Reply to the letter to the editor ‘Second-line chemotherapy in advanced biliary cancer: the present now will later be past’ by Vivaldi et al.
Authors: A Lamarca, R A Hubner, W D Ryder, J W Valle
Journal: Annals of Oncology (2014)

We thank Vivaldi et al. for their supportive comments [1.Vivaldi C. Fornaro L. Cereda S. et al.Second-line chemotherapy in advanced biliary cancer: the present now will later be past.Ann Oncol. 2014; 25: 2443-2444Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] regarding our published work [2.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. We agree in one major respect: the need for prospective randomised second-line trials in advanced biliary tract cancer. Our systematic review identified a cohort of patients able to receive second-line chemotherapy with results comparable with the retrospective series by Vivaldi et al. A re-analysis excluding trials with targeted agents, as suggested, does not alter our conclusions (Table 1).Table 1Excluding the trials employing targeted therapies as suggested by Vivaldi et al. did not alter the conclusions of our analysisAll studiesTargeted therapies studies excludedWeighted mean OS (95% CI) (months)7.2 (6.2–8.2)7.4 (6.4–8.5)Weighted mean PFS (95% CI) (months)3.2 (2.7–3.7)3.3 (2.8–3.9)Weighted mean RR (95% CI) (%)7.7 (4.6–10.9)8.1 (4.2–12)Weighted mean DCR (95% CI) (%)49.5 (41.4–57.7)49.5 (39.9–59.2)Correlation OS/DCR (r; P value)0.19; 0.450.23; 0.4Correlation OS/RR (r; P value)0.34; 0.160.39; 0.13Correlation OS/PFS (r; P value)0.54; 0.010.59; 0.01OS, overall survival; PFS, progression-free survival; RR, response rate; DRC, disease control rate; CI, confidence interval; r, correlation index. Open table in a new tab OS, overall survival; PFS, progression-free survival; RR, response rate; DRC, disease control rate; CI, confidence interval; r, correlation index. Vivaldi et al. express concern regarding two aspects of the ABC-06 study (a 162-patient randomised phase III study comparing Active Symptom Control (ASC) versus ASC plus FOLFOX chemotherapy, developed by the UK National Cancer Research Institute Hepatobiliary Subgroup, NCT01926236): a non-chemotherapy control arm and potential recruitment difficulties of such a design, citing as an example the CONKO-003 trial [3.Pelzer U. Schwaner I. Stieler J. et al.Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.Eur J Cancer. 2011; 47: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar]. A major limitation of currently available evidence (level C, heavily subject to selection bias and non-representative of the whole patient group) is that a number of questions remain unanswered: is there a survival benefit of chemotherapy over ASC [a protocol-led proactive approach (contrasting with Best Supportive Care, a ‘hands-off’ approach) for which OS has not been defined]? If so, what is the magnitude of that benefit? What is the impact of toxicity and, importantly, what is the effect on patient-reported outcomes? It is incumbent on us to offer our patients ‘informed’ choice regarding pros/cons of treatment for what appears to be a modest gain [median progression-free survival (PFS) of 3.2 months in both analyses]. These questions, along with additional translational research, are addressed by ABC-06. Changing the control arm to single-agent chemotherapy (e.g. capecitabine or 5-fluorouracil), as suggested, would fail to answer the main survival question of ABC-06. There is insufficient evidence to select monotherapy as the current standard of care and a ‘negative’ study of combination chemotherapy versus monotherapy would leave us in the same position we are in now: with no standard of care, a status persisting for too long in first line before an adequately powered prospective phase III study [4.Valle J. Wasan H. Palmer D.H. et al.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med. 2010; 362: 1273-1281Crossref PubMed Scopus (2467) Google Scholar]. We shared concerns regarding physician/patient acceptability; a preparatory physician survey across 17 major centres showed unanimous agreement regarding equipoise between the treatment arms. Furthermore, both the trial design and the patient information sheet were supported by AMMF—The Cholangiocarcinoma Charity (UK). We are reassured by the current high rate of acceptance of the trial (61% consent rate of patients approached for ABC-06) along with the oversight of patient welfare provided by the IDMC. A similar degree of physician/patient engagement has recently resulted in completion of another study, also comparing chemotherapy with ASC, in oesophago-gastric cancer [5.Ford H.E. Marshall A. Bridgewater J.A. et al.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial.Lancet Oncol. 2014; 15: 78-86Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. Finally, the sample size of ABC-06 limited us to three stratification factors; review of previously published literature led us to include first-line PFS (as suggested by Vivaldi et al.), disease stage and serum albumin. A future pooled analysis of homogeneous datasets may improve our understanding of prognostic factors with greater statistical power and we look forward to such a collaboration. Only robust clinical trials will allow ‘the present’ to ‘later be past’. The authors have declared no conflicts of interest.