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Re: Herr et al.: BCG-refractory vs. BCG-relapsing non–muscle-invasive bladder cancer: A prospective cohort outcomes study (Urol Oncol 2015; 33: 108.el-108.e4)
Urologic Oncology: Seminars and Original Investigations 33 (2015) 335–336
Letter to the Editor Re: Herr et al.: BCG-refractory vs. BCG-relapsing non–muscle-invasive bladder cancer: A prospective cohort outcomes study (Urol Oncol 2015; 33: 108.el-108.e4) Dear Sir, The article cited above is of great relevance because it addresses the very topical issue of different outcomes between diverse patients in whom bacille CalmetteGuérin (BCG) failed, i.e., BCG-refractory and BCGrelapsing patients. As the authors suitably point out, segregating BCG failures into different prognostic groups is not a new concept and one gaining increasing support from other groups. In fact, a similar conclusion/observation was noted in our study in BCG failures treated with Mycobacterium phlei cell wall-nucleic acid complex (MCNA) MCNA [1]. In our study, BCG failure type was a statistically significant factor, as evidenced by the considerably higher disease-free survival rate in BCGrelapsing patients as compared with BCG-refractory patients. However, notable differences in recurrence-free and progression-free survival rates can be evidenced between the BCG-refractory group enrolled at this single site (n ¼ 17) treated with MCNA as compared with the study as a whole (n ¼ 129), also treated with MCNA, and within the same protocol. The comparative differences are illustrated in the table: Recurrence-free survival
Progression-free survival
Morales Time point Herr Morales Time point Herr et al.b, et al., et al.a, et al., n ¼ 17 n ¼ 129 n ¼ 17 n ¼ 129 6 Months 12 Months 18 Months 24 Months a
23% 18% 6% 6%
38% 25% 21% 19%
12 Months 60% 24 Months 40% 36 Months 35%
87% 80% 78%
Values are approximations based on Fig. 1. Values are approximations based on Fig. 2.
b
There is also a discrepancy in the definition of “progression” that was considered as “new or persistent lamina propria (pT1) invasion, muscle invasion, or metastases” in the analysis by Herr et al. while anything ZpT2 was contemplated in the analysis by Morales et al. http://dx.doi.org/10.1016/j.urolonc.2015.05.010 1078-1439/r 2015 Elsevier Inc. All rights reserved.
The most obvious explanation would be the large difference in sample size in both the studies (n ¼ 17 vs. 129). In survival analysis, small sample sizes tend to lead to wide intervals, raising the question of the reliability and accuracy of the estimates. Another important consideration in this significant discrepancy would be single-site data vs. multicenter data. The shortcoming of single-center data is in its limited external validity, i.e., results from a single clinical environment are not necessarily generalizable to a broader population [2], something that is clearly seen when comparing both the cohorts (n of 17 vs. 129). Indeed, multicenter studies are usually recommended, not only for accrual reasons (recruitment of sufficient subjects within a defined time) but also as it provides a better basis for generalization of its findings and evaluation of the treatment effect under a broader range of clinical settings [2]. In this regard, NMIBC is agreed to be a heterogeneous disease with many different genotypes and phenotypes and an array of diverse host factors that may be obscured in a limited cohort of patients [3]. In addition, it is commonly accepted that highly specialized oncology institutions, such as Memorial Sloan Kettering Cancer Center, tend to treat the most recalcitrant malignancies. On a separate issue that requires clarification concerns the eligibility of subjects in the study by Morales et al. BCG-relapsing patients were considered eligible, as detailed in the Appendix under “Key inclusion criteria,” using the currently commonly accepted definition. BCG-relapsing was identified as “evidence of bladder cancer within 2 years from the start of the last full BCG induction course after achieving disease-free status 6 months after induction with the relapsing tumor evident within 6 months after receiving a dose of BCG.” On the surface, it appears that significant discrepancies exist between the overall group and the selected subgroup of the report by Herr et al. A comparative analysis may not be appropriate because of the disparities presented earlier. However, the common ground is that MCNA exhibits antitumor activity in the highly intractable NMIBC, namely those who are relapsing or refractory to BCG. Respectfully submitted. Alvaro Morales, M.D. Queen's University, Kingston, Canada Ashish Kamat, M.D. MD Anderson Cancer Center, Houston, Texas
336
A. Morales et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 335–336
Gary Steinberg, M.D. University of Chicago Medical Center, Chicago, Illinois Robert Given, M.D. Urology of Virginia, Virginia Beach, Virginia John Amrhein, M.Sc. McDougall Scientific, Toronto, Canada Zvi Cohen, Ph.D. Telesta Therapeutics, Pointe-Claire, QC, Canada
Harry Herr, M.D. Memorial Sloan Kettering Cancer Center, New York, NY References [1] Morales A, Herr H, Steinberg G, et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guerin. J Urol 2015;193:1135–43. [2] ICH E9. Statistical Principles for Clinical Trials; February 1998. [3] Eifler JB, Scarpato KR, Clark PE. Management of noninvasive bladder cancers. Curr Opin Oncol 2015;27:185–90.
