Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-α be better?

Background: The optimal dose of TNF-α delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown. Patients and methods: Randomised phase II trial comparing hyperthermic ILP (38-40°) with melphalan and one of the four assigned doses of TNF-α: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2-3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group. Results: One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-α. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively. Conclusion: At the range of TNF-α doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-α doses. Efficacy and safety of low-dose TNF-α could greatly facilitate ILP procedures in the near futur

Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group

Background: There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). Patients and methods: Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. Results: The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. Conclusion: As for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial settin

Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: An EORTC-STBSG study

Background: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.Methods:Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.Results:At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS 12wks), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P=0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS 12wks, and OS (both P=0.05).Conclusion:Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment

How to think about health promotion ethics

Health promotion ethics is moral deliberation about health promotion and its prac­ tice. Although academics and practitioners have been writing about ethics, and especially values, in health promotion for decades, health promotion ethics is now regaining attention within the broader literature on public health ethics. Health promotion is difficult to define, and this has implications for health promotion ethics. Health promotion can be approached in two complementary ways: as a normative ideal, and as a practice. We consider the normative ideal of health promotion to be that aspect of public health practice that is particularly concerned with the equity of social arrangements: it imagines that social arrangements can be altered to make things better for everyone, whatever their health risks, and seeks to achieve this in collaboration with citizens.This raises two main ethical questions. First: what is a good society? And then: what should health promotion contribute to a good society? The practice of health promotion varies widely. Discussion of its ethical implications has addressed four main issues: the potential for health promotion to limit or increase the freedom of individuals; health promotion as a source of collective benefit; the possibility that health promotion strategies might “blame the victim” or stigmatise those who are disabled, sick or at higher risk of disease; and the importance of distributing the benefits of health promotion fairly. Different people will make different moral evaluations on each of these issues in a way that is informed by, and informs, their vision of a good society and their understanding of the ends of health promotion. We conclude that future work in health promotion ethics will require thoughtfully connecting social and political philosophy with an applied, empirically informed ethics of practice. Key Words:Ethics, health education, health promotion, moral philosophy, political philosophy, public healthNHMR

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial.

PURPOSE: Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). PATIENTS AND METHODS: Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS: Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION: Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib