Bladder Cancer: A Condition Worthy of Clinical Investigation

Bladder cancer is a complex neoplasm with multiple histologic subtypes and a wide spectrum of clinical states, ranging from relatively nonlethal Ta cancers to virulent M1 disease. Given that bladder cancer, primarily urothelial, is the fourth most common cancer in US men in 2011,[1] and given the historically modest rate of accrual to bladder cancer clinical trials, it might be the most clinical-trial-underrepresented major cancer. Kamat and Mathew have reviewed the current state of bladder cancer from the earliest stages to advanced lethal disease, with an educated eye toward the translational keys to future progress in treatment. At the same time, they remind us that prevention (ie, tobacco cessation) is a low-hanging fruit that needs attention.

While Kamat and Mathew have focused on the primary role of surgery in the management of non-metastatic invasive urothelial bladder cancer, it seems reasonable to expand a bit further on the nonsurgical options for this condition, especially in the context of prospective clinical trials that are investigating aspects of organ-preserving approaches. For example, in the case of superficially invasive T1 cancer, it is clear that tumors are occasionally undertreated-leading to metastatic disease-or overtreated, such as when cystectomy is used for T1 cases not destined to become muscle invasive. Thus, based on data from Erlangen,[2] the Radiation Therapy Oncology Group (RTOG) has embarked on a phase II protocol for patients with stage T1, grade 2-3 urothelial bladder cancer (NCT00981656, PI Dahl). The goal is to offer patients who might otherwise be candidates for immediate radical cystectomy an opportunity for bladder preservation using standard doses of radiotherapy along with the active radiosensitizer, cisplatin. Salvage cystectomy is expected in a subset of patients, but with careful surveillance it is hoped that this approach will result in no loss of curability in this patient population with relatively early invasive disease.

For more advanced, muscle-invasive T2-T4 tumors, radical cystectomy is frequently the mainstay of local disease management, along with appropriate use of neoadjuvant or perhaps adjuvant chemotherapy. The option of bladder preservation in cystectomy candidates should not be overlooked, however,. Kamat and Mathew note that the current European Association of Urology (EAU) guidelines indicate that combined-modality, selective bladder preservation (with transurethral resection of bladder tumor [TURBT], radiotherapy, and chemotherapy) should be employed only in patients who are medically unfit[3]; however, this approach is contrary to US-based National Comprehensive Cancer Network (NCCN) guidelines,[4] which highlight bladder preservation as one of the available options even for cystectomy-eligible patients. Additionally, the EAU apparently based their "medically unfit" 2011 recommendation on a 2001-2 Cochrane report[5] that used limited clinical trial information from a still earlier era. Only three relevant trials were found that compared bladder preservation (using radiotherapy without chemotherapy) to cystectomy (with preoperative radiation therapy), and these three studies were analyzed by the Cochrane meta-analysis team. The trials accrued patients from 1964 to 1986 (mostly before 1975), so it is unclear whether the outcomes are relevant in settings in which modern techniques are available, and the authors of the review conclude that new studies are required.[6] Modern overall survival results with chemoradiotherapy following TURBT in patients who for the most part have clinical T2 disease are approximately 70% at 3 years.[7] These results are comparable to findings of modern surgical series that consist primarily of pathologically staged patients.

Radiation oncologists are frequently asked to treat those patients who are truly medically unfit for radical cystectomy, and these patients often have comorbidities that make them ineligible for treatment with cisplatin, which is considered the most effective chemotherapy agent in this setting. Based on translational work using the RTOG tissue repository, Chakravarti determined that HER2 expression was significantly associated with a reduced rate of complete response following bladder-preserving chemotherapy, compared with patients who did not have HER2 expression.[8] Thus, HER2 was selected for targeted intervention in an RTOG clinical trial (NCT00238420, PI Michaelson). Patients who are medically unfit for radical cystectomy have tissue tested for HER2 expression, and those with a positive result (approximately 50% are expected to be HER2-positive) are treated with radiotherapy and weekly concurrent paclitaxel and trastuzumab (Herceptin), while those without HER2 expression are treated with radiotherapy and paclitaxel alone. This trial is accruing well, will reach its accrual goal, and will provide information about a potentially useful target that will enhance the effect of radiation on urothelial tumors. The trial highlights the importance of prospective tissue collection, of interaction between clinical scientists and basic science, and of the availability of an agile mechanism for testing the hypothesis generated by the preclinical assessments.

Bladder cancer is a complex condition that includes many disease states. Surgery is a mainstay of management, but as highlighted in these comments, there are nonsurgical options-that either fall within NCCN guidelines or are under active clinical investigation-for the medically unfit, for those who elect not to undergo radical cystectomy, and perhaps for those with early invasive, T1 urothelial carcinoma.

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

References:

REFERENCES

1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212-36.

2. 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.

3. Stenzl A, Cowan NC, De Santis M, et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol. 2011;59:1009-18.

4. NCCN clinical practice guidelines in oncology: bladder cancer, version 2.2011. Available from: http://www.nccn.org. Accessed August 19, 2011.

5. Shelley MD, Barber J, Wilt T, Mason MD. Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev. 2002;CD002079.

6. Shelley MD, Barber J, Wilt T, Mason MD. A meta-analysis of randomised trials suggests a survival benefit for combined radiotherapy and radical cystectomy compared with radical radiotherapy for invasive bladder cancer: are these data relevant to modern practice? Clin Oncol (R Coll Radiol). 2004;16;166-71.

7. Kaufman DS, Winter KA, Shipley WU, et al. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009;73:833-7.

8. Chakravarti A, Winter K, Wu CL, et al. Expression of the epidermal growth factor receptor and HER-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2005;62:309-17.