International Journal of Clinical Oncology (2024) 29:1538–1547

https://doi.org/10.1007/s10147-024-02598-w

ORIGINAL ARTICLE

Comparative analysis of dual immune checkpoint inhibitor

combination therapy versus immune checkpoint inhibitor
plus tyrosine kinase inhibitor combination therapy for renal cell
carcinoma with inferior vena cava tumor thrombosis
Kazuhiko Yoshida1 · Naoki Nagasaka2 · Tsunenori Kondo2 · Yuki Kobari1 · Hiroki Ishihara1 · Hironori Fukuda1 ·
Junpei Iizuka1 · Hideki Ishida1 · Toshio Takagi1

Received: 29 April 2024 / Accepted: 30 July 2024 / Published online: 7 August 2024
© The Author(s) under exclusive licence to Japan Society of Clinical Oncology 2024

Abstract
Background Whether immune checkpoint inhibitor (ICI) plus ICI combination therapy or ICI plus tyrosine kinase inhibi-
tor (TKI) combination therapy is useful for renal cell carcinoma (RCC) with inferior vena cava tumor thrombosis (IVCTT)
remains unclear.
Methods We retrospectively evaluated the therapeutic effects and incidence of treatment-related adverse events (TRAEs)
associated with ICI-based combination therapy in 36 patients with advanced RCC with IVCTT.
Results The median age at initiation of treatment was 71 years; the IVCTT stages were cT3b in 22 patients and cT3c in 14.
The ICI–ICI and ICI–TKI groups comprised 15 and 21 patients, respectively. Median tumor shrinkage at the best response
showed that the primary tumor diameter decreased by 1.8 cm (22%), and the IVCTT height decreased by 1.5 cm (26%). A
higher proportion of patients in the ICI–TKI group experienced tumor shrinkage than those in the ICI–ICI group (primary
tumor, p = 0.0325; IVCTT, p = 0.0112). Approximately 27% of patients experienced an increase in the IVCTT height with
ICI–ICI combination therapy. No significant difference was observed in the relative tumor shrinkage of IVCTT, primary or
level-down staging of IVCTT, other treatment effects, incidence of TRAEs, surgical outcomes, or prognosis between the
groups.
Conclusion ICI-based combination therapy is effective against IVCTT and primary RCC. Although ICI–ICI is associated
with a higher probability of tumor growth compared with ICI–TKI in the frequency of tumor regression, both therapies may
be almost equally effective against primary RCC with IVCTT.

Keywords Immune checkpoint inhibitor · Inferior vena cava · Thrombus · Renal cell carcinoma

* Kazuhiko Yoshida Junpei Iizuka

kzyoshida1@yahoo.co.jp jpiizuka@gmail.com
Naoki Nagasaka Hideki Ishida
nagasaka.naoki@twmu.ac.jp kzykz123-456@yahoo.co.jp
Tsunenori Kondo Toshio Takagi
kondo.tsunenori@twmu.ac.jp t.takagi1192@gmail.com
Yuki Kobari 1
Department of Urology, Tokyo Women’s Medical
yuukikobari17@gmail.com
University, 8‑1, Kawada‑cho, Shinjuku‑ku, Tokyo 162‑8666,
Hiroki Ishihara Japan
ishihara.hiroki@twmu.ac.jp 2
Department of Urology, Tokyo Women’s Medical University
Hironori Fukuda Adachi Medical Center, 4‑33‑1, Kouhoku, Adachi‑ku, Tokyo,
5613fdk@live.jp Japan

Vol:.(1234567890)
International Journal of Clinical Oncology (2024) 29:1538–1547 1539

Introduction The following clinical data were collected from patients’

