ORIGINAL ARTICLE

# Clinical outcomes of systemic anticancer therapies in solid cancer patients with liver and kidney transplant: an observational cross-sectional study

E. Chen<fnref n="1" />, N. Belkaid<fnref n="1" />, C. Duvoux², D. Sahali³, P. Grimbert³, M.-B. Matignon³, A. Hulin<fnref n="4" />, S. Babai⁵, C. Chouaïd⁶, J. B. Assié⁶, M. Carvalho<fnref n="1" />, C. Tournigand⁷ & E. Kempf⁷*

Available online 29 September 2025

**Background:** Solid cancer patients with liver transplant (LT) or kidney transplant (KT) receiving systemic anticancer therapies (SACT) are likely to present an increased risk of treatment-related infections. We aimed to describe their clinical outcomes.

**Patients and methods:** This retrospective study included SACT-treated patients from two university medical oncology centers between 2000 and 2023, identified through automated extraction and manual record review. We excluded patients treated with immune checkpoint inhibitors. We manually collected immunosuppressant and SACT administration, patient SACT grade 3 to 5 toxicities, cause of death, and overall survival.

**Results:** Fifty-three patients were included: 39 (74%) men, 33 (62%) LT, and 20 (38%) KT; median age was 62 years (interquartile range 32-82 years); 19 (58%) and 15 (75%) LT and KT patients, respectively, had stage IV diseases. Primary cancer was liver (n = 16; 45%) and digestive (n = 10; 30%) for LT patients; digestive (n = 7; 35%), kidney, breast, and lung (all three n = 3; 15%) for KT patients. From the time before cancer diagnosis to SACT administration, the immunosuppressant regimen was changed in both subgroups. Overall, 29 (88%) LT patients and 17 (85%) KT patients were exposed at least once to standard cytotoxic drugs, and 8 (24%) LT patients and 3 (15%) KT patients to tyrosine kinase inhibitors. Thirty-three patients had grade 3-4 toxicities, 52% LT patients and 30% KT patients. Twenty-four patients had grade 5 toxicities (79% LT and 86% KT patients treatment-related infections, respectively). One-year overall survival rates were 52% for LT patients and 50% for KT patients. After treatment-related infections, death was due to tumor progression for 9 LT patients (32%) and 5 (42%) KT patients, respectively.

**Conclusions:** Treatment-related infections drive the prognosis of LT and KT patients undergoing SACT.

**Key words:** antineoplastic agents, immunosuppressive agents, organ transplantation, drug-related side-effects and adverse reactions, oncology

INTRODUCTION

With an aging population, the number of living transplant patients keeps rising worldwide. Around 28 000 organ transplants were carried out in the European Union alone in 2022,<fnref n="1" /> and around 40 000 across the wider European region the same year, representing an increase of 6% compared with 2021.² Among solid organ transplant, kidney transplant (KT) is the one most frequently carried out, followed by liver transplant (LT). Recent decades have seen significant

improvements in the short-term survival of transplant patients due to advances in immunosuppression and transplant techniques.³ Until recently, acute and chronic rejection were the main parameters to be taken into account in transplant management. By impairing immunosurveillance, chronic immunosuppressants seem to be linked to the appearance of *de novo* cancers, with a two to four times greater risk of malignancy.<fnref n="4" /> Nowadays, *de novo* cancers are the third leading cause of death in transplant patients.⁵ Thus, it becomes important to rethink the management of immunosuppressants throughout the cancer management process. Due to their fragility, LT and KT patients with solid cancer are not included in clinical trials. Therefore in this context, there are only few data on systemic anticancer therapy (SACT) use, no data on SACT toxicity, and the literature consists mainly of case reports, with only few studies involving a cohort of solid organ transplant patients.⁶,⁷

<footnote n="1">¹Internal Use Pharmacy, Assistance Publique — Hôpitaux de Paris, Henri Mondor Teaching Hospital, Créteil; Departments of ²Hepatology; ³Nephrology;</footnote>

<footnote n="4">⁴Pharmacology; ⁵Pharmacovigilance, Assistance Publique — Hôpitaux de Paris, Henri Mondor Teaching Hospital, Créteil; ⁶Pneumology Department, Créteil Intercommunal Center, Créteil; ⁷Medical Oncology Department, Assistance Publique — Hôpitaux de Paris, Henri Mondor Teaching Hospital, Créteil, France</footnote>

<footnote>*Correspondence to: Prof. Emmanuelle Kempf, Department of Medical Oncology, Henri Mondor Teaching Hospital, 1 rue Gustave Eiffel, 94000 Créteil, France. Tel: +33-1-49-81-45-31
E-mail: emmanuelle.kempf@aphp.fr (E. Kempf).</footnote>

<footnote>2949-8201/© 2025 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>
The primary objective of this study was to describe the toxicity profile of SACT in solid cancer patients with LT or KT transplant, and the related clinical outcomes.

## METHODS

We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for the reporting of our cross-sectional study. Our study protocol was approved by the CRM national ethics committee on September 29th 2024 (reference number CRM-2409-418).

## Patients' identification

This cross-sectional observational study was retrospective and took place in two Greater Paris area hospitals. We identified the patient cohort following two steps: firstly, an automatic phase using cohort 360,⁸ a tool used to visualize patient cohorts from both automatically selected and manually refined cohorts. We used claims data (PMSI, Information Systems Medicalization Program) codes based on ICD-10 related to solid cancer patients with LT or KT ≥18 years of age, who had at least one visit in the medical oncology department (day hospital or full hospitalization) related to an SACT administration between 1 January 1 2000 and 31 December 2023. We excluded patients treated with immune checkpoint inhibitors (ICIs) from our analysis, due to the specific risk of graft rejection. Then, a second manual phase of population verification was carried out by analyzing each patient electronic health record (EHR) in order to select patients whose cancer diagnosis (de novo or relapse of primitive cancer) followed the date of their last transplant. We divided the patients into LT and KT subgroups.

## Data extraction

We extracted manually from the EHRs the following patient characteristics: patient age at cancer diagnostic, gender, comorbidities (retrieved from the medical history of hospitalization or consultation reports. We deliberately focused on clinically significant histories; cancer characteristics: cancer types (de novo or relapse of primitive cancer), number of cancers, cancer stage at diagnosis; SACT characteristics: SACT exposure (percentage of patients who were provided with at least one infusion of SACT); SACT Common Terminology Criteria for Advance Events (CTCAE) grade 3, 4 and 5 toxicities. SACT toxicity grade was attributed by the clinician taking care of the patient according to CTCAE criteria, as indicated in the patient's medical record; transplant characteristics: number of solid transplants, transplant etiology, total duration of immunosuppressant exposure (from the date of the first day of transplant to cancer onset or relapse), immunosuppressant modifications (therapeutic class and drug dose) before cancer diagnosis, at cancer diagnosis, and after SACT administration; type of immunosuppression (drug dose and number of combined immunosuppressants).

## Patient outcomes

We assessed the following endpoints: 1-year survival; median overall survival (OS) and causes of death from the day of the first SACT administration. Deaths were attributed by the clinician taking care of the patient at the end of life, as indicated in the patient's medical record. OS was estimated by using the Kaplan-Meier method. OS was defined as the time from the start of SACT to the date of death from any cause measured at the last contact date or the cut-off date (December 2023).

Data were analyzed using descriptive statistics: calculation of the mean, median, standard deviation, quartiles for the different variables, Kaplan-Meier for survival data, using the 2016 version of the Excel software.

## RESULTS

### Patient characteristics

We selected 53 patients after excluding patients who did not meet the inclusion criteria as indicated in the study flowchart (Figure 1). Some 33 patients were followed for LT (62%) and 20 for KT (38%). Patients and cancer characteristics are summarized in Table 1. A total of 34 patients (64%) had a metastatic cancer, of whom 19 (58%) were in the LT subgroup and 15 (75%) in the KT subgroup. The most frequent primitive cancer types in LT patients were liver (n = 15; 45%, including 87% relapses) and digestive (n = 10; 30%), whereas KT patients exhibited more diverse malignant tumors including digestive (n = 7; 35%), lung, breast and kidney (n = 3 equally for the three; 15%). Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.esmorw.2025.100185, display the cancer types according to the transplant etiology.

### Transplant characteristics and immunosuppressant characteristics

The median time from transplant to cancer onset or relapse was 4 years for LT (IQR <1-21 years) and 6 years (<1-16 years) for KT patients. LT etiologies were liver cancers (n = 19; 58%) and cirrhosis (n = 9; 27%), whereas KT resulted from nephropathies of various origins (n = 19; 95%) (Table 2). One LT patient underwent two transplant procedures.

From the time before cancer diagnosis to SACT administration, the number of LT patients exposed to tacrolimus decreased from 22 to 16 (−27%), to mycophenolate mofetil (MMF) decreased from 25 to 18 patients (−28%), and to everolimus increased from 4 to 11 patients (+175%). The number of KT patients exposed to tacrolimus and MMF decreased from 14 to 10 patients (−29%) and from 14 to 11 patients (−21%), respectively; and those exposed to everolimus increased from 6 to 13 patients (+116%). KT patients were exposed to corticosteroids all the time, while we observed for LT patients a decrease in corticosteroid exposure by 65% (from 17 to 6 patients). These results are displayed in Supplementary Figure S1A and B, available at https://doi.org/10.1016/j.esmorw.2025.100185.
<figure><img src="image_1.png" /><figcaption>**Figure 1.** Study flow chart.
SACT, systemic anticancer therapy.</figcaption></figure>

Before cancer diagnosis, 17 (52%) LT patients were exposed to triple immunosuppressive therapy (which in 94% of cases was a combination of tacrolimus, MMF, and corticosteroids), and 9 (27%) monotherapy. After SACT administration, the number of LT patients exposed to triple immunosuppressive therapy decreased from 17 to 3 (–82%); and to monotherapy and dual therapy increased from 9 to 14 patients (+55%) and from 7 to 16 patients (+129%), respectively. Dual immunosuppressive therapy combined MMF in 88% (n = 14) of cases with everolimus (n = 5) or tacrolimus (n = 4).

In KT patients before cancer diagnosis, triple immunosuppressant therapy consisted of a combination of tacrolimus, MMF, and prednisone (n = 11; 58%). At cancer diagnosis and after SACT administration, it consisted of a combination of everolimus, MMF, and prednisone (both n = 11; 69% and 65%, respectively). At any time, >80% of KT patients had triple immunosuppressive therapy, and no patient had immunosuppressant monotherapy. Variation in exposure to immunosuppressive drug combinations over the course of care are displayed in Supplementary Figure S1C and D, available at https://doi.org/10.1016/j.esmorw.2025.100185, and immunosuppressant median dose variations over the course of care are reported in Table 3.

## SACT characteristics

The median number of SACT lines, median duration of SACT exposure, and patients' exposure rate to SACT

are displayed for each subgroup in Supplementary Table S3, available at https://doi.org/10.1016/j.esmorw.2025.100185. Over the study period, LT and KT patients SACT exposure rate was, respectively: 88% (n = 29) and 85% (n = 17) to standard cytotoxic drugs, and 24% (n = 8) and 15% (n = 3) to tyrosine kinase inhibitors. Table 4 summarizes both subgroup CTCAE SACT grade 3, 4, and 5 toxicities.

In the LT subgroup, a total of 31 grade 3-4 toxicities were observed in 17 patients (52%). In the KT subgroup, six (30%) patients experienced a total of 14 grade 3-4 toxicities. In both subgroups, toxicities were mainly observed after standard chemotherapies, and the main grade 3-4 toxicity observed was general status deterioration (13 cases in LT patients, 5 cases in KT patients). Grade 3-4 cytopenia was observed in nine cases in seven LT patients, and in one case in KT patients, only after standard chemotherapy administrations. Hematological grade 3-4 toxicities accounted for 19% (n = 9) of all toxicities recorded, including grade 5 toxicities. Supplementary Table S4, available at https://doi.org/10.1016/j.esmorw.2025.100185, displays SACT treatment associated with the cytopenia. A total of 24 patients (17 LT and 7 KT) had grade 5 toxicities. Infection grade 5 represented 88% (n = 15) of grade 5 toxicities in LT patients, and 86% (n = 6) in KT patients. Among patients with metastatic cancer, SACT grade 3-4 toxicities occurred in 11 (65%) LT patients and 4 (67%) KT patients, respectively. SACT grade 5 toxicities occurred in 10 (36%) LT patients and 5 (42%) KT patients, respectively, as displayed in Supplementary
<table><caption>**Table 1. Patient characteristics**</caption><thead><tr><th>Variables</th><th>Liver transplant (N = 33)</th><th>Kidney transplant (N = 20)</th></tr></thead><tbody><tr><td>Age (years), median (IQR)</td><td>64 (32-82)</td><td>59 (41-77)</td></tr><tr><td>Gender, n (%)</td><td></td><td></td></tr><tr><td>Men</td><td>25 (78)</td><td>14 (70)</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td></tr><tr><td>Hypertension</td><td>19 (58)</td><td>14 (70)</td></tr><tr><td>Diabetes</td><td>15 (45)</td><td>9 (45)</td></tr><tr><td>Dyslipidemia</td><td>5 (15)</td><td>1 (5)</td></tr><tr><td>Chronic heart disease</td><td>13 (39)</td><td>8 (40)</td></tr><tr><td>Hepatitis B</td><td>5 (15)</td><td>1 (5)</td></tr><tr><td>Hepatitis C</td><td>16 (48)</td><td>1 (5)</td></tr><tr><td>Primary cancer types, n (%)</td><td></td><td></td></tr><tr><td>Liver cancer</td><td>15 (46)</td><td>—</td></tr><tr><td>Cholangiocarcinoma</td><td>4 (26)</td><td>—</td></tr><tr><td>Hepatocholangiocarcinoma</td><td>2 (13)</td><td>—</td></tr><tr><td>Hepatocellular carcinoma</td><td>7 (48)</td><td>—</td></tr><tr><td>Mixed</td><td>2 (13)</td><td>—</td></tr><tr><td>Digestive cancer</td><td>10 (30)</td><td>7 (35)</td></tr><tr><td>Colon</td><td>2 (20)</td><td>5 (72)</td></tr><tr><td>Esophagus</td><td>4 (40)</td><td>—</td></tr><tr><td>Stomach</td><td>1 (10)</td><td>1 (14)</td></tr><tr><td>Duodenal</td><td>1 (10)</td><td>—</td></tr><tr><td>Pancreas</td><td>2 (20)</td><td>1 (14)</td></tr><tr><td>Breast</td><td>1 (3)</td><td>3 (15)</td></tr><tr><td>Kidney</td><td>1 (3)</td><td>3 (15)</td></tr><tr><td>Prostate</td><td>—</td><td>1 (5)</td></tr><tr><td>Bladder</td><td>—</td><td>1 (5)</td></tr><tr><td>Urethra</td><td>—</td><td>1 (5)</td></tr><tr><td>Lung</td><td>3 (9)</td><td>3 (15)</td></tr><tr><td>ENT (ear, nose, throat)</td><td>1 (3)</td><td>1 (5)</td></tr><tr><td>Neuro-endocrine</td><td>1 (3)</td><td>—</td></tr><tr><td>Testicular</td><td>1 (3)</td><td>—</td></tr><tr><td>Concomitant primary cancer types</td><td></td><td></td></tr><tr><td>Tongue</td><td>1</td><td>—</td></tr><tr><td>Lung</td><td>1</td><td>—</td></tr><tr><td>Prostate</td><td>1</td><td>—</td></tr><tr><td>Colorectal</td><td>1</td><td>—</td></tr><tr><td>Cancer stage, n (%)</td><td></td><td></td></tr><tr><td>Localized</td><td>10 (30)</td><td>3 (15)</td></tr><tr><td>Locally advanced</td><td>4 (12)</td><td>2 (10)</td></tr><tr><td>Metastatic</td><td>19 (58)</td><td>15 (75)</td></tr></tbody></table>

