Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction.

This paper presents a summary of the evidence review group (ERG) report into trastuzumab for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic adenocarcinoma of the stomach (mGC) or gastro-oesophageal junction. HER2 positivity is defined by immunohistochemistry (IHC)3+ or IHC2+/fluorescence in situ hybridisation (FISH)+. The decision problem addressed was the testing of the whole mGC population with IHC and, for IHC2+ patients, also with FISH, followed by treatment of HER2-positive patients with trastuzumab combined with cisplatin and either capecitabine or 5-fluorouracil (5-FU) [HCX (trastuzumab, cisplatin, capecitabine)/fluorouracil (F)] compared with current standard NHS therapy. The manufacturer's submission contained direct evidence from the ToGA trial, a well-conducted, multinational, phase III randomised controlled trial (RCT) that compared HCX/F with cisplatin and a fluoropyrimidine alone [cisplatin, capecitabine (CX)/F]. HCX/F showed statistically significantly better overall survival in the European Medicines Agency-licensed population subgroup (74%) (hazard ratio 0.65, 95% confidence interval 0.51 to 0.83), corresponding to median survival of 16 months versus 11.8 months. No other evidence exists for the efficacy of any therapy in a known HER2-positive mGC population; other comparisons extrapolate from trials in mixed HER2 status populations. The ERG accepted the manufacturer's view that a meaningful network meta-analysis to establish a comparison for HCX/F compared with current standard NHS therapy [epirubicin, cisplatin, capecitabine (ECX)/epirubicin, oxaliplatin, capecitabine (EOX)/epirubicin, cisplatin, 5-FU (ECF)] was not possible, but was unconvinced by arguments advanced in the alternative narrative synthesis. These involved disregarding evidence from a meta-analysis and interpreting non-significant results of small RCTs comparing epirubicin-containing triplets with cisplatin, 5-FU (CF)/capecitabine (X) doublets as evidence of no difference between triplet and doublet regimens. The high CX/F dose in the ToGA trial was an additional basis for the contention of equivalence. An appropriate de novo economic evaluation, including an economic model that separately compared HCX or trastuzumab, cisplatin, 5-FU (HCF) with the triplet regimens ECX, EOX and ECF, based on a simple, three-state cohort model (progression-free, disease, progression and death), was submitted. Utility weights were applied to estimate quality-adjusted life-years (QALYs). Costs were assessed from an NHS perspective, and incorporated the acquisition and monitoring costs of the alternative regimens, HER2 testing, adverse events and other supportive care costs. An 8-year time horizon was used to represent a lifetime analysis. Results from the ToGA trial were combined with a series of assumptions on relative treatment effects and testing strategies. The manufacturer's results produced an incremental cost-effectiveness ratio (ICER) of £ 53,010 per QALY for HCX versus ECX. Although the manufacturer undertook a detailed set of sensitivity analyses, several alternative model assumptions were not evaluated. The ERG undertook a series of alternative base-case analyses. As a result of these analyses, EOX replaced ECX as the appropriate comparator, and the ICER for the comparison of HCX vs EOX increased to between £ 66,982 and £ 71,636 per QALY. The impact of implementation of alternative testing strategies remained unclear. There is also considerable uncertainty surrounding the true estimate of effectiveness for the comparison between triplet regimens containing epirubicin (ECX/ECF/EOX) and doublet CX/F regimens. Consequently, the view of the ERG was that there is insufficient evidence on the efficacy of HCX/F compared with current NHS standard therapy for an ICER to be determined with any degree of certainty.

Treatment of urinary schistosomiasis: methodological issues and research needs identified through a Cochrane systematic review.

Guidelines recommend praziquantel (PZQ) for the treatment and control of schistosomiasis, with no real alternative. Metrifonate was still widely used against Schistosoma haematobium in the 1990s, and then withdrawn. Experimental studies and clinical trials suggest that artemisinin compounds are active against S. haematobium. In a Cochrane systematic review assessing the efficacy and safety of drugs for treating urinary schistosomiasis, 24 randomized controlled trials (n=6315 individuals) met our inclusion criteria. These trials compared a variety of single agent and combination regimens with PZQ, metrifonate or artemisinin derivatives. The review confirmed that both the standard recommended doses of PZQ (single 40 mg/kg oral dose) and metrifonate (3x7.5-10 mg/kg oral doses administered fortnightly) are efficacious and safe in treating urinary schistosomiasis, but there is no study comparing these two regimens head-to-head. There is currently not enough evidence to evaluate artemisinin compounds. Most of the studies included in the Cochrane systematic review were insufficiently powered, lacked standardization in assessing and reporting outcomes, and had a number of methodological limitations. In this paper we discuss the implications of these findings with respect to public health and research methodology and propose priority research needs.

Determinants of health-seeking behaviour for schistosomiasis-related symptoms in the context of integrating schistosomiasis control within the regular health services in Ghana.

Morbidity control of schistosomiasis through integration within existing health care delivery systems is considered a potentially sustainable and cost-effective approach. We conducted a questionnaire-based field study in a Ghanaian village endemic for both urinary and intestinal schistosomiasis to determine whether infected individuals self-reported to health centres or clinics and to identify factors that influenced their decision to seek health care. A total of 317 subjects were interviewed about having signs and symptoms suggestive of schistosomiasis: blood in urine, painful urination, blood in stool/bloody diarrhoea, abdominal pain, diarrhoea, swollen abdomen and fatigue within 1 month of the day of the interview. Fever (for malaria) was included as a disease of high debility for comparison. Around 70% with blood in urine or painful urination did not seek health care, whilst diarrhoea, blood in stool, abdominal pain and fever usually led to action (mainly self-medication, with allopathic drugs being used four to five times more often than herbal treatment). On average 20% of schistosomiasis-related signs and symptoms were reported to health facilities either as the first option or second and third alternative by some of those that self-medicated. A few of those who visited a clinic or health centre as first option still self-medicated afterwards. Children under 10 years and adults were more likely to seek health care than teenagers. Also, females were more likely to visit a health facility than males of the same age groups. Socio-economic status and duration of symptoms did not appear to affect health-seeking behaviour. 'Do not have the money' (43%) and 'Not serious enough' (41%) were the commonest reasons for not visiting a clinic, reported more frequently by lower and higher socio-economic classes, respectively, for both urinary or intestinal schistosomiasis. The regular health service shows some potential in passive control of schistosomiasis as some, but far too few, people visit a health facility as first or second option.