Presurgical immune-oncology/tyrosine kinase inhibitor combination therapy for renal cell carcinoma with a vena cava tumor thrombus: a single-institution case series
Introduction
Current guidelines recommend administering adjuvant immunotherapy following resection of primary renal cell carcinoma (RCC) (1). However, no consensus exists regarding presurgical immunotherapy. In this case series, we present cases of RCC that developed an inferior vena cava (IVC) tumor thrombus (ITT) and discuss the potential role of presurgical immune-oncology/tyrosine kinase inhibitor (IO/TKI) therapy for these cases. We present this article in accordance with PROCESS (2) and AME Case Series reporting checklists (available at https://tau.amegroups.com/article/view/10.21037/tau-23-203/rc).
Case presentation
Patients were eligible for inclusion if they had RCC with ITT and underwent radical nephrectomy. We retrospectively reviewed the cases of five patients who received IO/TKI combination therapy as presurgical therapy. All patients underwent nephrectomy at The Jikei University Hospital (Tokyo, Japan) between August 2020 and July 2021. As treatment regimens, a combination of pembrolizumab (120 mg every 3 weeks) and axitinib (5 mg twice daily) was selected in 4 cases, while a combination of avelumab (10 mg per kilogram of body weight every 2 weeks) and axitinib (5 mg twice daily) was chosen in one case. The regimens and cycles were determined at the discretion of the treating physicians. To assess tumor and thrombus volume, the calculation of major axis multiplied by minor axis and height was performed using CT images. Postoperative complications were evaluated using the Clavien-Dindo classification scale. Progression-free survival (PFS) was defined as the time from the nephrectomy to disease progression or death. Treatment-free survival (TFS) was defined as the time from the nephrectomy to the first dose of subsequent systemic therapy or death. The clinical characteristics of the patients are shown in Table 1.
Table 1
| Case | Age (y) | Gender | BMI (kg/m2) | KPS | Laterality | cT stage | cN stage | Metastatic sites | Tumor thrombus (level per Mayo classification) | Regimen [No. cycles] | No. of days between IO and surgery | Any AE (≥ G2) prior to surgery |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 51 | Male | 22.5 | 0 | Left | cT3b | cN0 | Lung (multiple) | 1 | Pem [6] + Axitinib | 33 | None |
| 2 | 71 | Male | 20.7 | 0 | Right | cT3b | cN0 | Lung (multiple) | 1 | Pem [4] + Axitinib | 36 | None |
| 3 | 70 | Male | 27.9 | 0 | Left | cT3b | cN2 | None | 2 | Ave [20] + Axitinib | 36 | HFS (G2) |
| 4 | 79 | Male | 22.7 | 0 | Left | cT3b | cN1 | None | 1 | Pem [3] + Axitinib | 29 | Constipation (G2) |
| 5 | 72 | Female | 28.2 | 0 | Right | cT3c | cN0 | None | 4 | Pem [6] + Axitinib | 24 | Fatigue (G2) |
y, years; BMI, body mass index; KPS, Karnofsky Performance Status; IO, immune-oncology therapy; AE, adverse event; Pem, pembrolizumab; HFS, hand-foot syndrome.
