SUO 2024: Management of the Bladder in Metastatic Patients Following Complete Response to Systemic Therapy: Is There a Role for Consolidative Local Therapy?

(UroToday.com) The 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, TX was host to an Advanced Disease and Adjuvant Therapy session. Dr. Fady Ghali discussed whether there is a role for consolidative local therapy in the management of metastatic bladder cancer patients who achieve a complete response following systemic therapy.

Dr. Ghali began by noting that patients with metastatic urothelial carcinoma have poor prognoses, with estimated 5-year survival rates of 5–15%.¹

Furthermore, these patients have worse quality-of-life outcomes, compared to those with localized bladder cancer, and there is sparse data available on the role of palliative local therapy.

What is the rationale for palliative therapy in metastatic urothelial carcinoma of the bladder? These patients are at increased likelihood of:

• Bleeding
• Lower urinary tract symptoms
• Malignant ureteral obstruction
• Pain

What are the outcomes of palliative cystectomy in patients with locally advanced pT4 bladder cancer? In a retrospective study of 76 patients with pT4 disease who underwent radical cystectomy with palliative intent, of whom 52% were classified as ASA≥3, only 30% did not experience any complications within 30 days of surgery. The 30-day rates of severe complications and any-cause mortality were 21% and 9%, respectively. Notably, 86% of those who experienced mortality within 30 days were ASA ≥3.³ In comparison, in the IROC randomized trial of robotic versus open radical cystectomy, 40% did not experience any complications within 30 days, and only 2% experienced mortality within 30 days.⁴

There appears to be ‘light at the end of the tunnel’ for metastatic urothelial carcinoma patients, with the recently published EV-302 trial demonstrating that the combination of enfortumab vedotin + pembrolizumab outperform platinum-based chemotherapy both for progression-free (12.5 vs 6.3 months; HR: 0.45, p<0.001) and overall survivals (31.5 vs 16.1 months; HR: 0.47, p<0.001).⁵ However, the question remains – what do we do with those patients that remain free of disease progression following systemic therapy?

What do the guidelines recommend in this setting? For M1a patients with evidence of a complete or partial response following systemic therapy, the NCCN guidelines recommend considering consolidative local therapy in select cases. Conversely, patients with stable disease (and those with disease progression) should be treated with systemic treatment regimens for metastatic disease.

Next, Dr. Ghali addressed the rationale for consolidative local therapy, starting with the available clinical evidence. The earliest report of consolidative local therapy for metastatic urothelial carcinoma of the bladder was published in 1982. Six patients with pelvic disease and lung metastases only underwent extirpative pelvic surgery plus a lung wedge resection. 4/6 patients remained alive with no evidence of disease at ≥5 years follow-up.

Significantly, the majority of patients (74%) who experience disease relapse following a prior response to cisplatin-based combination chemotherapy experience this relapse at a similar site.⁷ This provides a strong rationale for consolidative local therapy to minimize such recurrences.

This approach was adopted at many centers, with Miller et al. publishing a case series of 64 patients with advanced urothelial carcinoma of the bladder who underwent chemotherapy with cisplatin, methotrexate, and vinblastine followed by aggressive surgical resection of residual disease, between 1982 and 1990. Of 55 patients evaluable for response, 20% had a pathological complete response, 25% achieved a complete response following resection of residual disease, and 9% whose disease was not surgically restaged had a clinical complete response. The overall complete response rate was 55%. With a median follow-up exceeding 50 months, 14 patients (22% of all patients entered into the study) remained free of disease.⁸

How do the outcomes of patients with a complete response to chemotherapy plus surgery compare to those of patients who achieve a complete response with chemotherapy alone? In a retrospective analysis of 203 patients with unresectable primary tumors or metastatic urothelial carcinoma of the bladder who received MVAC chemotherapy, 30 had evidence of residual viable transitional cell carcinoma that was completely resected, resulting in a ‘complete response’ to chemotherapy plus surgery. At 5 years, 33% of patients remained alive, which is similar to the proportion of patients who attained a complete response to chemotherapy alone (41%).⁹

Further rationale for consolidative local therapy is the fact that the historic median overall survival for patients who relapse following an initial complete response to chemotherapy and subsequently undergo a metastasectomy is only about 31 months.¹⁰ Given these poor outcomes, albeit historical in nature, Dr. Ghali argued that waiting for a relapse in these patients is too late and early consolidative local therapy may be of value in this setting.

