Tumor Lysis Syndrome in a Patient with BRAF^V600E Mutated Colon Cancer Treated with Cetuximab and Encorafenib

Abstract

Tumor lysis syndrome (TLS) is a fatal complication associated with chemotherapy. We herein report a case of TLS in a 73-year-old woman with metastatic BRAF^V600E mutated colon cancer after she received combined treatment with cetuximab and encorafenib. The serum uric acid, urea nitrogen, and creatinine levels were elevated on day four of the first cycle. The fibrin degradation product (FDP) and D-dimer levels were also high. Diuresis and rasburicase were initiated for TLS, and the laboratory data all normalized on day 8. Thus, the possibility of TLS being induced by targeted drugs in patients with solid tumors, including colorectal cancer, must not be overlooked.

Introduction

Tumor lysis syndrome (TLS) is an oncologic emergency characterized by massive tumor cell lysis accompanied by the excessive release of large amounts of intracellular electrolytes and metabolites into the bloodstream, and this syndrome occurs either spontaneously or in response to systemic cancer treatment (1-3). TLS leads to metabolic abnormalities, such as hyperuricemia, hypocalcemia, hyperkalemia, and hyperphosphatemia. These metabolic complications further lead to clinical toxicities such as renal failure, cardiac arrhythmias, and seizures (1-3). TLS is most frequently associated with hematological malignancies, and it rarely occurs in patients with chemosensitive solid tumors, such as germ-cell tumors and small cell lung cancers (SCLC) (1-3).

Recent developments in molecular profiling have promoted a new concept of genome-based tumor subclassification. The microsatellite instability-high (MSI-H) phenotype is present in 15% of early stage metastatic colorectal cancers (CRC) (4,5). Although many studies have evaluated the role of microsatellite instability (MSI) as a prognostic marker in mCRC, MSI-H is recognized as a predictor of the benefit of 5-fluorouracil based treatment (5), and its impact on outcomes is controversial (4,5). BRAF mutations were found in approximately 10% of patients with CRC. The prognosis of BRAF-mutated CRC is poor because of its high proliferative capacity, rapid disease progression, and resistance to standard therapies (6-8).

The development of targeted therapies has achieved remarkable progress in both common and rare cancers, mostly those with driver mutations. Recently, in patients with metastatic CRC with BRAF^V600E mutation, the combined use of cetuximab and encorafenib resulted in significantly higher response rates and a longer overall survival than with standard therapy (9-13). In addition, TLS has been described in nearly every class of targeted therapy (14). We herein report a case of TLS observed in a patient with colon cancer associated with a BRAF^V600E mutation after receiving combined therapy with cetuximab and encorafenib.

Case Report

A 73-year-old woman presented to our hospital with right lower abdominal pain and anorexia. Abdominal computed tomography revealed a mass in the ascending colon, along with the presence of multiple hepatic nodules (Figure). The patient complained of right-sided abdominal pain. After a histologically confirmed diagnosis of moderately differentiated adenocarcinoma of the ascending colon with multiple liver metastases, despite the patient's stage IV disease, laparoscopic right hemicolectomy and D2 lymphadenectomy were endoscopically performed because of significant stenosis of the ascending colon. Biomarker analysis revealed high MSI, a positive BRAF^V600E mutation, negative rat sarcoma protein mutation, and no amplification of human epidermal growth factor type 2. gene.

Figure.

Computed tomography (CT) showing the spread of liver metastasis and emergence of ascites. Contrast CT of the liver metastasis (A-C) and plain CT (D). Liver metastasis before laparoscopic right hemicolectomy (A), and after hemicolectomy and before starting pembrolizumab (B). Liver metastasis before initiating cetuximab and encorafenib (C) and 1 month after initiating cetuximab and encorafenib (D).

We initiated pembrolizumab monotherapy at a dose of 200 mg, and we did not observe either myelosuppression or immune-related adverse events (irAEs) during and after the end of 1st line pembrolizumab treatment. We also observed no carryover effects of irAEs, including endocrinological disorders, lung injury, cardiac dysfunction, and diarrhea. No clinical activity of 1st line pembrolizumab treatment was observed (Figure).