Responses and patient outcomes
The changes in the size of the primary tumor (PT) and ITT from pre-IO/TKI imaging to surgery are summarized in Figure 1, Figure S1, and Table S1. Pathological assessments of each case are provided in Table 2. Four cases were of clear cell histology, while one case was papillary type II. Two cases had multiple lung metastases, and they achieved a complete response before surgery. During the neoadjuvant IO/TKI therapy, all patients received the IO drugs at the recommended dosage. However, in the cases of adverse events, the oral administration of axitinib was adjusted to 1 mg twice daily (case 4), 2 mg twice daily (case 5), and 3 mg twice daily (case 6). Four patients underwent open radical nephrectomy with thrombectomy, and one patient underwent laparoscopic radical nephrectomy (LRNx) due to downstaging from cT3b to cT3a (case 2). In case 5, a level IV ITT shrank to level III, thus avoiding the need for an open sternotomy (Figure S1). The median operating time and estimated blood loss were 431 min and 3,100 mL, respectively (Table S2). Surgeons reported the presence of fibrosis and inflammatory changes at the surgical sites in all cases. The percentage of residual viable tumor cells in the ITT and primary RCC after presurgical therapy varied among the cases (Table 2). No major intraoperative complications were reported. One patient required a lymphatic intervention due to abdominal lymphatic leakage (Clavien IIIa) within 90 days after operation. The median total length of stay and follow-up was 10 and 691 days, respectively. The PFS curve was estimated using the Kaplan-Meier method (Figure 2). Our case series demonstrated a median PFS of 11 months (95% CI: 5.5–22.5 months). Excluding one patient who received IO within 1 month after surgery at the discretion of his physician, the median TFS was 10 months (95% CI: 5.8–18.7 months). No patient died during the follow-up period.
Table 2
| Case | Histology | Primary tumor size (mm) | Grade | pT stage | pN stage | Tumor thrombus (level per Mayo classification) | Surgical margin | Viable tumor cells in IVC thrombus (%) | Viable tumor cells in primary RCC (%) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Clear cell | 55×55×51 | 3 | pT3b | pN0 | 1 | Negative | 5 | 0 |
| 2 | Clear cell | 110×110×90 | 3 | pT3a | pN0 | 0 | Negative | 5 | 20 |
| 3 | Papillary type II | 70×50×30 | 3 | pT3b | pNx | 2 | Negative | 70 | 60 |
| 4 | Clear cell | 55×46×43 | 2 | pT3b | pN0 | 1 | Negative | 80 | 70 |
| 5 | Clear cell | 53×43×35 | 2 | pT3b | pNx | 3 | Negative | 0 | 0 |
Size: height × major axis × minor axis. IVC, inferior vena cava; RCC, renal cell carcinoma.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committees and with the Helsinki Declaration (as revised in 2013). This study was approved by the Institutional Review Board of The Jikei University School of Medicine [No. 33-260(10878)]. Written informed consent was obtained from the patients for publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Discussion
This investigation was a case series carried out at a single institution, focusing on patients with ≥ cT3b RCC who were treated with presurgical combination therapy of IO/TKI and underwent nephrectomy. Presurgical therapy has been employed in various cancer types to reduce tumor size and improve surgical morbidity. Presurgical therapy has gained attention for its potential to reduce thrombus size and surgical risk in patients with RCC and ITT. Several reports have demonstrated the effectiveness of presurgical IO/TKI combination therapy for RCC with ITT (3-6). In previous case reports, presurgical IO/TKI combination therapy has resulted in the downstaging of ITT. In our case series, we observed a reduction in the volume of ITT in all cases, with 60% of cases (n=3/5) experiencing downstaging at the ITT level. One case was downstaged to cT3a, allowing for LRNx to be performed, and open sternotomy was avoided in another case.
Labbate et al. (7) reported on the differences in viable cells between PT and ITT. Similarly, we observed a difference in the percentage of viable tumor cells between PT and ITT in our study. This difference was attributed to the heterogeneity of the tumor microenvironment. Notably, Kim et al. (8) reported that clonal evolution contributes to genomic diversity between PT and ITT, which could explain why the relative change in the size of the PT and ITT is not always consistent.
Pignot et al. (9) reported that surgeons face difficulties finding dissection planes, due to fibrosis in the kidney and surrounding tissues. Graafland et al. (10) also reported on surgical complexity resulting from adhesions in 71% of cases, including 38% with major difficulties. In our cases, the surgeons reported fibrosis and inflammatory changes during the surgeries in all cases. One patient experienced lymphorrhea (Clavien IIIa), highlighting the potential risks of the surgery beyond the clinical stage. Nevertheless, downstaging the thrombus level reduced the invasiveness of the surgery, and there was still the risk of dislodgement and pulmonary embolism after IO/TKI combination therapy. Furthermore, patients received a drug-free period after the surgery. Thus, radical nephrectomy following presurgical IO/TKI therapy for RCC with ITT should be considered.
