PHOTOSTENT-02: Porfimer Sodium Photodynamic Therapy Plus Stenting Versus Stenting Alone in Patients with Locally Advanced Or Metastatic Biliary Tract Cancer
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Open access Original research ESMO Open: first published as 10.1136/esmoopen-2018-000379 on 23 July 2018. Downloaded from PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer Stephen P Pereira,1,2 Mark Jitlal,3 Marian Duggan,3 Emma Lawrie,3 Sandy Beare,3 Pam O'Donoghue,4 Harpreet S Wasan,5 Juan W Valle,6 John Bridgewater,7 on behalf of the PHOTOSTENT-02 investigators To cite: Pereira SP, ABSTRACT Key questions Jitlal M, Duggan M, et al. Background Endobiliary stenting is standard practice for PHOTOSTENT-02: porfimer palliation of obstructive jaundice due to biliary tract cancer sodium photodynamic therapy What is already known about this subject? (BTC). Photodynamic therapy (PDT) may also improve plus stenting versus stenting In patients with obstructive jaundice due to unre- biliary drainage and previous small studies suggested ► alone in patients with locally sectable cholangiocarcinoma, small studies have survival benefit. advanced or metastatic biliary suggested that photodynamic therapy (PDT) may Aims To assess the difference in outcome between tract cancer. ESMO Open improve biliary drainage and patient survival. 2018;3:e000379. doi:10.1136/ patients with BTC undergoing palliative stenting plus PDT esmoopen-2018-000379 versus stenting alone. What does this study add? Methods 92 patients with confirmed locally advanced ► We conducted a large randomised controlled trial or metastatic BTC, ECOG performance status 0–3 and of porfimer sodium PDT in patients with confirmed JWV and JB contributed equally. adequate biliary drainage were randomised (46 per locally advanced or metastatic biliary tract cancer. Received 14 April 2018 group) to receive porfimer sodium PDT plus stenting or ► Patients undergoing PDT plus stenting had a worse Revised 6 June 2018 stenting alone. The primary end point was overall survival outcome than those who underwent stenting alone. Accepted 7 June 2018 (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced How might this impact on clinical practice? http://esmoopen.bmj.com/ for baseline factors and prior therapy. ► We conclude that PDT for this indication cannot be Results No significant differences in grade 3–4 toxicities recommended outside of clinical trials. and no grade 3–4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS malignancies associated with an unfavour- and PFS were worse in patients receiving PDT compared able 5-year survival rate. Characterised by with stent alone group (OS median 6.2 vs 9.8 months (HR a relatively silent clinical course, they are 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 often diagnosed at a late stage where cura- vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), tive resection can only be offered to <20% of on 9 October 2018 by guest. Protected copyright. respectively). patients.1 2 Conclusion In patients with locally advanced or In advanced and metastatic disease, the metastatic BTC, PDT was associated with worse outcome mainstay of treatment is limited to palliative than stenting alone, explained only in part by the chemotherapy using a combination treatment differences in chemotherapy treatments. We conclude of gemcitabine and cisplatin with improved that optimal stenting remains the treatment of choice for overall survival (OS).3 Palliative endoscopic malignant biliary obstruction and the use of PDT for this © Author (s) (or their indication cannot be recommended outside of clinical or percutaneous biliary tree stenting allowing employer(s)) 2018. Re-use tumour-related biliary tract drainage, is often permitted under CC BY. trials. Published by BMJ on behalf Trial registration number ISRCTN 87712758; EudraCT required in order to avoid life-threatening of the European Society for 2005-001173-96; UKCRN ID: 1461. biliary obstruction and subsequent infec- Medical Oncology. tion in non-resectable disease. Despite these, For numbered affiliations see the prognosis remains poor with a median end of article. INTRODUCTION survival of <6 months in patients with complex 4 Correspondence to Cholangiocarcinoma and carcinoma of the hilar lesions. Nevertheless, novel palliative Professor Stephen P Pereira; gall bladder, collectively known as biliary tract approaches are needed to improve quality of stephen. pereira@ ucl. ac. uk cancer (BTC), are rare but highly aggressive life and survival in this patient group. Pereira SP, et al. ESMO Open 2018;3:e000379. doi:10.1136/esmoopen-2018-000379 1 Open access ESMO Open: first published as 10.1136/esmoopen-2018-000379 on 23 July 2018. Downloaded