medical records and electronic databases: sex, age at the
Renal cell carcinoma (RCC) is the most common type of initiation of initial treatment, Eastern Cooperative Oncol-
kidney cancer. The prevalence of RCC with inferior vena ogy Group performance status (ECOG-PS), tumor laterality,
cava tumor thrombosis (IVCTT) is approximately 4–10% International Metastatic RCC Database Consortium (IMDC)
[1]. [12], and 2009 tumor, node, metastasis classification [13]).
Currently, immune checkpoint inhibitors (ICIs) and IVCTT was staged using the Neves–Zincke’s classification
ICI-based combination therapies are rapidly advanc- [14].
ing therapeutic strategies for the systemic treatment of
advanced RCC. Recent guidelines strongly recommend Treatment outcomes of ICI‑based combination
ICI-based combination therapy as the first-line treatment therapy
for advanced RCC [2–4]. Several clinical trials and reports
on ICI-based combination therapies have also demon- This study assessed the effectiveness of ICI-based combina-
strated higher efficacy for primary lesions in RCC [5–10]. tion therapy by evaluating tumor factors, e.g., the maximum
However, the efficacy of ICI-based combination therapy, diameter of the primary tumor, height of the IVCTT distance
which is currently recommended as the first-line treatment above the renal vein, and IVCTT level category change at
for IVCTT in RCC, remains underexplored. We previously the best response during treatment [11]. There were assessed
reported ICI-based combination therapies’ benefits for using computed tomography (CT) or magnetic resonance
RCC with IVCTT [11]. ICI-based combination therapies imaging. Histopathological diagnosis was evaluated using
are attracting increasing interest owing to their potential pretreatment renal biopsy. Surgical outcomes of selected
to reduce IVCTT and achieve less invasive treatments. patients with RCC with IVCTT were also examined. Addi-
The combination therapies of ICI–ICI or ICI–tyrosine tionally, the histopathological effects after ICI-based com-
kinase inhibitor (TKI) differ in terms of efficacy, safety, bination therapy were evaluated in patients who underwent
and appropriate use; selection should be based on indi- radical nephrectomy and inferior vena cava thrombectomy.
vidual patient factors. Whether to use ICI–ICI or ICI–TKI Progression-free survival and overall survival were calcu-
combination therapy for RCC with IVCTT is frequently lated from the initiation of ICI-based combination therapy
considered in clinical practice. Furthermore, no reports until disease progression and death, respectively. Safety
have compared the efficacies of the treatment options for considerations included the development rate of treatment-
IVCTT. Thus, we compared the effectiveness and safety related adverse events (TRAEs), interruption rates of ICI-
of ICI–ICI and ICI–TKI combination therapies in patients based combination treatments, and administration of high
with RCC with IVCTT. doses of corticosteroids. TRAEs were evaluated using the
Common Terminology Criteria for Adverse Events version
5.0.

Patients and methods ICI‑based combination treatment protocol

and surgery technique
Study design
We applied a previously reported protocol of ICI-based
This study was approved by the Institutional Review Board combination therapy as a first-line treatment for RCC with
of Tokyo Women’s Medical University (ID: 2021–0061) and IVCTT [15]. Briefly, for the ICI–ICI group, nivolumab plus
conducted in accordance with the principles of the 1964 ipilimumab was administered to patients with intermediate
Declaration of Helsinki. The requirement for informed con- and poor risk based on the IMDC criteria. For the ICI–TKI
sent was waived owing to the retrospective study design. group, pembrolizumab plus axitinib, avelumab plus axitinib,
nivolumab plus cabozantinib, or pembrolizumab plus len-
vatinib was administered regardless of the patients’ IMDC
Patients and data collection risk classifications [2–4]. The selection of an ICI-ICI or ICI-
TKI combination therapy for advanced RCC varied depend-
At Tokyo Women’s Medical University and Tokyo Women’s ing on the era. Patient factors, tumor factors, treatment effi-
Medical University Adachi Medical Center, 201 patients cacy, and other individual characteristics were considered for
with advanced RCC received ICI-based combination therapy the selection. After treatment, regular follow-ups included
as a first-line treatment between January 2020 and October CT of the chest, abdomen, and pelvis every 4–12 weeks.
2023. Of these, 36 patients with RCC with IVCTT received Additional assessments were also considered, as necessary.
ICI-based combination therapies. The administration of the drugs was continued until clinical
1540 International Journal of Clinical Oncology (2024) 29:1538–1547

disease progression or intolerable adverse events occurred. of tumor reduction because of ICI-based combination treat-
In some cases, treatment was discontinued if a complete ments. Progression-free survival and overall survival were
surgical response was achieved. We considered deferred evaluated using the Kaplan–Meier method and compared
cytoreductive nephrectomy (CN) in patients with RCC with using the log-rank test.
IVCTT during ICI-based combination therapy if there was
a complete or near-complete response at the metastatic sites.
The open and robotic surgical procedures were essentially Results
similar, using techniques described previously [16–18].
Patient characteristics
Statistical analyses
Table 1 summarizes the clinical and demographic character-
All statistical analyses were performed using JMP Pro 17 istics of the patients. Overall, 22 males and 14 females with
software (SAS Institute, Cary, NC, USA), and statistical RCC and concomitant IVCTT received ICI-based combina-
significance was set at a p value of < 0.05. Parameters were tion therapies. The median age at the start of treatment was
compared using the Mann–Whitney U test and Fisher’s exact 71 years (interquartile range [IQR], 55–75 years). Almost all
test. Univariable and multivariable logistic regression analy- patients had an ECOG-PS of 0–1. Statistically, the ICI–TKI
ses were used to evaluate the predictive factors associated group tended to be slightly older and had a relatively higher
with the proportion of patients who experienced any degree prevalence of right renal tumors than the ICI–ICI group.