The primary limitations of our study are its retrospective design and the small sample size derived from a single institution. Furthermore, we did not juxtapose the outcomes with those of neoadjuvant TKI treatments. In a recent publication, Klatte et al. (11) proposed a possible role for neoadjuvant TKI treatment in the management of RCC patients with ITT, whereas IO/TKI is a more modern systemic approach to RCC management. Thus, an imperative requirement exists for a prospective randomized trial to substantiate the survival benefits associated with neoadjuvant IO/TKI treatments for RCC patients with ITT.
Conclusions
We reviewed five patients with RCC and ITT who received IO/TKI combination therapy as presurgical therapy. Despite the potential challenges of the surgery, this approach could provide patients with favorable oncological outcomes and the opportunity to avoid systemic treatment. A larger sample size and longer follow-up period are needed to determine the feasibility of presurgical IO/TKI combination therapy.
Acknowledgments
The authors thank Textcheck for English-language editing.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the PROCESS and AME Case Series reporting checklists. Available at https://tau.amegroups.com/article/view/10.21037/tau-23-203/rc
Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-203/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-203/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committees and with the Helsinki Declaration (as revised in 2013). This study was approved by the Institutional Review Board of The Jikei University School of Medicine [No. 33-260(10878)]. Written informed consent was obtained from the patients for publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021;385:683-94. [Crossref] [PubMed]
- Agha RA, Sohrabi C, Mathew G, et al. The PROCESS 2020 Guideline: Updating Consensus Preferred Reporting Of CasESeries in Surgery (PROCESS) Guidelines. Int J Surg 2020;84:231-5. [Crossref] [PubMed]
- Singla N, Elias R, Ghandour RA, et al. Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma. Urol Oncol 2019;37:924-31. [Crossref] [PubMed]
- Suzuki I, Kijima T, Takada-Owada A, et al. A case of clear cell renal cell carcinoma with vena cava thrombus responding to presurgical avelumab, and axitinib. IJU Case Rep 2021;4:412-6. [Crossref] [PubMed]
- Hara T, Terakawa T, Hyodo T, et al. Pathological complete response of renal cell carcinoma with vena cava tumor thrombus to neoadjuvant TKI/IO combination therapy. Urol Case Rep 2021;39:101800. [Crossref] [PubMed]
- Machida A, Ikarashi D, Yanagawa N, et al. Pathological Complete Response to Preoperative Nivolumab Plus Cabozantinib for Renal Cell Carcinoma With Inferior Vena Cava Thrombus: A Case Report. Cancer Diagn Progn 2023;3:124-9. [Crossref] [PubMed]
- Labbate C, Hatogai K, Werntz R, et al. Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy. J Immunother Cancer 2019;7:66. [Crossref] [PubMed]
- Kim K, Zhou Q, Christie A, et al. Determinants of renal cell carcinoma invasion and metastatic competence. Nat Commun 2021;12:5760. [Crossref] [PubMed]
- Pignot G, Thiery-Vuillemin A, Albigès L, et al. Oncological Outcomes of Delayed Nephrectomy After Optimal Response to Immune Checkpoint Inhibitors for Metastatic Renal Cell Carcinoma. Eur Urol Oncol 2022;5:577-84. [Crossref] [PubMed]
- Graafland NM, Szabados B, Tanabalan C, et al. Surgical Safety of Deferred Cytoreductive Nephrectomy Following Pretreatment with Immune Checkpoint Inhibitor-based Dual Combination Therapy. Eur Urol Oncol 2022;5:373-4. [Crossref] [PubMed]
- Klatte T, Welsh SJ, Riddick ACP, et al. Tyrosine kinase inhibitor treatment for renal cell carcinoma with inferior vena cava tumour thrombus: a quantitative summary. BJU Int 2023;131:566-8. [Crossref] [PubMed]
