ASCO 2017: The clinical role of purified protein derivative skin test reaction in patients with non-muscle invasive bladder cancer treated with bacillus-Calmette Guerin

Chicago, IL ( Non-muscle invasive bladder cancer (NMIBC) still represents 70% of the patients who present with bladder cancer (BC). High-grade NMIBC represents a particularly troublesome cohort for whom clinical progression to MIBC remains a high risk, but for whom there are not many treatment options. BCG (Bacillus Calmette-Guerin) instillations (induction and maintenance) remain the standard of care for this patient population. While alternative treatment regimens, both systemic and intravesical have been explored, none have proven superior to BCG alone without significantly increasing the morbidity of treatment.

However, predictors of BCG response have been difficult to come by. If effective predictors were available, potential non-responders could be recommended for clinical trial and/or early cystectomy.

In this study, the group from Tokyo specifically looked at the utility of the purified protein derivative (PPD) skin test as a predictor of BCG response. They tested the PPD response of 288 NMIBC patients prior to BCG therapy. The PPD skin test reaction was categorized into three groups: positive (presence of induration), slightly positive (absent induration, but erythema 10 mm or more), and negative (no induration and erythema < 10 mm).

Sixty-six (22.9%), 149 (51.7%), and 73 (25.3%) patients had positive, slightly positive, and negative PPD skin test results, respectively. Positive PPD patients were more likely to be high-grade. There was also some distribution differences in BCG strain used (Tokyo vs. Connaught) and tumor multiplicity.

The 5-year recurrence-free survival rates (RFS) were 89.41%, 65.5%, 56.4% for the positive, slightly positive and negative, respectively; positive PPD was an independent predictor of recurrence on multivariable analysis as well (HR 0.213, p<0.001), but was not a predictor of stage progression. In terms of adverse events, patients with a positive PPD were more likely to have side effects (33%), than patients with slightly positive (26.8%) and negative PPD skin tests (13.7%). Specifically, they were at higher risk of fevers, but not hematuria and LUTS.

It would appear that a positive PPD predicts better response to BCG therapy (lower tumor recurrence rate), but also indicates more side effects due to non-specific immune response. This is consistent with the results of smaller study by Bilen et al.,1 in which they assessed 61 patients with NMIBC. They also found that PPD positive patients (induration > 10 mm) had the highest rate of side effects, and that there was trend towards improved RFS in this population (p=.054).

Zlotta et al.2 used a whole blood assay to assess T cell response against purified protein derivative, BCG extract and whole BCG in 79 patients with superficial bladder tumors before BCG treatment. They found an increased lymphoproliferation against mycobacterial antigens compared to control subjects. They attributed this to a nonspecific activation of the immune system, but suggested that it may also be due to bladder cancer antigens that are cross-reactive with mycobacterial antigens. This may explain PPD positivity prior to BCG exposure.

These results are interesting, and further studies are warranted. However, BCG strain should be normalized to remove that as a potential confounding variable.

Presented By: Eiji Kikuchi

Co-Authors: Naoya Niwa, Nozomi Hayakawa, Ryuichi Mizuno, Mototsugu Oya

Institution(s): Department of Urology, Keio University School of Medicine, Tokyo, Japan

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

1. Bilen CY, Inci K, Erkan I, Ozen H. The predictive value of purified protein derivative results on complications and prognosis in patients with bladder cancer treated with bacillus Calmette-Guerin. J Urol. 2003 May;169(5):1702-5.
2. Zlotta AR, Drowart A, Van Vooren JP, Shekarsarai H, De Cock M, Pirson M, Palfliet K, Jurion F, Simon J, Schulman CC, Huygen K. Superficial bladder tumors and increased reactivity against mycobacterial antigens before bacillus Calmette-Guerin therapy. J Urol. 1998 Jun;159(6):1885-91.