J Gastrointest Canc DOI 10.1007/s12029-015-9711-6
CASE REPORT
Tumor Lysis Syndrome in Metastatic Colon Cancer Following Treatment with Regorafenib Bilal Farooqi 1 & Josh Simmons 2 & Zhonglin Hao 2
# Springer Science+Business Media New York 2015
Introduction
Case Presentation
Tumor lysis syndrome (TLS) is an oncologic emergency that occurs more often in hematological malignancies, such as non-Hodgkin’s lymphomas or acute leukemias [1]. It is caused by the rapid breakdown of tumor cells allowing the release of intracellular components such as nucleic acids, potassium, and phosphates into the bloodstream. The nucleic acids are catabolized into uric acids leading to hyperuricemia. Increased uric acid excretion in the renal tubules can result in acute renal failure. Electrolyte and metabolic disturbances can also lead to other complications, such as arrhythmias, seizures, and even death [2–3]. TLS most often occurs in tumors with a considerable tumor burden, rapid proliferative rate, or high sensitivity to systemic chemotherapy [4–5]. We present a unique case of a 52-year-old male with metastatic colon cancer who developed TLS 1 week after the initiation of regorafenib. Regorafenib is a targeted multi-kinase inhibitor approved for the treatment of metastatic colorectal cancer and gastrointestinal stromal tumors [6, 7]. To date, there has not been a report of tumor lysis syndrome with the use of this targeted agent.
Our patient is a 52-year-old male with metastatic colorectal cancer with the cecum as the primary site. Upon diagnosis, he was found to have metastatic disease to both lungs as well as multiple lesions in the liver, consistent with stage IV disease (Tx, Nx, M1b by AJCC 7th edition). The cancer was noted to be stable on microsatellite instability testing and KRAS mutated. He was initially treated with mFOLFOX6 (leucovorin, 5-fluorouracil, and oxaliplatin) with the addition of bevacizumab. Therapy was complicated by an upper extremity venous thromboembolism and accompanied segmental pulmonary emboli leading to the initiation of enoxaparin. Oxaliplatin was ultimately discontinued due to grade III peripheral neuropathy, and the patient was continued with three additional cycles without oxaliplatin. Imaging at 10 months showed progression of his previously known sites in the bilateral lungs and liver with innumerable lesions in both organs. Therapy was then switched to second-line treatment with FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) with continuation of bevacizumab, which was continued for a total of 6 cycles. Repeat imaging showed further progression of the disease in the lungs and liver. At this point, therapy was changed to regorafenib as third-line therapy. CEA level was measured at 3252 ng/mL which had increased from 899 ng/ mL approximately 3 weeks and 528 ng/mL 4 month prior. Nearly 1 week after starting regorafenib, the patient presented to the emergency department (ED). On presentation to the ED, 1 week after initiation of regorafenib, his main complaint was intractable nausea and vomiting. Patient had poor oral intake but verbalized compliance with his medications. He was also noted to have progressing fatigue limiting his daily activities over the last week. His brother was present on evaluation and noted increasing confusion and somnolence with occasional visual
* Bilal Farooqi [email protected] 1
Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA
2
Division of Hematology and Oncology, Department of Medicine and Cancer Center, Georgia Regents University, Augusta, GA, USA
J Gastrointest Canc
