Transarterial chemoembolization of unresectable renal cell carcinoma with doxorubicin-loaded CalliSpheres drug-eluting beads

The safety and efficacy of drug-eluting beads transarterial chemoembolization (DEB-TACE) for unresectable renal cell carcinoma (RCC) still unknown. We aimed to assess the feasibility, safety and clinical efficacy of DEB-TACE with doxorubicin-loaded CalliSpheres beads (CB) in patients with unresectable RCC. Between 2016 and 2020, thirty-five patients with unresectable RCC underwent DEB-TACE with doxorubicin-loaded CB. The objective response rate (ORR) was the primary endpoint, and overall survival (OS) and progression-free survival (PFS) were the secondary endpoints. Fifteen-seven times of DEB-TACE were performed in 35 patients using doxorubicin-loaded (median 60 mg) CB. Fifteen patients underwent an additional session of DEB-TACE, with intervals of 1 to 1.5 months. Twenty-one patients underwent transarterial infusion with cisplatin or oxaliplatin before DEB-TACE. The median follow-up time was 9.0 months (Range 1.8–43.6 months). ORR and DCR were 47.1% and 94.1%, 29.0% and 87.1%, 23.1% and 84.6% respectively at 1-, 3-, and 6- months after DEB-TACE. The median PFS was 21.4 months, and the 3-, 6- and 12- month PFS rates were 84.7%, 73.7% and 62.3%, respectively. The median OS was 24.6 months, and the 3-, 6- and 12- month OS rates were 93.9%, 87.6% and 65.2%, respectively. There were no treatment-related deaths or severe adverse events of grade 3 or more. In conclusion, DEB-TACE with doxorubicin-loaded CB is a safe, feasible and effective palliative treatment option for patients with unresectable RCC.


Patients and methods
Study design. The observational study was approved by the Institutional Review Board of Zhengzhou university committee on human investigation. Written informed consent was obtained from all patients. All methods were performed in accordance with the relevant guidelines and regulations. This study was conducted in 35 patients with unresectable RCC who underwent DEB-TACE using doxorubicin-loaded CB from July 2016 to May 2020. Indications for DEB-TACE: age < 85 years; pathological confirm of RCC (Fig. 1A); recurrence or progression after operation or standard treatments; refused or ineligible to receive standard treatments due to severe visceral dysfunction; no life-threatening diseases. Exclusion criteria: with other carcinoma but receive no treatment; white blood cell count < 3.0 × 10 9 /L; platelets count < 40.0 × 10 9 /L; active and severe infection; breastfeeding woman; pregnant woman.
Data collection. We retrospectively collected baseline data such as demographic data, clinical data, illness history, complications, tumor size, tumor markers, white blood cell count, computed tomography (CT) imaging (  Fig. 4E,F). Right femoral artery was accessed and a 5F-pigtail catheter (Terumo, Japan) was introduced to the level of kidney, then abdominal aortic angiography was performed to show the bilateral kidneys. A Cobra catheter was used to identify the tumor-feeding arteries of RCC. A microcatheter (Asahi, Japan) was advanced selectively into feeding arteries. Cisplatin or oxaliplatin was infused if patient received no platinum-based chemotherapy previously. doxorubicin (20-60 mg) was loaded with 100-300 μm or 300-500 μm of CB (Jiangsu Hengrui Medicine Co. Ltd., Nanjing, China) for about 30 min, with shaking every 5 min. Then CB was slowly injected into tumor-feeding arteries after mixture with iodixanol. Polyvinyl alcohol of 350-560 μm (Merit, American) was used if embolization was insufficient by CB.
Endpoint. ORR, the sum of CR and PR, the primary endpoint, was assessed by abdominal CT. The disease control rate (DCR), the sum of CR, PR and SD, is also the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).
Safety assessment. According to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) 11 , adverse events and serious adverse events were recorded.

Results
Patient characteristics. This study enrolled 19 men and 16 women (mean age 67.5 ± 10.8 years, range 37-84 years). Patient characteristics on admission are listed in Table 1. Twenty-seven patients were diagnosed with clear-cell type RCC and four patients were Bellini duct carcinoma. Local or distant metastases were present in 13 and 6 patients, respectively. Three patients showed recurrence after surgery, and 5 patients received radiotherapy or chemotherapy before DEB-TACE.