from Photodynamic therapy (PDT) consists of endoscopi- obtained, and all patients gave written informed consent. cally accessed localised delivery of light (most conveniently The trial was run in accordance with the Declaration of from a low-power, red laser) after prior systemic admin- Helsinki. An Independent Data Monitoring Committee istration of a photosensitising agent, thereby initiating a regularly reviewed the data on safety and efficacy. focal, non-thermal, cytotoxic effect, tissue necrosis and 5 apoptosis. PDT has been used for palliation in patients Patients with unresectable cholangiocarcinoma, with uncon- Patients were eligible if they had a histopathological trolled studies reporting an improvement in cholestasis, or cytological diagnosis of non-resectable, recurrent quality of life and survival of patients compared with 6 7 or metastatic biliary tract carcinoma (intrahepatic or historical controls. These results have been supported extrahepatic cholangiocarcinoma or gallbladder carci- by small randomised controlled trials which report a noma); had an ECOG performance status of 0, 1, 2 or survival benefit for PDT with stenting over stenting 3; were aged ≥18 years and had an estimated life expec- alone for unresectable cholangiocarcinoma. Ortner et al tancy of >3 months. Patients were also required to have randomised 39 patients to stenting with or without PDT adequate biliary drainage before randomisation, with no and demonstrated a survival advantage of 493 vs 98 days 8 evidence of active uncontrolled infection. Patients with in favour of PDT. The patients in this study were those highly suspicious findings for malignancy were permitted in whom jaundice could not be relieved by stenting, so following central review and study entry was based on it remains unclear whether PDT may also improve the a case-by-case decision. Patients who had undergone survival of the majority of patients whose cholestasis can non-curative surgery, had received prior radiotherapy be relieved by biliary stenting. Zoepf et al randomised and chemotherapy were eligible. 32 patients to stenting with or without PDT and demon- Patients were excluded if they had received treat- strated a survival advantage of 21 vs 7 months in favour of ment with curative intent for current disease (ie, a PDT.9 These studies were small and in keeping with the prior resection, radical radiotherapy or chemotherapy) standard of care at the time, few patients received pallia- within the last 12 weeks; or palliative chemotherapy or tive chemotherapy. Adverse events (AEs) related to PDT radiotherapy within the previous 4 weeks. If they had were minor and there was no early mortality. Cheon et any of these prior treatments, there had to have been al reported a retrospective analysis of 232 patients with clear evidence of disease progression prior to inclusion. cholangiocarcinoma, where the outcome in patients Additional exclusion criteria included a history of prior receiving PDT and endoscopic biliary drainage versus malignancy that could interfere with response evalua- drainage alone was compared. Improved survival was tion, porphyria, pregnancy or breast feeding or lack of observed in the PDT group with a median survival of 9.8 informed consent. Once the eligibility and exclusion months compared with 7.3 months in the stent alone criteria were checked at the registration telephone to group. Moreover, longer stent patency time was observed http://esmoopen.bmj.com/ the trial centre, patients were randomised to either following PDT.10 Reports of other non-randomised trials PDT+stenting or stenting alone. Treatment allocation exist in the literature. A meta-analysis which included 531 was given during the call and subsequently confirmed via subjects in five different trials (out of which 230 received fax and sent together with the case report forms. Rando- PDT), reported improved survival after PDT compared misation used a minimisation algorithm, stratified for with stenting alone.11 Lastly, in a three-centre, single-arm primary tumour site, disease extent (locally advanced phase II trial of 36 patients with locally advanced BTC, we vs metastatic), performance status, type of prior therapy showed that PDT was associated with a low toxicity profile and recruiting centre. and a median survival of 12 months.12 Given these encouraging reports, a UK multicentre, on 9 October 2018 by guest. Protected copyright. randomised, phase III study was designed to assess the Study entry efficacy and safety of porfimer sodium PDT with biliary The initial patient evaluation included a history and stenting versus biliary stenting alone in advanced or meta- physical examination, laboratory studies (complete static BTC. blood count,