ABSTRACT
BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.
Subject(s)
Drug Tapering , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/drug therapy , Female , Humans , Mutation , Neoplasm Recurrence, Local/chemically induced , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Phthalazines , Piperazines , Poly(ADP-ribose) Polymerases , Treatment OutcomeABSTRACT
BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.
Subject(s)
Anastrozole/administration & dosage , Endometrial Neoplasms/drug therapy , Endometrial Stromal Tumors/drug therapy , Aged , Anastrozole/adverse effects , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/adverse effects , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometrial Stromal Tumors/metabolism , Endometrial Stromal Tumors/pathology , Female , Humans , Middle Aged , Neoplasm Grading , Progression-Free Survival , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolismABSTRACT
BACKGROUND: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. RESULTS: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms. CONCLUSIONS: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used. CLINICAL TRIAL REGISTRATION: Clinicaltrials.govNCT01610869.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/adverse effects , Fallopian Tube Neoplasms/drug therapy , Indoles/adverse effects , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Administration, Metronomic , Administration, Oral , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cyclophosphamide/administration & dosage , Fallopian Tube Neoplasms/diagnosis , Fallopian Tube Neoplasms/mortality , Fallopian Tube Neoplasms/pathology , Female , Humans , Indoles/administration & dosage , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/diagnosis , Peritoneal Neoplasms/mortality , Peritoneal Neoplasms/pathology , Progression-Free Survival , Quality of LifeABSTRACT
BACKGROUND: Malignant bowel obstruction is a common complication of ovarian cancer, resulting in limited oral intake. Home parenteral nutrition (HPN) may be offered to patients in this condition to meet nutritional requirements. However, it is not known how they experience being unable to eat. The present study reports how patients related to food when receiving HPN. METHODS: The investigation was a qualitative study underpinned by phenomenology with women with advanced ovarian cancer in bowel obstruction receiving parenteral nutrition. Interview transcripts were analysed thematically guided by the techniques of Van Manen. RESULTS: We recruited 20 women to the study. Participants were interviewed a maximum of four times and a total of 39 in-depth longitudinal interviews were conducted. Participants could tolerate minimal amounts of food, if they had a venting gastrostomy. Not being able to eat engendered a sense of sadness and loss, and most women found it challenging to be in the presence of others eating. They adopted strategies to cope, which included fantasising about food and watching cookery programmes. These approaches were not a long-term solution; either participants came to terms with their loss or the strategies became less effective in providing relief. CONCLUSIONS: Home parenteral nutrition meets the nutritional requirements of patients with malignant bowel obstruction but cannot replace the non-nutritive functions of food. Healthcare professionals can offer a patient-centred approach by acknowledging the difficulties that patients may face and, wherever possible, encourage them to focus on the positive benefits of interacting with people rather than the loss of eating on social occasions.
Subject(s)
Feeding Behavior/psychology , Intestinal Obstruction/psychology , Ovarian Neoplasms/psychology , Parenteral Nutrition, Home/psychology , Quality of Life/psychology , Adaptation, Psychological , Aged , Cost of Illness , Female , Humans , Intestinal Obstruction/etiology , Intestinal Obstruction/therapy , Longitudinal Studies , Middle Aged , Ovarian Neoplasms/complications , Qualitative Research , Social BehaviorABSTRACT
BACKGROUND: The use of home parenteral nutrition (HPN) for palliative indications is increasing internationally and is the leading indication in some countries. Discharge on HPN can be complex in metabolically unstable patients and requires intestinal failure expertise. METHODS: Between 2012 and 2018, we performed a retrospective analysis aiming to assess the impact of a novel remote discharge pathway for palliative HPN patients. This was evaluated using a quality improvement approach. RESULTS: One hundred and twenty-five patients with active malignancy [mean (range) age 58 (25-80) years] were referred to the intestinal failure unit (IFU) for remote discharge. Of 82 patients were discharged from the oncology Centre on HPN using the pathway. The remaining 43 patients either declined HPN or the Oncology team felt that the patient became too unwell for HPN or died prior to discharge. There was an increase in patients referred for remote discharge from 13 in 2012 to 43 in 2017. The mean number of days between receipt of referral by the IFU to discharge on HPN from the oncology centre reduced from 29.4 days to 10.1 days. Following remote discharge, the mean number of days on HPN was 215.9 days. Catheter-related blood stream infection rates in this cohort were very low at 0.169 per 1000 catheter days. CONCLUSIONS: This is the first study to demonstrate the remote safe, effective and rapid discharge of patients requiring palliative HPN between two hospital sites. This allows patients with a short prognosis more time in their desired location.
