Cisplatin-based neoadjuvant chemotherapy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It yields a 30% to 40% pathologic complete response rate and correlates with improved overall survival. However, many patients are deemed ineligible for cisplatin due to their less-than-optimal kidney function. Renal & Urology News interviewed Srikala S. Sridhar, MD, MSc, of the Princess Margaret Cancer Centre, University of Toronto in Toronto, Ontario, Canada, about her team’s new algorithm to reduce cisplatin underutilization in MIBC, which was recently published in Nature Reviews Urology.
- Your team has proposed a new algorithm for determining cisplatin eligibility among patients with MIBC. Why?
The main reason we proposed a new algorithm for this patient population is because the current consensus criteria were developed for patients with metastatic disease, and not for patients with potentially curable MIBC where cisplatin-based chemotherapy plays a key role in the curative approach. Instead of relying on an absolute renal function threshold of 60 mL/min, which excludes a significant proportion of patients with MIBC from receiving cisplatin, the new algorithm is less stringent and would allow more patients with MIBC to receive and potentially benefit from perioperative cisplatin-based chemotherapy.
2. Please describe the new algorithm. How can it be incorporated into decision-making?
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Our new algorithm takes a patient-centered and multidisciplinary approach to assessing cisplatin eligibility.
The first step in the algorithm is to determine if a patient is fit to receive cisplatin based on 4 key aspects of the Galsky criteria, which include performance status, peripheral neuropathy, hearing loss, and heart failure. The next step is to determine the patient’s baseline renal function, using a 24-hour urine collection if feasible or the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) for estimated glomerular filtration rate (eGFR), until a better formula is developed.
Patients with an eGFR of more than 60 mL/min/1.73 m2 are cisplatin eligible.
Novelly, patients with an eGFR of 40 to 60 mL/min/1.73 m2 are potentially cisplatin-eligible but require additional strategies to minimize their risk of nephrotoxicity.
Patients with an eGFR of less than 40 mL/min/1.73 m2 should not be offered cisplatin-based chemotherapy owing to the limited evidence of its safety in this setting.
3. What would you advise a patient with an eGFR of greater than 50 mL/min/1.73 m2 to do?
For a patient with an eGFR of greater than 50 mL/min/1.73 m2, who is otherwise fit for cisplatin-based chemotherapy according to the Galsky criteria, we would recommend a cisplatin-based combination chemotherapy regimen. We would also strongly encourage the use of mitigation strategies as outlined in the algorithm to minimize the risk of nephrotoxicity.
4. And a patient with an eGFR of 40 to 50 mL/min/1.73 m2?
We would discuss the risks and benefits of cisplatin-based chemotherapy and whether it is best administered in the neoadjuvant or adjuvant setting. For chemotherapy, we would offer a split-dose cisplatin-based regimen, consider extra hydration, and refer to nephrology. It’s important to monitor renal function closely during chemotherapy and offer dose adjustments if needed.
5. What mitigation strategies do you suggest to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function?
Our team uses the following nephrotoxicity mitigation strategies:
• Decompression if acute obstructive uropathy is present
• Nephrology consultation before cisplatin administration
• Aggressive hydration before, during, and after treatment
• Minimization of concomitant nephrotoxic medications, such as non-steroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. We also suggest avoiding contrast use.
• Dose reduction of conventional cisplatin regimens by 25% to 50%
• Cisplatin dose fractionation using the split-dose gemcitabine and cisplatin regimen (cisplatin 35 mg/m² on day 1 and day 8)
6. What has been your institution’s experience using the new algorithm for determining cisplatin eligibility?
The staff at the Princess Margaret Cancer Centre frequently use the new algorithm. It allows us to treat more patients with cisplatin-based chemotherapy in the neoadjuvant setting. We hope this translates into more pathologic responses and improved overall outcomes.
We’re fortunate to have dedicated onco-nephrology clinics to advise us when a patient’s cisplatin eligibility is unclear, renal function needs to be optimized, or renal function deteriorates during chemotherapy.
For institutions without onco-nephrology clinics, we recommend creating a multidisciplinary team to address both cancer-related and kidney-related issues to optimize outcomes. Nephrologists knowledgeable in the complex aspects of cancer treatments are a valuable part of that team. Treating patients with MIBC and chronic kidney disease is particularly challenging because many of our current treatment strategies, including cisplatin-based chemotherapy, are potentially nephrotoxic. In addition, some of the novel therapies currently under investigation, such as immune checkpoint inhibitors also have the potential to be nephrotoxic.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Reference
Jiang DM, Gupta S, Kitchlu A, Meraz-Munoz A, North SA, Alimohamed NS, Blais N, and Sridhar SS. Defining cisplatin eligibility in patients with muscle-invasive bladder cancer. Nat Rev Urol. 2021;18:104-114. doi:10.1038/s41585-020-00404-6
