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The RESIRT trial is the first clinical trial to evaluate selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) resin microspheres as a potential treatment for primary renal cell carcinoma (RCC).
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No dose-limiting toxicity was observed at intended radiation doses of 75, 100, 150, 200, 300 Gy and “imminent stasis.”
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Best overall tumour responses were partial response in 4.8%, stable disease in 90.5%, and progressive disease in 4.8% of patients, suggesting that SIRT with Y-90 resin microspheres may be a feasible treatment option for RCC.
Abstract
Introduction
Selective internal radiation therapy (SIRT) is a potential treatment of primary renal cell carcinoma (RCC) deemed unsuitable for conventional therapy. RESIRT is the first-in-human study to evaluate safety and feasibility of SIRT for primary RCC.
Patients and Methods
Patients with RCC, unsuitable for, or who declined conventional therapy, were eligible. A single transfemoral micro-catheter administration of yttrium-90 (Y-90) resin microspheres (SIR-Spheres) was delivered super selectively via the renal artery to the tumour at intended radiation doses of 75, 100, 150, 200, 300 Gy and a final cohort with a procedural endpoint of “imminent stasis,” in a dose-escalation design. Post-SIRT follow-up was 12 months. Study endpoints included safety and toxicity 30-days and 12-months post-SIRT and tumour response (RECIST v1.1).
Results
In total, 21 patients were enrolled, mean (SD) age was 75 (9.3) years, WHO performance status was 0 in 81%, 12 (57%) had stage 3 chronic kidney disease, and 7 (33%) had prior contralateral nephrectomy. Overall, 71% of patients completed 12 months of follow-up. Intended doses were delivered without any dose-limiting toxicity. Seventeen out of 21 (81%) patients experienced an adverse event (AE) from any cause within 30 days post-SIRT; all SIRT-related AEs were grade 1 to 2. Best overall tumour responses were partial response 1/21 (4.8%), stable disease 19/21 (90.5%) and progressive disease 1/21 (4.8%).
Conclusion
This study demonstrated good tolerability of SIRT at all dose levels including “imminent stasis” in treating primary tumours in RCC patients otherwise unsuitable for conventional therapy. SIRT with Y-90 resin microspheres may be a feasible treatment option for RCC.
According to The Global Cancer Observatory, there were over 400,000 new cases of, and nearly 180,000 deaths from, renal cell carcinoma (RCC) worldwide in 2020.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Version 4.2022. 2021 [cited 2022 18 January]; Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf (Access date: 18 January 2022).
but a proportion of patients are not suitable for surgery. Patients may be too old or frail, or harbour co-morbidities that pose an anaesthetic challenge, or nephron loss from the surgical procedure may risk renal failure. Furthermore, up to 5% of patients in stage 1 RCC (ie, small tumours confined to kidney and with no nodal involvement or metastases) and 30% to 70% of patients in stages 2 to 4 RCC (ie, larger tumours and/or nodal involvement and/or metastases) at the time of surgery will relapse and will have a poor prognosis.
Management approaches for patients with RCC not suitable for surgery currently include active surveillance or ablation (eg, radiofrequency ablation [RFA] or cryoablation) for localised disease, and stereotactic body radiotherapy (SBRT) for medically inoperable patients with stage I or stage II/III RCC.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Version 4.2022. 2021 [cited 2022 18 January]; Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf (Access date: 18 January 2022).
Novel treatment approaches are required for patients with RCC unsuitable for nephrectomy or ablation.
Tumour-directed radiotherapy may be effective for patients with advanced RCC who require local disease control, including those with haematuria or pain, existing co-morbidities and/or chronic kidney disease (CKD).
Selective internal radiation therapy (SIRT; also known as radioembolisation) – an established procedure for treating liver tumours – may have a potential role in controlling primary RCC by taking advantage of its hypervascular nature which enhances treatment uptake by the tumour. The potential to use SIRT directed to the kidney has been assessed and demonstrated in a porcine model in pre-clinical studies,
in which we showed that highly targeted intra-arterial radiotherapy to the kidney was feasible and safe. In pigs, SIRT with 90yttrium (Y-90) resin microspheres (SIR-Spheres, SIRTEX Medical) produced highly localised necrosis/fibrosis, without any effect on surrounding nephrons. Moreover, this effect was more marked with Y-90 resin microspheres than with bland microspheres.