Table 1  Clinical characteristics of patients with RCC with IVCTT treated with ICI-based combination treatments
Total ICI–ICI ICI–TKI p value
n = 36 n = 15 n = 21

Patient factors
Sex, n (%) Male 22 (61) 11 (73) 11 (52) 0.2036
Age, years, median (IQR) 71 (55–75) 62 (47–72) 72 (65–77) 0.0266
ECOG-PS 0 21 (58) 9 (60) 12 (57) 0.8639
Laterality, n (%) Right 28 (78) 9 (60) 19 (90) 0.0301
IMDC risk classification, n (%)
Intermediate 10 (28) 5 (33) 5 (24) 0.2923
Poor 23 (64) 10 (67) 13 (62)
Unknown 3 (8) 0 3 (14)
Clinical stage, n (%) cT3b 22 (61) 7 (47) 15 (71) 0.1330
cT3c 14 (39) 8 (53) 6 (29)
IVC level category, n (%) I 2 (6) 0 2 (10) 0.3461
II 15 (42) 6 (40) 9 (43)
III 7 (19) 2 (13) 5 (24)
IV 12 (33) 7 (47) 5 (24)
Histopathology, n (%)
Clear cell carcinoma 23 (64) 8 (53) 15 (71) 0.2651
Non-clear cell carcinoma 13 (36) 7 (47) 6 (29)
ICI combination therapy
Nivolumab plus ipilimumab, n (%) 15 (42) 15 (100) – -
Pembrolizumab plus axitinib, n (%) 4 (11) – 4 (19)
Avelumab plus axitinib, n (%) 1 (3) – 1 (5)
Nivolumab plus cabozantinib, n (%) 8 (22) – 8 (38)
Pembrolizumab plus lenvatinib, n (%) 8 (22) – 8 (38)
Post-treatment outcomes
Treatment duration, months, median (IQR) 5 (3–11) 5 (2–15) 5 (3–11) 0.6168
Follow-up period, months, median (IQR) 17 (7–24) 19 (8–32) 13 (5–21) 0.2609

RCC​renal cell carcinoma, IVCTT​inferior vena cava tumor thrombus, ICI immune checkpoint inhibitor, TKI tyrosine kinase inhibitor, ECOG-PS
Eastern Cooperative Oncology Group performance status, IMDC International Metastatic Renal Cell Carcinoma, IQR interquartile range
International Journal of Clinical Oncology (2024) 29:1538–1547 1541

However, other patient and tumor factors were not signifi- at the time of best response were 1.6 cm in the ICI–ICI group
cantly different between the two groups. and 1.9 cm in the ICI–TKI group (p = 0.8572). The tumor
reduction rates were 16% in the ICI–ICI group and 24% in
Efficacy of ICI‑based combination therapy the ICI–TKI group (p = 0.6049). Shrinkage of the primary
against primary tumors and IVCTT​ tumor was observed in 8 patients (53%) in the ICI–ICI group
and 18 patients (86%) in the ICI–TKI group, indicating
The efficacy of the two combination therapies against pri- that the percentage of patients with tumor shrinkage in the
mary tumors and IVCTT is summarized in Table 2. Addi- ICI–TKI group was statistically higher (p = 0.0325). In the
tionally, the best percentage change from baseline in the multivariable analysis, the difference in ICI-based combina-
height of the IVCTT and the diameter of the primary tumor tion therapy, along with the primary tumor, was a significant
in each case are shown in Fig. 1. factor affecting the proportion of patients who experienced
First, treatment efficacy against primary tumors in the tumor shrinkage (Table 3). There were no other statistically
ICI–ICI and ICI–TKI groups was assessed. A significant significant differences between the efficacies of ICI–ICIs and
effect was observed with ICI-based combination therapy, ICI–TKIs against primary tumors.
resulting in a 22% reduction in the primary tumor diameter. Subsequently, the treatment efficacy for IVCTT was
The median reductions in the diameter of the primary tumor assessed in both treatment groups. A significant effect was

Table 2  Efficacy and safety of ICI-based combination treatments for primary tumor and IVCTT​
Total ICI–ICI ICI–TKI p value
n = 36 n = 15 n = 21

