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Albumin-Bound Paclitaxel plus Gemcitabine in Pancreatic Cancer To the Editor: The article by Von Hoff et al. (Oct. 31 issue)1 is entitled “Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine.” This title strikes us as inappropriately rosy, given the modest benefits and substantial toxic effects observed. The addition of nab-paclitaxel increased the median survival by 1.8 months, or 55 days. The chance of being alive at 2 years was increased from 4% to 9%. Meanwhile, an additional 10% of patients had grade 3 (severe) fatigue. Grade 2 fatigue (moderate, not relieved by rest) and duration of fatigue are not mentioned. Grade 3 (severe) neuropathy was increased by 16%. No data on grade 2 (moderate) neuropathy are presented. No data on the out-of-pocket costs of the nab-paclitaxel are provided, even though negative financial consequences represent another source of “toxicity” and a driver of bankruptcies.2,3 In this study, the incremental cost of

nab-paclitaxel was around $25,000 on the basis of Medicare reimbursement rates. A more neutral title, such as “Nab-Paclitaxel plus Gemcitabine in Pancreas Cancer,” might help avoid an imbalanced perception of the study findings. Leonard B. Saltz, M.D. Peter B. Bach, M.D. Memorial Sloan-Kettering Cancer Center New York, NY No potential conflict of interest relevant to this letter was reported. 1. 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. 2. Ramsey S, Blough D, Kirchhoff A, et al. Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Aff (Millwood) 2013; 32:1143-52. 3. Ubel PA, Abernethy AP, Zafar SY. Full disclosure — out-ofpocket costs as side effects. N Engl J Med 2013;369:1484-6. DOI: 10.1056/NEJMc1314761

this week’s letters

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478

Albumin-Bound Paclitaxel plus Gemcitabine in Pancreatic Cancer

480

Tiotropium and the Risk of Death in COPD

483

Saxagliptin, Alogliptin, and Cardiovascular Outcomes

484

Preparing for Responsible Sharing of Clinical Trial Data

485

Access to Patient-Level Trial Data

486

Maraviroc and JC Virus–Associated Immune Reconstitution Inflammatory Syndrome

To the Editor: The prognosis of patients with metastatic pancreatic adenocarcinoma is very poor. In the study by Von Hoff et al. and in the study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) by Conroy et al.,1 an increased proportion of patients had tumors located in a region other than the head of the pancreas. This is in contrast to an earlier study by Cunningham et al.2 (Table 1). Patients with tumors in the head of the pancreas are at increased risk for life-threatening cholangitis during neutropenia. Tumors elsewhere in the pancreas were associated with inferior outcomes, as compared with tumors in the head of the pancreas.3 Von Hoff et al. do not provide details regarding the

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correspondence

Table 1. A Comparison of Three Phase 3 Clinical Trials in Patients with Advanced Pancreatic Adenocarcinoma.* Gemcitabine plus nab-Paclitaxel vs. Gemcitabine

Variable Patients with metastatic disease — %

FOLFIRINOX vs. Gemcitabine†

Gemcitabine plus Capecitabine vs. Gemcitabine‡

100

100

 71§

62 (27–86)

61 (25–76)

62 (37–82)

0 to 1

 93

 99

81

2

  7

  1

19

Head of pancreas

 44

 39

70

Body or tail of pancreas

 55

 57

22

Multicentric or unknown

  1

  4

 8

 38

 46

35

Median age (range) — yr¶ ECOG performance status — %¶

Tumor location — %¶

Neutropenia — %¶ Grade 3 or 4 Febrile Overall survival for combination therapy vs. gemcitabine alone — mo

  3

  5

 4

8.5 vs. 6.7

11.1 vs. 6.8

7.1 vs. 6.2

* ECOG denotes Eastern Cooperative Oncology Group. † Data are from Conroy et al.1 ‡ Data are from Cunningham et al.2 § The remaining 29% of patients had locally advanced disease. ¶ Values are for the combination group only.