RESIRT is the first human study of SIRT in patients with RCC who are unsuitable for conventional curative treatment. The primary objective of the study was to assess safety and toxicity of Y-90 resin microspheres using a dose escalation study design.
Materials and Methods
Study Design
This dose escalation study of SIRT using Y-90 resin microspheres was conducted at a single centre (Australian New Zealand Trials Registry: Trial ID. ACTRN12610000690055). All relevant institutional and local ethical committee approval was gained before commencing the study, and patients gave informed consent.
Patients were serially recruited into dose escalating cohorts and received 75 Gray (Gy), 100 Gy, 150 Gy, 200 Gy, and 300 Gy intended radiation dose to the tumour, with 3 patients in each dose cohort according to a standard 3+3 Phase I dose-escalation design. If no dose-limiting toxicity (DLT) was evident at the given radiation dose, the next 3 recruited patients received the next highest radiation dose. If no DLT was evident following completion of recruitment into the 300 Gy cohort, then a final cohort of 6 patients was recruited with the angiographic observation of “imminent stasis” (where the back-pressure resulting from the microspheres in the renal artery was just below that required to stop forward flow) serving as the endpoint for delivery of Y-90 resin microspheres regardless of the actual dose delivered. If a DLT was detected at any radiation dose level, the remaining patients were given the same radiation dose or a lower radiation dose level until the maximum tolerated dose (MDT) was determined. A DLT was defined as any grade ≥3 adverse event occurring during the first 30 days after the administration of Y-90 resin microspheres that were judged as possibly, probably, or certainly related to SIRT excluding abdominal pain, nausea, vomiting and fever.
Study Patients
Adult patients with histologically confirmed (n = 13) or radiologically or clinically classified (n = 8) primary RCC, a life expectancy of at least 3 months, and unequivocal and measurable magnetic resonance imaging (MRI) evidence of primary RCC for which treatment by surgical resection, local ablation or other conventional techniques with curative intent was not suitable, required immediately or was declined by the patient, were included in the study. Patients with all tumour stages including metastatic disease (other than untreated central nervous system metastases) were permitted. Other than radiotherapy to the kidney, previous therapy for primary RCC was allowed, provided that such therapy was administered and completed at least 45 days before study entry. Patients also had a WHO performance status 0 to 2, and adequate haematological (neutrophils >1.5 × 109/L; platelets >100 × 109/L) and renal (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2 or ≥25 mL/min/1.73 m2 provided eGFR increased to ≥30 mL/min/1.73 m2 after hydration) function. Patients were excluded if they were pregnant or breastfeeding or if they had: previous external beam radiotherapy to the kidney or within a 5 cm margin; subsequent therapy planned within 32 days of the delivery of SIRT; renal-to-lung shunt fraction that indicated potential exposure of the lung to an absorbed radiation dose of more than 20 Gy from the microspheres; inadequate renal function; or equivocal, immeasurable, or unevaluable primary RCC in the kidney.
Procedures
Pre-SIRT assessment conducted within 45 days of study entry included: a non-contrast computed tomography (CT) scan of the chest to assess the presence and extent of metastases; MRI of the abdomen and pelvis, and ultrasound of the kidney to assess the extent of kidney disease and presence and extent of metastases; and diethylenetriamine pentaacetate (DTPA) clearance to qualitatively assess baseline renal function (eGFR calculated from serum creatinine values using the Cockcroft-Gault formula).
Typical characteristics of RCC on an MRI scan was used to confirm the diagnosis of RCC if no histological evidence or cytological evidence was available.
Suitability for SIRT was also assessed within 45 days of study entry. Angiographic evaluation to determine the vascular anatomy of the kidney and assess kidney-to-lung shunt (using technetium-99m macroaggregated albumin [99mTc-MAA]) was performed before SIRT (Supplementary Table 1). A safety cut-off of ≤20 Gy total lung radiation was set. A modification of the Partition Model formula was used to calculate the relative activity to the target tumour and the lungs.
Patients received a single trans-femoral micro-catheter administration of SIRT using Y-90 resin microspheres, delivered super-selectively to the tumour via the renal artery via femoral puncture access. Details of the procedure are given in the Supplementary Materials.
