Tumour Lysis Syndrome in Solid Tumours Associated with Tyrosine Kinase Inhibitors – A Case Illustrated Review

European Oncology & Haematology, 2016;12(1):51–4 DOI: http://doi.org/10.17925/EOH.2016.12.01.51

Abstract:

There are a variety of tyrosine kinase inhibitors (TKIs) that are used in oncology for the treatment of malignancies now and consequently there have been increased observations of tumour lysis syndrome (TLS) associated with these drugs. As per the Cairo-Bishop criteria, laboratory and clinical TLS is typically diagnosed within 3 days before and 7 days after cytotoxic chemotherapy is started. In this report, we describe a case of TLS in a patient with gastrointestinal stromal tumour (GIST) that occurred 15 days after commencement of imatinib. In addition, in a review of the literature, we have found that TLS in solid tumours is observed on average 10 days (95% confidence interval [CI] 7.8–13.7) and up to 3 weeks after initiating TKIs. By comparison, TLS in patients with solid organ tumours treated with cytotoxic chemotherapy occurs within 3 days (95% CI 2.9–4.4). Given the high rate of mortality and the morbidity inherent to TLS, clinicians should be aware that in solid tumour, TKIs may be associated with a delayed onset of TLS.
Keywords: Gastrointestinal stromal tumour, imatinib, sorafenib, sunitinib, acute kidney injury, Cairo-Bishop criteria, renal cell carcinoma, hepatocellular carcinoma
Disclosure: Dominick Bossé, E Celia Marginean, D Blair Macdonald, Garth Nicholas and Shailendra Verma have nothing to disclose in relation to this article. No funding was received for the publication of this article.
Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this case study
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: April 12, 2016 Accepted May 04, 2016
Correspondence: Shailendra Verma, The Ottawa Hospital, 501 Smyth Rd. Ottawa, Ontario, Canada, K1H 8L6. E: sverma@toh.on.ca

Tyrosine kinase inhibitors (TKIs) are small anticancer molecules targeting protooncogenic tyrosine kinase signalling pathways.1 TKIs are now therapies used routinely in the treatment of many solid tumours such as gastrointestinal stromal tumour (GIST), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), medullary thyroid cancer, breast cancer and non-small-cell lung carcinoma (Table 1). As opposed to cytotoxic chemotherapy, TKIs target specific mutated kinases that promote tumour angiogenesis and neoplastic cells growth, proliferation, and resistance to apoptosis. In some cases, such as the c-Kit mutation observed in GIST, tumour cells can be highly “addicted” to one or more oncogenic kinases2–4 and the inhibition of these kinases with a TKI can lead to a striking tumour response and trigger tumour lysis syndrome (TLS).5 It is noteworthy that in high-risk patients with haematological malignancies, targeted therapy including TKIs, monoclonal antibodies, chimeric antigen receptors and proteasome inhibitors are often associated with TLS.6

The pathophysiology of TLS is characterised by an extensive breakdown of tumour cells releasing intracellular contents into the bloodstream, leading to acidosis, hyperuricemia, hyperphosphatemia, and hyperkalemia.7 These metabolic disturbances may in turn cause hypocalcaemia, acute kidney injury (AKI), cardiac arrhythmia, seizures, and death. Albeit considerably more common in haematological malignancies such as acute leukaemia and Burkitt’s lymphoma, it is now recognised that TLS may also occur in solid tumours.8 Most authors and oncologic societies define TLS according to the laboratory and clinical criteria proposed by Cairo & Bishop in 2004 (Table 2).9 As per this definition, TLS is typically diagnosed within a specific timeframe – i.e. 3 days before or 7 days after cytotoxic therapy initiation. However, TLS in solid tumours treated with TKIs has been repeatedly described during the second and third weeks following the initiation of therapy rather than within the first week.5 Against this background, we report a case of delayed TLS in a patient with advanced GIST treated with imatinib.

Case report
A 63-year-old female of Mediterranean origin presented with a three-month history of tiredness, anorexia, 20-kg weight loss and one-month history of vague abdominal discomfort. She was referred to our centre after a computed tomography (CT) scan had revealed extensive intra-abdominal neoplasm along with tumour deposit in the liver and along the hepatic and renal capsules (Figure 1). A core needle biopsy of the omentum demonstrated a neoplasm composed of mixed spindle and epithelioid cytology. The spindle component showed interlacing fascicles of blend tumour cells with spindle nuclei (Figure 2). The tumour had a low mitotic index of < 5/50 high-powered fields (HPF). Immunostaining revealed a strong expression of CD117 (c-Kit), DOG1

("Diagnosed on GIST-1") and CD34, consistent with a diagnosis of GIST, mixed cellularity subtype.

