Radiotherapy directed to inferior vena cava tumor thrombus among patients with renal cell carcinoma: an illustrative case and review of the literature

Introduction

Renal cell carcinoma (RCC) accounts for about 3 % of all malignancy cases and is the most common histology of kidney cancer [1]. It is classified based on cell type characteristics into multiple histological subtypes, including clear cell carcinoma, papillary, and chromophobe, which represent the most common variants [2]. Its propensity to spread via hematogenous and lymphatic routes, combined with direct invasion into the venous system in approximately 25 % of cases, often leads to the formation of tumor thrombus (TT) [3]. Since TT is often asymptomatic, its detection typically occurs incidentally during routine follow-up computed tomography (CT) scans, notwithstanding its potential to provoke a varied spectrum of symptoms [4].

In patients with inferior vena cava tumor thrombus (IVC-TT) presenting with locally advanced disease, the current standard treatment approach involves complete surgical excision of the TT along with radical nephrectomy. However, this procedure carries high mortality rates (which increase depending on the degree of caval invasion), perioperative complications (e.g. transfusion, cardiac thromboembolism), and a high incidence of treatment failures [5]. Considering the complexity of such surgery, patients with IVC-TT, especially in cases of metastatic or inoperable disease, pose a significant therapeutic challenge. In such cases, alternative therapeutic strategies may include medical therapies such as tyrosine kinase inhibitors and/or immunotherapy. These treatments have shown potential in reducing thrombus levels, thereby enabling surgery in patients with inoperable disease, although the data remain limited [6]. While surgery remains the cornerstone of treatment, another therapeutic option is radiotherapy, whose role in addressing IVC-TT is still unknown, with limited cases reported in the literature.

Here we present the clinical case of a 74-year-old male diagnosed with metastatic RCC and a recurrent, inoperable large IVC-TT, who underwent stereotactic body radiotherapy (SBRT). Furthermore, we provided a narrative literature review, summarizing the limited available evidence on the effectiveness of radiotherapy in managing RCC patients with IVC-TT, with a focus on its different applications across different treatment settings. From these review objectives, useful suggestions for designing specific trials may stem.

Case description

In October 2018, a 69-year-old male with a medical history of arterial hypertension presented to our clinic (REM Radioterapia) with a left renal neoplasm. At that time, as no evidence of metastases was detected, he was referred for surgery, which consisted of radical nephrectomy. The post-operative pathological finding was consistent with the Fuhrman grade 3 clear cell RCC, pathologic stage pT3N0M0. However, one year later, surveillance CT imaging revealed an IVC-TT with few micronodular liver metastases and retroperitoneal lymph node involvement. Then, thrombectomy and lymphadenectomy with reconstruction of the IVC were performed. Although the lymph nodes had appeared pathological on CT imaging, all 13 resected lymph nodes were negative. The liver metastases were not removed during the surgery. Subsequent postoperative CT of the chest and abdomen showed no residual tumoral thrombus. Postoperative pathological analysis confirmed disease recurrence. The liver micronodular metastases were neither removed nor biopsied. Indeed, these were micronodular lesions, and in any case, given the recurrence of the disease, confirmed by post-operative pathological findings, the patient was a candidate for systemic therapy.

Therefore, medical oncology recommended starting first-line therapy with Nivolumab plus Ipilimumab, which transitioned to maintenance with Nivolumab once stable disease was documented six months later. In April 2023, despite ongoing immunotherapy, a contrast-enhanced total body CT scan revealed progressive disease in the form of micronodular pulmonary metastases, mediastinal and abdominal lymphadenopaties, and a large TT recurrence extending from the intrahepatic course of the IVC to the right atrium (41 × 28 × 45 mm). The patient had only mild bilateral leg edema. Since the extent of TT filling the IVC lumen and the elevated levels of direct bilirubin (0.58 mg/dL) and fibrinogen (527 mg/dL) discouraged any further surgical procedure, the patient was offered palliative radiotherapy after discontinuation of immunotherapy as he was considered developing immune resistance. His good performance status (ECOG 0) encouraged us to also consider the SBRT option.