No systemic therapy during the study was allowed for any patient. Following SIRT, patients should receive the best available care as determined by the treating-physician. Further systemic chemotherapy or biological therapy should be initiated no sooner than 3 months post-SIRT, and subsequent therapy was at the discretion of the treating physician.
Study Assessments and Endpoints
All patients were assessed for 12 months after SIRT with assessments at 14 days, 30 days, and 3, 6, 9 and 12 months after SIRT. At all timepoints, a physical examination, haematology, biochemistry and urinalysis, and adverse event assessment were conducted. At all timepoints except the 14-day visit, MRI of the pelvis and abdomen, ultrasound of the kidney, and quality of life (QoL) assessment (RCC-specific QoL questionnaire)
The primary study endpoint was the safety and toxicity up to 30 days post-SIRT, as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Secondary endpoints included: tumour response by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. (a maximum of 5 target lesions were identified using MRI or CT and the sum of the longest diameter recorded; best response was reported except when progressive disease [PD] was observed at the first follow-up, in which case the response was recorded as PD irrespective of subsequent follow-up measurement); progression-free survival (PFS) defined as the time between study entry and tumour progression (renal or extra-renal) on imaging; overall survival (OS) from study entry; and QoL assessed by the RCC QoL Symptom Index. Descriptive statistics were used for all endpoints. T-tests between baseline and each timepoint were also conducted for most parameters measured. Kaplan-Meier statistics using a log-rank test were conducted to assess median OS and PFS with 95% confidence intervals (CI).
Results
Patient Characteristics
Overall, 21 patients (mean age: 75 years; male: 71%) were recruited between 2011 and 2016; 3 in each dosage group and 6 in the “imminent stasis” cohort (Figure 1). Fifteen out of 21 patients (71.4%) completed 12 months of follow-up. One patient withdrew consent during the 12 months, and 5 patients died within 12 months of the SIRT procedure (1 in the 75 Gy cohort, 1 in the 300 Gy cohort and 3 in the ‘imminent stasis’ cohort). Median duration of follow-up was 12.0 months (95% CI, 11.9-12.1).
At baseline, 23.8% had CKD stage 1, 19.0% had CKD stage 2, and 57.1% had CKD stage 3 (Table 1). Nine patients had previous surgery or therapy, with some patients having multiple previous interventions for RCC (Table 1). In total, 8 (38.1%) patients had at least 1 non-target lesion. The average activity delivered was 233.9 MBq: 133.8 Gy to the renal tumour and 3.1 Gy to the lungs. Two patients received other cancer treatments after SIRT: after leaving the study (ie, more than 12 months after SIRT) 1 patient received pazopanib, radiotherapy and spinal surgery; and 1 patient received subsequent treatment with pazopanib.
Table 1Baseline patient and disease characteristics.
There was no DLT at any dose level. Within 30 days post-SIRT, 17 patients experienced an adverse event (AE) from any cause (Table 2). Of the AEs occurring in the first 30 days that were considered related to SIRT, all were grade 1 to 2 and none was a serious AE (SAE). All 21 patients experienced at least 1 AE during the 12 months’ follow-up (Table 2). A total of 240 AEs were reported before or after SIRT and 130 (54.2%) of these were grade 1 AEs, 81 (33.8%) grade 2, 17 (7.1%) grade 3, 1 (0.4%) grade 4, and 10 (4.2%) grade 5. Overall, 103 of the 240 AEs required treatment.
Table 2Safety Outcomes - Adverse Events
Adverse Events
75 Gy (n = 3)
100 Gy (n = 3)
150 Gy (n = 3)
200 Gy (n = 3)
300 Gy (n = 3)
Imminent stasis (n = 6)
All Patients (n = 21)
Primary endpoint: all-cause AEs in the 30 d after SIRT
Treatment-emergent AEs (TEAEs) occurring in >20% of patients in the 12 months’ follow-up period included fatigue (38.1%), back pain (28.6%), vomiting (28.6%), decreased appetite (23.8%), dyspnoea (23.8%), and peripheral oedema (23.8%). TEAEs considered possibly, probably, or definitely related to SIRT included: nausea (1 patient), discomfort/fatigue/pain (6 patients), contusion/procedural pain (2 patients), decreased appetite/hypomagnesaemia (2 patients), lethargy (1 patient), renal pain (1 patient), and hypertension (2 patients).