Subject(s)
Critical Pathways , Neoplasms/therapy , Parenteral Nutrition, Home/methods , Patient Discharge , Telemedicine/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Palliative Care/methods , Retrospective StudiesABSTRACT
This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.
ABSTRACT
BACKGROUND: Investigating tumour evolution and acquired chemotherapy resistance requires analysis of sequential tumour material. We describe the feasibility of obtaining research biopsies in women with relapsed ovarian high-grade serous carcinoma (HGSC). METHODS: Women with relapsed ovarian HGSC underwent either image-guided biopsy or intra-operative biopsy during secondary debulking, and samples were fixed in methanol-based fixative. Tagged-amplicon sequencing was performed on biopsy DNA. RESULTS: We screened 519 patients in order to enrol 220. Two hundred and two patients underwent successful biopsy, 118 of which were image-guided. There were 22 study-related adverse events (AE) in the image-guided biopsies, all grades 1 and 2; pain was the commonest AE. There were pre-specified significant AE in 3/118 biopsies (2.5%). 87% biopsies were fit-for-purpose for genomic analyses. Median DNA yield was 2.87 µg, and was higher in biopsies utilising 14 G or 16 G needles compared to 18 G. TP53 mutations were identified in 94.4% patients. CONCLUSIONS: Obtaining tumour biopsies for research in relapsed HGSC is safe and feasible. Adverse events are rare. The large majority of biopsies yield sufficient DNA for genomic analyses-we recommend use of larger gauge needles and methanol fixation for such biopsies, as DNA yields are higher but with no increase in AEs.
Subject(s)
Carcinoma/genetics , Carcinoma/secondary , DNA, Neoplasm/analysis , Image-Guided Biopsy , Liver Neoplasms/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Class I Phosphatidylinositol 3-Kinases , DNA Mutational Analysis , DNA, Neoplasm/isolation & purification , ErbB Receptors/genetics , Feasibility Studies , Female , Humans , Image-Guided Biopsy/adverse effects , Image-Guided Biopsy/instrumentation , Liver/pathology , Liver Neoplasms/secondary , Lymph Nodes/pathology , Lymphatic Metastasis , Middle Aged , Neoplasm Grading , Omentum/pathology , PTEN Phosphohydrolase/genetics , Pain/etiology , Peritoneal Neoplasms/secondary , Peritoneum/pathology , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
INTRODUCTION: Treatment on a clinical trial is considered to be beneficial to oncology patients. However, supportive evidence for this is scarce. Trial effect describes the phenomenon of improved health outcomes in patients treated with standard of care (SOC) on trial compared to those receiving SOC outside of a clinical trial. We evaluated trial effect in patients with ovarian cancer treated at our tertiary cancer centre. METHODS: We performed a retrospective cohort study of patients with ovarian cancer treated at The Christie National Health Service Foundation Trust. Patients treated on one of three first-line clinical trials: (SCOTROC-4, ICON-5, ICON-7) were matched (for age, International Federation of Gynaecology and Obstetrics stage, surgical status and performance status) with individuals receiving the same SOC off trial. Survival was calculated using Kaplan-Meier methodology. RESULTS: 60 patients were evaluated; 30 on trial and 30 on SOC off trial. The median progression-free survival (PFS) was 21.8â months (control group) and 25.9â months (trial group), median overall survival (OS) was 64.3â months (control group) and 68.9â months (trial group). There was no difference in PFS (log-rank test: HR 0.87 (95% CI 0.48 to 1.54), p=0.6) or OS (log-rank test: HR 0.87 (95% CI 0.46 to 1.64), p=0.7) between groups. CONCLUSIONS: Patient survival was similar regardless if treated on trial or as SOC. Our findings do not support trial effect, at least in a tertiary cancer centre. Clinical trial participation in specialised cancer centres promotes best practice to the benefit of all patients. These findings may impact discussions round consent of patients to trials and organisation of oncology services.