Letter to the Editor Re: Herr et al.: BCG-refractory vs. BCG-relapsing non–muscle-invasive bladder cancer: A prospective cohort outcomes study (Urol Oncol 2015; 33: 108.el-108.e4) Dear Sir, The article cited above is of great relevance because it addresses the very topical issue of different outcomes between diverse patients in whom bacille CalmetteGuérin (BCG) failed, i.e., BCG-refractory and BCGrelapsing patients. As the authors suitably point out, segregating BCG failures into different prognostic groups is not a new concept and one gaining increasing support from other groups. In fact, a similar conclusion/observation was noted in our study in BCG failures treated with Mycobacterium phlei cell wall-nucleic acid complex (MCNA) MCNA [1]. In our study, BCG failure type was a statistically significant factor, as evidenced by the considerably higher disease-free survival rate in BCGrelapsing patients as compared with BCG-refractory patients. However, notable differences in recurrence-free and progression-free survival rates can be evidenced between the BCG-refractory group enrolled at this single site (n ¼ 17) treated with MCNA as compared with the study as a whole (n ¼ 129), also treated with MCNA, and within the same protocol. The comparative differences are illustrated in the table: Recurrence-free survival
Progression-free survival
Morales Time point Herr Morales Time point Herr et al.b, et al., et al.a, et al., n ¼ 17 n ¼ 129 n ¼ 17 n ¼ 129 6 Months 12 Months 18 Months 24 Months a
23% 18% 6% 6%
38% 25% 21% 19%
12 Months 60% 24 Months 40% 36 Months 35%
87% 80% 78%
Values are approximations based on Fig. 1. Values are approximations based on Fig. 2.
b
There is also a discrepancy in the definition of “progression” that was considered as “new or persistent lamina propria (pT1) invasion, muscle invasion, or metastases” in the analysis by Herr et al. while anything ZpT2 was contemplated in the analysis by Morales et al. http://dx.doi.org/10.1016/j.urolonc.2015.05.010 1078-1439/r 2015 Elsevier Inc. All rights reserved.
The most obvious explanation would be the large difference in sample size in both the studies (n ¼ 17 vs. 129). In survival analysis, small sample sizes tend to lead to wide intervals, raising the question of the reliability and accuracy of the estimates. Another important consideration in this significant discrepancy would be single-site data vs. multicenter data. The shortcoming of single-center data is in its limited external validity, i.e., results from a single clinical environment are not necessarily generalizable to a broader population [2], something that is clearly seen when comparing both the cohorts (n of 17 vs. 129). Indeed, multicenter studies are usually recommended, not only for accrual reasons (recruitment of sufficient subjects within a defined time) but also as it provides a better basis for generalization of its findings and evaluation of the treatment effect under a broader range of clinical settings [2]. In this regard, NMIBC is agreed to be a heterogeneous disease with many different genotypes and phenotypes and an array of diverse host factors that may be obscured in a limited cohort of patients [3]. In addition, it is commonly accepted that highly specialized oncology institutions, such as Memorial Sloan Kettering Cancer Center, tend to treat the most recalcitrant malignancies. On a separate issue that requires clarification concerns the eligibility of subjects in the study by Morales et al. BCG-relapsing patients were considered eligible, as detailed in the Appendix under “Key inclusion criteria,” using the currently commonly accepted definition. BCG-relapsing was identified as “evidence of bladder cancer within 2 years from the start of the last full BCG induction course after achieving disease-free status 6 months after induction with the relapsing tumor evident within 6 months after receiving a dose of BCG.” On the surface, it appears that significant discrepancies exist between the overall group and the selected subgroup of the report by Herr et al. A comparative analysis may not be appropriate because of the disparities presented earlier. However, the common ground is that MCNA exhibits antitumor activity in the highly intractable NMIBC, namely those who are relapsing or refractory to BCG. Respectfully submitted. Alvaro Morales, M.D. Queen's University, Kingston, Canada Ashish Kamat, M.D. MD Anderson Cancer Center, Houston, Texas
336
A. Morales et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 335–336
Gary Steinberg, M.D. University of Chicago Medical Center, Chicago, Illinois Robert Given, M.D. Urology of Virginia, Virginia Beach, Virginia John Amrhein, M.Sc. McDougall Scientific, Toronto, Canada Zvi Cohen, Ph.D. Telesta Therapeutics, Pointe-Claire, QC, Canada
Harry Herr, M.D. Memorial Sloan Kettering Cancer Center, New York, NY References [1] Morales A, Herr H, Steinberg G, et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guerin. J Urol 2015;193:1135–43. [2] ICH E9. Statistical Principles for Clinical Trials; February 1998. [3] Eifler JB, Scarpato KR, Clark PE. Management of noninvasive bladder cancers. Curr Opin Oncol 2015;27:185–90.