hallucinations. Other than his history of progressive metastatic colon cancer, upper-extremity port-associated venous thromboembolism with bilateral segmental pulmonary emboli, the patient’s past medical history was significant for hypertension, asthma, and a recent stroke a few weeks earlier with minor residual motor deficits in right upper and lower extremities and mild slurring of speech. Upon presentation, the patient was afebrile with vital signs revealing a respiratory rate of 24/min and blood pressure of 107/64, with a heart rate of 88/min. The patient appeared confused. Physical exam demonstrated a flapping hand tremor in both hands, more noticeable on the left side. Patient’s complete blood count demonstrated white blood cell count of 16,500/mm3, hemoglobin of 8.2 g/dL, and platelet count of 565,000/mm3. Chemistry panel revealed a potassium level of 8.0 mEq/L and a serum BUN and creatinine of 79 and 8.25 mg/dL, respectively. Liver function test revealed an ALT of 525 U/L, AST 66 U/L, AKP 502 U/L, and total bilirubin of 4.9 mg/dL. The patient’s baseline creatinine was less than 1.0 mg/dL with mildly elevated AST of 122 U/L, AST 63 U/L, AKP of 400 U/L, and total bilirubin of 1.5 mg/ dL. EKG demonstrated a widened QRS complex. Patient was treated with insulin and glucose, calcium gluconate, and kayexalate with resolution of previously noted EKG changes. He was transferred to the medical intensive care unit for further management. Additional blood work revealed a calcium level of 7.5 mg/dL, a phosphate level of 11.9 mg/dL (normal 2.4–5.1), and a uric acid of 23.1 mg/dL (normal 3.5–7.2). CT scan continued to show significant metastasis of the patient’s cancer in the liver (Fig. 1) and lungs. Upon admission, he was started on dialysis. He continued to have an increased white blood cell count, but it was thought
to be of a non-infectious etiology since he was afebrile with negative initial blood and urine cultures. Chest imaging was without evidence of airspace disease. Patient’s electrolytes, uric acid, and creatinine level improved with dialysis, but his general condition including his mentation continued to deteriorate. In his delirious state, he was observed to aspirate leading to respiratory insufficiency. The patient’s family admired his wishes for no heroic measures and his status was changed DNR/DNI (do not resuscitate/do not intubate). Shortly after, patient went into cardiopulmonary arrest and expired.
Discussion Tumor lysis syndrome is a medical emergency that is infrequently observed in solid tumors [5]. It has a worse prognosis when observed in solid malignancies, with specific sources citing a morality rate up to 35 % [8]. TLS is rare in solid tumors. Occurrence after initiation of a targeted therapy shortly after multiple recent therapies is even rarer. In our review of the literature on TLS in metastatic colon cancer, we discovered eight reported cases [9–16]. Of the eight reported cases, one case was spontaneous and noted in a patient with undiagnosed metastatic colon cancer [9]. Another case was observed in a patient who had been treated with surgical resection of the primary lesion approximately 2 years prior to presentation [16]. Other observed cases were associated with multi-drug, frontline chemotherapy regimens ± immunotherapy including oxaliplatin, irinotecan, and bevacizumab-containing regimens [10–15]. Refer to Table 1 for a brief overview of the colon cancer cases with TLS that have been reported in the literature. The onset of the TLS ranged from within 1 to 8 days after the onset of treatment. All reported cases of colon cancer were metastatic. The patients’ ages ranged from 27 to 82 years of age. All patients, except the patient reported by Vaisban et al., expired shortly after their hospital admission, further
Table 1 Tumor lysis syndrome in colon cancer patients reported in the literature
Fig. 1 CT of abdomen. Shown are numerous hypodense liver metastases (white arrows)
Age of Treatment patient
Onset after treatment
Reference no.