ABSTRACT
AIMS: Ovarian cancer is the principal cause of gynaecological cancer death in developed countries, yet overall survival in the UK has been reported as being inferior to that in some Western countries. As there is a range of survival across the UK we hypothesised that in major regional centres, outcomes are equivalent to the best internationally. MATERIALS AND METHODS: Data from patients treated in multicentre international and UK-based trials were obtained from three regional cancer centres in the UK; Manchester, University College London and Leeds (MUL). The median progression-free survival (PFS) and overall survival were calculated for each trial and compared with the published trial data. Normalised median survival values and the respective 95% confidence intervals (ratio of pooled MUL data to trial median survival) were calculated to allow inter-trial survival comparisons. This strategy then allowed a comparison of median survival across the UK, in three regional UK centres and in international centres. RESULTS: The analysis showed that the trial-reported PFS was the same in the UK, in the MUL centres and in international centres for each of the trials included in the study. Overall survival was, however, 45% better in major regional centre-treated patients (95% confidence interval 9-73%) than the median overall survival reported in UK trials, whereas the median overall survival in MUL centres equated with that achieved in international centres. CONCLUSION: The data suggest that international survival statistics are achieved in UK regional cancer centres.
Subject(s)
Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Aged , Disease-Free Survival , Female , Humans , Middle AgedABSTRACT
BACKGROUND: We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients with platinum-resistant ovarian, fallopian tube or primary peritoneal cancer were randomised 2 : 1 to receive 8-week cycles of weekly paclitaxel (wPxl; 80 mg/m(2)/week ×6 with 2-week break) plus saracatinib (S; 175 mg o.d.) or placebo (P) continuously, starting 1 week before wPxl, until disease progression. Patients were stratified by taxane-free interval (<6 versus ≥6 months/no prior taxane). The primary end point was progression-free survival (PFS) rate at 6 months. Secondary end points included overall survival (OS) and response rate (RR). RESULTS: A total of 107 patients, median age 63 years, were randomised. Forty-three (40%) had received >2 lines of prior chemotherapy. The 6-month PFS rate was 29% (wPxl + S) versus 34% (wPxl + P) (P = 0.582). Median PFS was 4.7 versus 5.3 months (hazard ratio 1.00, 95% confidence interval 0.65-1.54; P = 0.99). RR (complete + partial) was 29% (wPxl + S) versus 43% (wPxl + P), P value = 0.158. Grade 3/4 adverse events were 36% versus 31% (P = 0.624); the most frequent G3/4 toxicities were vomiting (5.8% saracatinib versus 8.6% placebo), abdominal pain (5.8% versus 0%) and diarrhoea (4.3% versus 5.7%). Febrile neutropenia was more common in the saracatinib arm (4.3%) than placebo (0%). Response, PFS and OS were all significantly (P < 0.05) better in patients with taxane interval ≥6 months/no prior taxane (n = 85) than those <6 months (n = 22), regardless of randomisation. CONCLUSIONS: Saracatinib does not improve activity of weekly paclitaxel in platinum-resistant ovarian cancer. Taxane-free interval of ≥6 months/no prior taxane was associated with better outcome in both groups. TRIALS REGISTRATION: Clinicaltrials.gov NCT01196741; ISRCTN 32163062.