The patient was a life-long non-smoker and never consumed alcohol. She denied personal or familial history of cancer. Her past medical history was significant for type 2 diabetes mellitus treated with metformin and sitagliptin; hypertension treated with losartan, hydrochlorothiazide, and bisoprolol; and gastroesophageal reflux disease managed with omeprazole. On physical examination, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and was somewhat cachectic. The abdomen was diffusely tender with right flank fullness.

As per current recommendations, the patient was initiated on imatinib mesylate, at a dose of 400 mg daily. During the second week of treatment, she developed progressive anorexia, nausea, vomiting, and loose stools. Fifteen days after initiation of imatinib, she presented to the emergency department with dyspnoea, hypotension, tachycardia and confusion. Laboratory tests (with pre-therapy baseline) revealed: Creatinine 527 (53) [22–75 μmol/L], pH <6.8 [7.33–7.46] with undetectable bicarbonate, lactate was 12.9 [0.4–2 mmol/L], potassium 5.8 [3.5–5.1mmol/L], phosphorus 3.04 (1.25) [0.81–1.58 mmol/L],

corrected calcium 2.39 (2.57) [2.12–2.52 mmol/L], urate 1094 (547) [155–357 μmol/L], white blood count 17 [3.5–105 x 109/L], haemoglobin

References:
1. Arora A, Scholar EM, Role of tyrosine kinase inhibitors in cancer therapy, J Pharmacol Exp Ther, 2005;315:971–9.
2. Ma Y-Y, Yu S, He X-J, et al., Involvement of c-KIT mutation in the development of gastrointestinal stromal tumors through proliferation promotion and apoptosis inhibition, Onco Targets Ther, 2014;7:637–43.
3. Demetri GD, Mehren von M, Blanke CD, et al., Efficacy and safety of imatinib mesylate in atdvanced gastrointestinal stromal tumors, N Engl J Med, 2002;347:472–80.
4. Weinstein IB, Joe AK, Mechanisms of Disease: oncogene addiction - a rationale for molecular targeting in cancer therapy, Nat Clin Pract Oncol, 2006;3:448–57.
5. Mirrakhimov AE, Ali AM, Khan M, Barbaryan A, Tumor lysis syndrome in solid tumors: an up to date review of the literature, Rare Tumors, 2014;6:5389.
6. Howard SC, Trifilio S, Gregory TK, et al., Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review, Ann Hematol, 2016;95:563–73.
7. Wilson FP, Berns JS, Onco-nephrology: tumor lysis syndrome, Clin J Am Soc Nephrol, 2012;7:1730–9.
8. Gemici C, Tumour lysis syndrome in solid tumours, Clin Oncol, 2006;18:773–80.
9. Cairo MS, Bishop M, Tumour lysis syndrome: new therapeutic strategies and classification, Br J Haematol, 2004;127:3–11.
10. Choi H, Charnsangavej C, Faria SC, et al., Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria, J Clin Oncol, 2007;25:1753–9.
11. Saylor PJ, Reid TR, Tumor lysis syndrome after treatment of a gastrointestinal stromal tumor with the oral tyrosine kinase inhibitor sunitinib, J Clin Oncol, 2007;25:3544–6.
12. Pinder EM, Atwal GSS, Ayantunde AA, et al., Tumour lysis syndrome occurring in a patient with metastatic gastrointestinal stromal tumour treated with glivec (imatinib mesylate, gleevec, sti571), Sarcoma, 2007;2007:1–5.
13. Coiffier B, Altman A, Pui CH, et al., Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review, J Clin Oncol, 2008;26:2767–78.
14. Hande KR, Garrow GC, Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma, Am J Med, 1993;94:133–9.
15. Kudo C, Miura M, Gamoh M, Niitani T, Tumor lysis syndrome after treatment with sorafenib for hepatocellular carcinoma, Int Canc Conf J, 2015;4:147–50.