27 38 42 59 62 64 66 82
N/A 6 days 8 days 3 days 2 days 1 day 3 days 2 years after surgery
9 10 11 12 13 14 15 16
Untreated Irinotecan Irinotecan FOLFOX FOLFOX+bevacizumab Cetuximab FOLFIRI Surgery only
J Gastrointest Canc
cementing the concept that the prognosis of TLS is worse in solid tumors. In our review of the literature, TLS has not been reported with the use regorafenib. It is metabolized by the liver and does not require a dose reduction in renal impairment. It has various toxicities listed in the package insert, but tumor lysis syndrome has not been previously reported. Regorafenib is a multi-kinase inhibitor targeting cellular pathways involved with tumor angiogenesis, oncogenesis, and the tumor microenvironment resulting in anti-tumor activity. Specifically, it inhibits VEGF receptors 1-3, KIT, PDGFR, RET, FGFR, TIE2, RAF-1. BRAF, and BRAFV600E. Regorafenib is currently approved by the Food and Drug Administration for use in metastatic colorectal cancer as well as advanced gastrointestinal stromal tumors [6, 7]. For metastatic colorectal cancer, regorafenib is indicated specifically for use in patients previously treated with oxaliplatin, irinotecan, VEGF, or antiEGFR therapy (if KRAS wild type) [6, 7]. It is impossible to say with absolute certainty whether our patient’s case was secondary to the use of regorafenib or if it was the result of rapid progression and high tumor volume triggering spontaneous TLS. It should be recognized, however, that TLS is more frequently chemotherapy-induced when compared to spontaneous occurrence. Also, large tumor burden with high sensitivity to chemotherapy may be considered as a potential cause for TLS in itself [1]. It is possible that spontaneous tumor lysis could have partially contributed to the TLS here, but when compared to the known case report [8], spontaneous tumor lysis appears to have played a minor if any role. The case reported by Frestad et al. presented with extensive retroperitoneal and mesenteric lymphadenopathy as well as disease in the liver leading to hepatic necrosis. In comparison, our case was noted to have extensive disease but not to the point of causing spontaneous organ necrosis. In our case, ALT was 525 U/L, which is far less compared to the typical of more than 800 U/L; the ALT/AKP ratio was 1 compared to the typical of more than 10 seen in acute liver necrosis [17, 18]. Furthermore, the timing of the TLS 1 week after initiation of regorafenib strongly suggests our case is drug-induced. Moreover, sorafenib, which is structurally similar to regorafenib, has been reported to induce TLS [6, 19, 20]. Therefore, we feel that the etiology of TLS was most likely due to increasing tumor burden and sensitivity to the recently initiated targeted therapy with regorafenib. An important lesson learned with our case is that it may be necessary to optimize prevention of TLS in patients with colorectal cancer or gastrointestinal stromal tumors with high tumor burden, even in later line therapy.
References 1. 2.
3.
4. 5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18. 19.
20.
Conflicts of Interest The authors report no conflict of interests.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844–54. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis. 2010;55 Suppl 3:S1–13. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578–86. Gertz MA. Managing tumor lysis syndrome in 2010. Leuk Lymphoma. 2010;51:179–80. Gemici C. Tumour lysis syndrome in solid tumours. Clin Oncol (R Coll Radiol). 2006;18:773–80. Ferraro D, Zalcberg J. Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy. Ther Adv Med Oncol. 2014;6(5):222–8. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863):303–12. Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93(12):1877–85. Frestad D, Perner A, Pedersen UG. Acute onset and rapid progression of multiple organ failure in a young adult with undiagnosed disseminated colonic adenocarcinoma. BMJ Case Rep. 2014;24: 2014. Nikolic-Tomasevic Z, Jelic S, Popov I, Radosavljevic D. Colorectal cancer: dilemmas regarding patient selection and toxicity prediction. J Chemother. 2000;12:244–51. Boisseau M, Bugat R, Mahjoubi M. Rapid tumour lysis syndrome in a metastatic colorectal cancer increased by treatment (CPT-11). Eur J Cancer. 1996;32:737–8. Kim HD, Ha KS, Woo IS, Jung YH, Han CW, Kim TJ. 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(2):204–7. Hentrich M, Schiel X, Scheidt B, Reitmeier M, Hoffmann U, Lutz L. Fatal tumor lysis syndrome after irinotecan/5-FU/folinic acid/ bevacizumab-containing therapy in a patient heavily pretreated for metastatic colon cancer. Acta Oncol. 2008;47:155–6. Krishnan G, D’Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol. 2008;26: 2406–8. Oztop I, Demirkan B, Yaren A, Tarhan O, Sengul B, Ulukus C, et al. Rapid tumor lysis syndrome in a patient with metastatic colon cancer as a complication of treatment with 5-fluorouracil/leucoverin and irinotecan. Tumori. 2004;90:514–6. Vaisban E, Braester A, Mosenzon O, Kolin M, Horn Y. Spontaneous tumor lysis syndrome in solid tumors: really a rare condition? Am J Med Sci. 2003;325(1):38–40. Patterson DJ, Dew EW, Gyorkey F, Graham DY. Niacin hepatitis. South Med J. 1983;76:239–41. Pye E, Northcote RJ, Cobbe SM. Acute hepatitis after parenteral amiodarone administration. Br Heart J. 1988;59:690–1. Huang WS, Yang CH. Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient. World J Gastroenterol. 2009;15(35):4464–6. Shiozawa K, Watanabe M, Takenaka H, Nagai H, Ishii K, Sakai K, et al. Tumor lysis syndrome after sorafenib for hepatocellular carcinoma: a case report. Hepatogastroenterology. 2010;57(101):688–90.
