Organ Preservation Approaches in Muscle-Invasive Bladder Cancer

Amy N. Solan, MD

Selective bladder preservation has been suggested as a potential alternative to cystectomy in patients with bladder cancer who have a transitional cell carcinoma pathology. The goal is to improve long-term quality of life without compromising oncologic outcomes, according to Amy N. Solan, MD, a clinical instructor in the Department of Radiation Oncology at NYU Langone Heath.

The current standard treatment for muscle-invasive bladder cancer is radical cystectomy with bilateral pelvic lymphadenectomy, with the addition of neoadjuvant cisplatin-based combination chemotherapy.

However, in a presentation during the 2018 OncLive^® State of the Science Summit^TM on Genitourinary Malignancies, Solan discussed bladder preservation following maximal transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy as an approach to organ preservation in bladder cancer.¹

The bladder preservation approach may be a reasonable option for patients who are not candidates for surgery—such as those who are older or are current or former smokers—as well as those who refuse cystectomy. Although there have been a number of trials evaluating the role of chemotherapy, sequencing of treatment, and radiotherapy volumes or dosage—the optimal bladder-sparing approach has not been identified, said Solan.

Solan emphasized that patient selection is key when bladder preservation is being considered in surgical candidates. These are patients with clinically node-negative disease with a preferred stage of T2 or T3. While T4a disease is included in many of the studies, it is often underrepresented, said Solan.

Patients who are not considered for bladder preservation are those with diffuse carcinoma in situ or those with hydronephrosis, as the latter is a well-known poor prognostic indicator; patients with adenocarcinoma and squamous cell carcinoma have not been studied enough.

Previous data on bladder preservation come from single-institution studies in the United States and Europe, as well as phase II trials from the Radiation Therapy Oncology Group (RTOG).

“Comparisons of results to cystectomy outcomes are very difficult, as they are limited by selection bias—typical chemoradiation trials don't like to include higher-risk patients, which makes thing complicated. Commonly, there is discordance between clinical and pathologic staging,” said Solan.

Results of bladder preservation in selected patients appear comparable with modern cystectomy series, with 5-year survival rates of 50% and 60% and about 70% of these patients maintaining an intact bladder.²

A second option of a bladder-sparing approach would be neoadjuvant chemotherapy, Solan added. Patients who undergo systemic surgery often benefit from neoadjuvant chemotherapy, leading to the basis of the RTOG-89 trial in patients undergoing organ preservation. In the RTOG 89-03 trial, patients were randomized to concurrent chemoradiotherapy with cisplatin with or without neoadjuvant CMV (cisplatin, methotrexate, vinblastine). Results showed that there was no difference in survival at a median follow-up of 5 years.³

Solan said that for patients with medical comorbidities or poor renal function, bladder preservation approaches, such as alternative agents for radiosensitization, may be of benefit, including concurrent capecitabine, paclitaxel, paclitaxel/carboplatin, 5-FU/Mitomycin C, and gemcitabine.

Another preservation approach would be mid-course cystoscopy, of which RTOG trials have shown that up to 70% of patients achieve a complete response to induction.⁴ That is associated with improved 5-year disease free survival, Solan noted.

However, mid-course cystoscopy has been a topic of debate, proponents of which argue that having an early cystoscopy will let clinicians readily identify patients who are not responders and refer them to salvage cystectomy. On the other side, Solan added, other trials have shown that having a split course of radiation therapy has shown to decrease local control rates.

Additional preservation approaches include hypofractionation and radiation fields.

Quality of life of bladder preservation is also a focus of this treatment, and was evaluated in an analysis of organ conservation in invasive bladder cancer by transurethral resection, chemotherapy, and radiation.⁵ The analysis showed that the majority of patients with an intact bladder maintained normal bladder functions, and also had low rates of urinary incontinence and bowel symptoms.

Following bladder preservation, 20% to 30% of patients will have residual tumor at restaging TURBT, Solan said. Additionally, 20% to 30% of patients will develop new or recurrent disease in the bladder. Patients with muscle-invasive resistant or recurrent disease will be required to undergo a salvage cystectomy.

"It is important when a patient is going to undergo bladder preservation that they understand that salvage cystectomy may be a part of the equation,” said Solan.

Immunotherapy is now also being explored as an approach in combination with radiation therapy. For example, an ongoing, single-arm phase II clinical trial at NYU Langone’s Perlmutter Cancer Center is evaluating pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated therapy as bladder-sparing treatment for patients with muscle-invasive bladder cancer (NCT02621151).

References

1. Solan A. Radiation Therapy for Organ Preservation in Bladder Cancer. In: Proceedings from the 2018 OncLive State of the Science Summit on Genitourinary Malignancies; January 25, 2018; Brooklyn, New York.
2. Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol. 2006;24(35):5536-5544. doi: 10.1200/JCO.2006.07.6729.
3. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998;16(11):3576-3583. doi: 10.1200/JCO.1999.17.4.1326a.
4. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. 5). 2014;32(34):3801-3809. doi: 10.1200/JCO.2014.57.5548.
5. Zietman AL, Sacco D, Skowronski U, et al. Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J Urol. 2003;170(:1772-17766.