APPENDICES - NIHR Health Technology Assessment Programme

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248 Study details Population details Treatment details ResultsInterpretation Appendix 16 Authors’ conclusions This trial shows that PDT with Photofrin is a clinically and statistically effective therapy in producing long-term ablation of HGD and reducing the potential impact of cancer compared with OM Brief study appraisal This was a RCT with procedures for blinding of outcome assessors. Outcomes were defined and appropriately assessed and AEs noted. Longer-term FU was used to trace the development of dysplasia and progression to cancer. The results of this trial appear to be reliable with the caveat being the large number of recruiting centres (and very small numbers of patients at some sites) which may have resulted in betweensite differences, such as the delivery of the intervention (e.g. varying expertise in delivering PDT), which may have affected the overall results. The number recruited at individual sites ranged from one to 51 participants Mortality Two patients in the PHOPDT and one patient in the OM group died within the 1st 2 yr from events unrelated to Barrett’s disease. No deaths were related to the treatment. There were no additional patients who died over the course of the additional 3 yr of FU Morbidity The proportion of responders (complete ablation of HGD) was significantly higher in PHOPDT than with OM (77% vs 39%, p < 0.0001). Of the omeprazole alone responders there were 26% of the PHOPDT and 52% of the OM patients who terminated the trial with either HGD or cancer. Analysis of responders for both treatment groups at 10 specific time points showed a proportion of responders almost twice as large in PHOPDT compared with OM at all assessment periods (data not shown). There was a significant difference between the median time to CR in the 2 groups: PHOPDT, 113 d and OM, 551 d, p < 0.0001. Over the trial period 10% of PHOPDT patients had HGD compared with 31% of the OM patients By the end of the 5-year FU period, the probability of maintaining complete ablation of HGD was 48% in PHOPDT compared with 4% in OM, p < 0.0001. The median duration of the CR was 44.8 mth in the PHOPDT group and 3.2 mth in the OM group. A 2-yr responder in the PHOPDT group had a 90% chance of maintaining the response for 5 yr compared with 30% for a 2-yr responder in the OM group. Comparison between the 2 groups showed that patients in the PHOPDT group had a significant delay in progression to cancer compared with patients in the OM group. In the PHOPDT group, 21 (15%) patients progressed to cancer from d48 to 1793. In the OM group, 20 (29%) patients progressed to cancer from d63 to 1092. After 5yr of FU, the rate of patients who progressed to cancer in PHOPDT was significantly lower than in OM (p = 0.027). There was no significant difference in squamous overgrowth between groups when compared per patient or per biopsy or when the average no. of biopsies with squamous overgrowth were compared per patient. Squamous overgrowth did not obscure the most advanced neoplasia in any patient AEs In the initial phase of the trial, the most common AEs were photosensitivity (69%) and oesophageal strictures (36%). All photosensitivity events were resolved and 94% of patients with strictures were stricture free during the course of the initial phase. Events of severe intensity were similar for PHOPDT (16%) and OM (15%) with 65% of the PHOPDT group being related to the treatment compared with 2% in the OM group. From years 2 to 5, there were no SAEs and of those AEs reported, none was attributed to the treatments. There were no photosensitivity AEs occurring during the long term phase. Full details of all AES, both related and unrelated to treatment are available in the paper Resource use Not assessed Trial treatments PDT with PHOPDT vs OM alone Intervention PHOPDT: Patients in this arm received a maximum of three courses of PDT over 5 yr separated by at least 3 mth. One course of PDT consisted of a 2-mg/kg PHO injection followed by one laser light session (630 nm) applied to the oesophageal segment with HGD 40–50 hr after injection. The light dose was 130 J/cm of diffuser length with a centring balloon. A 2nd light application of 50 J/cm without the cantering balloon could be given 96–120hr after PHO injection but only for areas with insufficient mucosal response after the 1st light application. A maximum of 7 cm of BO was treated during one course of PDT. It was required that the entire length of Barrett’s mucosa be treated. Patients also received 20 mg of OM twice daily. Patients had to avoid exposure of eyes and skin to direct sunlight and high intensity light for at least 30 d. They were told to wear dark sunglasses for a 30-d period when outdoors Comparator OM: Patients received 20 mg OM twice daily Treatment intention Curative Type(s) of cancer and histology BO with HGD Main eligibility criteria Patients were eligible if they were diagnosed with BO with HGD proven by biopsy and be ≥ 18yr. Exclusion criteria were: cancer other than nonmelanoma skin cancer within the last 5yr; prior PDT to the oesophagus, oesophageal strictures unresponsive to dilatation and further criteria detailed in full in the paper Patient characteristics % Male: 85 Mean age: 67 yr Further patient characteristics were reported Concomitant treatment 9% of patients in the PHOPDT group underwent an oesophagectomy or other endoscopic ablation (3%). 19% of the patients in the OM group had PHOPDT treatment, 10% underwent an oesophagectomy and 2.9% had another endoscopic ablation technique Authors Overholt et al. (2007) 99 Linked publications206–209 Data source Full published paper Country Not stated Language English Study design RCT No. of participants Total: 208 (61 in long-term phase group) Intervention: PHOPDT: 138 (48 in long-term phase group) Comparator: OM: 70 (13 in long term phase group) No. of recruiting centres 30 (in four unnamed countries) Follow-up period and frequency Every 3 mth until four consecutive biopsy results were negative for HGD, then biannually until 5 yr OM, omeprazole; PHOPDT, Photofrin and omeprazole.
DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37 Study details Population details Treatment details Results Interpretation Authors’ conclusions PDT and APC are equally effective in eradicating Barrett’s mucosa. However, PDT is more effective in eradicating dysplasia. Long-term FU is needed to assess cancer prevention and the durability of the neosquamous epithelium. These interventions cannot be recommended as yet for routine practice Brief study appraisal This was a small trial that will likely have been underpowered to detect treatment differences for all outcomes. This would also have impacted on the cost effectiveness analysis, which accompanied this trial. Treatment protocols are well described but study methods such as procedures for randomisation and blinding are less well described. The authors advise a larger trial and also highlight the need for longer-term FU Mortality Not assessed Morbidity Median length of BO eradicated at 4-mth FU: PDT 57% (3 cm); APC 65% (3 cm) Median length of BO eradicated at 12-mth FU: PDT 60% (3 cm); APC 56% (2.5 cm) Dysplasia eradication at 4 mth: PDT 77%; APC 62% (p = 0.03) Dysplasia eradication at 12 mth: PDT 77%; APC 67% NS Development of malignancy at 12 mth: PDT one; APC zero AEs Severe AEs: PDT: four of 13 (31%), photosensitivity two; oesophageal stricture two APC: three of 13 (23%), Oesophageal stricture, two; severe chest pain, odynophagia and fever requiring hospital admission, one Resource use A cost-effectiveness analysis was conducted from the perspective of the UK NHS. The cost of PDT per patient was calculated at £2804 and that of APC £1341. The ICERs were calculated based on differences in cost and effects between the two procedures for BO length eradication and dysplasia eradication at 4 and 12 mth. At 4 mth APC was the dominant strategy being less expensive and more effective. At 12 mth the incremental cost ratio was £266, i.e. it would cost an additional £266 for every percentage reduction in Barrett’s using PDT. Full details of the cost-effectiveness analysis are provided in the paper Trial treatments PDT with Photofrin vs APC Intervention 2 mg/kg of Photofrin was injected intravenously 48 hr before illumination with laser. PDT was performed using 630-nm red laser light with a power output of 840 mW delivering 200 J/cm through an endoscopically inserted PDT balloon. Endoscopy was performed under intravenous sedation with midazolam 5–15 mg and fentanyl 50–100 µg. Intravenous buscopan was used as an antimotility agent. A 3-cm window PDT balloon was inserted over a guidewire and inflated after positioning, adjacent to the Barrett’s segment. The laser fibre was inserted into the balloon and positioned to allow uniform laser light distribution. The procedure was repeated for every additional 3 cm of the Barrett’s segment. Further treatment parameters were described. All patients were admitted to the gastroenterology ward and nursed in a semi-dark room. The ward nursing staff and the patients were given instructions and an information leaflet about avoiding direct sunlight and bright indoor lights for 4–8 wk Comparator APC: Endoscopy was performed under intravenous sedation with midazolam 5–15 mg. After assessment of the Barrett’s segment, APC was performed using the ERBE ICC 200 Argon Beamer. APC was applied until a white coagulum appeared at a power setting of 65 W and argon gas flow of 1.8 l/min. Depending on the length of the Barrett’s segment and patient tolerability, APC was carried out in one or more sessions with an interval of 2–4 wk between the sessions. The treatment goal was complete ablation of BO and dysplasia or a maximum of six sessions when complete ablation was not achieved. Further details were provided in the paper Treatment intention Curative Type(s) of cancer and histology BO with LGD or HGD Main eligibility criteria Patients with BO ≥ 3 cm and LGD or HGD with histological diagnosis confirmed on biopsy no more than 3 mth before study entry were eligible. The following were excluded: patients with oesophageal malignancy of any form, previous oesophageal resection, previous mucosal ablative therapy or endoscopic mucosal resection, patients with predominantly tongues rather than circumferential Barrett’s oesophagus, patients with porphyria or patients intolerant to endoscopy. Patients pregnant, trying to get pregnant or not using contraception were also excluded Patient characteristics % Male: 81 Median age: 60 yr Age range: 35–86 yr Median BO length: 4 cm Dysplasia: HGD, 3(12%), 23(88%) Concomitant treatment After the procedures, patients received a high-dose PPI, lansoprazole 60 mg/d, during the treatment period and were then maintained on 30 mg/d. All patients also received two tablets of co-codamol, to be taken every 6 hr as pain relief for 24–48 hr after the treatment. A few patients also received 1 g of sucralfate every 6 hr for retrosternal discomfort and transient dysphagia Authors Ragunath et al. (2005) 100 Linked publications210 Data source Full published paper Country UK Language English Study design RCT No. of participants Total: 26 Intervention: PDT: 13 Comparator: APC: 13 No. of recruiting centres Not stated Follow-up period and frequency 4 mth and 12 mth © 2010 Queen’s Printer and Controller of HMSO. All rights reserved. 249
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