Opportunistic infection prophylaxis in the women's interagency HIV study (WIHS).
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
M E Gore
Publications and source records attributed to M E Gore.
The treatment of advanced renal cell cancer with high-dose oral thalidomide.
Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-alpha, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34-76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1-29), 7 (32%; 95% CI: 14-55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8-45) had stable disease for between 3 and 6 months. We also measured levels of TNF-alpha, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD > or = 3 months or an objective response, a statistically significant decrease in serum TNF-alpha levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (> or = grade II, 10 patients), constipation (> or = grade II, 11 patients) and neuropathy (> or = grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies.
Administration, Oral↗
Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.
PURPOSE: To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with epithelial ovarian carcinoma that recurred after or didn't respond to first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Patients with measurable and assessable disease were randomized to receive either PLD 50 mg/m(2) as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m(2)/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. RESULTS: A total of 474 patients were treated (239 PLD and 235 topotecan). They comprised the intent-to-treat population. The overall progression-free survival rates were similar between the two arms (P =.095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P =.390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P =.037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P =.455). Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product utilization. CONCLUSION: The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population.
Adult↗
Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma.
BACKGROUND: Previous studies on prognostic factors in stage I invasive epithelial ovarian carcinoma have been too small for robust conclusions to be reached. We undertook a retrospective study in a large international database to identify the most important prognostic variables. METHODS: 1545 patients with invasive epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stage I) were included. The records of these patients were examined and data extracted for univariate and multivariate analysis of disease-free survival in relation to various clinical and pathological variables. FINDINGS: The multivariate analyses identified degree of differentiation as the most powerful prognostic indicator of disease-free survival (moderately vs well differentiated hazard ratio 3.13 [95% CI 1.68-5.85], poorly vs well differentiated 8.89 [4.96-15.9]), followed by rupture before surgery (2.65 [1.53-4.56]), rupture during surgery (1.64 [1.07-2.51]), FIGO 1973 stage Ib vs Ia 1.70 [1.01-2.85]) and age (per year 1.02 [1.00-1.03]). When the effects of these factors were accounted for, none of the following were of prognostic value: histological type, dense adhesions, extracapsular growth, ascites, FIGO stage 1988, and size of tumour. INTERPRETATION: Degree of differentiation, the most powerful prognostic indicator in stage I ovarian cancer, should be used in decisions on therapy in clinical practice and in the FIGO classification of stage I ovarian cancer. Rupture should be avoided during primary surgery of malignant ovarian tumours confined to the ovaries.
Cell Differentiation↗
Therapy naivete in the era of potent antiretroviral therapy.
Antiretroviral therapy (ART) use was examined in a cohort of homosexual men infected with HIV-1 for long periods. Multivariate logistic regression models, stratified by clinical indication (below and above 500 CD4 cells/microl or prior AIDS), were used to determine predictors of ART naivete. Of the 673 men seen at visit 28 (10/97-4/98), 89 (13.2%) never used ART and 548 (81.4%) were current users; 55% of the therapy-naive were ART eligible. Lower CD4 cell counts predicted (P <.001) ART use. Determinants of therapy naivete differed by clinical indication. African-American race and no prior ambulatory visit predicted (P <.05) ART naivete in men with > or =500 CD4 cells/microl. Among those with clinical indications, less education, younger age, multiple sexual partners, and no prior ambulatory visit significantly predicted ART naivete. In this era of effective ART, use was not universal. Besides disease markers, these nonclinical determinants need to be considered for promoting population therapy effectiveness.
Adult↗
Caelyx: phase II studies in ovarian cancer.
While there have been significant advances in first-line chemotherapy for advanced ovarian cancer, most patients still relapse with drug-resistant disease. For patients refractory to the two most active agents (platinum and paclitaxel), there are few salvage regimens that possess significant clinical activity together with minimal treatment-related toxicities. Caelyx is a new treatment for advanced ovarian cancer, which delivers doxorubicin encapsulated in long-circulating Stealth liposomes, resulting in a prolonged circulation and enhanced tumour targeting of the drug, together with a markedly different safety profile compared with native doxorubicin. Recent phase II clinical trials in relapsed ovarian cancer have demonstrated efficacy in patients with platinum-refractory disease (defined as progression on or relapse within 6 months of previous therapy). In those with combined platinum/paclitaxel-refractory disease, the response rate was 14.5% (95% Confidence Interval (CI): 7.8-21.4%), with many patients demonstrating a prolonged duration of response of beyond 6 months. The most frequent severe (grade 3/4) toxicity with Caelyx was palmar-plantar erythrodysesthesia (PPE), which occurred in 25% of patients and was managed by dose modification or lengthening the treatment cycle. The incidence of neutropenia and alopecia was much reduced, and the cardiac safety profile was also improved compared with equivalent cumulative anthracycline doses for native doxorubicin. In summary, the evidence of clinical efficacy in patients with platinum-refractory ovarian cancer together with an improved safety profile are all strongly supportive of a positive benefit-risk profile for Caelyx in the treatment of advanced ovarian cancer following failure of first-line platinum-based therapy
Antineoplastic Agents↗
Clinico-pathological features of relapsing very thin melanoma.