Of the 10 (47.6%) patients that experienced 31 SAEs in the 12 months after SIRT (Table 2), the most common system organ classes (>10% of patients) were: general disorders (4 patients [19.0%]), injury/procedural (3 [14.3%]), neoplasms (3 [14.3%] all metastatic RCC), and respiratory disorders (3 [14.3%]). SAEs in the 12 months after SIRT were observed in 2, 1, 1, 2, and 4 patients in the 75 Gy, 100 Gy, 200 Gy, 300 Gy and “imminent stasis” cohorts, respectively. No SAEs or grade ≥3 AEs were considered to be related to SIRT.
Overall, 5 patients experienced an AE with an outcome of death. One patient in the 75 Gy cohort had the cause of death as renal failure. One patient in the 300 Gy cohort had 2 SAEs with an outcome of death (general physical health deterioration and mRCC) due to disease progression. One patient in the ‘imminent stasis’ cohort had 2 SAEs (multiple organ dysfunction syndrome and mRCC) and the cause of death was recorded as multiple organ failure. One patient in the “imminent stasis” cohort had an SAE of peri-renal haematoma (but with no evidence of disease progression according to the investigator) with an outcome of death. One patient in the “imminent stasis” cohort had 4 unresolved SAEs (cellulitis, respiratory tract infection, pulmonary congestion, and pulmonary oedema) when they died; the specific cause of death was recorded as mRCC disease progression. Of these, the grade 5 renal failure occurred suddenly 7 months after SIRT in the context of disease progression and possible sepsis, as well as hypercalcemia and possible immune suppression (long term steroids for polymyalgia rheumatica); it was not considered a cause of death or related to study procedure by the treating physician. The patient who developed a haematoma around the kidney was admitted with over-warfarinisation (INR >4) 11 months after SIRT, with an asymptomatic finding of peri-renal hematoma; there was no evidence of bleeding within the kidney itself, suggesting this was not the source of the hematoma; this event was considered unrelated to the SIRT by the treating physician.
Renal Function
There was a minor reduction in mean creatinine clearance from baseline to 12 months (baseline: 76.1 mL/min; 12 months: 66.5 mL/min; Figure 2) that was not considered to be clinically meaningful. Since eGFR overestimates renal function due to creatinine secretion by the proximal tubule, we also evaluated GFR by DTPA, which is considered a better measurement of renal function in this patient population. There was no deterioration in DTPA-determined renal function (Figure 3), where the median remained between approximately 60 mL/min and 50 mL/min for 12 months. There was also a minor increase in blood creatinine and urea levels from baseline to 12 months (creatinine: 103.8 μmol/L at baseline, 110.6 μmol/L at 12 months; urea: 7.9 mmol/L at baseline, 8.5 mmol/L at 12 months); however, these differences were also not considered to be clinically meaningful. GFR, measured by DTPA clearance, remained near to the baseline value throughout the study (Figure 3). Other biochemical markers, including albumin levels and aspartate aminotransferase, were statistically significantly reduced from baseline at 12 months but these changes were not considered to be clinically important. No patient required dialysis.
Figure 2Creatinine clearance from baseline to 12 months.
At the end of study, best overall tumour responses were partial response (PR) in 1/21 (4.8%), stable disease (SD) in 19/21 (90.5%), and PD in 1/21 (4.8%). Best renal target tumour response was PR 9.5%, SD 85.7% and PD 4.8% (Figure 4).
Figure 4Sum of target lesions volume response per patient: maximal percentage decrease from baseline.
OS at 12 months was 76.2% (16/21) (Figure 5A), and not enough deaths occurred to calculate a median OS. PFS at 12 months was 52.4% (11/21) (Figure 5B), and median (95% CI) PFS was 12 (7.2-not reached) months.
Figure 5Overall (A) and progression-free (B) survival until end of study, intent to treat (ITT) population.
QoL scores remained relatively stable from baseline up to 12 months. The mean RCC transformed composite QoL score (range from 0 [worst] to 100 [best]) was 74.6 at baseline and 75.8 at 12 months post-SIRT. At 12 months, the mean (SD) change from baseline in RCC transformed composite QoL score was -3.5 (14.4; P = .364). There were no significant changes from baseline in the 12 domains related to QoL over the 12 months of follow-up, except for an improved incontinence score at day 30 (P = .020).
