Durvalumab plus carboplatin-etoposide treatment in a patient with small-cell lung cancer on hemodialysis: a case report and literature review

Abstract

Little is known about the efficacy and safety of durvalumab plus carboplatin-etoposide treatment in patients with extensive-disease (ED) small-cell lung cancer (SCLC) on hemodialysis. Here, we present a case of a 67-year-old man with pleuroperitoneal communication on continuous ambulatory peritoneal dialysis who was diagnosed with ED-SCLC based on a cytological analysis of the peritoneal fluid. He was switched from peritoneal dialysis to hemodialysis and received durvalumab (1500 mg/body on day 1) plus carboplatin (area under the concentration–time curve = 5, 125 mg on day 1) and etoposide (50 mg/m² on days 1 and 3) as first-line therapy. During the first cycle, grade 2 anemia, grade 3 neutropenia, and grade 3 upper gastrointestinal bleeding occurred; therefore, durvalumab and reduced doses of carboplatin and etoposide were administered. No other severe adverse events occurred, and a partial response was observed after four cycles. Our findings indicate that durvalumab plus carboplatin-etoposide treatment is safe and effective even in patients on hemodialysis.

Introduction

Lung cancer is a leading cause of cancer-related deaths worldwide [1]. Small-cell lung cancer (SCLC) accounts for approximately 13–17% of all lung cancers and is recognized as a high-grade tumor with a rapid growth rate and early lymph node and distant metastases. It is characterized by high sensitivity to radiation therapy and chemotherapy [2, 3]. For many years, there have been no therapeutic advances in the treatment of extensive-disease (ED)-SCLC. Platinum-based chemotherapy has been the only treatment of choice; however, it affords a 5-year survival rate of only 2% for patients with ED-SCLC [3, 4].

Inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have been developed as novel treatment options. The addition of durvalumab to conventional chemotherapy has been shown to be associated with prolonged overall survival and is considered standard therapy for ED-SCLC [5]. However, data concerning the efficacy and safety of these inhibitors or their combination therapies in patients with cancer undergoing hemodialysis are limited because these patients are commonly excluded from clinical studies [6].

The number of patients undergoing dialysis for chronic kidney disease or end-stage renal disease (ESRD) is increasing annually worldwide, including in Japan [7]. Patients with cancer, including SCLC, have poor prognoses and limited treatment options [8, 9]. Adjustments of dosage and the timing of cytotoxic chemotherapy have been proposed for patients on hemodialysis [10]. However, although durvalumab plus carboplatin-etoposide treatment is one of the standard chemotherapies for ED-SCLC, there have been few reports describing the safety and efficacy of this combination in patients with ED-SCLC on hemodialysis. In this report, we describe the case of a patient with ED-SCLC on hemodialysis who was treated with durvalumab plus carboplatin-etoposide.

Case report

The patient was a 67-year-old man who had been on peritoneal dialysis for ESRD after nephrectomy for left renal cancer in 2012. The Eastern Cooperative Oncology Group performance status score was 1. The patient had a smoking history of 46 packs/year. He was referred to the Department of Thoracic Surgery in our hospital for treatment of pleuroperitoneal communication. Preoperative chest radiography and computed tomography (CT) revealed a rapidly growing tumor in the right lower lobe of the lung with pleural effusion (Fig. 1A). After a cytological analysis of the peritoneal fluid, the patient was diagnosed with stage IVA ED-SCLC (cT2bN2M1b).

Fig. 1.

Computed tomography image showing the tumor response. Before the initiation of the combination therapy (a) and after four cycles of treatment (b). Arrows indicate the primary tumor (left), mediastinal (middle), and right hilar (right) lymph node metastases.

