Correspondence
EGFR TKI therapy, including in EGFRmutant cancers that become resistant to new third-generation EGFR-TKIs,6 suggests that EGFR inhibition favours or accelerates SCLC transformation, but might not be absolutely essential for transformation. Finally, Chen and colleagues raise the interesting idea of using small-cell neuroendocrine serum markers, such as concentrations of neuron-specific enolase or pro-gastrin-releasingpeptide, as early predictors of transformation. We agree that it will be interesting to establish whether an increase in serum neuroendocrine markers or circulating tumour cells that express neuroendocrine markers might be used to accurately identify which EGFR-mutant cancers have undergone SCLC transformation. These serum markers could potentially overcome the limitations of biopsies of a single lesion, which might miss a different metastatic lesion that has transformed into SCLC. Indeed, we know that such heterogeneity can occur in patients.5,6 JAE has received funding from Genentech, Novartis, Roche, and AstraZeneca, and has a financial interest in Gatekeeper Pharmaceuticals, which has IP on an EGFR inhibitor. JAE’s interests were reviewed and managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. LVS reports noncompensated consulting fees from Clovis Oncology, Boehringer Ingelheim, Merrimack Pharmaceuticals, AstraZeneca, Novartis, Taiho, and GlaxoSmithKline. MGO and MJN declare no competing interests.
*Jeffrey A Engelman, Matthew G Oser, Matthew J Niederst, Lecia V Sequist [email protected] Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA 1
2
3
e310
Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015; 16: e165–72. Zhang Y, Li XY, Tang Y, et al. Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer 2013; 81: 302–05. Norkowski E, Ghigna MR, Lacroix L, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol 2013; 8: 1265–71.
4
5
6
Tatematsu A, Shimizu J, Murakami Y, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res 2008; 14: 6092–96. Niederst MJ, Sequist LV, Poirier JT, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 2015; 6: 6377. Piotrowska Z, Niederst MJ, Karlovich CA et al. Heterogeneity underlies the emergence of EGFR T790 wild-type clones following treatment of T790M-positive cancers with a third generation EGFR inhibitor. Cancer Discov 2015; published online May 1. DOI:10.1158/2159-8290.CD-15-0399.
Taxane-related nail toxicity In their recent Review, Caroline Robert and colleagues1 discussed chemotherapy-related nail toxicity. The authors stated that onycholysis is a characteristic (albeit not specifically) of nail toxic effects induced by taxanes and that the incidence of nail changes increases with higher frequency of, and prolonged exposure to, chemotherapy.1 However, in a phase 2 study we did not observe an increase in nail changes, including onycholysis, in patients given high-dose, dose-dense paclitaxel.2 Moreover, the systemic exposure, evaluated as the area under the curve to unbound paclitaxel (pharmacologically active form) and its vehicle, polyoxyethylated castor oil (Cremophor EL, BASF, Limburgerhof, Germany), depends on the duration of the paclitaxel infusion. Cremophor EL levels were higher with short infusion than with prolonged infusion, whereas unbound paclitaxel levels were substantially reduced with the short infusion.3 Thus, we can argue that onycholysis is associated with 1 h paclitaxel infusions given once per week and that it could be related to increased Cremophor EL exposure. Because the vehicle for docetaxel, Tween 80 (Sigma-Aldrich, St Louis, MO, USA), shares some elements and effects with Cremophor EL, it could be involved in its drug-related nail
toxicity. Furthermore, in a previous study4 of oral paclitaxel given once per week, with no absorption of Cremophor EL, no nail changes were found. The new formulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a solvent-free, colloidal suspension of paclitaxel and human serum albumin that does not need other vehicles, has shown few cases of changes in pigmentation or discolouration of the nail bed, and no cases of onycholysis.5 Moreover, the incidence of all-grade nail changes was reported to be inferior with nab-paclitaxel compared with other taxanes. In several studies6,7 evaluating nab-paclitaxel in patients with breast cancer and patients with pancreatic cancer, nail changes were uncommon or mild and readily managed. In a systematic review8 and meta-analysis, the incidence of all-grade nail changes has been reported to be close to 19% with nab-paclitaxel, versus 35% with docetaxel and 44% with paclitaxel. In conclusion, we suggest that onycholysis might represent a sideeffect related to specific taxane drugs such as paclitaxel given once per week and docetaxel, but not nab-paclitaxel, probably as an effect related to their vehicles. This observation could be of interest when managing nail toxicity in these patients. We declare no competing interests.