16. Liu P-H, Hsu J-W, Kung W-C, et al., Tumor lysis syndrome occurring after transarterial embolization in a 70-year-old man with a hepatocellular carcinoma ruptured in a motor vehicle accident, Int J Gerontol, 2014;8:100–2.
17. Ali AM, Barbaryan A, Zdunek T, et al., Spontaneous tumor lysis syndrome in a patient with cholangiocarcinoma,J Gastrointest Oncol, 2014;5:E46–9.
18. Mehrzad R, Saito H, Krahn Z, Feinstein A, Spontaneous tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma, Med Princ Pract, 2014;23:574–6.
19. Yamashita N, Ooho A, Yamasaki A, et al., Tumor lysis syndrome after sorafenib for hepatocellular carcinoma, Acta Hepatologica Japonica, 2014;55:228–34.
20. Nishida H, Hatano E, Tomiyama K, et al., A case of desensitization of sorafenib after tumor lysis syndrome and erythema multiform in the patient with advanced hepatocellular carcinoma, Acta Hepatologica Japonica, 2014;55:221–7.
21. Goyal H, Sawhney H, Bekara S, Singla U, Spontaneous acute tumour lysis syndrome in gastric adenocarcinoma: a case report and literature review, J Gastrointest Cancer, 2014;45 Suppl 1:208–11.
22. Kim HD, Ha KS, Woo IS, et al., Tumor lysis syndrome in a patient with metastatic colon cancer after treatment with 5-fluorouracil/leucovorin and oxaliplatin: case report and literature review, Cancer Res Treat, 2014;46:204–7.
23. Ascierto PA, Simeone E, Sileni VC, et al., Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort, J Transl Med, 2014;12:116.
24. Dar L, Gendelman O, Amital H, Tumor lysis syndrome presenting in a patient with metastatic melanoma treated with radiation therapy, Isr Med Assoc J, 2014;16:456–7.
25. Noyes AM, Lonial K, Siegel RD, Tumor lysis syndrome in a nonsmall cell lung cancer, Conn Med, 2014;78:421–3.
26. Norberg SM, Oros M, Birkenbach M, Bilusic M, Spontaneous tumor lysis syndrome in renal cell carcinoma: a case report, Clin Genitourin Cancer, 2014;12:e225–7.
27. Wang Y, Yuan C, Liu X, Cutaneous metastatic adenocarcinoma complicated by spontaneous tumor lysis syndrome: A case report, Oncol Lett, 2014;8:905–7.
28. Huang WS, Yang CH, Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient, World J Gastroenterol, 2009;15:4464–6.
29. Joshita S, Yoshizawa K, Sano K, Kobayashi S, A patient with advanced hepatocellular carcinoma treated with sorafenib tosylate showed massive tumor lysis with avoidance of tumor lysis syndrome, Intern Med, 2010;49:991–4.
30. Shiozawa K, Watanabe M, Takenaka H, et al., Tumor lysis syndrome after sorafenib for hepatocellular carcinoma: a case report, Hepatogastroenterology, 2010;57:688–90.
31. Habib G, Nashashibi M, Fatal Tumor Lysis Syndrome Following Sorafenib Treatment, J Med Cases, 2013;4:269–70.
32. Abbass K, Dewani S, Markert R, Kaplon MK, All that glitters: sorafenib, Intern Med, 2010;50:797.
33. Debiec-Rychter M, Sciot R, Le Cesne A, et al., KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours, Eur J Cancer, 2006;42:1093–103.
34. Corless CL, Barnett CM, Heinrich MC, Gastrointestinal stromal tumours: origin and molecular oncology, Nat Rev Cancer, 2011;11:865–78.
35. Joensuu H, Hohenberger P, Corless CL, Gastrointestinal stromal tumour, Lancet Oncol, 2013;382:973–83.
36. Marrari A, Wagner AJ, Hornick JL, Predictors of response to targeted therapies for gastrointestinal stromal tumors, Arch Pathol Lab Med, 2012;136:483–9.
37. Howard SC, Jones DP, Pui C-H, The tumor lysis syndrome, N Engl J Med, 2011;364:1844–54.
Keywords: Gastrointestinal stromal tumour, imatinib, sorafenib, sunitinib, acute kidney injury, Cairo-Bishop criteria, renal cell carcinoma, hepatocellular carcinoma