IQR, interquartile range.

Figure S2, available at https://doi.org/10.1016/j.esmorw.2025.100185.

## Patient outcomes

At the time of analysis, 40 patients died (75%), 28 LT (85%) and 12 KT (60%) patients. One-year OS rate reached 52% (n = 17) and 50% (n = 10) in LT and KT subgroups, respectively. For patients with metastatic cancer, 1-year OS rate reached 37% (n = 7) and 40% (n = 6) in LT and KT patients, respectively. In the whole cohort, 1-year OS for cancers like pancreas or gastric was null, while breast or ENT (ear, nose, throat) cancers had a 1-year OS equal to 100%. No patient had transplant-related complications during the study period. The two main causes of death were infections in 15 LT (53%) and 6 KT (50%) patients and tumor progression in 9 LT (32%) and 5 KT (42%) patients (Figure 2C). In addition, Supplementary Figure S2, available at https://doi.org/10.1016/j.esmorw.2025.100185, displays causes of death by cancer stage, according to transplant

<table><caption>**Table 2. Transplant characteristics**</caption><thead><tr><th></th><th>Liver transplant (N = 33)</th><th>Kidney transplant (N = 20)</th></tr></thead><tbody><tr><td>Total duration of immunosuppression or time from transplant to cancer onset or relapse (years), median (IQR)</td><td>4 (&lt;1-21)</td><td>6 (&lt;1-16)</td></tr><tr><td>Number of transplant(s)</td><td></td><td></td></tr><tr><td>1</td><td>32</td><td>20</td></tr><tr><td>2</td><td>1</td><td>—</td></tr><tr><td>Cause of transplant, n (%)</td><td></td><td></td></tr><tr><td>Cancer</td><td>21 (64)</td><td>1 (5)</td></tr><tr><td>Liver</td><td></td><td>—</td></tr><tr><td>Hepatocellular carcinoma</td><td>16 (76)</td><td>—</td></tr><tr><td>Other liver cancers</td><td>5 (24)</td><td>—</td></tr><tr><td>Kidney</td><td>—</td><td>1 (100)</td></tr><tr><td>Non-cancer</td><td>12 (36)</td><td>19 (95)</td></tr><tr><td>Cirrhosis</td><td>10 (84)</td><td>—</td></tr><tr><td>Alcoholic</td><td>6 (60)</td><td>—</td></tr><tr><td>Viral</td><td>2 (20)</td><td>—</td></tr><tr><td>Mixed</td><td>2 (20)</td><td>—</td></tr><tr><td>Hepato-pulmonary syndrome</td><td>1 (8)</td><td>—</td></tr><tr><td>Liver vascular disease</td><td>1 (8)</td><td>—</td></tr><tr><td>Nephropathies with kidney failure</td><td>—</td><td>19 (100)</td></tr><tr><td>Nephroangiosclerosis and diabetes</td><td>—</td><td>5 (26)</td></tr><tr><td>Glomerulopathy</td><td>—</td><td>2 (11)</td></tr><tr><td>Berger disease</td><td>—</td><td>3 (15)</td></tr><tr><td>Polycystic kidney disease</td><td>—</td><td>2 (11)</td></tr><tr><td>Renal tuberculosis</td><td>—</td><td>1 (5)</td></tr><tr><td>Renal amyloidosis</td><td>—</td><td>2 (11)</td></tr><tr><td>Malformative uropathy</td><td>—</td><td>1 (5)</td></tr><tr><td>Iatrogenic acute tubular necrosis</td><td>—</td><td>1 (5)</td></tr><tr><td>Unknown</td><td>—</td><td>2 (11)</td></tr></tbody></table>

IQR, interquartile range.

type. Supplementary Table S5, available at https://doi.org/10.1016/j.esmorw.2025.100185, summarizes the death rate and patient outcome according to cancer type in the whole patient cohort. Median OS was 12 months (IQR 2-103 months) and 17 months (IQR <1-117 months) in LT and KT patients, respectively (Figure 2A and B). Among grade 5 infections, bacteria were found in 10 (67%) LT patients and 3 (50%) KT patients, mostly Enterobacteriaceae [6 (40%) LT patients and 2 (33%) KT patients, respectively]. There was one viral infection to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and no fungal infection documented. Supplementary Figure S3, available at https://doi.org/10.1016/j.esmorw.2025.100185, displays the germs found in grade 5 infections, according to transplant type.

