 to 68 years) and 13 had State I cancers. The mean delay between diagnosis and staging was 6.5 weeks. CONCLUSION: Guidelines on the use of minimal access surgery in the management of adnexal masses need to be agreed. Women who have an ovarian cancer diagnosed whilst having minimal access surgery should have an accepted staging procedure. We do not recommend the routine use of minimal access surgery for the treatment of ovarian cancer outside a trial.
PURPOSE: Our study examined the impact of the addition of doxorubicin to ovarian cancer regimens in general, while removing the confounding influence of other drugs. MATERIALS AND METHODS: We performed an overview using the data from two large analyses, the Advanced Ovarian Cancer Trialists Group (AOCTG [Br Med J 303:884-893, 1991] and Williams et al [Seminars in Oncol 19:120-128, 1992 (suppl 2)]) and the Ovarian Cancer Meta-Analysis Project (OCMP [J Clin Oncol 9:1668-1674, 1991]). RESULTS: Our data suggest that the addition of doxorubicin significantly improves survival (hazards ratio, 0.85; 95% confidence interval [CI], 0.76 to 0.95; P = .003) and that the size of this benefit is of a similar magnitude to that of platinum. CONCLUSION: The implication of our results is that the basic drugs for the standard treatment of advanced ovarian should be a combination of platinum and doxorubicin. The addition of an alkylating agent may add toxicity and lead to a dose reduction of these two drugs. In view of recent data on combination therapy with paclitaxel and platinum, it would be appropriate to compare this regimen with a combination of doxorubicin and platinum.