T1 High-Grade Bladder Cancer Recurring After BCGTherapy: A Curative Alternative to Radical Cystectomy Exists

Patients with T1 bladder tumors who experience a recurrence following transurethral resection (TUR) and adjuvant bacillus Calmette-Gurin (BCG) intravesical therapy represent a subset of patients with potentially aggressive disease. While alternative intravesical regimens exist for such patients, they are plagued by high failure rates and a lack of strong data to support their use.[1] These patients often require radical therapy that, in the view of many urologists, should consist only of radical cystectomy. While radical cystectomy is a highly effective treatment for this subgroup, many elderly or otherwise infirm patients are not considered candidates for this procedure. Furthermore, many patients refuse radical cystectomy, given its associated morbidity and effects on health-related quality of life. Might there exist an alternative but still potentially curative therapy to help fulfill the unmet need of these patients?

Before use of BCG therapy became widespread, radical radiotherapy was commonly used to treat T1 bladder cancer. This eventually led to a randomized phase III comparison of radiotherapy alone vs conservative measures (observation after TUR or intravesical BCG/mitomycin C) for patients with grade 3 T1 tumors. While both approaches were well tolerated, no difference was seen between the trial arms in terms of overall or progression-free survival.[2] Many viewed the results of this trial as the final word on use of radiotherapy in these patients. However, a number of limitations, including not requiring maximal TUR for all patients (leading to abnormally high local failure rates of 69% for radiotherapy and 71% for conservative therapy), call into question the applicability of these results to modern treatment. These limitations are even more apparent in light of level 1 evidence suggesting that outcomes are better when radiotherapy is combined with concurrent chemotherapy.

Indeed, the University of Erlangen-Nuremberg in Germany has long used maximal TUR and chemoradiotherapy as initial treatment in patients with high-risk T1 disease. In the most recent publication by investigators from that institution, this approach resulted in a progression rate of just 19% at 5 years.[3] Additionally, their reported 10-year disease-specific survival and overall survival rates of 73% and 51%, respectively, with TUR plus chemoradiotherapy are comparable to those achieved with primary cystectomy.

The astute observer will note, and rightfully so, that these data pertain to an alternative primary therapy for T1 disease rather than to salvage therapy for the specific subpopulation who have a recurrence after BCG therapy. While there are currently no published reports investigating the role of chemoradiotherapy in a large cohort of patients with recurrent T1 disease, one series does address the use of chemoradiotherapy in patients who have failed to respond to BCG and progressed to clinical stage T2 (cT2).[4] Given that nearly half of patients undergoing radical cystectomy for T1 disease are found to have muscle invasion or positive lymph nodes, this report is highly relevant to the ongoing debate.[5] Of these cT2 patients treated with maximal TUR and chemoradiotherapy, 59% were free of any bladder recurrence at a median follow-up of 7 years, and disease-specific survival was 70%.

Decades of experience now exist to support the use of chemoradiotherapy in the treatment of muscle-invasive bladder cancer, including toxicity data showing very low rates of late complications.[6] Taken together with the aforementioned studies, chemoradiotherapy for T1 tumors that recur following BCG therapy is promising and provides an important curative alternative for those unable or unwilling to undergo radical cystectomy. The Radiation Therapy Oncology Group (RTOG) has undertaken a phase II study of this approach (the RTOG 0926 trial, open at 45 centers) that should provide the robust data needed to allow for more widespread adoption of this well-tolerated and potentially curative therapy.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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REFERENCES

1. Yates DR, Brausi MA, Catto JW, et al. Treatment options available for bacillus Calmette-Guérin failure in non-muscle-invasive bladder cancer. Eur Urol. 2012;62:1088-96.

2. Harland SJ, Kynaston H, Grigor K, et al. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol. 2007;178:807-13.

3. Weiss C, Wolze C, Engehausen DG, et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J Clin Oncol. 2006;24:2318-24.

4. Wo JY, Shipley WU, Dahl DM, et al. The results of concurrent chemo-radiotherapy for recurrence after treatment with bacillus Calmette-Guérin for non-muscle-invasive bladder cancer: is immediate cystectomy always necessary? BJU Int. 2009;104:179-83.

5. Gray PJ, Fedewa SA, Shipley WU, et al. Clinical-pathologic stage discrepancy in patients with bladder cancer treated with radical cystectomy: associations with clinical variables and survival. J Clin Oncol. 2013(suppl 6);31:abstr 248.

6. Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009;27:4055-61.