A case of postoperative pancreatitis in patients with renal cell carcinoma with an inferior vena cava tumor thrombus treated by presurgical lenvatinib plus pembrolizumab

Abstract

Pancreatic injury is a rare, but noted complication of nephrectomy. We report a case involving a 56-year-old man who presented with cT3bN0M0 left locally advanced renal cell carcinoma with an inferior vena cava thrombus. Nephrectomy with thrombectomy was performed given the remarkable shrinkage of the primary tumor and thrombus following lenvatinib plus pembrolizumab administration. The patient developed postoperative pancreatitis associated with unrecognized minor pancreatic injury, which was treated conservatively. To our knowledge, this has been the first case that underwent nephrectomy for RCC with an IVC thrombus after presurgical lenvatinib plus pembrolizumab and received conservative treatment for postoperative pancreatitis.

Introduction

Surgical treatment for advanced renal cell carcinoma (RCC) with an inferior vena cava (IVC) thrombus requires careful surgical management owing to its high risk for surgery-related death [1]. Although pancreatic injury is one of the complications that can cause significant morbidity and mortality, its incidence in open nephrectomy is quite rare, at 0.2% [2].

Presurgical therapy for RCC with an IVC thrombus is expected to shrink the primary and thrombus size and reduce such surgical risks. In recent years, combination therapy, such as immune checkpoint inhibitors (ICIs) plus ICIs or tyrosine kinase inhibitors (TKIs), has been proven effective as a first-line treatment for unresectable or metastatic RCC. In particular, lenvatinib plus pembrolizumab has demonstrated substantial efficacy as a first-line treatment in patients who have metastatic RCC, with the highest reported objective response rate, including complete response and progression-free survival, among all other RCC treatments [3]. However, the efficacy of presurgical lenvatinib plus pembrolizumab for RCC with an IVC thrombus and its association with perioperative complications remains unclear.

Here, we detail our experience with a case of RCC with an IVC thrombus who was treated with presurgical lenvatinib plus pembrolizumab and whose postoperative pancreatitis was treated conservatively.

Case presentation

A 59-year-old male with no medical history presented to our hospital with gross hematuria. Abdominal contrast-enhanced computed tomography (CT) showed an 83 mm left renal mass with a tumor thrombus extending from the left renal vein to the IVC (Fig. 1a, b). A clinical diagnosis of cT3bN0M0 advanced RCC was then established with International Metastatic RCC Database Consortium prognostic risk scores suggesting favorable risk.

Fig. 1.

Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) showing shrinkage of the primary tumor and inferior vena cava (IVC) tumor thrombus: upon diagnostic imaging (a, c); after 15 cycles of combination therapy with lenvatinib plus pembrolizumab (b, d)

First, we performed CT-guided biopsy of the primary tumor and placed a temporary IVC filter in the diaphragm position. Pathological findings revealed clear cell RCC. Second, we provided presurgical therapy with the aim of shrinking the size of the primary tumor and thrombus to lessen the invasiveness of the surgery. Therefore, lenvatinib (20 mg once daily) and pembrolizumab (200 mg every 3 weeks) were started. After three cycles of pembrolizumab, the patient developed Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hypothyroidism. Moreover, he developed CTCAE grade 3 diarrhea presumably due to the five cycles of lenvatinib. Hence, lenvatinib was temporarily withdrawn and resumed at 10 mg. Given that the patient had no further adverse events and the tumor was shrinking, the dose of lenvatinib was increased to 14 mg. After 15 cycles, CT revealed that the shrinkage of the primary tumor and thrombus was sufficient for a safe surgery (Fig. 1c, d). After withdrawing lenvatinib 1 week prior to surgery and the last dose of pembrolizumab was given 5 weeks prior to surgery, an open left nephrectomy and thrombectomy was performed (Fig. 2). Intraperitoneal adhesions were noted throughout the perirenal area during surgery, and no organ injury was identified at this time. Drains were placed in the retroperitoneal and in front of the IVC, respectively. On the second postoperative day, the drain was removed from the retroperitoneal. Five days after the surgery, the patient developed low-grade fever, epigastric pain, and jaundice with elevation of biliary enzymes, and enhanced CT indicated acute pancreatitis and secondary cholangitis (Fig. 3a). Considering the lack of an increase in amylase levels in the blood, slight elevation of drain amylase level, and the lack of damage to the main pancreatic duct at this time, the patient was treated conservatively after consultation with the Department of Hepatology. Follow-up CT showed amelioration of the patient’s pancreatitis (Fig. 3b) after 2 weeks of fasting, with broad-spectrum antibiotics and nafamostat mesylate. The patient’s jaundice and epicardial pain improved quickly, and his biliary enzymes and drain amylase improved to normal levels. After resumption of diet, no recurrence of pancreatitis was evident, and the drain was removed from the in front of IVC 21 days after surgery. The patient was discharged 25 days after surgery. Follow-up CT 2 months after discharge showed more improvement in the patient’s pancreatitis (Fig. 3c).