*Giuseppe Schepisi, Vincenza Conteduca, Cristian Lolli, Matelda Medri, Ugo De Giorgi [email protected] Department of Medical Oncology (GS, VC, CL, UD) and Skin Cancer Unit (MM), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy 1
2
3
Robert C, Sibaud V, Mateus C, et al. Nail toxicities induced by systemic anticancer treatments. Lancet Oncol 2015; 16: e181–89. De Giorgi U, Rosti G, Monti M, Frassineti GL, Marangolo M. Onycholysis secondary to multiple paclitaxel 1-hour infusions: possible role for its vehicle (Cremophor EL). Ann Oncol 2003; 14: 1588–89. Gelderblom H, Mross K, ten Tije AJ, et al. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 2002; 20: 574–81.
www.thelancet.com/oncology Vol 16 July 2015
Correspondence
4
5
6
7
8
Kruijtzer CM, Boot H, Beijnen JH, et al. Weekly oral paclitaxel as first line treatment in patients with advanced gastric cancer. Ann Oncol 2003; 14: 197–204. Abraxane, prescribing information. Revised December, 2014. http://www.abraxane.com/ downloads/Abraxane_PrescribingInformation. pdf (accessed May 26, 2015). Takashima S, Kiyoto S, Takahashi M, et al. Clinical experience with nanoparticle albuminbound paclitaxel, a novel taxane anticancer agent, and management of adverse events in females with breast cancer. Oncol Lett 2015; 9: 1822–26. von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691–703. Capriotti K, Capriotti JA, Lessin S, et al. The risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta-analysis. Br J Dermatol 2015; published online Feb 21. DOI:10.1111/ bjd.13743.
Nilotinib versus imatinib for GIST In the ENESTg1 study, Blay and colleagues1 report large differences between the activities of imatinib and nilotinib as firstline treatment for patients with advanced gastrointestinal stromal tumours (GIST). When analysed by KIT mutation status, imatinib and nilotinib seemed to have similar activity in patients with KIT exon 11 mutations, but imatinib was more active than nilotinib in patients with tumours harbouring a KIT exon 9 mutation. However, as mentioned by Blay and colleagues, preclinical data are not in line with such clinical findings, since imatinib and nilotinib show similar in-vitro activity against tumour cells harbouring KIT exon 9 mutations. We believe that, beyond tumour molecular characteristics, other patient-related factors could have affected the pharmacokinetics of nilotinib but not those of imatinib, thereby resulting in different antitumour activity. First, the pharmacokinetics of nilotinib are substantially affected by previous digestive surgery, and patients with GIST who have underwww.thelancet.com/oncology Vol 16 July 2015
gone major gastrectomy have lower plasma concentrations of nilotinib, and worse outcomes than those who have not undergone gastrectomy.2 By contrast, no data support a relation between previous surgery and imatinib bioavailability. Notably, in the study by Blay and colleagues,1 32–38% of patients had a primary gastric GIST, and some probably underwent previous gastrectomy. Second, intake of acid-suppressing drugs decreases plasma concentrations of various tyrosine kinase inhibitors, such as pazopanib3 and erlotinib,4 and could therefore diminish their clinical activity. Such co-medications could decrease nilotinib plasma concentrations. Indeed, nilotinib has two acid groups with pKa values of 2·1 and 5·4, and its solubility is substantially decreased when pH is more than 4·0.5,6 By contrast, no detrimental effect of acid-suppressing drugs on imatinib pharmacokinetics has been reported so far.5,6 These observations could be explained by various pathophysiological mechanisms, including induction of efflux pumps (eg, ABCB1), free:bound ratio of imatinib and nilotinib, albumin and orosomucoid concentrations, and drug-metabolising enzymes (notably CYP3A4) by proton pump inhibitors5 and by increased gastric and gut pH.6 In the USA, up to 20–55% of patients with cancer are prescribed proton pump inhibitors or H2 receptor antagonists, mainly to control gastroesophageal reflux symptoms.6 Therefore, we believe that such pharmacokinetic interactions are very likely to occur in clinical trials and in routine clinical practice. In this context, it would be of interest to retrospectively investigate in the ENESTg1 study whether past history of major gastrectomy, intake of acid-suppressing drugs, or both could contribute to the differences observed between activities of imatinib and nilotinib in patients with GIST.