## DISCUSSION

In our 53-patient cohort, grade 3-4 toxicities occurred in 52% LT patients and 30% KT patients. A total of 24 patients in our cohort had grade 5 toxicities, and 21 (88%) of them were infection-related toxicities (88% cases in LT patients, 86% in KT patients). One year-OS rate was low, ranging from 52% in LT patients to 50% in KT patients. Patients mostly died from severe infections (53% LT and 50% KT), or tumor disease progression (32% LT and 42% KT). In addition, most patients had metastatic cancer (64%). Throughout the complex
<table><caption>**Table 3.** Median immunosuppressant dose modifications (in mg) over the course of care</caption><thead><tr><th rowspan="2">Immunosuppressive drugs, median (IQR)</th><th colspan="3">Liver transplant (n = 33)</th><th colspan="3">Kidney transplant (n = 20)</th></tr><tr><th>Before cancer diagnosis</th><th>At cancer diagnosis</th><th>After SACT</th><th>Before cancer diagnosis</th><th>At cancer diagnosis</th><th>After SACT</th></tr></thead><tbody><tr><td>Tacrolimus</td><td>4.5 (1.5-10)</td><td>3 (0.5-8)</td><td>2 (1-6)</td><td>4 (1-13)</td><td>4 (1.5-13)</td><td>4 (1.5-13)</td></tr><tr><td>Everolimus</td><td>1.75 (1-3)</td><td>2 (1-4)</td><td>2 (1-3)</td><td>2.75 (1.25-4)</td><td>1.5 (0.5-4)</td><td>2 (0.5-5)</td></tr><tr><td>Mycophenolate</td><td>2000 (360-2000)</td><td>1500 (360-2000)</td><td>1040 (360-2000)</td><td>1000 (500-2000)</td><td>500 (500-2000)</td><td>735 (500-1500)</td></tr><tr><td>Cyclosporin</td><td>150 (100-200)</td><td>50</td><td>100 (50-2000)</td><td>200 (125-400)</td><td>128 (75-150)</td><td>125 (100-150)</td></tr><tr><td>Prednisone</td><td>15 (2.5-20)</td><td>10 (5-20)</td><td>7.5 (5-20)</td><td>5 (3-15)</td><td>5 (3-60)</td><td>5 (3-60)</td></tr><tr><td>Azathioprine</td><td>50</td><td>0</td><td>0</td><td>50</td><td>25</td><td>25</td></tr></tbody></table>

IQR, interquartile range; SACT, systemic anticancer therapy.

management of transplanted patients with cancer, many changes in the immunosuppressive therapy were made over the course of care, in terms of drug class, number of combined drugs, and median doses. From the time before cancer diagnosis to SACT administration, we observed that the number of patients exposed to everolimus increased by 175% and by 116% in LT and KT patients, respectively, to tacrolimus decreased by 27% and 29% in LT and KT patients, respectively, and to MMF decreased by 28% and 21% in LT and KT patients, respectively.

In our study, LT main cancer type was relapses of liver cancer (45%) followed by *de novo* gastrointestinal tract cancers (30%), which seems compatible with other studies.⁹,¹⁰ In the literature, KT patients are likely to be diagnosed with urogenital tract, kidney or gastrointestinal tract which is consistent with our results.¹¹,¹² LT was mostly

carried out for liver cancers (64%), particularly hepatocellular carcinoma, followed by alcoholic cirrhosis (30%). Yet, in the literature, alcohol-related liver disease and hepatitis C virus infection cirrhosis are LT leading causes.¹³ In our study, KT was mostly carried out for nephroangiosclerosis (26%), which is compatible with other studies.¹⁴ Overall, the most common cancers occurring in solid organ transplant patients are skin, hematological, lung, and ENT cancers.¹⁵⁻²⁰ The patients reported in this study came only from the oncology departments of our two hospitals; this recruitment bias may explain the absence of usual cancer types in our cohort, as reported in the literature.¹⁵⁻²⁰

Patients were mostly exposed to standard chemotherapies like oxaliplatin or 5-fluorouracil in both subgroups, and to gemcitabine in LT patients. Patients with metastatic cancers seemed more likely to develop SACT-related