The outcomes of response in the primary tumor

The diameter of the primary lesion before treatment mm, median (IQR) 95 (77–109) 100 (89–111) 87 (68–102) 0.0541
The diameter of the primary lesion at best response time mm, median (IQR) 74 (55–88) 79 58–108) 69 (54–84) 0.2287
The differences in treatment efficacy on the maximum diameter mm, median (IQR) 18 (0–36) 16 (-1–43) 19 (5–31) 0.8572
of the primary tumor
Reduction ratio of the diameter of the primary lesion %, median (IQR) 22 (1–40) 16 (-1–41) 24 (6–38) 0.6074
Time to achieve the best response of the diameter of the primary months, median (IQR) 3 (2–7) 6 (3–7) 3 (2–7) 0.3439
tumor
Cases experienced the primary tumor shrinkage of at least any n (%) 26 (72) 8 (53) 18 (86) 0.0325
grade
Cases experienced the primary tumor enlargement of at least any n (%) 5 (14) 3 (20) 2 (10) 0.1736
grade
The outcomes of response in the IVCTT height
The distance of the IVCTT above the renal vein before treatment mm, median (IQR) 70 (38–111) 87 (45–130) 65 (30–92) 0.0803
The distance of the IVCTT above the renal vein at the best mm, median (IQR) 40 (21–85) 70 (25–128) 34 (14–65) 0.1312
response time
The differences in treatment efficacy on the distance of the mm, median (IQR) 15 (2–29) 18 (-14–37) 14 (10–27) 0.5632
IVCTT above the renal vein
Reduction ratio of the height of the IVCTT above the renal vein %, median (IQR) 26 (2–59) 17 (-20–58) 33 (12–62) 0.2046
Time to achieve the best response of the height of the IVCTT​ months, median (IQR) 3 (2–6) 5 (3–7) 3 (2–4) 0.0554
Cases experienced the level-down staging of the IVCTT​ n (%) 15 (42) 7 (47) 8 (38) 0.6071
Cases experienced the level-up staging of the IVCTT​ n (%) 1 (3) 1 (7) 0 0.2301
Cases experienced the IVCTT shrinkage of at least any grade n (%) 27 (75) 8 (53) 19 (90) 0.0112
Cases experienced the IVCTT enlargement of at least any grade n (%) 5 (14) 4 (27) 1 (5) 0.0610
The safety of ICI-based combination therapy
All TRAEs, n (%) n (%) 32 (89) 13 (87) 19 (90) 0.7199
TRAE G1, 2, n (%) n (%) 20 (56) 7 (47) 13 (62) 0.3643
TRAE G3, 4, n (%) n (%) 20 (56) 8 (53) 12(57) 0.8206
irAEs, n (%) n (%) 20 (56) 11 (73) 9 (43) 0.0696
Sustained high-dose steroid, n (%) n (%) 11 (31) 4 (27) 7 (33) 0.6686

ICI immune checkpoint inhibitor, IVCTT​inferior vena cava tumor thrombus, IQR interquartile range, IVCTT​Inferior vena cava tumor thrombus,
TRAE treatment-related adverse event, irAE immune-related adverse event, PD progressive disease
1542 International Journal of Clinical Oncology (2024) 29:1538–1547

Fig. 1  Waterfall Plot analysis: the best percentage change from base- inferior vena cava tumor thrombus, ICI immune checkpoint inhibitor,
line in the height of the IVCTT above the renal vein and the diameter TKI tyrosine kinase inhibitor
of the primary tumor after ICI-based combination treatments. IVCTT​