OM has acted as consultant for Amgen, AstraZeneca, Bayer, Glaxo-Smith Kline, Novartis, Pfizer, Roche, and Servier. AP has acted as consultant or speaker for Amgen and Pierre Fabre Oncology. RC has acted as consultant for Amgen, Merck, Novartis, Roche, and Sanofi-Aventis. PG and SU declare no competing interests.
Paul Gougis, Angelo Paci, Romain Coriat, Saik Urien, *Olivier Mir [email protected] Gustave Roussy Cancer Campus, Villejuif, France (PG, AP, OM); University Paris Descartes Cochin Teaching Hospital, Paris, France (RC); and University Paris Descartes INSERM CIC1419, Paris, France (SU, OM) 1
2
3
4
5
6
Blay JY, Shen L, Kang YK, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; 16: 550–60. Kim KP, Ryu MH, Yoo C, et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol 2011; 68: 285–291. Tan AR, Gibbon DG, Stein MN, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 2013; 71: 1635–43. Kletzl H, Giraudon M, Ducray PS, Abt M, Hamilton M, Lum BL. Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine. Anticancer Drugs 2015; 26: 565–72. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug–drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315–26. Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 2012; 92: 203–13.
Authors’ reply We acknowledge the interesting points raised by Paul Gougis and colleagues with respect to the differential effects of patient-related and treatment-related factors on the pharmacokinetics of nilotinib compared with imatinib, and their potential effects on anti-tumour activity observed in the ENESTg trial.1 Our trial1 was not specifically designed to examine these associations and no specific analyses of these issues were pre-planned. However, analysis of the dataset and published literature regarding previous gastrectomy and use of proton pump inhibitors suggests that a large effect on overall efficacy results is unlikely. e311
EGFR TKI therapy, including in EGFRmutant cancers that become resistant to new third-generation EGFR-TKIs,6 suggests that EGFR inhibition favours or accelerates SCLC transformation, but might not be absolutely essential for transformation. Finally, Chen and colleagues raise the interesting idea of using small-cell neuroendocrine serum markers, such as concentrations of neuron-specific enolase or pro-gastrin-releasingpeptide, as early predictors of transformation. We agree that it will be interesting to establish whether an increase in serum neuroendocrine markers or circulating tumour cells that express neuroendocrine markers might be used to accurately identify which EGFR-mutant cancers have undergone SCLC transformation. These serum markers could potentially overcome the limitations of biopsies of a single lesion, which might miss a different metastatic lesion that has transformed into SCLC. Indeed, we know that such heterogeneity can occur in patients.5,6 JAE has received funding from Genentech, Novartis, Roche, and AstraZeneca, and has a financial interest in Gatekeeper Pharmaceuticals, which has IP on an EGFR inhibitor. JAE’s interests were reviewed and managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. LVS reports noncompensated consulting fees from Clovis Oncology, Boehringer Ingelheim, Merrimack Pharmaceuticals, AstraZeneca, Novartis, Taiho, and GlaxoSmithKline. MGO and MJN declare no competing interests.
*Jeffrey A Engelman, Matthew G Oser, Matthew J Niederst, Lecia V Sequist [email protected] Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA 1
2
3
e310
Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015; 16: e165–72. Zhang Y, Li XY, Tang Y, et al. Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer 2013; 81: 302–05. Norkowski E, Ghigna MR, Lacroix L, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol 2013; 8: 1265–71.
4
5
6
Tatematsu A, Shimizu J, Murakami Y, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res 2008; 14: 6092–96. Niederst MJ, Sequist LV, Poirier JT, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 2015; 6: 6377. Piotrowska Z, Niederst MJ, Karlovich CA et al. Heterogeneity underlies the emergence of EGFR T790 wild-type clones following treatment of T790M-positive cancers with a third generation EGFR inhibitor. Cancer Discov 2015; published online May 1. DOI:10.1158/2159-8290.CD-15-0399.
