The inclusion of individuals with end-stage kidney disease (ESKD) or on dialysis in clinical trials for cancer therapy is a vital step toward ensuring that this patient population receives equitable access to innovative treatments. Historically, such individuals have been underrepresented in clinical trials, leading to a gap in understanding the efficacy and safety of cancer therapies specifically tailored to their unique medical circumstances.

Phase I and II clinical trials typically involve individuals with normal or mildly reduced kidney function. The problem persists into phase III studies, where only a subset of patients with moderately decreased glomerular filtration rate (GFR) are included. Consequently, data related to patients with severely decreased estimated GFR ([eGFR] < 30 ml/min/1.73 m2), kidney failure, or those undergoing dialysis are notably scarce or completely absent before drug approval. Due to limited data and lack of experience concerning the safety of drugs use in these populations, technical data sheets often state that the drug is contraindicated in patients with advanced kidney failure [19].

To address this issue, regulatory bodies such as the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have issued specific recommendations that encourage the inclusion of CKD patients in clinical trials, outlining defined methods for estimating GFR and establishing drug dose adjustments [1, 2].

Nonetheless, a 2018 study by Kitchlu et al. highlighted that, of 310 clinical trials analyzed from 2012 to 2017 regarding oncologic drugs for the treatment of the five most common tumors (bladder, breast, colorectal, lung, and prostate), 85% categorically excluded patients with CKD, and 100% excluded patients on dialysis [20]. Similarly, a retrospective study in 2022 by Delaye et al., evaluating the percentage of phase 3 clinical trials on systemic oncology drugs excluding patients with CKD, found that 68% (185 trials) had at least one exclusion criterion based on kidney function [21].

These findings are significant considering the above-mentioned high incidence of tumors in patients with CKD. The exclusion of such patients from trials means that clinicians are unsure how to navigate dosing when the pharmaceutical company lists CKD as a contraindication, or mentions no studies in that population. As a result, these patients are sometimes not considered for oncological treatments.

Importantly, patients with CKD are not only excluded from trials involving drugs with high nephrotoxic potential or a high risk of adverse events due to reduced renal excretion, but also from trials in which the kidney plays a less decisive role in pharmacokinetics and pharmacodynamics [20].

Addressing this gap is essential; by including patients with ESKD or on dialysis, researchers can gather valuable data to tailor therapies that take into consideration the specific needs and challenges associated with severe kidney impairment.

In 2020, Sprangers et al. proposed measures to enhance cancer care for patients with kidney failure. They specifically recommended that national and international regulatory authorities, such as the FDA and the EMA, mandate the inclusion of patients with CKD in clinical trials of drugs, or generate distinct but specific clinical data regarding patients with kidney failure before drug approval. Additionally, they urged carrying out secondary studies on patients with CKD or ESKD following drug approval. Their suggestions included involving nephrologists in the early stages of clinical drug development (and beyond), and organ dysfunction teams to boost the recruitment of CKD patients [22]. They also advocated the establishment of national groups to elevate awareness of this issue [23].

Similar proposals were presented by Delaye et al., who suggested the creation of a method for estimating kidney function that could be applied across all clinical trials. They proposed setting dose modifications for patients with reduced GFR in the initial phases of trials to facilitate the management of CKD patients in later phases, and to prevent the exclusion of ESKD and dialysis patients from clinical trials for drugs that might pose a risk based on pharmacokinetic and pharmacodynamic characteristics [21]. More drug trials inclusive of CKD patients would enable a better understanding of the pharmacokinetics and pharmacodynamics in patients on dialysis.

Currently, clinical data on the use of chemotherapy drugs in dialysis primarily come from case reports, case series, or small retrospective studies. These studies encompass patients treated with a variety of drugs, making it challenging to draw statistically significant and homogeneous conclusions regarding the optimal drug dosage, timing of administration with regard to dialysis sessions, type of dialysis, safety and efficacy profile, and fluid administration [24,25,26,27,28].

The Candy study [29], a retrospective multicenter investigation conducted from 1997 to 2010 on 178 hemodialysis patients, aimed to provide insights into the management of oncological drugs in patients on dialysis who developed tumors after initiating dialysis (with an average time between dialysis initiation and cancer diagnosis of 2.6 years). Among the 178 patients, 50 underwent chemotherapy, resulting in a total of 96 prescriptions involving 36 different drugs. Of these prescriptions, 45% required dose adjustments based on limited literature data or were drugs for which no recommendations were available for dialysis patients. Notably, 75% of the prescribed drugs were administered after the dialysis session. Among the 50 patients treated, 72% received at least one drug needing dose adjustment or lacking recommendations for dialysis patients. Overall, the study revealed that 88% of patients treated with oncology drugs required specific management of the dose or timing of administration for at least one drug [29], although no specific guidelines were available.

However, this study has notable limitations. It lacks guidance on how to adjust the drug dose (only indicating need for adjustment), provides no data on patients treated with reduced doses, and relies on information about the need for dose adjustment or dialyzability derived from individual clinical cases or small case series due to the absence of high-level evidence in this patient setting. Moreover, and perhaps even more importantly, the study lacks data on the response to therapy [29].