Subject(s)
Benzodioxoles/administration & dosage , Fallopian Tube Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel/administration & dosage , Quinazolines/administration & dosage , Retroperitoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols , Disease-Free Survival , Drug Resistance, Neoplasm/drug effects , Fallopian Tube Neoplasms/pathology , Female , Humans , Middle Aged , Ovarian Neoplasms/pathology , Platinum/adverse effects , Platinum/therapeutic use , Retroperitoneal Neoplasms/pathologyABSTRACT
BACKGROUND: Thrombotic events are common in cancer patients and have been associated with an adverse prognosis in large registry-based studies. METHODS: A retrospective cohort of 417 patients with ovarian cancer treated at a tertiary cancer centre between 2006 and 2009 was studied to identify the incidence and risk factors for thrombotic events and the prognostic impact of thrombosis. Patient outcomes were evaluated against a matched control group without thrombosis. RESULTS: Ninety-nine thrombotic events occurred in 90 patients (21.6%) from 8 months before diagnosis to 56 months following diagnosis, peaking in the 4 months following diagnosis. Patients with thrombosis were older (mean 65 vs 61 years, P=0.007), had a worse performance status (PS ≥2: 29.9% vs 9.5%, P<0.0001) and had a more advanced FIGO stage (FIGO III/IV 75.6% vs 56.9%, P<0.0001) than patients without thrombosis. Shorter overall survival was seen in patients with pulmonary embolism and pelvic/lower limb deep vein thrombosis than without thrombosis (P=0.001). When the control group was matched for stage and PS, no survival difference was seen (P=0.91). CONCLUSION: Ovarian cancer patients with thrombotic events had a shorter survival. However, when matched for prognostic factors (PS and FIGO stage), thrombosis did not impact upon prognosis.
Subject(s)
Ovarian Neoplasms/blood , Thrombosis/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Incidence , Middle Aged , Pilot Projects , Prognosis , Retrospective Studies , Risk Factors , Young AdultABSTRACT
Relatively few Chinese patients access tertiary cancer services in North West England. We investigated the reasons behind this using a culturally sensitive questionnaire. The questionnaire, completed by 214 Chinese people in English, Cantonese or Mandarin, evaluated the Chinese population's access and satisfaction with primary care, understanding of cancer and awareness of local cancer services. Ninety-five per cent of respondents were registered with a general practitioner (GP) and 75% had accessed primary care in the last year. Satisfaction with GP consultations was high but a third of respondents reported a lack of confidence in local National Health Service (NHS) services. Only 57% of eligible women had attended cervical screening programmes. The overall understanding of the causes and treatment of cancer and cancer services in the North West was poor. Despite registration with primary healthcare, the Chinese population under-utilise cancer prevention programmes and tertiary cancer services because of a lack of awareness and understanding of cancer services in the North West. A significant proportion of the population is dissatisfied with the perceived slow service and lack confidence in services, with 41% considering using healthcare abroad. These data highlight the critical need to engage with, educate and support the Chinese population if they are to access NHS cancer services.