Taxane-related nail toxicity In their recent Review, Caroline Robert and colleagues1 discussed chemotherapy-related nail toxicity. The authors stated that onycholysis is a characteristic (albeit not specifically) of nail toxic effects induced by taxanes and that the incidence of nail changes increases with higher frequency of, and prolonged exposure to, chemotherapy.1 However, in a phase 2 study we did not observe an increase in nail changes, including onycholysis, in patients given high-dose, dose-dense paclitaxel.2 Moreover, the systemic exposure, evaluated as the area under the curve to unbound paclitaxel (pharmacologically active form) and its vehicle, polyoxyethylated castor oil (Cremophor EL, BASF, Limburgerhof, Germany), depends on the duration of the paclitaxel infusion. Cremophor EL levels were higher with short infusion than with prolonged infusion, whereas unbound paclitaxel levels were substantially reduced with the short infusion.3 Thus, we can argue that onycholysis is associated with 1 h paclitaxel infusions given once per week and that it could be related to increased Cremophor EL exposure. Because the vehicle for docetaxel, Tween 80 (Sigma-Aldrich, St Louis, MO, USA), shares some elements and effects with Cremophor EL, it could be involved in its drug-related nail
toxicity. Furthermore, in a previous study4 of oral paclitaxel given once per week, with no absorption of Cremophor EL, no nail changes were found. The new formulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a solvent-free, colloidal suspension of paclitaxel and human serum albumin that does not need other vehicles, has shown few cases of changes in pigmentation or discolouration of the nail bed, and no cases of onycholysis.5 Moreover, the incidence of all-grade nail changes was reported to be inferior with nab-paclitaxel compared with other taxanes. In several studies6,7 evaluating nab-paclitaxel in patients with breast cancer and patients with pancreatic cancer, nail changes were uncommon or mild and readily managed. In a systematic review8 and meta-analysis, the incidence of all-grade nail changes has been reported to be close to 19% with nab-paclitaxel, versus 35% with docetaxel and 44% with paclitaxel. In conclusion, we suggest that onycholysis might represent a sideeffect related to specific taxane drugs such as paclitaxel given once per week and docetaxel, but not nab-paclitaxel, probably as an effect related to their vehicles. This observation could be of interest when managing nail toxicity in these patients. We declare no competing interests.
*Giuseppe Schepisi, Vincenza Conteduca, Cristian Lolli, Matelda Medri, Ugo De Giorgi [email protected] Department of Medical Oncology (GS, VC, CL, UD) and Skin Cancer Unit (MM), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy 1
2
3
Robert C, Sibaud V, Mateus C, et al. Nail toxicities induced by systemic anticancer treatments. Lancet Oncol 2015; 16: e181–89. De Giorgi U, Rosti G, Monti M, Frassineti GL, Marangolo M. Onycholysis secondary to multiple paclitaxel 1-hour infusions: possible role for its vehicle (Cremophor EL). Ann Oncol 2003; 14: 1588–89. Gelderblom H, Mross K, ten Tije AJ, et al. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 2002; 20: 574–81.
www.thelancet.com/oncology Vol 16 July 2015
Correspondence
4
5
6
7
8
Kruijtzer CM, Boot H, Beijnen JH, et al. Weekly oral paclitaxel as first line treatment in patients with advanced gastric cancer. Ann Oncol 2003; 14: 197–204. Abraxane, prescribing information. Revised December, 2014. http://www.abraxane.com/ downloads/Abraxane_PrescribingInformation. pdf (accessed May 26, 2015). Takashima S, Kiyoto S, Takahashi M, et al. Clinical experience with nanoparticle albuminbound paclitaxel, a novel taxane anticancer agent, and management of adverse events in females with breast cancer. Oncol Lett 2015; 9: 1822–26. von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691–703. Capriotti K, Capriotti JA, Lessin S, et al. The risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta-analysis. Br J Dermatol 2015; published online Feb 21. DOI:10.1111/ bjd.13743.