DEB-TACE treatments.
Fifteen-seven times of DEB-TACE were performed in 35 patients using doxorubicin-loaded DEB-TACE, with a median dose of 60 mg (IQR 40, 60). CB of 100-300 μm was used in 17 patients, and CB of 300-500 μm was used in the remained 18 patients. Polyvinyl alcohol of 350-560 μm was used in 25 patients after DEB-TACE. Twenty-one patients also received transarterial infusion with cisplatin (n = 7) or oxaliplatin (n = 14). Fifteen patients underwent an additional session of DEB-TACE, with an interval of 1 to 1.5 months. One patient underwent bronchial transarterial chemoembolization, and one received placement of esophageal stent due to severe esophageal stenosis. Two patients underwent 125 I seeds implantation and 4 patients underwent thermal ablation for RCC after DEB-TACE. The median inpatient duration was 14.0 days (IQR 9.0, 17.5) and the mean cost of hospitalizations was (5.7 ± 2.3) × 10 4 ¥ ( Safety. No serious adverse event was observed, including perioperative deaths or treatment-related adverse events of grade 3 or more. Abdominal pain and abdominal distension were found in 12 and 4 patients, respectively. Five patients (14.3%) showed nausea or vomiting and were controlled within 2-3 days. One patient showed hematuria of grade 1 after DEB-TACE and was successfully treated by hemostatics. Three patients showed moderate fever for 2-3 days and physical cooling was used (Table 4).

Discussion
DEB-TACE is as a new embolization option for unresectable RCC, which can embolize the tumor-feeding arteries and block blood supply of tumor tissue 4,5 . DEB-TACE can also slowly release and increase local concentration of antitumor drug, and thus increasing retention time and efficacy of tumor necrosis [12][13][14] . Currently, DEB-TACE has been widely used in the treatment of unresectable carcinoma of substantial organs (e.g. liver 6,7 , uterus 8 or lung 9 ) rather than cavity organs such as bladder and digestive tract 3,15 . Our results indicated that DEB-TACE using doxorubicin-loaded CB is feasible, safe and showed good short-term efficacy without serious adverse events. doxorubicin-loaded DEB-TACE appears to be a well-tolerated treatment option for unresectable RCC. Doxorubicin-loaded DEB-TACE had been used for unresectable hepatocellular carcinoma, and showed significantly elevated ORR or DCR 5,6 . TACE using superabsorbent polymer microspheres is able to decrease tumor size of refractory lung cancer [16][17][18] . However, very few studies have reported the safety and efficacy of doxorubicinloaded DEB-TACE in patients with RCC. In our study, the ORR and DCR were 47.1% and 94.1%, 29.0% and 87.1%, 23.1% and 84.6% respectively at 1, 3, and 6 months after doxorubicin-loaded DEB-TACE. Our data indicated that doxorubicin-loaded DEB-TACE showed a good disease control rate during a short-term follow up.
When compared with the conventional TACE, DEB-TACE using CB showed survival benefit for the treatment of hepatocellular carcinoma 19 . However, some investigator reported no survival benefit 20 . In our study, the median PFS and OS were 21.4 and 24.6 months after DEB-TACE, respectively. The 3-, 6-and 12-month PFS rates were 84.7%, 73.7% and 62.3%, and the 3-, 6 and 12-month OS rates were 93.9%, 87.6% and 65.2%, respectively.   21 , and combined therapeutic options should be used to improve prognosis, such as thermal ablation, 125 I seeds implantation and targeted therapy, and so on [21][22][23] . In this study, 4 patients underwent thermal ablation and 2 patients received 125 I seeds implantation. Additionally, other complications, such as thrombosis in inferior venae cava and esophageal stenosis, should be managed. In this study, one patient received esophageal stent insertion and 2 patients underwent inferior venae cava filter placement.
In line with previous studies, we found that DEB-TACE showed no serious adverse events. Only one patient showed hematuria and was successfully treated by hemostatics. Three patients showed moderate fever for 2-3 days and physical cooling was used. doxorubicin loaded DEB-TACE appears to be a safe treatment for unresectable RCC.
There are some shortcomings in our study. This is a retrospective observational study conducted in a single center, with a relatively small sample size. Cox regression analysis should be used to look for prognostic factors of patients with RCC, however, the sample of this preliminary study was too small to perform cox regression analysis. Fifteen patients rather than all patients received one more session, which may underestimate the efficacy of DEB-TACE. More studies with large sample size are needed to further study its safety, efficacy and prognostic factors.
In conclusion, DEB-TACE with doxorubicin-loaded CB is a safe, feasible and effective palliative treatment option for patients with unresectable RCC.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.   Figure 5. Follow up results. The median PFS was 21.4 months, and the 3-, 6-and 12 month PFS rates were 84.7%, 73.7% and 62.3%, respectively. The median OS was 24.6 months, and the 3-, 6 and 12 month OS rates were 93.9%, 87.6% and 65.2%, respectively.