The patient was switched from peritoneal dialysis to hemodialysis for renal replacement therapy because of the pleuroperitoneal communication. Hemodialysis was performed three times weekly for 4 h. The membrane of the dialyzer was cellulose triacetate (FB-130Uβeco, Nipro Corp., Osaka, Japan), and the dialysate (Kindaly Solution AF-2, Fuso Pharmaceutical Industries, Ltd., Osaka, Japan) flow rate was 500 ml/min with a blood flow rate of 150 ml/min. The pre-chemotherapy laboratory data are shown in Table 1. He received durvalumab (1500 mg/body on day 1) plus carboplatin (area under the concentration–time curve [AUC] = 5, 125 mg/body on day 1) and etoposide (50 mg/m², 89 mg/body on days 1 and 3) as first-line therapy. He underwent dialysis on day 2. During the first cycle, although no thrombocytopenia was observed, grade 2 anemia, grade 3 neutropenia, and grade 3 upper gastrointestinal bleeding occurred. Therefore, durvalumab plus reduced doses of carboplatin (AUC = 4, 100 mg/body on day 1) and etoposide (40 mg/m², 69 mg/body on days 1 and 3) were administered after the second cycle at the discretion of the physician. No other severe adverse events occurred, and CT revealed a partial response after four cycles of treatment (Fig. 1B). After two cycles of maintenance treatment with durvalumab, the disease progressed due to the growth of the primary tumor and pleural dissemination. At the end of treatment, no new safety signals were observed.

Table 1.

Laboratory test results at admission

Laboratory parameter	Values
White blood cells (109/L)	9.2*
Hemoglobin (g/dL)	11.5*
Platelets (109/L)	313
Urea nitrogen (mg/dL)	64.8*
Creatinine (mg/dL)	8.66*
Sodium (mEq/L)	134*
Potassium (mEq/L)	3.8
Magnesium (mg/dL)	2.1
Bilirubin (mg/dL)	0.4
Alanine aminotransferase (U/L)	14
Aspartate aminotransferase (U/L)	7*
Albumin (g/dL)	3.9*
C-reactive protein (mg/dL)	2.28*
Neuron-specific enolase (ng/mL)	97.1*
Pro-gastrin-releasing peptide (pg/mL)	7187.9*
Brain natriuretic peptide (pg/mL)	133.8*

*Indicates an out-of-range value

Discussion

Durvalumab is a PD-L1 inhibitor, and a combination of this agent with platinum plus etoposide chemotherapy was approved for the management of ED-SCLC by the Pharmaceuticals and Medical Devices Agency in Japan in 2020 based on the CASPIAN study, which demonstrated significantly improved progression-free and overall survival [5]. PD-1/PD-L1 inhibitors, including durvalumab, are high-molecular-weight proteins that are degraded to small peptides and individual amino acids through numerous physiological mechanisms. However, most of these are deemed to occur by nonspecific degradation within plasma and tissues, indicating a minimal effect on pharmacokinetics in patients with impaired renal or liver function, even in patients on hemodialysis [11, 12]. Indeed, in previous reports describing the utility of PD-1/PD-L1 inhibitors in patients with lung cancer on hemodialysis [13–16], although standard doses of these inhibitors were administered to all patients, no severe immune-related adverse events (irAEs) were observed (Table 2). Although the mortality from causes other than cancer is reported to be high in patients on hemodialysis who receive chemotherapy [17], real-world data from an electronic health record database showed that patients with cancer, including lung cancer with ESRD, receiving pembrolizumab, nivolumab, or nivolumab plus ipilimumab, were not at an increased risk of irAEs compared with matched patients without ESRD [18]. Based on these observations, the use of immune checkpoint inhibitors in hemodialysis patients is suggested in the Japanese guidelines [19]. In our case, similar to these reports, although the blood levels of durvalumab were not measured, the standard dose of durvalumab (1500 mg/body) combined with carboplatin plus etoposide was safe and effective in patients with ED-SCLC on hemodialysis.

Table 2.