Discussion
RESIRT is the first human study to evaluate SIRT as treatment for primary RCC that aimed to assess safety as its primary objective. The RESIRT study demonstrated good tolerability of SIRT at all dose levels, including “imminent stasis,” in treating primary tumours in RCC patients unsuitable for conventional therapy. Reasons for patients being considered unsuitable for conventional therapy included age and frailty, significant co-morbidities precluding a general anaesthetic for surgery, or borderline renal function where nephron ablating surgery may have been deemed high risk for subsequent renal failure.
In designing this study, the investigators were concerned about the potential for radioactive microspheres to cause more renal dysfunction, despite the lack of renal toxicity in our porcine model.
As a precaution, patients could be admitted to hospital overnight after the procedure (at the investigator's discretion), but minimal acute toxicity was observed (Table 2). Moreover, careful evaluation of renal function over 12 months showed no clinically meaningful fall in eGFR in the study population and no deterioration in renal function in patients with CKD at baseline (n = 12).
No DLT was reached at any dose level. SIRT was technically feasible for RCC in all patients enrolled in the study. The most common system organ classes of AE were expected given that this was a cancer study, and all SIRT-related AEs were grade 1 or 2. Some SIRT-related AEs were associated with the procedure (eg, 2 patients had contusion/procedural pain). Five (23.8%) patients died; however, no deaths were considered related to SIRT or the procedures by the treating physicians. One death from sudden onset renal failure and 1 death due to over-warfarinisation and a peri-renal haematoma occurred at 7 and 11 months post-SIRT, without any intervening complications or deterioration in organ function. Late effects of radiation damage including fibrosis and ectatic blood vessels in the irradiated area typically occur years after radiation treatment, and whilst these may be possible mechanisms implicated in the death of these 2 patients, this is unlikely, given the timeframe and the alternative diagnoses considered by the treating physicians. As outlined in the results, there were other disease and patient factors that could readily explain these deaths, but a possible relationship to the SIRT procedure cannot be fully ruled out. The number of deaths reported here following the study was also not unexpected given the nature of the study and the poor baseline health characteristics of the study population that precluded a general anaesthetic in the first place.
Radiofrequency ablation, cryoablation, and SBRT are now considered alternative treatment options for medically inoperable RCC. Radiofrequency ablation has shown to be safe, nephron-sparing, and effective, but its use is generally limited to tumours less than 4 cm in diameter. Cryoablation may be used for larger tumours but its use for tumours greater than 3 and 3.5 cm may lead to increases in the probability of tumour recurrence, and intraoperative complications, respectively.
The RESIRT study was initiated before these options became broadly available in Australia. SBRT has also been assessed for RCC, with promising data on toxicity (a systematic review suggested grade ≥3 AEs occurring in just 3.8% of patients) and efficacy (local control rates ranged from 84% to 100%).
While results from our study suggest that SIRT would appear to have similar renal safety and function profiles versus other tumour-directed radiotherapies, more studies are needed to assess the comparative safety of SIRT versus other alternative non-surgical treatment options for RCC, in the same patient population. RESIRT was primarily a safety, feasibility and dose-finding study with a small patient population.