effect of tumor location on rates of overall sur- 3. Worni M, Guller U, White RR, et al. Survival trends of patients with metastatic pancreatic cancer: a Surveillance Epidemivival and febrile neutropenia, and such informa- ology and End Results registry trend analysis from 1988 to 2008. tion could help in planning different cytotoxic J Clin Oncol 2012;30:Suppl:e14544. abstract (http://meetinglibrary backbones for patients with respect to tumor .asco.org/content/96619-114). 4. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, location in the future. It has been suggested intratumor paclitaxel concentrations, and endothelial cell transthat nab-paclitaxel may deplete the tumor stroma port of cremophor-free, albumin-bound paclitaxel, ABI-007, comthrough the binding of albumin to fibroblasts pared with cremophor-based paclitaxel. Clin Cancer Res 2006; 12:1317-24. [Erratum, Clin Cancer Res 2006;12:3869.] containing secreted protein acidic and rich in 4 cysteine (SPARC). It would be interesting to DOI: 10.1056/NEJMc1314761 know whether the presence of SPARC differs between tumors in the head of the pancreas and tumors elsewhere in the pancreas. The authors reply: In response to Saltz and Bach: the benefit of therapy with nab-paclitaxel Ranjit K. Sahoo, M.D. plus gemcitabine needs to be evaluated in the Lalit Kumar, D.M. context of innovations for advanced pancreatic All India Institute of Medical Sciences New Delhi, India cancer and other cancer treatments. Since 1997, [email protected] more than 30 large trials involving patients with No potential conflict of interest relevant to this letter was repancreatic cancer have been conducted, and only ported. 3 have shown a statistically significant improve1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; ment in survival, as compared with gemcitabine 364:1817-25. alone. The survival curves in our study separate 2. Cunningham D, Chau I, Stocken DD, et al. Phase III random- early and continue to diverge. It is important to ized comparison of gemcitabine versus gemcitabine plus capeci­ tabine in patients with advanced pancreatic cancer. J Clin Oncol note that the rate of long-term survival was in2009;27:5513-8. creased at 1 year (35% vs. 22%) and beyond. Our

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relative increase in median survival of 26.9% (hazard ratio, 0.72) is similar to results observed in studies that led to drug approvals by the Food and Drug Administration from January 2009 through November 2013 across nine tumor types, with a mean hazard ratio of 0.70 (range, 0.44 to 0.82) and a mean relative increase in median survival of 27.6% (range, 14.3 to 67.2).1 The rates of grade 1 or 2 fatigue with the combination therapy were increased by 5 percentage points, from 36% to 41%. A detailed analysis of neuropathy was presented, showing that grade 2 occurred in 14% of patients and grade 3 in 17% of patients, predominantly late in their treatment. For patients who received the average 4 months of treatment, rates of grade 2 and grade 3 neuropathy were 6% and 7%, respectively.2 Neuropathy was rapidly reversible, and for nearly half the patients, treatment resumed after interruption. On that basis, this regimen can be built on as the backbone for combinations to enhance this initial advance. For the incremental treatment cost, analyses must be viewed in the context of the total cost of care, including drugs, drug administration, growth factors, supportive care, and duration of illness. To address these factors, a pharmacoeconomic analysis of this complex multinational study is needed. The cited Washington State study involving cancer patients in which younger patients with local disease were at increased risk for bankruptcy is less relevant for patients with

of

m e dic i n e

metastatic pancreatic cancer, in whom the median age at diagnosis is more than 70 years. In response to Sahoo and Kumar: in a prespecified subanalysis, among patients with lesions in the pancreatic head, the overall improvements in rates of survival (hazard ratio, 0.59) and progression-free survival (hazard ratio, 0.53) were higher than for those with tumors in the pancreatic body or tail. The rate of febrile neutropenia was too low for a subgroup analysis. However, the rate of sepsis was not related to tumor location but was related to the presence of biliary stents. Detailed analyses of results according to tumor location and SPARC are ongoing. Daniel D. Von Hoff, M.D. Translational Genomics Research Institute Phoenix, AZ [email protected]

David Goldstein, M.D. Prince of Wales Hospital Sydney, NSW, Australia

Markus F. Renschler, M.D. Celgene Summit, NJ Since publication of their article, the authors report no further potential conflict of interest. 1. FDA approved drugs. 2013 (http://www.centerwatch.com/

drug-information/fda-approved-drugs).

2. Goldstein D, Von Hoff DD, Moore M, et al. Evaluation of

peripheral neuropathy in a phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (gem) vs gem alone for patients with metastatic adenocarcinoma of the pancreas. Presented at ECCO17-ESMO38-ESTRO32-ESSO33, Amsterdam, September 27–October 1, 2013:2.583. abstract. DOI: 10.1056/NEJMc1314761

Tiotropium and the Risk of Death in COPD To the Editor: We assessed the risk of myocardial infarction among patients in the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial reported by Wise et al. (Oct. 17 issue),1 and we found a significant association between the use of a tiotropium Respimat inhaler at a dose of 5 μg per day and fatal myocardial infarction (Table 1). This risk persisted among all patients who used a Respimat inhaler (patients in both Respimat intervention groups) as compared with those who used a HandiHaler device. Our analysis of nonfatal and fatal myocardial infarction did not yield conclusive evidence of an elevated risk among patients in each Respimat group in isolation, but the results for the combined Respimat 480

groups as compared with the HandiHaler group are on the threshold of statistical significance; this indicates a signal of potential harm. The Respimat 2.5-μg daily dose showed nonsignificant elevated point estimates of a lesser magnitude than Respimat 5 μg daily, raising the possibility of a dose–response relationship. We believe that focusing on overall mortality or composite cardiovascular end points may mask differences in cause-specific mortality, such as from myocardial infarction. The significant association between Respimat at a dose of 5 μg per day and fatal myocardial infarction is consistent with previous observational data.2 Our findings cast serious doubt on assertions (in the

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