- Email: [email protected]
Quadruple or triple therapy to eradicate H pylori
Comment
Quadruple or triple therapy to eradicate H pylori
www.thelancet.com Vol 377 March 12, 2011
7-day regimen.4 Per-protocol analysis showed a 77% versus a 94% eradication rate with 7 and 14 days of treatment, respectively, as second-line treatment for H pylori when empirical triple therapy had failed.4 Therefore, 14 days of bismuth-containing quadruple therapy might be more appropriate in regions where metronidazole resistance is high. The effectiveness of quadruple therapy could depend on resistance to metronidazole, and this resistance might be a determinant for the duration of quadruple therapy. A second issue is the dose of tetracycline. Malfertheiner and colleagues used 1500 mg, which is lower than the routine dose (2000 mg daily) of tetracycline in bismuthcontaining quadruple therapy. Tetracycline resistance has been reported to be low, but was rather high (12·3%) in South Korea.5 Thus whether there is any difference in eradication depending on the dose of tetracycline warrants further study. Finally, the high rate of side-effects with classic quadruple therapy has negatively affected compliance, to result in a low eradication rate. However, Malfertheiner and colleagues did not report low compliance, so this 10-day bismuth-containing quadruple therapy needs to be compared with the other modalities, such as concomitant or sequential therapy as first-line therapy. The efficacy of concomitant treatment and sequential therapy for H pylori eradication has been reported at 92–98%,6–8 and 91–98%6,7,9,10 in per-protocol analyses. Such results are similar to those found by Malfertheiner and colleagues. However, there is also a report that shows
Published Online February 22, 2011 DOI:10.1016/S01406736(11)60168-2 See Articles page 905
Science Photo Library
There have been many trials to eradicate Helicobacter pylori since the hazard from this organism in terms of gastric or extra-gastric diseases became known. However, it remains tough to eradicate H pylori. Empirical triple therapy (proton-pump inhibitor, clarithromycin, amoxicillin) is the first choice. As antibiotic resistance to clarithromycin (which has a crucial role in eradication) has increased, however, the eradication rate with triple therapy has gradually decreased below 80%, and even down to 70%. Sequential therapy, concomitant therapy, or bismuth-containing quadruple therapy has been tried in an effort to resolve clarithromycin resistance with metronidazole. Metronidazole resistance can be overcome by increasing the dose of metronidazole and giving the metronidazole-containing treatment for longer, which is not the case with clarithromycin resistance. In The Lancet, Peter Malfertheiner and colleagues (the Pylera Study Group)1 nicely show that bismuth-containing quadruple therapy is effective and acceptable for first-line therapy to eradicate H pylori in regions with high levels of clarithromycin resistance. The study had a multicentre, randomised, non-inferiority design. The test treatment was omeprazole plus a single capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline for 10 days; the control was 7 days of omeprazole, amoxicillin, and clarithromycin. Eradication rates were 80% with quadruple therapy and 55% with triple therapy. Usually, the side-effects of quadruple therapy are common when four drugs are taken separately, but here the test treatment’s side-effects were similar to those of the triple therapy. It is intriguing that the side-effect profile is different between giving the four drugs separately compared with giving them in a combined capsule. Treatment duration with bismuth-containing quadruple therapy remains controversial. In a recent meta-analysis,2 this modality was not superior to empirical triple therapy given for 7 or 10 days. In Malfertheiner and colleagues’ study, in which metronidazole resistance was 29% in the quadruple therapy group, resistance did not affect eradication (resistance at 90·5%, sensitivity at 95·1%). However, a similar study with the single three-in-one capsule showed a marginal difference (80·4% and 91·7%, respectively; p=0·067) in a situation with 40% resistance to metronidazole.3 Furthermore, in our Korean study, quadruple therapy for 14 days was more effective than a
877
Comment
less efficacy with sequential therapy in a region where dual resistance to clarithromycin and metronidazole is common.11 Thus further prospective study is necessary to compare bismuth-containing quadruple therapy with the non-bismuth modalities as first-line therapy, not only for eradication rate but also for compliance and side-effects, to establish the most efficient modality to eradicate H pylori. Byoung Hwan Lee, *Nayoung Kim Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea (BHL, NK); and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-774, Korea (NK) [email protected]
3
4
5
6 7
8
9
We declare that we have no conflicts of interest. 1
2
Malfertheiner P, Bazzoli F, Delchier J-C, et al, for the Pylera Study Group. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011; published online Feb 22. DOI:10.1016/S0140-6736(11)60020-2. Luther J, Higgins PD, Schoenfeld PS, Moayyedi P, Vakil N, Chey WD. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol 2010; 105: 65–73.