CASE REPORT
Tumor Lysis Syndrome in Metastatic Colon Cancer Following Treatment with Regorafenib Bilal Farooqi 1 & Josh Simmons 2 & Zhonglin Hao 2
# Springer Science+Business Media New York 2015
Introduction
Case Presentation
Tumor lysis syndrome (TLS) is an oncologic emergency that occurs more often in hematological malignancies, such as non-Hodgkin’s lymphomas or acute leukemias [1]. It is caused by the rapid breakdown of tumor cells allowing the release of intracellular components such as nucleic acids, potassium, and phosphates into the bloodstream. The nucleic acids are catabolized into uric acids leading to hyperuricemia. Increased uric acid excretion in the renal tubules can result in acute renal failure. Electrolyte and metabolic disturbances can also lead to other complications, such as arrhythmias, seizures, and even death [2–3]. TLS most often occurs in tumors with a considerable tumor burden, rapid proliferative rate, or high sensitivity to systemic chemotherapy [4–5]. We present a unique case of a 52-year-old male with metastatic colon cancer who developed TLS 1 week after the initiation of regorafenib. Regorafenib is a targeted multi-kinase inhibitor approved for the treatment of metastatic colorectal cancer and gastrointestinal stromal tumors [6, 7]. To date, there has not been a report of tumor lysis syndrome with the use of this targeted agent.
Our patient is a 52-year-old male with metastatic colorectal cancer with the cecum as the primary site. Upon diagnosis, he was found to have metastatic disease to both lungs as well as multiple lesions in the liver, consistent with stage IV disease (Tx, Nx, M1b by AJCC 7th edition). The cancer was noted to be stable on microsatellite instability testing and KRAS mutated. He was initially treated with mFOLFOX6 (leucovorin, 5-fluorouracil, and oxaliplatin) with the addition of bevacizumab. Therapy was complicated by an upper extremity venous thromboembolism and accompanied segmental pulmonary emboli leading to the initiation of enoxaparin. Oxaliplatin was ultimately discontinued due to grade III peripheral neuropathy, and the patient was continued with three additional cycles without oxaliplatin. Imaging at 10 months showed progression of his previously known sites in the bilateral lungs and liver with innumerable lesions in both organs. Therapy was then switched to second-line treatment with FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) with continuation of bevacizumab, which was continued for a total of 6 cycles. Repeat imaging showed further progression of the disease in the lungs and liver. At this point, therapy was changed to regorafenib as third-line therapy. CEA level was measured at 3252 ng/mL which had increased from 899 ng/ mL approximately 3 weeks and 528 ng/mL 4 month prior. Nearly 1 week after starting regorafenib, the patient presented to the emergency department (ED). On presentation to the ED, 1 week after initiation of regorafenib, his main complaint was intractable nausea and vomiting. Patient had poor oral intake but verbalized compliance with his medications. He was also noted to have progressing fatigue limiting his daily activities over the last week. His brother was present on evaluation and noted increasing confusion and somnolence with occasional visual
* Bilal Farooqi [email protected] 1
Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA
2
Division of Hematology and Oncology, Department of Medicine and Cancer Center, Georgia Regents University, Augusta, GA, USA
J Gastrointest Canc