Subject(s)
Health Services Accessibility , Health Services Needs and Demand , Neoplasms/therapy , Primary Health Care , Tertiary Healthcare , Adult , Aged , China/ethnology , Early Detection of Cancer , England , Female , Humans , Male , Middle Aged , Neoplasms/prevention & control , Young AdultABSTRACT
BACKGROUND: There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases. METHODS: Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan. RESULTS: In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan. CONCLUSION: Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/diagnosis , Contrast Media , Liver Neoplasms/diagnosis , Liver Neoplasms/drug therapy , Magnetic Resonance Imaging , Aged , Antibodies, Monoclonal, Humanized , Bevacizumab , Biomarkers, Tumor , Colorectal Neoplasms/drug therapy , Drug Therapy, Combination , Female , Fluorouracil/therapeutic use , Gadolinium DTPA , Humans , Leucovorin/therapeutic use , Liver Neoplasms/secondary , Male , Organoplatinum Compounds/therapeutic use , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Patients with recurrent ovarian cancer often achieve partial response following chemotherapy, resulting in persistent small volume disease. After completion of treatment, the dilemma of when to initiate subsequent chemotherapy arises. Identification of biomarkers that could be used to predict when subsequent treatment is needed would be of significant benefit. DESIGN: Twenty-three patients with advanced ovarian cancer and residual asymptomatic disease following chemotherapy underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at study entry, 4, 8, 12, 18 and 26 weeks or disease progression. A subgroup of patients provided plasma samples within which a panel of angiogenic biomarkers was quantified. RESULTS: By 4 weeks, significant differences in whole tumour volume, enhancing fraction and Ca125 were observed between patients whose disease progressed by 26 weeks and those who remained stable. Significant correlations between plasma soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and sVEGFR-2 concentrations, and blood volume and tumour endothelial permeability surface area product measured by DCE-MRI were observed. CONCLUSIONS: Imaging markers have a potential role in early prediction of disease progression in patients with residual ovarian cancer and may supplement current measures of progression. The correlation of DCE-MRI and serological biomarkers suggests that tumour angiogenesis affects these markers through common biological means and warrants further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Cystadenocarcinoma, Serous/diagnosis , Neoplasm Recurrence, Local/diagnosis , Neoplasm, Residual/diagnosis , Ovarian Neoplasms/diagnosis , Peritoneal Neoplasms/diagnosis , CA-125 Antigen/blood , Contrast Media , Cystadenocarcinoma, Serous/blood , Cystadenocarcinoma, Serous/drug therapy , Enzyme-Linked Immunosorbent Assay , Female , Humans , Magnetic Resonance Imaging , Membrane Proteins/blood , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/drug therapy , Neoplasm Staging , Neoplasm, Residual/blood , Neoplasm, Residual/drug therapy , Neovascularization, Pathologic , Ovarian Neoplasms/blood , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/blood , Peritoneal Neoplasms/drug therapy , Prognosis , Survival Rate , Vascular Endothelial Growth Factor Receptor-1/blood , Vascular Endothelial Growth Factor Receptor-2/bloodABSTRACT
Ovarian cancer continues to be a major cause of morbidity and mortality in women. Antiangiogenic treatments have emerged as a promising strategy to treat ovarian cancer. This article reviews the rationale supporting the use of antiangiogenic treatments in ovarian cancer, the clinical development of this group of drugs and the toxicities specific to this modality of treatment.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Ovarian Neoplasms/drug therapy , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Bevacizumab , Endothelial Cells/drug effects , Endothelial Cells/physiology , Female , Humans , Neovascularization, Pathologic/drug therapy , Ovarian Neoplasms/blood supply , Ovary/blood supply , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bleomycin/administration & dosage , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Follow-Up Studies , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Male , Middle Aged , Proportional Hazards Models , Survival Rate , Treatment Outcome , Vincristine/administration & dosageABSTRACT
PURPOSE: OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. METHOD: A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. RESULTS: Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. CONCLUSIONS: The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Thymidylate Synthase/antagonists & inhibitors , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Female , Glutarates/administration & dosage , Humans , Isoindoles/administration & dosage , Liposomes , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Pharmacogenetics , Polymorphism, Genetic , Quinazolines/administration & dosage , Thymidylate Synthase/geneticsABSTRACT