observed with ICI-based combination therapy, resulting the ICI–TKI group. In the prognostic analysis, there was
in a 26% reduction in IVCTT height and a decrease in the no significant difference in the progression-free survival
IVCTT stage in 15 patients (42%). The median reductions in (p = 0.1072, Fig. 2a) or overall survival between the two
the IVCTT length at the time of best response were 1.8 cm groups (p = 0.4593, Fig. 2b).
in the ICI–ICI group and 1.4 cm in the ICI–TKI group
(p = 0.5632). The IVCTT reduction rates were 17% in the TRAEs of ICI‑based combination therapy
ICI–ICI group and 33% in the ICI–TKI group (p = 0.2046).
The ICI–TKI group had a significantly higher percentage of The safety profiles of the two groups are summarized in
patients who experienced a decrease in the IVCTT height Table 2. G1 or 2 TRAEs were observed in 20 patients (56%),
compared with the ICI–ICI group (ICI–ICI group: 8 patients whereas ≥ G3 TRAEs were observed in 20 patients (56%).
[53%]; ICI–TKI group: 19 patients [90%]; p = 0.0112). Even The incidences of immune-related adverse events (irAEs)
in multivariable analysis, it was shown that compared with were 73% (11 patients) in the ICI–ICI group and 43% (9
ICI–ICI combination therapy, ICI–TKI combination therapy patients) in the ICI–TKI group (p = 0.0696). Eleven patients
was a significant factor influencing the proportion of patients (31%) required high-dose steroid replacement therapy
experiencing tumor regression in IVCTT and the primary (ICI–ICI: four patients [27%] vs. ICI–TKI: seven patients
tumor (Table 3). However, there was no statistically signifi- [33%]; p = 0.6686). There was no difference in the incidence
cant difference in the level-down staging of IVCTT between of TRAEs or irAEs between the two groups, and no cases of
the ICI–ICI group (eight patients [53%]) and the ICI–TKI pulmonary embolism occurred during treatment.
group (eight patients [38%]) (p = 0.3643). Conversely, more
patients experienced an increase in the IVCTT height in the Surgical outcomes after ICI‑based combination
ICI–ICI group (four patients [27%]) than in the ICI–TKI therapy
group (one patient [5%]) (p = 0.0610). Only one patient in
the ICI–ICI group was staged up in the IVCTT level cat- Table 4 details the surgical outcomes of deferred nephrec-
egory. The median durations until the best response of the tomy. In our cohort, deferred nephrectomy was performed
primary lesion were 6 [IQR, 3–7] months in the ICI–ICI on 21 patients, and some patients refused surgery. There
group and 3 [IQR, 2–7] months in the ICI–TKI group, while were no statistically significant differences in operative
those for the IVCTT height were 5 [IQR, 3–7] months in time (ICI–ICI group: 271 min vs. ICI–TKI group: 259 min;
the ICI–ICI group (p = 0.1736) and 3 [IQR, 2–4] months p = 0.4117), estimated blood loss (ICI–ICI group: 1,280 mL
in the ICI–TKI group (p = 0.0554). Although the difference vs. ICI–TKI group: 545 mL; p = 0.1675), or hospitaliza-
was not statistically significant, there was a trend toward a tion duration (ICI–ICI group: 9 days vs. ICI–TKI group:
shorter duration until the best response in IVCTT height in 8 days; p = 0.5241) between the two groups. Additionally, no
International Journal of Clinical Oncology (2024) 29:1538–1547 1543

Table 3  Univariable and multivariable analyses of predictors affecting the proportion of patients with tumor shrinkage against the primary tumor
and IVCTT​
Primary Tumor IVCTT​
Univariable Multivariable Univariable Multivariable
Category factor OR (95% CI) p value OR (95% CI) p value OR (95% CI) p value OR (95% CI) p value

Sex Male (ref. female) 0.9325 0.2233

Age < 70 years 0.8360 2.9091 0.1750 2.1930 0.3675
(ref. ≥ 70 years) (0.6264– (0.3956–
16.2261) 13.305)
ECOG–PS 0 (ref. ≥ 1) 0.5310 0.5548
Laterality Left (ref. right) 0.4954 0.8320
IMDC clas- Intermediate (ref. 4.2000 0.0727 4.2463 0.0925 0.6712
sification poor・unknown) (0.8747– (0.7864–
21.6756) 26.2816)
Clinical T stage T3b (ref. T3c) 0.1155 0.6944
Tumor size ≥ 95 mm 1.0000 0.7008
(ref. < 95 mm)
IVC length ≥ 70 mm 0.1325 0.7001
(ref. < 70 mm)
IVC width ≥ 30 mm 0.7386 0.4396
(ref. < 30 mm)
IVC level IVC I, II (ref. III, 0.1938 0.8470
IV)
Histopathology Clear cell (ref. 0.2873 0.5514
non–clear cell)
ICI combina- ICI–TKI (ref. 5.2500 0.0322 5.2955 0.0405 8.3125 0.0105 7.3832 0.0188
tion therapy ICI–ICI) (1.1476– (1.0730– (1.6068– (1.3766–
29.6879) 33.2947) 64.7287) 58.4045)
TRAE Presence (ref. 0.6668 0.7764
absence)
irAE Presence (ref. 0.5892 0.3090
absence)