hallucinations. Other than his history of progressive metastatic colon cancer, upper-extremity port-associated venous thromboembolism with bilateral segmental pulmonary emboli, the patient’s past medical history was significant for hypertension, asthma, and a recent stroke a few weeks earlier with minor residual motor deficits in right upper and lower extremities and mild slurring of speech. Upon presentation, the patient was afebrile with vital signs revealing a respiratory rate of 24/min and blood pressure of 107/64, with a heart rate of 88/min. The patient appeared confused. Physical exam demonstrated a flapping hand tremor in both hands, more noticeable on the left side. Patient’s complete blood count demonstrated white blood cell count of 16,500/mm3, hemoglobin of 8.2 g/dL, and platelet count of 565,000/mm3. Chemistry panel revealed a potassium level of 8.0 mEq/L and a serum BUN and creatinine of 79 and 8.25 mg/dL, respectively. Liver function test revealed an ALT of 525 U/L, AST 66 U/L, AKP 502 U/L, and total bilirubin of 4.9 mg/dL. The patient’s baseline creatinine was less than 1.0 mg/dL with mildly elevated AST of 122 U/L, AST 63 U/L, AKP of 400 U/L, and total bilirubin of 1.5 mg/ dL. EKG demonstrated a widened QRS complex. Patient was treated with insulin and glucose, calcium gluconate, and kayexalate with resolution of previously noted EKG changes. He was transferred to the medical intensive care unit for further management. Additional blood work revealed a calcium level of 7.5 mg/dL, a phosphate level of 11.9 mg/dL (normal 2.4–5.1), and a uric acid of 23.1 mg/dL (normal 3.5–7.2). CT scan continued to show significant metastasis of the patient’s cancer in the liver (Fig. 1) and lungs. Upon admission, he was started on dialysis. He continued to have an increased white blood cell count, but it was thought
to be of a non-infectious etiology since he was afebrile with negative initial blood and urine cultures. Chest imaging was without evidence of airspace disease. Patient’s electrolytes, uric acid, and creatinine level improved with dialysis, but his general condition including his mentation continued to deteriorate. In his delirious state, he was observed to aspirate leading to respiratory insufficiency. The patient’s family admired his wishes for no heroic measures and his status was changed DNR/DNI (do not resuscitate/do not intubate). Shortly after, patient went into cardiopulmonary arrest and expired.
Discussion Tumor lysis syndrome is a medical emergency that is infrequently observed in solid tumors [5]. It has a worse prognosis when observed in solid malignancies, with specific sources citing a morality rate up to 35 % [8]. TLS is rare in solid tumors. Occurrence after initiation of a targeted therapy shortly after multiple recent therapies is even rarer. In our review of the literature on TLS in metastatic colon cancer, we discovered eight reported cases [9–16]. Of the eight reported cases, one case was spontaneous and noted in a patient with undiagnosed metastatic colon cancer [9]. Another case was observed in a patient who had been treated with surgical resection of the primary lesion approximately 2 years prior to presentation [16]. Other observed cases were associated with multi-drug, frontline chemotherapy regimens ± immunotherapy including oxaliplatin, irinotecan, and bevacizumab-containing regimens [10–15]. Refer to Table 1 for a brief overview of the colon cancer cases with TLS that have been reported in the literature. The onset of the TLS ranged from within 1 to 8 days after the onset of treatment. All reported cases of colon cancer were metastatic. The patients’ ages ranged from 27 to 82 years of age. All patients, except the patient reported by Vaisban et al., expired shortly after their hospital admission, further
Table 1 Tumor lysis syndrome in colon cancer patients reported in the literature
Fig. 1 CT of abdomen. Shown are numerous hypodense liver metastases (white arrows)
Age of Treatment patient
Onset after treatment
Reference no.