Nilotinib versus imatinib for GIST In the ENESTg1 study, Blay and colleagues1 report large differences between the activities of imatinib and nilotinib as firstline treatment for patients with advanced gastrointestinal stromal tumours (GIST). When analysed by KIT mutation status, imatinib and nilotinib seemed to have similar activity in patients with KIT exon 11 mutations, but imatinib was more active than nilotinib in patients with tumours harbouring a KIT exon 9 mutation. However, as mentioned by Blay and colleagues, preclinical data are not in line with such clinical findings, since imatinib and nilotinib show similar in-vitro activity against tumour cells harbouring KIT exon 9 mutations. We believe that, beyond tumour molecular characteristics, other patient-related factors could have affected the pharmacokinetics of nilotinib but not those of imatinib, thereby resulting in different antitumour activity. First, the pharmacokinetics of nilotinib are substantially affected by previous digestive surgery, and patients with GIST who have underwww.thelancet.com/oncology Vol 16 July 2015
gone major gastrectomy have lower plasma concentrations of nilotinib, and worse outcomes than those who have not undergone gastrectomy.2 By contrast, no data support a relation between previous surgery and imatinib bioavailability. Notably, in the study by Blay and colleagues,1 32–38% of patients had a primary gastric GIST, and some probably underwent previous gastrectomy. Second, intake of acid-suppressing drugs decreases plasma concentrations of various tyrosine kinase inhibitors, such as pazopanib3 and erlotinib,4 and could therefore diminish their clinical activity. Such co-medications could decrease nilotinib plasma concentrations. Indeed, nilotinib has two acid groups with pKa values of 2·1 and 5·4, and its solubility is substantially decreased when pH is more than 4·0.5,6 By contrast, no detrimental effect of acid-suppressing drugs on imatinib pharmacokinetics has been reported so far.5,6 These observations could be explained by various pathophysiological mechanisms, including induction of efflux pumps (eg, ABCB1), free:bound ratio of imatinib and nilotinib, albumin and orosomucoid concentrations, and drug-metabolising enzymes (notably CYP3A4) by proton pump inhibitors5 and by increased gastric and gut pH.6 In the USA, up to 20–55% of patients with cancer are prescribed proton pump inhibitors or H2 receptor antagonists, mainly to control gastroesophageal reflux symptoms.6 Therefore, we believe that such pharmacokinetic interactions are very likely to occur in clinical trials and in routine clinical practice. In this context, it would be of interest to retrospectively investigate in the ENESTg1 study whether past history of major gastrectomy, intake of acid-suppressing drugs, or both could contribute to the differences observed between activities of imatinib and nilotinib in patients with GIST.
OM has acted as consultant for Amgen, AstraZeneca, Bayer, Glaxo-Smith Kline, Novartis, Pfizer, Roche, and Servier. AP has acted as consultant or speaker for Amgen and Pierre Fabre Oncology. RC has acted as consultant for Amgen, Merck, Novartis, Roche, and Sanofi-Aventis. PG and SU declare no competing interests.
Paul Gougis, Angelo Paci, Romain Coriat, Saik Urien, *Olivier Mir [email protected] Gustave Roussy Cancer Campus, Villejuif, France (PG, AP, OM); University Paris Descartes Cochin Teaching Hospital, Paris, France (RC); and University Paris Descartes INSERM CIC1419, Paris, France (SU, OM) 1
2
3
4
5
6
Blay JY, Shen L, Kang YK, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; 16: 550–60. Kim KP, Ryu MH, Yoo C, et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol 2011; 68: 285–291. Tan AR, Gibbon DG, Stein MN, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 2013; 71: 1635–43. Kletzl H, Giraudon M, Ducray PS, Abt M, Hamilton M, Lum BL. Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine. Anticancer Drugs 2015; 26: 565–72. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug–drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315–26. Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 2012; 92: 203–13.
Authors’ reply We acknowledge the interesting points raised by Paul Gougis and colleagues with respect to the differential effects of patient-related and treatment-related factors on the pharmacokinetics of nilotinib compared with imatinib, and their potential effects on anti-tumour activity observed in the ENESTg trial.1 Our trial1 was not specifically designed to examine these associations and no specific analyses of these issues were pre-planned. However, analysis of the dataset and published literature regarding previous gastrectomy and use of proton pump inhibitors suggests that a large effect on overall efficacy results is unlikely. e311