Published reports on patients with lung cancer undergoing hemodialysis who received PD-1/PD-L1 inhibitors

Reference	N	Disease	Treatment	Grade 3/4 adverse event	Response
Imaji et al. [13]	1	SCLC	Carboplatin (AUC = 5, 125 mg/body on day1)	Neutropenia	PR
			Etoposide (40 mg/m2 on day1-3)
			Atezolizumab (1200 mg/body)
Ishizuka et al. [14]	1	SQ	Pembrolizumab (200 mg/body)	None	PR
Osa et al. [15]	1	AD	Pembrolizumab (200 mg/body)	None	No data
Strohbehn et al. [16]	2	Lung cancer	Pembrolizumab (200 mg/body)	None	No data
			Atezolizumab (1200 mg/body)
Our case	1	SCLC	Carboplatin (AUC = 5, 125 mg/body on day1)	Neutropenia, anemia	PR
			Etoposide (50 mg/m2 on day1 and 3)
			Durvalumab (1500 mg/body)

AD adenocarcinoma, AUC area under the concentration–time curve, NSCLC non–small-cell lung cancer, PD-1, programmed death ligand 1, PD-L1 programmed death ligand 1, PR partial response, SCLC small cell lung cancer, SQ squamous cell carcinoma

Regarding ED-SCLC, Imaji et al. reported a similar case of a patient on hemodialysis treated with carboplatin plus etoposide combined with atezolizumab instead of durvalumab [13]. The difference in the treatment between this report and ours, except for the PD-L1 inhibitor, was the dose and schedule of etoposide administration (Table 2). The main excretion pathways for etoposide are through bile and urine, with approximately 40% of the drug excreted by the kidneys [20]. Therefore, in patients on hemodialysis, a 25–50% dose reduction of etoposide is recommended, resulting in an actual dose of 25–75 mg/m² [10, 21]. Because etoposide is not removed during hemodialysis, it can be administered before and after hemodialysis [20]. In our case, etoposide was administered at a dose of 50 mg/m² on days 1 and 3, based on a previous study that confirmed that the AUC of etoposide was within the range achieved in patients with normal renal function [22]. On the other hand, carboplatin is excreted mainly by the kidneys and removed by hemodialysis [23]. The calculation of the carboplatin dose in patients on hemodialysis was conducted in several ways [22, 24, 25]. In our case, the carboplatin dose was calculated using Calvert’s formula, in which the glomerular filtration rate was set to 0 owing to the absence of renal function [10]. In previous studies, including a report from our hospital, in which this calculation method was used, hemodialysis was conducted 16–24 h after the completion of carboplatin administration, resulting in an actual-to-target AUC of 0.886–1.74 [26–29]. Some patients in these studies, especially Japanese patients, received an overdose of carboplatin. This may be explained by a lower non-renal clearance of carboplatin in Japanese patients [30]. For Japanese patients with cancer, the constant in the Calvert formula is proposed to be 15 instead of 25, which could be greatly associated with carboplatin dosing in the Calvert formula, especially among patients with ESRD because the glomerular filtration rate is low. The optimal method for carboplatin dosing in patients on hemodialysis remains unclear; however, Calvert’s formula is commonly used for carboplatin dosing in patients with normal renal function [31], and an acceptable actual AUC was obtained in patients on hemodialysis in previous studies, indicating that Calvert’s formula can be preferentially used for carboplatin dosing in patients with cancer on hemodialysis.

Conclusion

The findings in our case showed that the administration of durvalumab combined with carboplatin and etoposide was safe and effective in patients with ED-SCLC on hemodialysis. Further studies are needed; however, this combination appears to be a treatment option for patients with ED-SCLC having renal insufficiency.

Author contributions

All authors contributed to the conception and design of the study. FU and TH wrote the first draft of the manuscript.

Funding

This work was not supported by funding, grants, or other sources.

Data availability

All data included in this report are available upon reasonable request from the corresponding author.

Declarations

Conflict of interest

T.H. received personal fees and research funding from AstraZeneca KK outside the submitted work. Y.A. received personal fees from Chugai Pharmaceutical Co., Ltd. and Bayer Holding Ltd., and research funding from Chugai Pharmaceutical Co., Ltd., Bayer Holding Ltd., BeiGene Inc., and Geo Holdings Co., Ltd. M.I. received personal fees from AstraZeneca KK outside the submitted work. All remaining authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Given that this is a case report without the inclusion of any identifying information, formal consent was not required.