In the UK the incidence of malignant melanoma is increasing and more patients with thinner primary lesions are diagnosed earlier. Most patients with very thin melanoma (< 0.76 mm Breslow thickness) are cured by surgical excision, however, 2-18% relapse over 0-11 years with local or distant metastatic disease and may die. There are still no recognized prognostic or predictive, clinical, serological or molecular markers that accurately determine which of these very thin melanoma will relapse: the Breslow thickness remains the single most important prognostic factor for melanoma in general. Improved prognostic indicators are therefore needed for this rare, but important, unusually aggressive group, to better direct new invasive and expensive investigations and treatment. This article reviews the clinical and histological aspects of relapsing very thin melanoma and discusses the findings of several recent studies, including our own. There is no clinical or biological evidence to support either wide surgical excision or sentinel node biopsy in these patients.
Back↗
Pursuit of optimum outcomes in ovarian cancer: methodological approaches to therapy.
The treatment of ovarian cancer is an evolving area and important clinical questions remain unanswered at all stages from early disease to relapse. This review outlines current practice at each disease stage, some of the current unanswered questions and issues surrounding the design of clinical trials to answer these questions. The gold standard test for new treatments must remain the randomised controlled trial with survival as the major endpoint because other outcome measures such as radiological response do not bear a strong relationship to survival. Patient factors greatly influence the likelihood of response to treatment and subsequent survival, hence failure to control for these in trial design may lead to spurious results. Quality of life is an important endpoint but quality-of-life measures in clinical trials should be interpreted carefully. The introduction of novel, target directed anticancer therapies will require new study designs as the phase I/II/III paradigm may not be relevant. It is current practice to offer adjuvant chemotherapy to women with early stage disease who are considered at high risk of relapse despite conflicting evidence from clinical trials. Current questions include the optimal choice of regimen and the duration of treatment. However, the relative rarity of early stage disease and the likely small difference between treatments makes evaluations difficult. Advanced disease is currently treated using a combination of surgical cytoreduction and platinum-paclitaxel chemotherapy. Women with poor risk disease are unlikely to be cured of their disease and the investigation of strategies to minimise treatment may be appropriate. Conversely, women with good risk disease may be better candidates for experimental treatment to increase cure rate. Strategies that have been tried include dose-intensification, high-dose therapy and intraperitoneal therapy. Whereas there is some evidence to support the latter, there is no current evidence for dose-intensification or high-dose therapy, and these must remain areas of investigation. Most current trials investigate the addition of agents to platinum-paclitaxel. Relapsed disease is an important area. Despite this, only 9 randomised controlled trials have been undertaken. Uncertainties exist in the role of surgery, both surgical cytoreduction and palliative surgery. The mainstay of treatment at disease relapse is chemotherapy and the choice of agent revolves around the concept of platinum sensitivity. Many agents are active in platinum-resistant disease, but uncertainties remain about the relative efficacies of each and the place of combination therapy.
Adult↗
A new standard of care for treatment of ovarian cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy.
Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.
Adult↗
GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma.
BACKGROUND: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy. PATIENTS AND METHODS: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days. RESULTS: Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha. CONCLUSIONS: The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.
Adult↗
Interferon-alpha (IFN-alpha) stimulates anti-melanoma cytotoxic T lymphocyte (CTL) generation in mixed lymphocyte tumour cultures (MLTC).
IFN-alpha administration after primary tumour resection improves the survival of melanoma patients at high risk of relapse. To investigate whether this response might be due to stimulation of anti-tumour immunity, the effect of IFN-alpha on anti-melanoma CTL generation in MLTC was measured. IFN-alpha increased both allogeneic and autologous anti-melanoma CTL generation from peripheral blood lymphocytes stimulated with irradiated primary melanoma cultures. IFN-alpha up-regulated MHC class I expression on primary melanoma cultures, whereas IFN-gamma up-regulated both MHC class I and II expression. However, the effect of IFN-alpha on anti-melanoma CTL generation was often more potent than that of IFN-gamma, equalling the effect of the optimal combination of IL-2 and IL-12. Pre-treatment of primary melanoma cultures with IFN-gamma was sufficient for CTL generation in MLTC, whereas IFN-alpha needed to be present during the MLTC. While direct anti-proliferative effects of IFN-alpha on some tumour cells have been described, IFN-alpha did not inhibit proliferation of primary melanoma cultures. These results suggest that the clinical effects of IFN-alpha in melanoma patients may be immune-mediated.