After failure of the 1st line pembrolizumab treatment, the treatment regimen was switched to a combination of daily administration of encorafenib (300 mg) and intravenous infusion of cetuximab (400 mg/m² for the first infusion, and 250 mg/m² from the second infusion) every alternate week targeting liver metastasis (Figure) (7). The performance status (PS) of ECOG was 1 before starting pembrolizumab, and PS was 2 just before starting 2nd line treatment with cetuximab and encorafenib due to rapid disease progression. Although hypoalbuminemia and elevated lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels were reported in a blood test before 2nd line chemotherapy (Table 1), we started the treatment. A blood workup conducted on day 4 of the first course, showed hyperuricemia of 9.8 mg/dL, urea nitrogen level of 53.1 mg/dL, and creatinine level of 3.28 mg/dL (Table 2). Fibrin degradation products (FDPs) and D-dimer levels were also elevated; however, the potassium, phosphorus, and calcium levels were within the normal ranges (Table 2). Comparing the data with “Cairo-Bishop definition” of TLS, we observed elevation of uric acid, phosphorus, and creatinine in the patient (Table 3), however, no elevation of the potassium or calcium levels was observed. In addition, clinical TLS of both cardiac events and seizures was not observed (Table 3). Although these findings did not exactly match the criteria for the classification of laboratory TLS (1-3), we diagnosed this patient with TLS based on acute high levels of creatinine, uric acid, phosphorus, FDP, and D-dimer. Radiological findings are not essential factors for the diagnosis of TLS based on “Cairo-Bishop definition” of TLS (1-3), we could not observe clear necrotic change in the liver metastasis by platin computed tomography scan (Figure), however, CA19-9 has dropped from 907.0 U/mL to 40.4 U/mL in 4 weeks, which suggests a significant tumor volume reduction.

Table 1.

Blood Counts and Biochemical Analysis before 2nd Line Treatment.

	Values		Normal range
WBC	7.7	×10-3/m	4 - 8	×10-3/m
Hemoglobin	11.2	g/dL	13.5 - 17.5	g/dL
Platelet	166	×10-3/m	150 - 350	×10-3/m
CRP	1.44	mg/dL	<0.24	mg/dL
Albumin	2.7	g/dL	4.1 - 5.1	g/dL
LDH	743	U/L	124 - 222	U/L
Creatinine	0.67	mg/dL	0.4 - 1.1	mg/dL
Total bilirubin	0.8	mg/dL	0.4 - 1.2	mg/dL
CEA	4.2	ng/mL	<5.0	ng/mL
CA19-9	907.0	U/mL	<37.0	U/mL

LDH: lactate dehydrogenase

Table 2.

Laboratory Date before 2nd Line Treatment until Recovery.

	Normal range		Baseline	Day 4	Day 5	Day 8	Day 11
BUN	8-20	mg/dL	14.8	53.1	52.7	5.8	3.2
Creatinine	0.4-1.1	mg/dL	0.63	3.28	3.91	0.61	0.44
Uric acid	2.5-5.4	mg/dL	5.0	9.8	<0.2	0.8	0.9
LDH (IFCC)	124-222	U/L	395	385	343	319	198
Calcium	8.8-11	mg/dL	7.6	6.8	8.0	6.9	6.6
Potassium	3.5-4.6	mEq/L	4.6	4.5	4.5	3.7	2.5
Phosphorous	2.5-4.5	mg/dL	1.0	3.2	3.8	1.8	1.3
FDP	<5.0	μg/mL	6.2	29.0	15.8	17.3	13.2
D-dimer	0-1	μg/mL	2.4	14.4	8.2	8.1	6.9

The treatment start date is set as Day 0.

BUN: blood urea nitrogen, LDH: lactate dehydrogenase, FDP: fibrinogen/fibrin degradation products

Table 3.

Cairo-Bishop Definition* of TLS and Data of the Patient.

Definition of laboratory TLS		Baseline	Highest values	% increase from baseline
Uric acid	≥476 µmol/L or 8mg/dL or 25% increase from baseline	172 µmol/L	582 µmol/L	338 % increase
Potassium	≥6.0 mmol/L or ≥6 mg/L or 25% increase from baseline	3.9 mg/L	4.6 mg/L	12 % increase
Phosphorous	≥1.45 mol/L for adults or 25% increase from baseline	0.32 mol/L	1.33 mol/L	415 % increase
Calcium	≤1.75 mmol/L or 25% decrease from baseline	1.91 mmol/L	1.99 mmol/L	0.4% increase
Definition of clinical TLS
Creatinine	≥1.5 ULN	0.56	3.91	698 % increase
Cardiac	Arrhythmia/sudden death	Grade 0	Grade 0	Grade 0
Seizure		Grade 0	Grade 0	Grade 0

*References 1 and 2. LDH: lactate dehydrogenase

We initiated TLS management with diuresis and rasburicase at a dose of 7.5 mg according to the guidelines (15-17). After halting the combination regimen, laboratory data were monitored daily. Her uric acid level decreased to 0.8 mg/dL, and renal function normalized on day 8 (Table 3). The combination of cetuximab and encorafenib was restarted, and the dose of encorafenib was reduced to 225 mg. TLS did not recur. However, we could not manage the rapid disease progression due to the deterioration of the patient's general condition and increasing ascites, despite the experience with TLS (Table 2). Our final evaluation of 2nd line treatment revealed progressive disease.