10
11
Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spénard J. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol 2003; 98: 562–67. Lee BH, Kim N, Hwang TJ, et al. Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. Helicobacter 2010; 15: 38–45. Kim JM, Kim JS, Kim N, Kim SG, Jung HC, Song IS. Comparison of primary and secondary antimicrobial minimum inhibitory concentrations for Helicobacter pylori isolated from Korean patients. Int J Antimicrob Agents 2006; 28: 6–13. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol 2010; 8: 36–41. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009; 14: 109–18. Sánchez-Delgado J, Calvet X, Bujanda L, Gisbert JP, Titó L, Castro M. Ten-day sequential treatment for Helicobacter pylori eradication in clinical practice. Am J Gastroenterol 2008; 103: 2220–23. Kwon JH, Lee DH, Song BJ, et al. Ten-day sequential therapy as first-line treatment for Helicobacter pylori infection in Korea: a retrospective study. Helicobacter 2010; 15: 148–53. Choi WH, Park DI, Oh SJ, et al. Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008; 51: 280–84 (in Korean).
EMBRACE, eribulin, and new realities of advanced breast cancer Published Online March 3, 2011 DOI:10.1016/S01406736(11)60280-8 See Articles page 914
878
In recent years, survival of women with metastatic breast cancer has improved because of advances in cancer-specific therapy and supportive care.1 Longer survival, better tolerated treatments, and many active drugs mean that most women with metastatic breast cancer who live in industrialised nations will be candidates for multiple lines of chemotherapy. Indeed, surveys of clinical practice in the USA suggest that women receive an average of four to six lines of chemotherapy for metastatic breast cancer. Some women can have had eight or more different chemotherapy regimens, particularly those with hormone-receptor-positive or HER2-positive tumours in whom effective treatments and the intrinsic trajectory of tumour growth might enable several lines of therapy. Despite the widespread use of chemotherapy beyond the second-line or third-line setting, data to quantify the actual benefits to most patients receiving treatment for refractory disease are scarce.2 Caring for patients with advanced breast cancer involves making decisions based on realistic tradeoffs of clinical benefit and side-effects,
but too often these choices are made on the basis of extrapolations and educated guesses. And yet, such treatments are given every day with the hope that they are valuable. There is a pressing need for better information and better treatments. Eribulin is a novel chemotherapeutic agent that binds to a unique site on tubulin and causes sequestration of tubulin into non-functional aggregates with cellular consequences, including irreversible mitotic block and inhibition of cancer cell growth. Eribulin achieved response rates of 10% in two phase 2 studies of heavily pretreated patients with metastatic breast cancer.3,4 Potentially serious side-effects of eribulin include neutropenia, febrile neutropenia, fatigue, and neuropathy. Now reported in The Lancet, EMBRACE was a phase 3 study that randomly assigned 762 women with advanced breast cancer to either eribulin or treatment of physician’s choice (TPC).5 For enrolment, the study required at least two previous chemotherapy regimens for advanced breast cancer, but accrued a more heavily pretreated population with a median of four previous www.thelancet.com Vol 377 March 12, 2011
Quadruple or triple therapy to eradicate H pylori
www.thelancet.com Vol 377 March 12, 2011
7-day regimen.4 Per-protocol analysis showed a 77% versus a 94% eradication rate with 7 and 14 days of treatment, respectively, as second-line treatment for H pylori when empirical triple therapy had failed.4 Therefore, 14 days of bismuth-containing quadruple therapy might be more appropriate in regions where metronidazole resistance is high. The effectiveness of quadruple therapy could depend on resistance to metronidazole, and this resistance might be a determinant for the duration of quadruple therapy. A second issue is the dose of tetracycline. Malfertheiner and colleagues used 1500 mg, which is lower than the routine dose (2000 mg daily) of tetracycline in bismuthcontaining quadruple therapy. Tetracycline resistance has been reported to be low, but was rather high (12·3%) in South Korea.5 Thus whether there is any difference in eradication depending on the dose of tetracycline warrants further study. Finally, the high rate of side-effects with classic quadruple therapy has negatively affected compliance, to result in a low eradication rate. However, Malfertheiner and colleagues did not report low compliance, so this 10-day bismuth-containing quadruple therapy needs to be compared with the other modalities, such as concomitant or sequential therapy as first-line therapy. The efficacy of concomitant treatment and sequential therapy for H pylori eradication has been reported at 92–98%,6–8 and 91–98%6,7,9,10 in per-protocol analyses. Such results are similar to those found by Malfertheiner and colleagues. However, there is also a report that shows
Published Online February 22, 2011 DOI:10.1016/S01406736(11)60168-2 See Articles page 905
Science Photo Library