Antigen Presentation↗
Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer.
To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.
Adult↗
Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer: a phase II study.
Our purpose was to assess the activity of alpha-interferon (IFN-alpha), interleukin-2 (IL-2) and 5 fluorouracil (5FU) administered by protracted venous infusion (PVI) as opposed to bolus injection. 55 patients with advanced renal cell cancer were treated as follows: IL-2 and IFN-alpha according to the schedule originally described by Atzpodien, with PVI 5FU 200 mg m(-2)day(-1)during weeks 5-9. 42 patients (76%) were of moderate or poor prognosis as defined by previous studies. The response rate by intention to treat was 31% (17 of 55, three complete response, 14 partial response; 95% CI = 19-45%) and in evaluable patients (completed one cycle, n = 42), it was 40% (95% CI = 26-57%). In addition, 24% (13 of 55) patients achieved disease stabilization. The overall median survival was 11 months with a 1-year survival of 45%. The median survival for evaluable patients was 18 months with 1- and 2-year survivals of 60% and 40% respectively. The median survival of responding patients was 31 months and the three patients achieving complete response remain progression-free at 14+, 18+ and 23+ months. Evaluable patients with poor prognostic features achieved a response rate of 54% and median survival of 18 months. Toxicity was significant yet manageable with 12 patients unable to complete one cycle due to side-effects and 36% experiencing grade 3-4 toxicities. The three on-treatment deaths were considered unlikely to be due to toxicity. The schedule of IFN-alpha, IL-2 and PVI 5FU has significant activity in advanced renal cell cancer with manageable toxicity. It is of particular interest that this regimen appears to have high activity in fit patients with poor prognostic features.
Adult↗
Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma.
We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.
Adult↗
Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases.
BACKGROUND: Combination chemotherapy has dramatically improved the prognosis of patients with nondysgerminomatous ovarian germ cell tumors (NDOGCT). However, guidelines are needed for the identification of patients at risk of relapse. METHODS: The authors performed a retrospective analysis of women with NDOGCT managed during the period 1970-1994 at the Royal Marsden Hospital and other hospitals of the London Gynaecological Oncology Group. RESULTS: Sixty-nine women were included; their median follow-up was 5.7 years (minimum, 12 months). The median age was 21 years (range, 4-44 years), with a histology of immature teratoma (IT) for 17 patients, endodermal sinus tumor (EST) for 20 patients, and mixed tumors for 32 patients. Thirty-five patients (51%) had Stage I disease. Nine patients with Stage I tumors were observed without further therapy (six with IT and three with mixed tumors), and one relapsed. Seven patients received non-platinum-based chemotherapy, and four relapsed. A total of 52 patients were treated with platinum-based chemotherapy, with relapse free and overall survival rates of 87% (95% confidence interval [CI], 73-93%) and 84% (95% CI, 70-91%), respectively. Of these patients, relapse was seen in 0 of 9 IT patients, 1 of 25 patients with mixed tumors, and 6 of 18 EST patients. With alpha-fetoprotein (AFP) > 1000 kU/L, relapse was seen in 6 of 18 patients compared with 1 of 33 relapses with lower AFP levels. In multivariate analysis, including all patients who received chemotherapy, AFP >1000 kU/L (P = 0.001) and non-platinum-based chemotherapy (P = 0.005) were associated with relapse. When only patients given platinum-based treatment were considered, EST histology (P = 0.003) and AFP >1000 kU/L (P = 0.003) were associated with relapse in univariate analysis; however, these factors were linked. No malignant tumor was found at second-look surgery performed on 24 patients. Of 26 women assessable for fertility, 24 subsequently recommenced regular menstrual function, and 11 patients had pregnancies. CONCLUSIONS: Platinum-based chemotherapy has been confirmed to be effective in the management of patients with NDOGCT. Relapses were principally seen among patients with AFP >1000 kU/L or pure EST histology. Efforts to improve outcome need to focus on patients with EST, whereas less intensive management strategies may be appropriate for some patients with IT.
Adolescent↗
ICON2 trial. UK consensus statement on standard practice for chemotherapy in ovarian cancer.
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Antineoplastic Agents↗