<table><caption>**Table 4.** Systemic anticancer therapies CTCAE grade 3-4 and grade 5 adverse events according to the transplant type</caption><thead><tr><th rowspan="3">Toxicities grades<br/>Type of toxicities</th><th colspan="6">Liver transplant (n = 33)</th><th colspan="6">Kidney transplant (n = 20)</th></tr><tr><th colspan="3">Grade 3-4</th><th colspan="3">Grade 5</th><th colspan="3">Grade 3-4</th><th colspan="3">Grade 5</th></tr><tr><th>SC</th><th>TKI</th><th>Others</th><th>SC</th><th>TKI</th><th>Others</th><th>SC</th><th>TKI</th><th>Others</th><th>SC</th><th>TKI</th><th>Others</th></tr></thead><tbody><tr><td>Adrenal insufficiency</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Alopecia</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Budd-Chiari syndrome</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diabetic decompensation</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Disseminated intravascular coagulation</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Cytopenia</td><td>9</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Anemia</td><td>2</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Neutropenia</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Pancytopenia</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Thrombocytopenia</td><td>5</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diarrhea</td><td>2</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td></tr><tr><td>Dyspnea</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>General status deterioration</td><td>10</td><td>3</td><td>—</td><td>—</td><td>—</td><td>—</td><td>3</td><td>2</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Hand foot syndrome</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Heart and kidney failure</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td></tr><tr><td>Mucositis</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Proteinuria</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Thyroiditis</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Vasculitis</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Vomiting</td><td>1</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Pneumopathy</td><td>—</td><td>—</td><td>—</td><td>6</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Sepsis</td><td>—</td><td>—</td><td>—</td><td>8</td><td>—</td><td>1</td><td>1</td><td>—</td><td>—</td><td>—</td><td>5</td><td>1</td></tr><tr><td>Total</td><td>24</td><td>7</td><td>0</td><td>18</td><td>0</td><td>1</td><td>8</td><td>5</td><td>1</td><td>5</td><td>1</td><td>1</td></tr></tbody></table>

In our patient cohort, 17 (35%) LT patients and 7 (34%) KT patients developed fatal toxicities among grade 3 to 5 SACT-related toxicities (48 in LT patients and 21 in KT patients).

In the KT subgroup: one patient had four different TKI lines and developed grade 3 toxicities each time. One patient who received everolimus developed grade 3 dyspnea. 'Others' refers to other therapies such as hormone therapies, targeted therapy or immunosuppressant.

CTCAE, Common Terminology Criteria for Adverse Events; KT, kidney transplant; LT, liver transplant; SACT, systemic anticancer therapy; SC, standard cytotoxic; TKI, tyrosine kinase inhibitor.
<figure><img src="image_2.png" /><figcaption>**Figure 2.** Patient overall survival and causes of death. A and B display LT and KT patients' overall survival curves, respectively. C displays LT and KT patients' causes of death, respectively. In the LT subgroup, 15 deaths (45%) were attributed to infection CTCAE grade 5 toxicities, comprising infectious pneumopathies and sepsis. In the KT subgroup, six deaths were attributed to infection CTCAE grade 5 toxicities.</figcaption></figure>

CTCAE, Common Terminology Criteria for Advance Events; KT, kidney transplant; LT, liver transplant; SACT, systemic anticancer therapy.

toxicities than non-metastatic cancer patients. In our study, grade ≥3 hematological toxicities in LT patients accounted for 19% of all toxicities recorded, which was much lower than the 42% grade ≥ 3 hematological toxicities presented in the study by Coupier et al.⁶ Their study was composed of 69 LT patients exclusively, who mostly developed lung carcinomas (24%), head and neck cancers (21%), and also lymphomas (17%), which for the latter was not included in our patient cohort. Thus, this may reflect a difference in cancer management and, consequently, in SACT-related toxicities. A Spanish study by Lee et al.²¹ comprising advanced solid cancer patients without solid organ transplant (n = 559) had a 19% grade 3-4 toxicities rate. Although we cannot extrapolate, our patient cohort seemed to develop more grade 3-4 toxicities.

During the study period, patients' 1-year OS rate was low (around 50% in both subgroups). The two main causes of death were infections mostly sepsis, followed by tumor progression despite conventional SACT treatment. One

hypothesis might be that tumor progression may be the consequence of inadequate SACT dose intensity in patients.²²

Immunocompromised patients are 20 times more susceptible to infections than the general population, mostly cytomegalovirus in solid organ transplant patients (15%-55%).²³ This was not the case in our study, as there were more bacterial infections, notably enterobacteria. According to Lyons and McEvoy,²⁴ sepsis mortality rate in solid cancer patients is 2.7 times higher than in the general population. Sepsis may occur more often as a result of reduced immunosurveillance due to long-term exposure to immunosuppressants.²⁵⁻²⁷

In our patient cohort, there was a decrease in the depth of immunosuppression because reducing immunosuppression may decrease the risk of cancer progression, and of infectious adverse events.⁶,²⁸ Yet, this issue is under debate in the literature.²⁹⁻³¹ Also, drug-drug interactions with immunosuppressants may increase renal toxicities (especially
with tacrolimus) and interactions involving cytochrome or P-gp interactors.⁶,³²,³³ For example, in our study, one KT patient presented confusion related to a tacrolimus over-dosage due to an interaction with concomitant erythro-mycin. Also, patients were more likely to receive everolimus due to a better toxicity profile and antitumor activity. Moreover, an early switch to everolimus after the diagnosis of post-KT cancer has shown reduction of skin cancer occurrence or Kaposi's sarcoma,³⁴⁻³⁶ and seems to lower hepatocellular carcinoma relapse in post-LT recipients.³⁷

In our cohort, we excluded patients who received ICIs due to the specific risk of transplant rejection. Indeed, organ rejection rate occurred in 28% of cases regardless of the number of ICIs used in combinations as observed in a study by Remon et al.⁷ comprising 31 patients with lung cancer (98% of whom had KT), and one-third of organ rejections occurred within 2 months after ICI initiation. In a study by Murakami et al.³⁸ comprising 69 KT patients with solid cancers, the organ rejection rate occurred in 42% of cases, compared with 5.4% in the non-ICI cohort. Wassmer et al.³⁹ estimated a 3-month washout period desirable between ICIs and LT to reduce the risk of acute rejection, but whenever possible, ICIs should be avoided after LT. Nevertheless, this population warrants further investigations.

