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suggest a considerable, unattributed risk of cardiovascular disease in these resource-limited settings. Atherosclerosis is a chronic inflammatory process that begins in early life,1 and several stimuli initiate and maintain the inflammatory state. Infectious diseases have long been implicated as potential contributors to the development of atherosclerosis and to plaque instability and rupture.2 Infections occur earlier in life and with greater frequency and severity in resourcelimited settings than they do in industrialized countries.3,4 The greater burden of infectious disease may contribute to the higher mortality from cardiovascular disease and more severe cardiovascular disease in income-poor settings than in asset-rich settings, despite the lower prevalence of traditional cardiovascular risk factors. Comparisons of country-specific rates of infection-related mortality and hospitalization, especially in childhood, should be feasible and may be informative regarding potentially modifiable but underappreciated risk factors for cardiovascular disease later in life. David Burgner, M.D., Ph.D. Michael Cheung, M.D., Ph.D. Matthew A. Sabin, M.D., Ph.D.

1. Libby P. Inflammation in atherosclerosis. Arterioscler

Murdoch Childrens Research Institute Melbourne, VIC, Australia

Since publication of his article, the author reports no further potential conflict of interest.

[email protected] No potential conflict of interest relevant to this letter was reported.

Thromb Vasc Biol 2012;32:2045-51.

2. Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis:

update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011;106:858-67. 3. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-128. 4. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-96. DOI: 10.1056/NEJMc1412846

The Author Replies: The investigators in our study agree that socioeconomic factors are important. We are validating approaches that can be used across countries at differing economic levels, and we intend to apply them to the study population. In future analyses, we will be relating levels of outdoor and indoor air pollution to cardiovascular disease and also infections in adulthood (but not in childhood, because these data were not collected) to incident cardiovascular diseases. Salim Yusuf, M.B., B.S., D.Phil. Population Health Research Institute Hamilton, ON, Canada

DOI: 10.1056/NEJMc1412846

FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer To the Editor: In their article on the Triplet plus Bevacizumab (TRIBE) study, Loupakis et al. (Oct. 23 issue)1 conclude that chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab improved the outcome of patients with metastatic colorectal cancer, as compared with a control group receiving fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab. However, I question the basis for this conclusion. First, although the median duration of progression-free survival was 12.1 months in the FOLFOXIRI group, as compared with 9.7 months in the control group, there was no significant improvement in overall survival with FOLFOXIRI. Second, FOLFOXIRI caused significantly more 290

grade 3 or 4 events of neurotoxicity, diarrhea, neutropenia, and stomatitis, which are serious side effects. Third, even though tumors with nonmutated KRAS occurred in 37.3% of patients in the FOLFOXIRI group and 38.7% of those in the control group, subsequent treatment with an anti–epidermal growth factor receptor antibody (anti-EGFR) was performed in only 33% of patients in the FOLFOXIRI group and 29% of those in the control group, and the KRAS mutation status is not indicated for any of these patients. In addition, anti-EGFR was administered as second-line treatment in 31% of the patients in the FOLFOXIRI group, as compared with only 15% of the patients in the control group. This study commenced around the same time

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correspondence

that reports first appeared showing that in pa- Ayumu Matsuoka, M.D. tients with advanced colorectal cancer with non- Osamu Maeda, M.D., Ph.D. mutated KRAS who did not have a response to Yuichi Ando, M.D., Ph.D. chemotherapy, cetuximab improved overall sur- Nagoya University Hospital vival from 4.8 months to 9.5 months.2,3 It seems Nagoya, Japan [email protected] that this apparent imbalance in the use of Dr. Ando reports receiving research grants from Taiho Pharproven effective follow-up treatment would make maceutical, Yakult Honsha, Kyowa Hakko Kirin, and Daiichi it difficult to properly compare the two treat- Sankyo. No other potential conflict of interest relevant to this letter was reported. ment groups in the TRIBE study. Ian E. Haines, F.R.A.C.P., F.A.Ch.P.M. Monash University Malvern, VIC, Australia [email protected] No potential conflict of interest relevant to this letter was reported. 1. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with

FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371:1609-18. 2. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357: 2040-8. 3. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65. DOI: 10.1056/NEJMc1413996

To the Editor: Loupakis et al. conclude that FOLFOXIRI plus bevacizumab significantly prolonged progression-free survival in patients with metastatic colorectal cancer, as compared with the control group. It is generally believed that administration of all three cytotoxic agents (i.e., fluorouracil, oxaliplatin, and irinotecan) can maximize overall survival.1 Therefore, the patients in the control group were supposed to receive oxaliplatin-based chemotherapy at the time of the initial diagnosis of disease progression, whereas those in the FOLFOXIRI group received all three of these drugs simultaneously. As expected, approximately 80% of the patients in the control group received second-line treatment, and most of these patients (64%) were given oxaliplatin-based chemotherapy. An important concern is that the TRIBE trial does not fully answer the question as to whether upfront use of oxaliplatin as first-line treatment really improves therapeutic efficacy, as compared with sequential use after initial progression. The time to disease progression or death during and after the subsequent oxaliplatin-based or second-line treatments in the control group should be compared with the progression-free survival in the FOLFOXIRI group.

1. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of

patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209-14. DOI: 10.1056/NEJMc1413996

The Authors Reply: Our conclusion that ­FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in the study patients is consistent with the results and is based on the following three points. First, the TRIBE study met its primary end point for progression-free survival, an outcome that has been confirmed as an appropriate end point for first-line trials involving patients with metastatic colorectal cancer, even in the era of new targeted agents.1 Second, preliminary overall survival results (involving 56.3% of events), a secondary end point, suggest a clear benefit (hazard ratio, 0.79) of borderline significance at the time of the primary analysis (P = 0.054) and a significant benefit after adjustment for prognostic variables (P = 0.01). Third, an increased incidence of specific adverse events in the FOLFOXIRI group was observed with no increase in serious or fatal events. Overall, no unexpected safety issues emerged in the population selected according to the inclusion criteria of the trial. Any imbalance in second or further lines of treatment could not have affected the primary end point of progression-free survival. More patients in the FOLFOXIRI group than in the control group received anti-EGFR therapy as second-line biologic treatment (31% vs. 15%), but more patients in the control group received these agents as third-line treatments (14% vs. 2%). Overall, no significant imbalance between the two groups was observed (29% vs. 33%, P = 0.47). Since the efficacy of anti-EGFR therapy is maintained in subsequent rounds of salvage ther­apy,2,3 whereas the effect of such therapy on overall survival is less clear in second-line treatment,4 it seems unlikely that this difference significantly influenced overall survival results.

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We agree with Matsuoka et al. that the TRIBE study did not compare two preplanned first-line and second-line strategies. Despite this fact, in the control group, 64% of candidates for secondline therapy received oxaliplatin, and an additional 14% received oxaliplatin in third-line treatment. Furthermore, 100% of the patients in the FOLFOXIRI group received all three cytotoxic agents, whereas 22% of the patients who were treated with a first-line doublet never received the third agent. Chiara Cremolini, M.D. Fotios Loupakis, M.D., Ph.D. Azienda Ospedaliero–Universitaria Pisana Pisa, Italy

Alfredo Falcone, M.D.

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Since publication of their article, the authors report no further potential conflict of interest. 1. Shi Q, de Gramont A, Grothey A, et al. Individual patient

data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the Analysis and Research in Cancers of the Digestive System database. J Clin Oncol 2014 November 10 (Epub ahead of print). 2. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65. 3. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626-34. 4. Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI +/- panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:107-16. DOI: 10.1056/NEJMc1413996

Università di Pisa Pisa, Italy [email protected]

Community-Acquired Pneumonia To the Editor: In their review article, Musher Eric Maury, M.D., Ph.D. and Thorner (Oct. 23 issue)1 favor performing Jonathan London, M.D. pneumococcal urinary antigen testing in hospi- Georges Offenstadt, M.D. talized patients with community-acquired pneu- Hôpital Saint Antoine monia (CAP). This assessment with the use of an Paris, France immunochromatographic card test (ICT) gives [email protected] No potential conflict of interest relevant to this letter was reresults in 15 minutes. International guidelines ported. recommend its use in patients with CAP, and it has been proposed to narrow the spectrum of 1. Musher DM, Thorner AR. Community-acquired pneumonia. empirical antibiotic therapy in such patients (i.e., N Engl J Med 2014;371:1619-28. changing from cephalosporin or fluoroquinolone 2. Yu VL. A clinical solution to antimicrobial resistance in community-acquired pneumonia: narrowing the spectrum of to amoxicillin).2 However, in a trial comparing antimicrobial therapy: comment on “Current and potential empirical treatment with targeted treatment on usefulness of pneumococcal urinary antigen detection in the basis of urinary antigen results in hospital- ­hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy”. Arch Intern Med 2011;171: ized patients with CAP, the authors did not find 172-3. any outcome-related or economic benefit of tar- 3. Falguera M, Ruiz-González A, Schoenenberger JA, et al. Progeted therapy, although they found more relaps- spective, randomised study to compare empirical treatment versus targeted treatment on the basis of the urine antigen results es among patients treated with targeted therapy.3 in hospitalised patients with community-acquired pneumonia. Furthermore, ICT provides positive results in the Thorax 2010;65:101-6. case of mixed infection including Streptococcus 4. Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalpneumoniae but also in the case of monomicrobial ized patients with community-acquired pneumonia to guide infection related to Escherichia coli, Klebsiella pneu- antimicrobial therapy. Arch Intern Med 2011;171:166-72. moniae, or E. cloacae.3-5 Tailoring antibiotic therapy 5. Smith MD, Derrington P, Evans R, et al. Rapid diagnosis of bacteremic pneumococcal infections in adults by using the Binax to the results of ICT in these situations could be NOW Streptococcus pneumoniae urinary antigen test: a proextremely deleterious. Physicians should be aware spective, controlled clinical evaluation. J Clin Microbiol 2003; that the ­results of this easy-to-perform test pro- 41:2810-3. vide information that should be interpreted with DOI: 10.1056/NEJMc1414306 caution, especially in patients with severe CAP. 292

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FOLFOXIRI and bevacizumab for metastatic colorectal cancer.

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