Real-world experience with doxorubicin and olaratumab in soft tissue sarcomas in England and Northern Ireland.

BACKGROUND: A randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone. The recently presented phase III study of doxorubicin and olaratumab in advanced soft tissue sarcoma was discordant with this finding. METHODS: We performed a retrospective analysis of adult patients with advanced-/metastatic STS treated with at least two cycles of doxorubicin and olaratumab at eight sarcoma units across England and Northern Ireland between May 2017 and March 2019. RESULTS: 172 patients were evaluable and 40 patients (23.3%) had died at the time of analysis. Median ECOG performance status (PS) was 1. Median progression free survival (PFS) was 6.8 months (95% CI 5.9-7.7 months). Leiomyosarcoma was the most common histological subtype (75 patients, 43.6%), followed by liposarcomas (19, 11.0%). The mean number of cycles was 5 (doxorubicin range 2-6; olaratumab range 2-23). Two patients (1.2%) had a complete response and 34 (19.8%) had a partial response. 79 (45.9%) had stable and 58 (33.7%) progressive disease. 57 patients (33.1%) experienced grade ≥ 3 neutropenia and 7 patients (4.1%) grade ≥ 3 febrile neutropenia. Grade ≥ 3 anaemia was seen in 21 patients (12.2%). Grade ≥ 3 non-haematological toxicities were seen in 35 patients (20.3%). A clinically significant drop in left ventricular ejection fraction was seen in 6 patients (3.5%). 48 patients (27.9%) required a dose reduction. Overall survival (OS) is pending. CONCLUSIONS: Our results are in keeping with the phase III study findings: response rate, PFS and OS were similar to those reported in the phase III ANNOUNCE trial.

Surgical excision and not chemotherapy is the most powerful modality in treating synovial sarcoma: the UK's North East experience.

BACKGROUND AND PURPOSE: We reviewed our experience of synovial sarcoma to identify factors predictive of local recurrence and overall survival, the impact of chemotherapy and outcomes after surgical excision alone. MATERIALS AND METHODS: 81 patients were treated between 1997 and 2014 of mean age 39 years (8-78). Tumours were in the extremity in 55 (67%). 9 patients presented with metastases and 10 with unresectable disease. Mean follow-up was 3.7 years (SD 3.8). Treatment groups were palliative, surgery only, surgery and radiotherapy, or surgery with chemotherapy (with or without radiotherapy). RESULTS: Local recurrence-free survival (LRFS) was 73% at 5 years, and 68% at 10 and 15 years. In multivariate analysis, positive surgical margins were an independent predictor of LRFS. Overall survival (OS) was 50% at 5 years for all patients, and 62% at 5 years for those treated with curative intent. Larger tumour size and non-extremity locations were predictors of poorer OS. Patients who had chemotherapy did not have significantly better OS or LRS than others. INTERPRETATION: These results show that where feasible, curative resection should not be delayed for chemotherapy. Treatment with surgery only can be associated with good outcomes in selected patients with smaller extremity tumours; although our series is small.

Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis.

AIM: To evaluate the evidence for denosumab for the treatment of bone metastases secondary to solid tumours and, using a network meta-analysis, indirectly compare denosumab with bisphosphonates and best supportive care. DATA SOURCES: MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), Cochrane Library (all sections) (issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011) and additional meeting abstracts (2010 and 2011) were searched. STUDY ELIGIBILITY, PARTICIPANTS AND INTERVENTIONS: Only randomised controlled trials assessing denosumab, bisphosphonates or best supportive care in patients with bone metastases from any solid tumour were included. SYNTHESIS: Direct evidence comparing denosumab and zoledronic acid was assessed for breast cancer, prostate cancer and other solid tumours. Denosumab was compared with pamidronate and best supportive care through a network meta-analysis for each tumour type. The primary outcomes were time to first skeletal related event (SRE) and time to first and subsequent SRE. Secondary outcomes were skeletal morbidity rate, pain, quality of life (QoL) and overall survival. RESULTS: Denosumab was found to be more effective in delaying the time to first SRE and reducing the risk of first and subsequent SRE compared to zoledronic acid, placebo and pamidronate. In breast and prostate cancer, denosumab was effective in reducing skeletal morbidity rate compared with placebo. The lack of published data on pain and QoL meant that firm conclusions could not be made. Denosumab did not appear to have an affect on overall survival. LIMITATIONS: Network meta-analyses are subject to uncertainties and potential biases. CONCLUSIONS: Denosumab is effective in preventing SRE, but the effect on pain and QoL is unclear.

Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype.

PURPOSE: To compare the frequency of visceral relapse of BRCA1/2-deficient ovarian cancer to that of nonhereditary controls. PATIENTS AND METHODS: All patients diagnosed in Scotland with epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and a germline BRCA1/2 mutation were identified. Those with previous malignancy were excluded. Each remaining patient who experienced relapse was matched with two nonhereditary controls. RESULTS: Seventy-nine patients with EOC/PPC and germline BRCA1/2 mutations were identified. Fifteen had inadequate clinical data, two had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission. Of the remaining 19 patients who were BRCA1/2 deficient, 14 patients (74%) developed visceral metastases compared with six (16%) of 38 patients in the control group. The percentages of liver, lung, and splenic metastases were 53%, 32%, and 32%, respectively, in the patients compared with 5%, 3%, and 5%, respectively, in the controls. When events occurring outside the matched follow-up period were omitted, the percentages of visceral, liver, lung, and splenic metastases were 58%, 42%, 16%, and 32% in the patients compared with 5%, 0%, 0%, and 3% in controls (P < .001, P < .001, P = .066, and P = .011, respectively). In an independent validation set, the corresponding percentages of visceral, liver, lung, and splenic metastases were 63%, 46%, 13%, and 17% in the patients compared with 11%, 4%, 2%, and 2% in controls (P < .001, P < .001, P = .153, and P = .052, respectively). CONCLUSION: Although sporadic EOC commonly remains confined to the peritoneum, BRCA1/2-deficient ovarian cancer frequently metastasizes to viscera. These data extend the ovarian BRCAness phenotype, imply BRCA1/2-deficient ovarian cancer is biologically distinct, and suggest that patients with visceral metastases should be considered for BRCA1/2 sequencing.

Molecular pathology and potential therapeutic targets in soft-tissue sarcoma.

The soft-tissue sarcomas are a diverse group of rare malignancies of mesenchymal tissue. Surgery is the principle modality of treatment but chemotherapy is used for the treatment of advanced or metastatic tumors. However, the response to chemotherapy is poor. Genetic factors are known to be important in the development of soft-tissue sarcomas and also have a role in response to treatment. This review discusses known genetic abnormalities in soft-tissue sarcomas. Molecular targets for treatment are also discussed along with a review of treatments that have been developed to date.

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.