PURPOSE: To study the effect of weekly paclitaxel in the treatment of recurrent ovarian and peritoneal carcinoma. METHODS: A retrospective analysis of patients treated at Christie Cancer Centre between May 2003 and May 2005 was carried out. RESULTS: Fortynine patients with recurrent ovarian and peritoneal carcinoma were treated. The mean duration of treatment was 11 weeks, with 27 (54%) patients receiving 12 or more treatments. The most frequent non-haematological toxicities reported were mild nausea, constipation, lethargy and neuropathy. Moderate anaemia was noted in 50% of patients. Radiological assessment by CT scanning showed that complete or partial responses were achieved in 28% of patients. CA125 response was demonstrated in 63% of patients. Median time to recurrence was 149 days and median survival was 359 days. CONCLUSION: This study provides evidence for the role of weekly paclitaxel in the treatment of recurrent ovarian and peritoneal carcinoma even in a drug-resistant setting following multiple lines of prior therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Ovarian Neoplasms/drug therapy , Paclitaxel/administration & dosage , Peritoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Retrospective Studies , Treatment OutcomeABSTRACT
Several angiogenic growth factors including fibroblast growth factors 1 and 2 (FGF1 and FGF2) depend on heparan sulphate (HS) for biological activity. We previously showed that all cellular elements in ovarian tumour tissue synthesised HS but biologically active HS (i.e. HS capable of binding FGF2 and its receptor) was confined to ovarian tumour endothelium. In this study, we have sought to explain this observation. Heparan sulphate sulphotransferases 1 and 2 (HS6ST1 and HS6ST2) attach sulphate groups to C-6 of glucosamine residues in HS that are critical for FGF2 activation. These enzymes were strongly expressed by tumour cells, but only HS6ST1 was found in endothelial cells. Immunostaining with the 3G10 antibody of tissue sections pretreated with heparinases indicated that HS proteoglycans were produced by tumour and endothelial cells. These results indicated that, in contrast to the endothelium, HS produced by tumour cells may be modified by cell-surface heparanase (HPA1) or endosulphatase (SULF). Protein and RNA analysis revealed that HPA1 was strongly expressed by ovarian tumour cells in eight of ten specimens examined. HSULF-1, which removes specific 6-O-sulphate groups from HS, was abundant in tumour cells but weakly expressed in the endothelium. If this enzyme was responsible for the lack of biologically active HS on the tumour cell surface, we would expect exogenous FGF2 binding to be preserved; we showed previously that this was indeed the case although FGF2 binding was reduced compared to the endothelium and stroma. Thus, the combined effects of heparanase and HSULF could account for the lack of biologically active HS in tumour cells rather than deficiencies in the biosynthetic enzymes.
Subject(s)
Carcinoma/enzymology , Carcinoma/metabolism , Heparitin Sulfate/biosynthesis , Heparitin Sulfate/metabolism , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/metabolism , Carcinoma/pathology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glucuronidase/genetics , Glucuronidase/metabolism , Humans , In Situ Hybridization , Ovarian Neoplasms/pathology , RNA, Messenger/metabolism , Sulfotransferases/genetics , Sulfotransferases/metabolismABSTRACT
AIMS: Ovarian cancer has a very poor prognosis, with 5-year survival rates of 5-20% for advanced-stage disease. This work was designed to verify whether the neoadjuvant approach had an effect on survival in patients with advanced-stage ovarian cancer. MATERIALS AND METHODS: Patients with stage III or IV disease who received neoadjuvant platinum-based chemotherapy (group 1) were compared with a group of conventionally treated patients (group 2). RESULTS: Most of the patients in group 1 (76%) had partial tumoral responses after chemotherapy. Patients from group 1 (n = 42) had a median survival that was not different from that in patients from group 2 (n = 348). Patients who received platinum-based chemotherapy with taxanes had the same survival of patients who received no taxanes. CONCLUSIONS: Our results showed similar responses and survival rates for patients with stage III or IV ovarian cancer treated with neoadjuvant platinum-based chemotherapy, when compared with patients who underwent primary suboptimal cytoreductive surgery. Our data therefore support the ongoing trials to determine the optimum timing of surgery for ovarian cancer.