Fig. 2.

a Kidney extraction. b Tumor embolization (the red arrow indicates the tip of the tumor plug)

Fig. 3.

a Contrast-enhanced computed tomography (CT) at onset of pancreatitis. b Decrease in peripancreatic effusion 1 week after conservative treatment. c 2 months after conservative treatment

Discussion

The CLEAR trial demonstrated the efficacy of lenvatinib plus pembrolizumab for metastatic RCC, which yielded an objective response rate and CR rate of 71 and 16%, respectively [2]. This objective response rate is the highest among currently available first-line drugs for RCC, which translates to the marked tumor shrinkage effect observed in the current case. A recent study by Yoshida et al. [4] reported that presurgical ICI-based combination therapy for RCC with an IVC tumor thrombus promoted shrinkage in both the primary tumor and thrombus, which prompted modifications to the surgical strategy and approach and reduced surgical risk. Therefore, we selected a combination of ICI plus TKI therapy with lenvatinib plus pembrolizumab with the aim of shrinking the tumor and thrombus. There were also case reports of neoadjuvant treatment of renal cancer with tumor plugs that resulted in pCR with nivolimab plus cabozantinib and avelumab plus axitinib, suggesting that it is an effective treatment strategy [5, 6]. Furthermore, the half-life of lenvatinib was 35 h, which was considered easier to use with a shorter preoperative withdrawal period compared to cabozantinib’s 111 h.

The present case developed postoperative pancreatitis. According to existing reports [7], all cases of pancreatitis after open nephrectomy were left pT3a or higher, with no pancreatic injuries having been recognized during surgery, similar to the present case. Most iatrogenic injuries to the pancreas are not noticed during surgery but become clinically evident after surgery. Moreover, in cases where a drain is placed postoperatively, measuring the drain amylase level facilitates diagnosis [8]. In our case, intraoperative pancreatic injury was also unrecognized, and the diagnosis was made based on postoperative clinical symptoms and drain amylase levels. Increased risk for pancreatitis has been reported during surgery for large above T3 renal masses [7], although presurgical therapy could potentially reduce this risk. However, concerns regarding TKI-induced adhesions cannot be ruled out. Harshman et al. [9] reported that the incidence and severity of intraoperative adhesions, which constitute a difficult technical challenge, were increased following presurgical TKI for advanced RCC. In addition, drug-induced pancreatitis may have been caused by lenvatinib and pembrolizumab used as neoadjuvant therapy in the present case. Autoimmune pancreatitis is a possible irAE of pembrolizumab, and autoimmune pancreatitis was reported in 1% of all patients in an adverse reaction analysis that included PD-1 and PD-L1 inhibitors in lung cancer cases [10]. The median time of occurrence was 74 days after the first administration, which is within 6 months, and diffuse pancreatic enlargement is often observed on CT scan [11, 12]. In this case, more than 6 months had passed since the first administration of pembrolizumab, and CT showed an increase in lipid density confined to the pancreatic head and no swelling of the entire pancreas, indicating acute pancreatitis rather than autoimmune pancreatitis. On the other hands, there have been no reports of pancreatitis as a side effect of lenvatinib to date. Taken together with these results, we believe that our present case was more likely to represent pancreatic injury than drug-induced pancreatitis.

Postoperative pancreatic fistula could cause infection and bleeding, and delayed treatment could increase mortality. The treatment of postoperative pancreatic fistula has been usually percutaneous drainage with or without endoscopic internal drainage [13]. Therefore, early correct diagnosis and a multidisciplinary approach through specialized departments may be to success the treatment.

Conclusions

We herein detail our experience with a case who underwent nephrectomy with thrombectomy performed for RCC with an IVC thrombus after presurgical lenvatinib plus pembrolizumab therapy promoted tumor shrinkage. In addition, the patient developed postoperative pancreatitis, which may have been caused by adhesions. Although presurgical therapy is expected to be effective in shrinking the tumor, complications due to adhesions during surgery need to be carefully considered. Surgeons should be aware of the potentially devastating postoperative complication in case of pancreatic injuries.

Author contributions

MK: conceptualization; data curation; writing–original draft; visualization; writing—review and editing. DI: conceptualization; data curation; supervision; writing—review and editing. RK: data curation; visualization. MK: data curation; writing—review and editing. TF: supervision. WO: supervision; writing—review and editing. All authors read and approved the final version of the manuscript.

Data availability

The authors declare that all the data in this article are available within the article.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.