There have been many trials to eradicate Helicobacter pylori since the hazard from this organism in terms of gastric or extra-gastric diseases became known. However, it remains tough to eradicate H pylori. Empirical triple therapy (proton-pump inhibitor, clarithromycin, amoxicillin) is the first choice. As antibiotic resistance to clarithromycin (which has a crucial role in eradication) has increased, however, the eradication rate with triple therapy has gradually decreased below 80%, and even down to 70%. Sequential therapy, concomitant therapy, or bismuth-containing quadruple therapy has been tried in an effort to resolve clarithromycin resistance with metronidazole. Metronidazole resistance can be overcome by increasing the dose of metronidazole and giving the metronidazole-containing treatment for longer, which is not the case with clarithromycin resistance. In The Lancet, Peter Malfertheiner and colleagues (the Pylera Study Group)1 nicely show that bismuth-containing quadruple therapy is effective and acceptable for first-line therapy to eradicate H pylori in regions with high levels of clarithromycin resistance. The study had a multicentre, randomised, non-inferiority design. The test treatment was omeprazole plus a single capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline for 10 days; the control was 7 days of omeprazole, amoxicillin, and clarithromycin. Eradication rates were 80% with quadruple therapy and 55% with triple therapy. Usually, the side-effects of quadruple therapy are common when four drugs are taken separately, but here the test treatment’s side-effects were similar to those of the triple therapy. It is intriguing that the side-effect profile is different between giving the four drugs separately compared with giving them in a combined capsule. Treatment duration with bismuth-containing quadruple therapy remains controversial. In a recent meta-analysis,2 this modality was not superior to empirical triple therapy given for 7 or 10 days. In Malfertheiner and colleagues’ study, in which metronidazole resistance was 29% in the quadruple therapy group, resistance did not affect eradication (resistance at 90·5%, sensitivity at 95·1%). However, a similar study with the single three-in-one capsule showed a marginal difference (80·4% and 91·7%, respectively; p=0·067) in a situation with 40% resistance to metronidazole.3 Furthermore, in our Korean study, quadruple therapy for 14 days was more effective than a
877
Comment
less efficacy with sequential therapy in a region where dual resistance to clarithromycin and metronidazole is common.11 Thus further prospective study is necessary to compare bismuth-containing quadruple therapy with the non-bismuth modalities as first-line therapy, not only for eradication rate but also for compliance and side-effects, to establish the most efficient modality to eradicate H pylori. Byoung Hwan Lee, *Nayoung Kim Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea (BHL, NK); and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-774, Korea (NK) [email protected]
3
4
5
6 7
8
9
We declare that we have no conflicts of interest. 1
2
Malfertheiner P, Bazzoli F, Delchier J-C, et al, for the Pylera Study Group. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011; published online Feb 22. DOI:10.1016/S0140-6736(11)60020-2. Luther J, Higgins PD, Schoenfeld PS, Moayyedi P, Vakil N, Chey WD. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol 2010; 105: 65–73.
10
11
Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spénard J. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol 2003; 98: 562–67. Lee BH, Kim N, Hwang TJ, et al. Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. Helicobacter 2010; 15: 38–45. Kim JM, Kim JS, Kim N, Kim SG, Jung HC, Song IS. Comparison of primary and secondary antimicrobial minimum inhibitory concentrations for Helicobacter pylori isolated from Korean patients. Int J Antimicrob Agents 2006; 28: 6–13. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol 2010; 8: 36–41. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009; 14: 109–18. Sánchez-Delgado J, Calvet X, Bujanda L, Gisbert JP, Titó L, Castro M. Ten-day sequential treatment for Helicobacter pylori eradication in clinical practice. Am J Gastroenterol 2008; 103: 2220–23. Kwon JH, Lee DH, Song BJ, et al. Ten-day sequential therapy as first-line treatment for Helicobacter pylori infection in Korea: a retrospective study. Helicobacter 2010; 15: 148–53. Choi WH, Park DI, Oh SJ, et al. Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008; 51: 280–84 (in Korean).
EMBRACE, eribulin, and new realities of advanced breast cancer Published Online March 3, 2011 DOI:10.1016/S01406736(11)60280-8 See Articles page 914
878
In recent years, survival of women with metastatic breast cancer has improved because of advances in cancer-specific therapy and supportive care.1 Longer survival, better tolerated treatments, and many active drugs mean that most women with metastatic breast cancer who live in industrialised nations will be candidates for multiple lines of chemotherapy. Indeed, surveys of clinical practice in the USA suggest that women receive an average of four to six lines of chemotherapy for metastatic breast cancer. Some women can have had eight or more different chemotherapy regimens, particularly those with hormone-receptor-positive or HER2-positive tumours in whom effective treatments and the intrinsic trajectory of tumour growth might enable several lines of therapy. Despite the widespread use of chemotherapy beyond the second-line or third-line setting, data to quantify the actual benefits to most patients receiving treatment for refractory disease are scarce.2 Caring for patients with advanced breast cancer involves making decisions based on realistic tradeoffs of clinical benefit and side-effects,
but too often these choices are made on the basis of extrapolations and educated guesses. And yet, such treatments are given every day with the hope that they are valuable. There is a pressing need for better information and better treatments. Eribulin is a novel chemotherapeutic agent that binds to a unique site on tubulin and causes sequestration of tubulin into non-functional aggregates with cellular consequences, including irreversible mitotic block and inhibition of cancer cell growth. Eribulin achieved response rates of 10% in two phase 2 studies of heavily pretreated patients with metastatic breast cancer.3,4 Potentially serious side-effects of eribulin include neutropenia, febrile neutropenia, fatigue, and neuropathy. Now reported in The Lancet, EMBRACE was a phase 3 study that randomly assigned 762 women with advanced breast cancer to either eribulin or treatment of physician’s choice (TPC).5 For enrolment, the study required at least two previous chemotherapy regimens for advanced breast cancer, but accrued a more heavily pretreated population with a median of four previous www.thelancet.com Vol 377 March 12, 2011