reply to the letter to the editor ‘Possible determinants of VSL#3 probiotic failure in preventing gastrointestinal adverse events associated with dacomitinib in patients with advanced non-small-cell lung cancer enrolled in ARCHER-1042 trial’ by Ceccarelli et al.
Authors: M.E. Lacouture
Journal: Annals of Oncology (2016)

We thank Dr Ceccarelli and colleagues [1.. 2016; 27: 2136-2137Google Scholar] for their interest in our article [2.Lacouture M.E. Keefe D.M. Sonis S. et al.A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer.Ann Oncol. 2016; 27: 1712-1718Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] on prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in patients with advanced non-small-cell lung cancer (NSCLC) in the ARCHER 1042 study. Dr Ceccarelli et al. question the dosage of the probiotic, VSL#3, administered to patients in Cohort II and state that higher doses have been used in other studies. We chose the dosage of four capsules once daily or one sachet daily since (i) a single dose each day within the recommended range would ensure better adherence than multiple doses, particularly for patients who were already receiving multiple medications including dacomitinib, and (ii) this was the recommended dose after our discussions with a key opinion leader. Dr Ceccarelli et al. question why fecal samples were not collected to quantify Bifidobacterium species after VSL#3 use. We suggest that, ideally, pre-VSL#3 and post-VSL#3 fecal samples could have been tested. However, this was not done since the patients had advanced Stage IIIB/IV NSCLC, and providing fecal samples would have placed undue burden on the patients. Dr Ceccarelli et al. state that adherence of patients to VSL#3 was not evaluated. We wish to point out that VSL#3, like the other study treatments in ARCHER 1042, was accounted for at each study visit including weekly through the first 8 weeks, until dacomitinib was discontinued, to ensure adherence. Dr Ceccarelli et al. state that we considered the incidence of all causality, all grade and grade ≥2 diarrhea as an additional primary end point in Cohort II but not in Cohort I and that the incidence of diarrhea is partially available only as a secondary end point aggregate with other data for Cohort I. Their assertion is that it is difficult to compare the two cohorts. We do not agree with their assertion. Although the incidence of all causality, all grade and grade ≥2 diarrhea was not a primary end point for Cohort I, we compared the data from all three arms of the study—placebo arm in Cohort I, doxycycline arm in Cohort I, alclometasone and probiotic arm in Cohort II—for all end points relevant to diarrhea: (i) incidence of all grade and grade ≥2 diarrhea (Table 1 in [1.. 2016; 27: 2136-2137Google Scholar]); (ii) diarrhea burden index (DBI) (Table 2 in [1.. 2016; 27: 2136-2137Google Scholar]); (iii) concomitant drug treatment of diarrhea (Table 2 in [1.. 2016; 27: 2136-2137Google Scholar]); and (iv) patient-reported outcomes on diarrhea (Supplementary Figure 3B in [1.. 2016; 27: 2136-2137Google Scholar]). In contrast to VSL#3, doxycycline, when compared with placebo, reduced the incidence of grade ≥2 diarrhea, although this did not reach statistical significance, decreased the incidence of concomitant drug treatment of diarrhea and reduced the mean DBI although this did not reach statistical significance. Dr Ceccarelli et al. suggest that the topical steroid administered to Cohort II patients may have itself caused diarrhea because of adrenal insufficiency or adrenal syndrome after systemic uptake. We did not observe adrenal insufficiency or adrenal syndrome in any patients. Furthermore, topical alclometasone and the frequency of application would result in negligible systemic absorption. MEL is funded in part through the NIH/NCI Cancer Center Support Grant (P30 CA008748).