Discussion

TLS is a common complication observed in hematological malignancies; however, it is rarely observed in solid tumors (18-20), and few cases of TLS in colon cancer have been reported to date (21). This TLS case highlights the following three points:

First, TLS was diagnosed by Cairo and Bishop proposed the definition of both laboratory and clinical TLS (1,2). In this patient, we observed a uric acid level ＞8.0 mf/dL; however, the serum potassium, phosphorous, and calcium levels were within the normal range (Table 1). A retrospective review of TLS associated with colorectal cancer reported that elevations in serum potassium, phosphorus, and calcium levels were not always reported in all patients with TLS (21). In addition, our patient had elevated level of both fibrinogen/FDP and D-dimer, which were not included in the definition of TLS by Cairo and Bishop (1,2). However, these observations were reported in a patient with small cell carcinoma of the lung who developed TLS (22). Although we did not observe clinical TLS, including cardiac events and seizure (1-3), we suppose that it was due to early intervention in the management of TLS. The laboratory and clinical findings of TLS improved immediately after starting diuresis and rasburicase on day 4. We reviewed the adverse events induced by the combination of cetuximab and encorafenib to distinguish TLS and found creatinine grade ＞3 by NCI-CTC AE Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (23) in 1.5% of 438 patients without elevation of blood urea nitrogen and uric acid in pivotal trials (12,13). A similar observation was published that serious renal dysfunction was reported in 0.3% of 550 Japanese colorectal patients without elevation of blood urea nitrogen and uric acid in post-marketing pharmacovigilance study of combination encorafenib, binimetinib, and cetuximab in BRAF^V600E-mutated colorectal cancer (24). Based on these findings, we diagnosed TLS induced due to the combination treatment of cetuximab and encorafenib.

Colorectal cancer and risk factors for TLS. TLS is observed in some patients with hematologic malignancies, such as high-grade lymphomas and acute lymphoblastic leukemia, if these patients receive cytotoxic therapy for their diseases. Despite the low risk and scarcity of solid tumors, such as SCLC, melanoma, ovarian cancer, and head and neck cancer (3), TLS has also been reported in patients with colorectal cancer (17-21). However, colorectal cancer is not highly sensitive to cytotoxic therapy or a highly proliferative tumor, such as SCLC, and is classified as low risk (＜1% chance) for TLS (3). According to a review article by Gemici, TLS risk associated with solid tumors, heavy tumor burden, liver metastasis, high LDH or urinary acid, high sensitivity to chemotherapy, renal failure before treatment, treatments associated with nephrotoxicity, infection, or dehydration are risk factors for TLS (25). However, the tumor burden in our case was not large, although multiple liver metastases were detected prior to treatment (Figure). This patient background does not always suggest a high risk for TLS development. However, BRAF-mutated CRC is a new subtype of CRC that has a highly proliferative nature and poor (6-8). This biological behavior appears to be a potential risk factor for TLS. Recently, TLS was reported in a patient with occult breast cancer who was treated with letrozole (26). This case report suggests that a higher tumor burden is not always an essential predictive factor for the development of TLS.

Third is the type of systemic treatment. Although chemotherapy has been recognized as a major factor in treatment-induced TLS (1-3), TLS has also been reported for targeted drugs (14) and immune checkpoint inhibitors (27). These therapeutic modalities sometimes induce dramatic tumor shrinkage and necrosis in various malignancies (28-31). Cetuximab, a chimeric monoclonal antibody targeting EGFR, has also been reported to induce TLS in colon cancer patients (32,33). Cetuximab is a suspected drug for inducing TLS, but the combination of cetuximab and encorafenib is a newly established standard treatment for colon cancer with a BRAF^V600E mutation. Under this regimen, we must consider unknown adverse events, including TLS. Although we observed TLS in our patient, the final evaluation of treatment revealed disease progression. We suspected that a subset of tumors may be controlled by the combination of cetuximab and encorafenib, because CA19-9 has dropped from 907.0 U/mL to 40.4 U/mL in 4 weeks. However, this treatment-insensitive subset of tumors has progressed rapidly.

In conclusion, this is the first report of TLS in a patient with colon cancer and a BRAF^V600E mutation following treatment with a combination of cetuximab and encorafenib. Therefore, the possibility of TLS being induced by newly developed targeted drugs or immune checkpoint inhibitors must not be overlooked.

The authors state that they have no Conflict of Interest (COI).