Despite an extensive manual data collection, this study is observational and bicentric, based on a patient cohort not representative of the main cancers which developed in transplant patients (lymphomas, skin cancers).

Guidelines regarding the cancer management of LT and KT patients are lacking, either in terms of SACT or immunosuppressive therapies prescribing practices. Immunosuppressants may play a crucial role in cancer development, and in patient clinical outcomes. The trend seems to be towards a reduction in the depth of immunosuppression while finding a balance between the efficacy of immunosuppressants in preserving the transplant, and their aggravating impact on SACT iatrogenicity. SACT-induced hematological toxicities such as neutropenia have to be monitored as they can aggravate the overall biological immunosuppression and a patient's outcomes such as sepsis. ICIs are also a therapeutic option but should be used with caution as they can lead to graft rejection. Our study would serve as a pilot for other, larger studies, such as a national prospective observational study, or the creation of a reference center for transplant cancer patients.

## CONCLUSION

Despite modifications of the immunosuppressive regimen carried out before the initiation of anticancer systemic therapy to mitigate associated risks, nearly half of solid cancer patients with kidney or liver transplants died from treatment-related adverse events. More than 80% of these cases were related to infectious complications. Our study highlights several avenues for further investigation, including the need to identify effective strategies for

preventing infections related to systemic anticancer therapy, as well as evaluating the safety/efficacy ratio of immune checkpoint inhibitors, especially when combined with other SACT and/or biologics affecting the immune system activation in this high-risk population.

## FUNDING

None declared.

## DISCLOSURE

The authors have declared no conflicts of interest.

## REFERENCES

1. European Commission. Public Health: Organs. European Commission. Available at https://health.ec.europa.eu/blood-tissues-cells-and-organs/ organs_en?utm_source=chatgpt.com. Accessed June 26, 2025.

2. Newsroom. Newsletter Transplant 2023 — Informing the future of transplantation. Council of Europe, European Directorate for Quality of Medicines & HealthCare. Available at https://www.edqm.eu/en/-/ newsletter-transplant-2023-informing-the-future-of-transplantation. Accessed June 26, 2025.

3. Lebranchu Y. [Advances in transplantation: Conclusion]. *Bull Acad Natl Med*. 2022;206(4):551-553.

4. Krisl JC, Doan VP. Chemotherapy and transplantation: the role of immunosuppression in malignancy and a review of antineoplastic agents in solid organ transplant recipients. *Am J Transplant*. 2017;17(8):1974-1991.

5. Guillemin A, Rousseau B, Neuzillet C, et al. Cancers solides après transplantation d'organe: épidémiologie, pronostic et spécificités de prise en charge. *Bull Cancer (Paris)*. 2017;104(3):245-257.

6. Coupier A, Gallien Y, Boillot O, et al. Antineoplastic chemotherapy and immunosuppression in liver transplant recipients: squaring the circle? *Clin Transplant*. 2023;37(1):e14841.

7. Remon J, Auclin E, Zubiri L, et al. Immune checkpoint blockers in solid organ transplant recipients and cancer: the INNOVATED cohort. *ESMO Open*. 2024;9(5):103004.

8. Greater Paris University Hospitals. Cohort360 - A web application to find patients, build cohorts and visualize health records. Available at https://github.com/aphp/Cohort360. Accessed December 5, 2024.

9. Carencó C, Assenat E, Faure S, et al. Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship. *Am J Transplant*. 2015;15(3):678-686.

10. Gong CS, Yoo MW, Kim BS, et al. De novo gastric cancer after liver transplantation. *Ann Transplant*. 2016;21:386-391.

11. Fröhlich FA, Halleck F, Lehner L, et al. De-novo malignancies after kidney transplantation: a long-term observational study. *PLoS One*. 2020;15(11):e0242805.

12. Rossetto A, Tulissi P, De Marchi F, et al. De novo solid tumors after kidney transplantation: is it time for a patient-tailored risk assessment? Experience from a single center. *Transplant Proc*. 2015;47(7):2116-2120.

13. Puigvéhí M, Hashim D, Haber PK, et al. Liver transplant for hepatocellular carcinoma in the United States: evolving trends over the last three decades. *Am J Transplant*. 2020;20(1):220-230.

14. Abramyan S, Hanlon M. Kidney transplantation. In: StatPearls. *Treasurer Island, FL*. StatPearls Publishing; 2025.

15. Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of cancer risk among US solid organ transplant recipients. *JAMA*. 2011;306(17):1891-1901.