SIRT demonstrated good disease control of the target tumours with most patients’ disease state remaining stable or achieving a partial response, in spite of being a Phase I study, where the primary aim was safety and feasibility, and where some patients were ‘under-dosed’ in a dose-escalation design. The patient with PD had a 25.6% increase in the sum of the longest diameters of target lesions at 30 days (Figure 4) and was classified as PD according to the protocol, but 12 months after receiving SIRT, the target lesion in this patient was reduced by 27.9% from baseline. Furthermore, 76.2% of patients survived throughout the study and 52.4% finished the study progression-free. SIRT had no major effect on 12 QoL-related domains over 12 months of follow-up. In at least 2 patients, the RCC was able to be retreated with Y-90 resin microspheres on compassionate use, more than 12 months after initial treatment with no additional toxicity noted. In no patients was surgery attempted after the SIRT procedure, confirming that this group of patients were not suitable for surgery at baseline. By comparison, in studies of patients with RCC undergoing active surveillance a mean tumour growth rate of 0.79 cm/yr
This is the first prospectively designed clinical trial to report on the safety of SIRT for RCC and it provides guidance on the dosimetry for future clinical investigations. Patients included in RESIRT were ineligible (or unwilling) for surgery, local ablation or other therapies with curative intent, and such a population may be the most suitable RCC patients to receive SIRT. Findings from this study do not provide information on the safety or efficacy of Y-90 resin microspheres in combination with other treatments. Anecdotal evidence following this study suggests that subsequent repeated SIRT, cryoablation, or cryoablation in combination with tyrosine kinase inhibitors was possible. Combination therapy may be an important focus of future research, as novel systemic therapies for RCC have emerged since the RESIRT study was conducted. In particular, there is a theoretical synergy between SIRT and immunotherapies that may augment the anti-tumour effect,
A phase II open-label, single-center, nonrandomized trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: CA 209-678.
A pilot feasibility study of yttrium-90 liver radioembolization followed by durvalumab and tremelimumab in patients with microsatellite stable colorectal cancer liver metastases.
Limitations of this study relate to the relatively small overall patient population and absence of a comparator arm. However, RESIRT is a Phase I study, and as such, designed only to provide information on safety and tolerability, as well as signals regarding potential efficacy. Comparisons cannot be made to other tumour-directed therapies, particularly cryoablation, radiofrequency ablation, and SABR, where randomised studies are yet to be conducted.
Conclusion
In summary, the RESIRT study suggests that SIRT with Y-90 resin microspheres is well tolerated, even up to 300 Gy doses. Blocking the super-selected artery with microspheres to the extent that blood flow ceased was a feasible strategy and did not cause deterioration in renal function. SIRT may ultimately be a reasonable treatment option for patients with RCC who are unsuitable for conventional therapy, and warrants further clinical study.
Clinical Practice Points
Partial or radical nephrectomy offers a potential cure for RCC, but a proportion of patients are not suitable for surgery. Furthermore, a considerable number of RCC patients relapse following surgery and have a poor prognosis. Novel treatment approaches are required for patients with RCC who are not suitable for conventional therapies. Tumour-directed radiotherapy may be effective for patients with advanced RCC who require local disease control. Selective internal radiation therapy (SIRT; also known as radioembolisation) may have a potential role in primary RCC in patients who are unsuitable for nephrectomy due to patient factors such as age and frailty, as well as tumour factors such as position or size of tumour, that creates challenges in maintaining kidney function while controlling the disease. This is the first prospectively designed clinical trial to report on the safety of SIRT for RCC and the results provide guidance on the dosimetry for future clinical investigations. In addition, SIRT demonstrated good disease control of the target tumours with most patients’ disease state remaining stable or achieving a partial response. Renal toxicity was minimal in this study.
Acknowledgments
The authors would like to thank Manish Patel, Justin Vass, David N. Cade for their contributions to this work. The authors take full responsibility for the content of this paper and thank Martin Gilmour of Empowering Strategic Performance (ESP) Ltd, Crowthorne, UK (supported by SIRTEX Medical) for editorial assistance in the preparation of the manuscript.
The RESIRT trial was funded by SIRTEX Medical . SIRTEX arranged funding, monitored the progress of the study, collated the findings, and provided assistance in the drafting of this manuscript according to Good Publication Practice. SIRTEX had no role in the study design, recruitment of patients, procedures, data collection, analysis or interpretation of the findings.
Disclosure
Paul L. de Souza is a consultant for Harbour Biomed, and served on a renal cancer advisory board for Eisai Australia Pty Ltd. The remaining authors have stated that they have no conflicts of interest.
CRediT authorship contribution statement
Paul L. de Souza: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. Peter Aslan: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. William Clark: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Project administration, Writing – original draft, Writing – review & editing. Ramy Nour: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Suresh de Silva: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Version 4.2022. 2021 [cited 2022 18 January]; Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf (Access date: 18 January 2022).
A phase II open-label, single-center, nonrandomized trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: CA 209-678.
A pilot feasibility study of yttrium-90 liver radioembolization followed by durvalumab and tremelimumab in patients with microsatellite stable colorectal cancer liver metastases.
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