OR odds ratio, Cl confidence interval, ECOG-PS Eastern Cooperative Oncology Group performance status, IMDC International Metastatic
Renal Cell Carcinoma, IVCTT​ inferior vena cava tumor thrombus, ICI immune checkpoint inhibitor, TKI tyrosine kinase inhibitor, TRAE treat-
ment-related adverse event, irAE immune-related adverse event

significant differences were observed in other perioperative The efficacy of systemic targeted molecular therapies
complications or transfusion rates. for advanced RCC with IVCTT remains elusive. In patients
Pathological findings showed that two patients (1 in each with metastasis controlled by systemic therapy, complete
group) demonstrated no residual tumor cells in the pri- resection with radical nephrectomy and thrombectomy can
mary tumor and IVCTT, achieving a complete pathologi- improve prognosis because of concerns about complica-
cal response. The number of postoperative progression-free tions such as pulmonary embolism, tumor thrombosis, dis-
cases was 4 (57%) in the ICI–ICI group and 11 (79%) in the ease progression, and new metastasis [19]. Moreover, the
ICI–TKI group (p = 0.3055) (Fig. 3). invasiveness of surgery and perioperative complication risks
are correlated with the extent of IVCTT progression [20].
Systemic therapy in a preoperative setting also mitigates
surgical risks by reducing the IVCTT height [11]. However,
Discussion preoperative treatment with TKIs alone may have a limited
reducing effect on IVCTT [21–24] in contrast to its effect on
This retrospective analysis focused on the effectiveness primary or metastatic tumors, which remains controversial
and safety of ICI-based combination therapy by comparing [25, 26].
ICI–ICI and ICI–TKI combination therapies for the manage- Recent guidelines recommend ICI-based combina-
ment of RCC with IVCTT. To our knowledge, this is the first tion therapy as the first-line treatment option for advanced
study to undertake this comparative analysis. RCC. Several case reports have described the efficacy of
1544 International Journal of Clinical Oncology (2024) 29:1538–1547

ICI-based combination therapies for RCC with IVCTT,

including ipilimumab plus nivolumab [27–29], pembroli-
zumab plus axitinib [30], avelumab plus axitinib [31, 32],
nivolumab plus cabozantinib [33], and pembrolizumab plus
lenvatinib [34]. A few reports have shown that a pathologi-
cal complete response was achieved despite the presence of
IVCTT. We previously reported the effectiveness of ICI-
based combination therapy (ipilimumab + nivolumab and
pembrolizumab + axitinib) for RCC with IVCTT, showing
tumor reduction in all cases [11]. The present study showed
that ICI-based combination therapy resulted in a median
22% reduction in the primary tumor size, a median 26%
reduction in the IVCTT height, and a median 42% reduc-
tion in the IVCTT level category. Our study showed that
ICI-based combination therapies could be sufficiently effec-
tive for RCC with IVCTT. Additionally, both ICI-based
combination therapies demonstrated similar and promising
reduction effects on the primary tumor and IVCTT, and no
significant differences were observed in these results. How-
ever, a higher proportion of patients in the ICI–TKI group
experienced tumor shrinkage than those in the ICI–ICI
group. Furthermore, in the multivariable analysis, the dif-
ference in ICI-based combination therapy, along with the
primary tumor and IVCTT, was a significant factor affect-
ing the proportion of patients experiencing tumor shrink-
age. Given the occurrence of enlargement in 27% of patients
who received ICI–ICI therapy, ICI–TKI therapy may be
superior to ICI–ICI therapy in inducing tumor reduction in
IVCTT. Even in patients with advanced RCC with IVCTT,
a deferred CN can be considered if metastases can be con-
Fig. 2  Survival in patients with RCC with IVCTT after the initiation trolled. Reducing the size of the primary tumor and IVCTT
of ICI-based combination treatments. a Progression-free survival. height in patients with RCC may reduce the risk of surgical
b Overall survival. ICI immune checkpoint inhibitor, TKI tyrosine complications. In some of our cases, downstaging of IVCTT
kinase inhibitor
was due to the potential of ICI-based regimens to provide

Table 4  Surgical outcomes after ICI-based combination treatments in selected patients with RCC wit IVCTT​
Total ICI–ICI ICI–TKI
n = 36 n = 15 n = 21 p value

Surgery after ICI combination therapy

The number of patients treated with deferred CN 21 (58) 7 (47) 14 (67) 0.2301
Open surgery/robot-assisted surgery 15 (71)/6 (29) 6 (86)/1 (14) 9 (64)/5 (36) 0.3055
Time from the initiation of therapy to surgery 4 (3–14) 7 (3–15) 4 (3–9) 0.5172
Operative time, min, median (IQR) 262 (203–375) 271 (218–468) 259 (197–350) 0.4117
Estimated blood loss, mL, median (IQR) 782 (149–1431) 1280 (353–4750) 545 (124–1167) 0.1675
Hospitalization, days, median (IQR) 8 (7–15) 9 (7–19) 8 (6–14) 0.5241
Perioperative complications (G* ≥ 2), n (%) 3 (14) 1 (17) 2 (17) 0.9477
Perioperative transfusion rate, n (%) 12 (57) 6 (86) 6 (43) 0.0614
Pathological findings
Achievement of pathological complete response, n (%) 2 (10) 1 (14) 1 (7) 0.5991
Postoperative progression-free cases, n (%) 15 (71) 4 (57) 11 (79) 0.3055