After weighing the pros and cons, we decided to perform stereotactic radiotherapy via a Novalis Truebeam STx (Varian, Palo Alto, CA, USA). CT simulation was performed using a “slow” four-dimensional (4D) computed tomography (4D-CT) capturing any target motion during the respiratory cycle with a slice thickness of 1.25 mm. Once the most stable individual respiratory phases were selected, the IVC-TT was delineated as gross tumor volume (GTV) on the CT simulation, which was also merged with the diagnostic contrast-enhanced CT scan aiming for a more precise delineation of the target. To compensate for target motion and ensure target coverage, considering the non-negligible intra-fraction target displacement observed during CT simulation due to heartbeats, the planning target volume (PTV) was generated by adding 5 mm of isometric margins to the GTV. The tumor location concerned us about possible radiation-related cardiac toxicity. To reduce the dose received by the heart, two prescription levels were chosen: a dose of 32.5 Gy in five daily fractions had to include the entire TT, including its tract abutting and invading the right atrium, while a simultaneous integrated boost (SIB) up to 40 Gy was planned to target the intrahepatic tract exclusively (Figure 1). The treatment was delivered with a Varian Truebeam linear accelerator (Varian Medical Systems, Palo Alto, CA, USA) using 10 MV Flattening Filter Free (FFF) photon beams for faster delivery.

Figure 1:

Axial (on the left) and sagittal (on the right) planes showing the 98 % dose distribution. Two prescription dose levels are depicted: the hotter yellowish/reddish dose color-wash refers to the highest dose prescription (40 Gy to the SIB volume), which gradually fades into the colder bluish lower dose (32.5 Gy) to the longitudinal section of the TT closer to the heart to reduce the risk of cardiac toxicity.

All dose-volume constraints for nearby organs at risk (OARs, e.g. heart, liver, spinal cord, lungs, esophagus) were met (Figure 2) as per Timmerman tables [7].

Figure 2:

Dose-volume histogram (DVH) of the treatment plan: It shows the relation between the cumulative radiation dose (x-axis) and volume (y-axis). The red lines are for the PTV 32.5 Gy (the leftmost) and the SIB volume at 40 Gy (the rightmost). Purple, magenta, green, light blue and yellow lines are for the heart, right atrium, left atrium, esophagus and lungs, respectively.

The PTV received at least 98 % of the prescribed dose by two coplanar volumetric arcs (181.0–45.0 CW – 45.0–181.0 CCW) and the treatment was delivered under respiratory gating and daily cone beam CT guidance to ensure proper positioning.

The patient tolerated radiation treatment well without any acute or late toxicity: no pulmonary embolism occurred. Total body CT scans performed after 3, 6, and 12 months showed a slow but continuous shrinkage of the IVC-TT, reaching 11 mm at the latest follow-up (April 2024, Figure 3). At the time of writing, we have documented an abscopal response with almost complete regression of most lung, liver and lymph node metastases, a few being still stable. Furthermore, the mild bilateral leg edema is completely resolved.

Figure 3:

Pre- and post-radiotherapy images: starting condition (A, B) and 12 months after radiotherapy treatment (C, D). The images show a partial response to the treatment (28 × 45 vs. 11 × 21 mm).

Thanks to the favorable response to radiotherapy, immunotherapy with Nivolumab, resumed after completion of SBRT, is still ongoing.

The patient’s disease course is summarized in Figure 4.

Figure 4:

Timeline of patient’s treatment. CT, computed tomography; IVC-TT, inferior vena cava tumor thrombus; SBRT, stereotactic body radiation therapy.

Literature review

A search of the literature published in PubMed and Scopus from the inception of electronic databases to February 2024 was performed, looking for articles on the use of radiotherapy to treat RCC patients with IVC-TT. We used the following English search terms: “renal cell” or “kidney” “cancer” or “carcinoma” and “inferior vena cava” and “radiotherapy” or “stereotactic body radiotherapy” or “hypofractionated radiotherapy” and “tumour thrombus”. Given the rarity of the use of radiotherapy in this clinical scenario, we also included case reports and case series. The only exclusion criterion was non-English language. Table 1 lists the seven papers we reviewed; the last row shows our case.

Conclusions

Based on this evidence, radiotherapy (especially SBRT) represents a valid therapeutic alternative for inoperable or metastatic patients with IVC-TT, offering a balance between efficacy and tolerability. Moreover, when combined with immunotherapy, stereotactic radiotherapy seems to hold promise in reversing immune resistance, thus allowing for the continuation of ongoing systemic therapy and postponing the therapeutic switch. Therefore, SBRT might play a pivotal role in the future management of these patients.