Reply to P. Prassopoulos et al

VOLUME

28

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NUMBER

5

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FEBRUARY

10

2010

JOURNAL OF CLINICAL ONCOLOGY

C O R R E S P O N D E N C E

Reply to P. Prassopoulos et al Prassopoulos et al1 cite three main issues regarding our report2: the number of patients available in the cohort with five or more lesions measured at baseline, the need to evaluate the number of lesions required to be monitored in a prospective trial, and the possible discordance of our findings with previous evaluations of response to treatment in patients with liver and lung lesions. Although our evaluation2 overall included data from 2,374 patients, we agree that the number of patients available in our cohort with five or more target lesions measured at baseline (n ⫽ 108 patients) was limited. Analyses were performed in just this subset, and in general, agreement rates remained high. The recent study by Bogaerts et al3 also involved this subset of patients and included a much larger cohort of 585 patients with five or more target lesions. In the analysis by Bogaerts et al, 90% agreement was observed in best response when considering two target lesions versus all, and 93% agreement was observed in the calculated reason for progression when considering two versus all lesions. In addition, when considering the end point of progression-free survival (PFS)—an increasingly prevalent end point in both phase II and III trials—in the subset of patients with five or more target lesions measured at baseline, the median PFS was remarkably consistent with the median of 5.22 months when three target lesions were considered versus 5.26 months when all lesions were considered.3 Prassopoulos et al1 raise the concern that the reported 3% difference in overall response rate observed in a single trial in our analysis2 actually translates to a 13% difference if only patients with more than two lesions were considered. In fact, the difference in response rate of 3% was the largest difference in study level response rate observed in the 23 trials we evaluated; in 19 of 23 trials, no difference whatsoever in overall response rate was demonstrated when comparing assessment of two versus all lesions. The suggestion to evaluate the optimal number of lesions to measure in a prospective manner is a valid consideration, but it is unclear how this would be accomplished in practice. In theory, one could treat all patients with the same regimen, randomly assign patients to be evaluated on the basis of all lesions or two lesions, and compare the response rate and time to progression metrics. However, it is unclear whether investigators and patients would be willing to participate in such a trial, which would likely require a rather large sample size to address the inherent variability in response between patients. In practice, prospectively specified analyses of data from previously conducted large trials are regularly used to inform and make decisions regarding optimal trial design and conduct.3-8 Prassopoulos et al1 note two additional investigations9,10 previously conducted to evaluate the number of lesions that should be measured to assess response to chemotherapy. Unfortunately, both of these cohorts were limited in the number of patients evaluated (n ⫽ 44 patients with metastatic liver lesions9 and n ⫽ 33 patients with pulmonary metastases10) compared with 2,374 patients in our study2 and

6,512 patients in that by Bogaerts et al.3 In both of the small evaluations cited by Prassopoulos et al, key data were only provided at the lesion level, so it remains unclear if a different response seen in an individual lesion would result in a change in overall patient-level response. In addition, in one of the evaluations, Chojniak et al10 noted that new lesions were a key criterion for determining disease progression; this was also the case in our much larger data set. In the case of new lesions, it does not matter if classification of individual lesions is different from that in the patient evaluation, because the presence of new lesions automatically results in an overall patient status of progression. Therefore, we remain convinced that in the setting of realworld clinical trials, assessment of a limited number of lesions (two or three) will provide accurate trial-level conclusions to guide additional drug development while greatly simplifying the conduct of trials and harmonizing with routine clinical practice.

Shauna L. Hillman and Daniel J. Sargent Mayo Clinic and Mayo Foundation, Rochester, MN

ACKNOWLEDGMENT

Our study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service Grant No. CA-25224. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Prassopoulos P, Mantatzis M: Metastatic disease response to treatment: How many lesions to measure? J Clin Oncol 28:e81, 2010 2. Hillman SL, An M-W, O’Connell MJ, et al: Evaluation of the optimal number of lesions needed for tumor evaluation using the Response Evaluation Criteria in Solid Tumors: A North Central Cancer Treatment Group investigation. J Clin Oncol 27:3205-3210, 2009 3. Bogaerts J, Ford R, Sargent D, et al: Individual patient data analysis to assess modifications to the RECIST criteria. Eur J Cancer 45:248-260, 2009 4. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 5. Sargent DJ, Wieand HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005 6. Mahoney MR, Sargent DJ, O’Connell MJ, et al: Dealing with a deluge of data: An assessment of adverse event data on North Central Treatment Group trials. J Clin Oncol 23:9275-9281, 2005 7. Collette L, Burzykowski T, Carroll KJ, et al: Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol 23:6139-6148, 2005 8. Buyse M, Burzykowski T, Carroll K, et al: Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol 25:5218-5224, 2007 9. Mantatzis M, Kakolyris S, Amarantidis K, et al: Treatment response classification of liver metastatic disease evaluated on imaging: Are RECIST unidimensional measurements accurate? Eur Radiol 19:1809-1816, 2009 10. Chojniak R, Yu LS, Younes RN: Response to chemotherapy in patients with lung metastases: How many nodules should be measured? Cancer Imaging 6:107-112, 2006

DOI: 10.1200/JCO.2009.24.6736; published online ahead of print at www.jco.org on October 19, 2009

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