ICI immune checkpoint inhibitor, CN cytoreductive nephrectomy, IQR interquartile range, G Clavien–Dindo grade (excluding blood transfu-
sions)
International Journal of Clinical Oncology (2024) 29:1538–1547 1545

combination therapy after deferred CN was either to sustain

maintenance ICI treatment or to prevent disease progression.
Approximately 71% of patients remained free from relapse
postoperatively following deferred CN (ICI–ICI group: 54%
vs. ICI–TKI group: 79%, p = 0.3055).
Perioperative management of RCC with IVCTT remains
to be established. Although the difference in ICI-based
combination therapy was a significant factor affecting the
proportion of patients with tumor shrinkage along with the
primary tumor and IVCTT, the lack of statistically signifi-
cant differences between the ICI–ICI and ICI–TKI groups
in terms of other treatment outcomes, surgical outcomes,
and prognoses suggests comparable efficacy between these
therapies. Several reports have described the unique charac-
teristics of each ICI-based combination therapy regimen [35,
Fig. 3  Postoperative progression-free survival after deferred CN in 36]. Our results offer flexibility in treatment choices based
patients treated with ICI-based combination treatments. CN cytore- on individual patient factors and preferences. This study sug-
ductive nephrectomy, ICI immune checkpoint inhibitor, TKI tyrosine gested that ICI-based combination treatments may influence
kinase inhibitor
the traditional sequence of treatment strategies for RCC with
IVCTT.
minimal surgical invasiveness with preoperative treatment. Our study has some limitations, including its retrospec-
Deferred CN was performed in 21 patients (58%). Notably, tive design, small number of patients, short observation
two patients demonstrated no residual tumor cells in the period, and potential bias in the selection of ICI-based com-
primary tumor or IVCTT (1 in each group). These results bination treatments. The lack of clear criteria for choosing
suggest that both ICI-based combination therapies have no ICI–ICI and ICI–TKI combination therapies and the evo-
statistically significant differences in surgical and oncologi- lution of combination therapy over time may have intro-
cal outcomes and have similar effects. Importantly, both the duced bias. Specifically, younger patients tended to choose
maximum primary tumor diameter and height of the IVCTT ICI–ICI; the laterality of renal cancer and the patient’s age
rapidly decreased within 3–6 months in most cases. may have influenced this finding. Moreover, some labora-
The occurrence of TRAEs is an inevitable considera- tory data and the initial status of the metastatic disease were
tion in ICI-based combination treatments. The incidence of not known, with a few patients being referred from another
TRAEs, including grade 3 or higher events, was observed in institution after the introduction of ICI-based combination
11 patients (31%) requiring high-dose steroid therapy inter- therapy, which may have affected the results. Prospective
vention in our study. These results were consistent with the studies with larger sample sizes and longer follow-up peri-
known safety profiles of ICI-based combination therapies ods are required to validate our findings.
[5–9]. ICI-based combination therapy and drug toxicity were The results of two phase 3 trials investigating the role of
as expected, and the effectiveness of ICI–ICI and ICI–TKI deferred CN following pretreatment with ICI-based combi-
combination therapies was similar. However, this result may nation therapy in primary metastatic RCC (NORDICSUN
have been influenced by the choice of ICI-ICI or ICI-TKI Trial: NCT03977571 and PROBE Trial: NCT04510597) are
combination therapy, depending on age. Compared with eagerly anticipated [37, 38]. We believe that reports from
upfront surgery, ICI-based combination treatments may lead these studies will contribute to new treatment strategies for
to drug discontinuation due to TRAEs, including serious RCC patients with IVCTT.
irAEs, and may lead to disease progression over time [11]. In conclusion, ICI-based combination therapy is expected
It is necessary to carefully consider the application of pre- to be useful in the treatment of IVCTT and primary RCC.
surgical treatment. If surgery is considered for such patients, Notably, this retrospective study’s findings also suggest that
careful observation is required until surgery. Contrastingly, although ICI–ICI combination therapy tended to be associ-
patients with controlled metastases undergoing ICI-based ated with a higher probability of tumor growth than ICI–TKI
combination therapy may discontinue systemic therapy combination therapy in terms of the frequency of tumor
after delayed CN, providing them with ongoing-systemic- regression, both ICI-based combination therapies exhibited
treatment-free periods. However, currently, there is no estab- comparable efficacy and safety against primary tumors and
lished evidence to clearly define the continuation or discon- IVCTT in RCC. Furthermore, these results may provide an
tinuation of ICI-based combination therapy after deferred option to use ICI-based combination therapy to eliminate
CN. In this study, the primary reason for resuming ICI-based the need for surgery owing to the achievement of a complete
1546 International Journal of Clinical Oncology (2024) 29:1538–1547

