Tyrosine kinase inhibitor treatment for renal cell carcinoma with inferior vena cava tumour thrombus: a quantitative summary.

Renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the inferior vena cava (IVC) occurs in about 4%–15% of cases [1]. Surgical complexity, as well as perioperative complications and morbidity, are significant (5%–15% mortality) and increase with the extent of the VTT [1, 2]. Neoadjuvant (i.e., pre-surgical) systemic treatment with tyrosine kinase inhibitors (TKIs) is a potential initial management strategy for these cases with the potential to reduce the level and height of the VTT, thereby impacting surgical morbidity and survival [3]. For this research communication, we have summarised the available evidence with TKIs through a quantitative analysis of published data, which may serve as a benchmark for future trials with immunotherapies (IO). We conducted a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The review was registered on the Open Science Framework Registry (https://doi.org/10.17605/OSF.IO/EMJY5). MEDLINE, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials databases were systematically searched without time limit. The last updated search was performed in December 2022. A PICOS (population [P], intervention [I], comparator [C], outcome [O] and study design [S]) framework was specified to assess study eligibility and consisted of: (P) patients with a renal mass and VTT-IVC (cT3b–T4); (I) TKI treatment (sunitinib, sorafenib, pazopanib, axitinib) with the renal mass in situ; (C) upfront surgery or none; (O) effect of TKI on VTT height and level; (S) prospective or retrospective studies with at least five patients. Bibliographies of included studies, previous reviews and conference proceedings were hand-searched for further eligible articles. The primary outcomes of interest were changes in VTT length and VTT level. Secondary outcomes included adverse events during TKIs and perioperative complications. The overall quality of evidence was assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) handbook [4]. For quantitative summaries, pooled estimates were obtained from random-effects models. A sensitivity analysis was conducted on studies reporting on patients with sunitinib only. Publication bias was assessed with funnel plots. We identified 10 retrospective observational studies and one prospective trial, which reported data on 137 patients. All except two studies [3, 5] did not include a control group. Four studies were multicentric and seven were from a single centre. Three reports originated from Europe, six from Asia and two from North America. Four studies focused on mixed groups of targeted therapies [6-9], four on sunitinib [3, 10-12], two on axitinib [5, 13] and one on pazopanib [14]. One large study [8] with 21 patients included a single patient with temsirolimus (a mammalian target of rapamycin [mTOR] inhibitor) and was included in the quantitative analysis. A summary of the data reported is provided in Table S1. The majority of patients had clear cell RCC. The median number of treatment cycles was two and the median duration of treatment was 3 months. Any adverse event was reported in 83.1% (95% CI 53.1%–100%) [3, 9, 11, 13] and Grade III–V adverse events in 28.9% (95% CI 13.7%–46.6%) of patients [5-7, 11, 13]. Overall, 73.1% (95% CI 58.9%–85.6%) of patients showed a measurable decrease in VTT length [5-14], with a mean (95% CI) length reduction of 1.4 (0.9–2.0) cm [3, 5-8, 10-14], while 10.0% (95% CI 4.3%–17.1%) showed an increase in VTT length [5-14]. The VTT level decreased in 29.7% (95% CI 19.4%–41.0%) of patients and increased in 1.3% (95% CI 0%–5.4%) (Fig. 1) [3, 5-14]. Major postoperative complications, defined as Grade III–V according to the Clavien–Dindo classification, were reported in 16.4% (95% CI 2.3%–37.0%) of cases [5-7, 11, 13]. In those who underwent surgery, perioperative death within 30 days occurred in 3.4% (95% CI 0%–11.0%) of patients [5-7, 11, 13]. In the two studies with a control group, one study showed improved cancer-specific survival after neoadjuvant treatment (hazard ratio 0.30, P = 0.021) [3], while the other study showed a lower incidence of perioperative Grade IV–V complications in the neoadjuvant group (0% vs 60%, P = 0.044) but no survival data [5]. A sensitivity analysis of studies with sunitinib showed comparable results to the overall analysis. There was no evidence of publication bias on funnel plots (data not shown). These analyses are limited by non-standardised inclusion criteria with regards to stage and subtype, thrombus level definition, evaluation of response, duration of treatment, dose regimen, toxicity reporting, limited patient numbers, no long-term oncological data and only one high-quality study [13], resulting in a high risk of bias. The quality of the available evidence was low according to GRADE. It is worth highlighting the only prospective evidence published to date, NAXIVA (NCT03494816) was a prospective, open-label, single-arm, phase II feasibility trial, which evaluated the effect of axitinib in patients with clear cell RCC prior to nephrectomy and renal vein or IVC thrombectomy. A total of 21 patients were recruited from December 2017 to January 2020 across five UK centres. In all, 16 patients had VTT-IVC, of which an improvement in VTT level was seen in six (37.5%). There was a median reduction in VTT length of 2 cm and 41% of patients had a change to a less invasive surgical approach than planned before axitinib. Four of the 21 patients recruited did not have surgery due to progression of metastatic disease but not VTT (two patients), worsening of performance status (one) and declining of surgery (one) [13]. In summary, the effect of TKIs on VTT-IVC is variable, but it may alter surgical management in a considerable proportion of patients. There is only a small risk of clinically relevant VTT progression. Concerns over toxicity delaying surgery have not been borne out. Although the data suggest a possible role for neoadjuvant TKI treatment in the management of patients with VTT-IVC, the existing evidence does not allow for a recommendation. There is an urgent need for prospective randomised trials using more modern systemic therapy regimens, such as IO/IO or IO/TKI, to assess whether radiological and pathological response rates can be further enhanced and whether it provides a survival advantage. The present analysis provides summary data of what is achievable with TKIs alone and shall serve as a benchmark for these trials. The authors have no conflicts of interest related to the manuscript. Open Access funding enabled and organized by Projekt DEAL. Table S1 Details of studies included. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.