An important variable to consider when evaluating patients for consolidative local therapy is the site metastatic disease. In a published report from the National Cancer Database (NCDB), patients with lymph node-only disease derived a benefit from a cytoreductive radical cystectomy, compared to conservative local therapy, but those with visceral metastases did not.¹¹

Additional rationale for consolidative local therapy in this setting is the presence of known intra-tumoral and inter-tumoral heterogeneity, with a high degree of heterogeneity existing between primary and metastatic sites.

Furthermore, there appears to be a divergent biologic response to systemic chemotherapy in patients with muscle-invasive bladder cancer.

Additionally, the Sanctuary site hypothesis theorizes that certain areas of the body, called sanctuary sites, are protected by filters that prevent larger drug molecules and infections from entering, which provides additional rationale for consolidative local therapy to remove the primary site of disease.

Dr. Ghali pledged that the time is now for a clinical trial that focuses on responders to systemic therapy, includes motivated, highly select patients, within the context of a multi-disciplinary team, and that assesses translational correlatives of treatment response. His concluding remarks were as follows:

• Metastatic urothelial carcinoma has a poor prognosis.
• Palliative Role
  • Cystectomy is high risk
  • Health status may be helpful for selection
  • Different than curative intent – more data needed
• Consolidative therapy in metastatic urothelial carcinoma has strong rationale
• There has been progress with:
  • New systemic therapies
  • New stratification tools
  • New consolidative therapies
• It is time to re-explore consolidative therapy in metastatic urothelial carcinoma

Presented by: Fady Ghali, MD, Assistant Professor, Department of Urology, Yale New Haven Hospital, New Haven, CT

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 Society of Urologic Oncology (SUO) Annual Meeting, Dallas, TX, Tues, Dec 3 – Fri, Dec 6, 2024. 

References:

1. Bilen MA, Robinson SB, Schroeder A, et al. Clinical and Economic Outcomes in Patients With Metastatic Urothelial Carcinoma Receiving First-Line Systemic Treatment (the IMPACT UC I Study). Oncologist. 2023; 28(9):790-8.
2. Smith AB, McCabe S, Deal AM, et al. Quality of Life and Health State Utilities in Bladder Cancer. Bladder Cancer. 2022; 8(1):55-70.
3. Maisch P, Lunger L, Duwel C, et al. Outcomes of palliative cystectomy in patients with locally advanced pT4 bladder cancer. Urol Oncol. 2021; 39(6): 368.e11-368.e17.
4. Catto JWF, Khetrapal P, Ricciardi F, et al. Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial. JAMA. 2022; 327(21):2092-103.
5. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med.2024; 390:875-88.
6. Cowles RS, Johnson DE, McMurtrey MJ. Long-term results following thoracotomy for metastatic bladder cancer. Urology. 1982; 20(4):390-2.
7. Dimopoulos MA, Finn L, Logothetis CJ. Pattern of failure and survival of patients with metastatic urothelial tumors relapsing after cis-platinum-based chemotherapy. J Urol. 1994; 151(3):598-600.
8. Miller RS, Freiha FS, Reese JH, Ozen H, Torti FM. Cisplatin, methotrexate and vinblastine plus surgical restaging for patients with advanced transitional cell carcinoma of the urothelium. J Urol. 1993; 150(1):65-9.
9. Dodd PM, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol. 1999; 17(8):2546-52.
10. Siefker-Radtke AO, Walsh GL, Pisters LL, et al. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol. 2004; 171(1):145-8.
11. Xu VE, Antar RM, Bertozzi L, et al. Efficacy of cytoreductive radical cystectomy in metastatic urothelial bladder cancer based on site and number of metastases. Urol Oncol. 2024; 42(5):162.e11-e.23.