response or to lower the IVCTT height and perform deferred N Engl J Med 380(12):1116–1127. https://​d oi.​o rg/​1 0.​1 056/​
CN in patients with RCC. NEJMo​a1816​714
7. Motzer RJ, Penkov K, Haanen J et al (2019) Avelumab plus
axitinib versus sunitinib for advanced renal-cell carcinoma.
N Engl J Med 380(12):1103–1115. https://​d oi.​o rg/​1 0.​1 056/​
NEJMo​a1816​047
Data availablity 8. Choueiri TK, Powles T, Burotto M et al (2021) Nivolumab plus
cabozantinib versus sunitinib for advanced renal-cell carcinoma.
N Engl J Med 384(9):829–841. https://​doi.​org/​10.​1056/​NEJMo​
No available. a2026​982
9. Motzer R, Alekseev B, Rha SY et al (2021) Lenvatinib plus
Acknowledgements We would like to thank Ms. Nobuko Hata for per-
pembrolizumab or everolimus for advanced renal cell carci-
forming secretarial work.
noma. N Engl J Med 384(14):1289–1300. https://​doi.​org/​10.​
1056/​NEJMo​a2035​716
Author contributions KY wrote the manuscript and prepared Tables
10. Singla N, Hutchinson RC, Ghandour RA et al (2020) Improved
and Figures. KY, TK, NN, YK, HI, HF, JI, HI, and TT cared for the
survival after cytoreductive nephrectomy for metastatic renal
patients and administered ICI-based combination therapy. KY, TK, and
cell carcinoma in the contemporary immunotherapy era: an
TT performed the surgery. All Authors contributed to the conception
analysis of the National cancer database. Urol Oncol 38(6):604.
and design of this study as well as to the acquisition, analysis, and
e609-604.e617. https://​doi.​org/​10.​1016/j.​urolo​nc.​2020.​02.​029
interpretation of data. All the authors have read and approved the final
11. Yoshida K, Hata K, Iizuka J et al (2022) Immune checkpoint
version of the manuscript.
inhibitor combination therapy for renal cell carcinomas with
concomitant inferior vena cava thrombi. In Vivo 36(2):1030–
Funding No funding was received for conducting this study.
1034. https://​doi.​org/​10.​21873/​invivo.​12798
12. Heng DY, Xie W, Regan MM et al (2009) Prognostic factors
Declarations for overall survival in patients with metastatic renal cell carci-
noma treated with vascular endothelial growth factor-targeted
Conflict of interest Tsunenori Kondo received honoraria from Pfizer, agents: results from a large, multicenter study. J Clin Oncol
Merck, Takeda Pharmaceutical, MSD, and Ono Pharmaceuticals. 27(34):5794–5799. https://​doi.​org/​10.​1200/​JCO.​2008.​21.​4809
Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono 13. Sobin LH, Compton CC (2010) TNM seventh edition: what’s
Pharmaceuticals. new, what’s changed: communication from the International
Union Against Cancer and the American Joint Committee on
Ethical approval All procedures performed in studies involving human Cancer. Cancer 116(22):5336–5339. https://​doi.​org/​10.​1002/​
participants were in accordance with the ethical standards of the insti- cncr.​25537
tutional and/or national research committee and with the 1964 Helsinki 14. Neves RJ, Zincke H (1987) Surgical treatment of renal cancer with
Declaration and its later amendments or comparable ethical standards. vena cava extension. Br J Urol 59(5):390–395. https://​doi.​org/​10.​
Ethical approval was obtained from the Institutional Review Board of 1111/j.​1464-​410x.​1987.​tb048​32.x
Tokyo Women’s Medical University (ID: 2021–0061). 15. Ishihara H, Nemoto Y, Nakamura K et al (2023) Comparison of
outcomes between therapeutic combinations based on immune
checkpoint inhibitors or tyrosine kinase inhibitor monotherapy
for first-line therapy of patients with advanced renal cell carci-
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