16. Al-Adra D, Al-Qaoud T, Fowler K, Wong G. De novo malignancies after kidney transplantation. *Clin J Am Soc Nephrol*. 2022;17(3):434-443.

17. Friman TK, Jäämaa-Holmberg S, Åberg F, et al. Cancer risk and mortality after solid organ transplantation: a population-based 30-year cohort study in Finland. *Int J Cancer*. 2022;150(11):1779-1791.
18. Wang R, Huo Z, Ge F, et al. Risk of hematological malignancies in solid organ transplant recipients: a meta-analysis. *Transplantation*. 2020;104(suppl 3):S596-S597.

19. Wang JH, Pfeiffer RM, Musgrove D, et al. Cancer mortality among solid organ transplant recipients in the United States during 1987–2018. *Transplantation*. 2023;107(11):2433-2442.

20. Doycheva I, Amer S, Watt KD. De novo malignancies after transplantation. *Med Clin North Am*. 2016;100(3):551-567.

21. Lee EM, Jiménez-Fonseca P, Galán-Moral R, et al. Toxicities and quality of life during cancer treatment in advanced solid tumors. *Curr Oncol Tor Ont*. 2023;30(10):9205-9216.

22. Leyvraz S, Ketterer N, Perey L, et al. Intensification of chemotherapy for the treatment of solid tumours: feasibility of a 3-fold increase in dose intensity with peripheral blood progenitor cells and granulocyte colony-stimulating factor. *Br J Cancer*. 1995;72(1):178-182.

23. Kalil AC, Sandkovsky U, Florescu DF. Severe infections in critically ill solid organ transplant recipients. *Clin Microbiol Infect*. 2018;24(12):1257-1263.

24. Lyons PG, McEvoy CA. Septic shock in patients with solid malignancies: what does the host response yield when the host is already under threat? *Chest*. 2022;162(5):951-953.

25. Mehtani R, Saigal S. Long term complications of immunosuppression post liver transplant. *J Clin Exp Hepatol*. 2023;13(6):1103-1115.

26. Jani AA, Chen P. Infections after Solid Organ Transplantation. Medscape. Available at https://emedicine.medscape.com/article/430550-overview?form=fpf. Accessed December 7, 2024.

27. Gudiol C, Albasanz-Puig A, Cuervo G, Carratalà J. Understanding and managing sepsis in patients with cancer in the era of antimicrobial resistance. *Front Med*. 2021;8:636547.

28. Cangemi M, Montico B, Faè DA, Steffan A, Dolcetti R. Dissecting the multiplicity of immune effects of immunosuppressive drugs to better predict the risk of de novo malignancies in solid organ transplant patients. *Front Oncol*. 2019;9:160.

29. Hellemans R, Pengel LHM, Choquet S, Maggiore U. for ESOT Work-stream 3 of the TLJ (Transplant Learning Journey) project. Managing immunosuppressive therapy in potentially cured post-kidney transplant cancer (excluding non-melanoma skin cancer): an overview of the available evidence and guidance for shared decision-making. *Transpl Int*. 2021;34(10):1789-1800.

30. Yang D, Thamcharoen N, Cardarelli F. Management of immunosuppression in kidney transplant recipients who develop malignancy. *J Clin Med*. 2019;8(12):2189.

31. Hope CM, Krige AJ, Barratt A, Carroll RP. Reductions in immunosuppression after haematological or solid organ cancer diagnosis in kidney transplant recipients. *Transpl Int*. 2015;28(11):1332-1335.

32. Gioco R, Corona D, Agodi A, et al. De novo cancer incidence and prognosis after kidney transplantation: a single center analysis. *Transplant Proc*. 2019;51(9):2927-2930.

33. Maggiore U, Palmisano A, Buti S, et al. Chemotherapy, targeted therapy and immunotherapy: which drugs can be safely used in the solid organ transplant recipients? *Transpl Int*. 2021;34(12):2442-2458.

34. Holdaas H, De Simone P, Zuckermann A. Everolimus and malignancy after solid organ transplantation: a clinical update. *J Transplant*. 2016;2016:4369574.

35. Wojciechowski D, Wiseman A. Long-term immunosuppression management: opportunities and uncertainties. *Clin J Am Soc Nephrol*. 2021;16(8):1264-1271.

36. Gutiérrez-Dalmau A, Revuelta I, Campistol JM. Renal transplantation and cancer: focus on immunosuppressive therapy. *Trends Transplant*. 2007;1:3-14.

37. De Simone P, Precisi A, Lai Q, et al. Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. *Medicine and Pharmacology*. 2024. Available at https://www.preprints.org/manuscript/202401.1027/v1. Accessed December 7, 2025.

38. Murakami N, Mulvaney P, Danesh M, et al. A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant. *Kidney Int*. 2021;100(1):196-205.

39. Wassmer CH, El Hajji S, Papazarkadas X, et al. Immunotherapy and liver transplantation: a narrative review of basic and clinical data. *Cancers*. 2023;15(18):4574.