27 38 42 59 62 64 66 82
N/A 6 days 8 days 3 days 2 days 1 day 3 days 2 years after surgery
9 10 11 12 13 14 15 16
Untreated Irinotecan Irinotecan FOLFOX FOLFOX+bevacizumab Cetuximab FOLFIRI Surgery only
J Gastrointest Canc
cementing the concept that the prognosis of TLS is worse in solid tumors. In our review of the literature, TLS has not been reported with the use regorafenib. It is metabolized by the liver and does not require a dose reduction in renal impairment. It has various toxicities listed in the package insert, but tumor lysis syndrome has not been previously reported. Regorafenib is a multi-kinase inhibitor targeting cellular pathways involved with tumor angiogenesis, oncogenesis, and the tumor microenvironment resulting in anti-tumor activity. Specifically, it inhibits VEGF receptors 1-3, KIT, PDGFR, RET, FGFR, TIE2, RAF-1. BRAF, and BRAFV600E. Regorafenib is currently approved by the Food and Drug Administration for use in metastatic colorectal cancer as well as advanced gastrointestinal stromal tumors [6, 7]. For metastatic colorectal cancer, regorafenib is indicated specifically for use in patients previously treated with oxaliplatin, irinotecan, VEGF, or antiEGFR therapy (if KRAS wild type) [6, 7]. It is impossible to say with absolute certainty whether our patient’s case was secondary to the use of regorafenib or if it was the result of rapid progression and high tumor volume triggering spontaneous TLS. It should be recognized, however, that TLS is more frequently chemotherapy-induced when compared to spontaneous occurrence. Also, large tumor burden with high sensitivity to chemotherapy may be considered as a potential cause for TLS in itself [1]. It is possible that spontaneous tumor lysis could have partially contributed to the TLS here, but when compared to the known case report [8], spontaneous tumor lysis appears to have played a minor if any role. The case reported by Frestad et al. presented with extensive retroperitoneal and mesenteric lymphadenopathy as well as disease in the liver leading to hepatic necrosis. In comparison, our case was noted to have extensive disease but not to the point of causing spontaneous organ necrosis. In our case, ALT was 525 U/L, which is far less compared to the typical of more than 800 U/L; the ALT/AKP ratio was 1 compared to the typical of more than 10 seen in acute liver necrosis [17, 18]. Furthermore, the timing of the TLS 1 week after initiation of regorafenib strongly suggests our case is drug-induced. Moreover, sorafenib, which is structurally similar to regorafenib, has been reported to induce TLS [6, 19, 20]. Therefore, we feel that the etiology of TLS was most likely due to increasing tumor burden and sensitivity to the recently initiated targeted therapy with regorafenib. An important lesson learned with our case is that it may be necessary to optimize prevention of TLS in patients with colorectal cancer or gastrointestinal stromal tumors with high tumor burden, even in later line therapy.
References 1. 2.
3.
4. 5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18. 19.
20.
Conflicts of Interest The authors report no conflict of interests.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844–54. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis. 2010;55 Suppl 3:S1–13. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578–86. Gertz MA. Managing tumor lysis syndrome in 2010. Leuk Lymphoma. 2010;51:179–80. Gemici C. Tumour lysis syndrome in solid tumours. Clin Oncol (R Coll Radiol). 2006;18:773–80. Ferraro D, Zalcberg J. Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy. Ther Adv Med Oncol. 2014;6(5):222–8. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863):303–12. Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93(12):1877–85. Frestad D, Perner A, Pedersen UG. Acute onset and rapid progression of multiple organ failure in a young adult with undiagnosed disseminated colonic adenocarcinoma. BMJ Case Rep. 2014;24: 2014. Nikolic-Tomasevic Z, Jelic S, Popov I, Radosavljevic D. Colorectal cancer: dilemmas regarding patient selection and toxicity prediction. J Chemother. 2000;12:244–51. Boisseau M, Bugat R, Mahjoubi M. Rapid tumour lysis syndrome in a metastatic colorectal cancer increased by treatment (CPT-11). Eur J Cancer. 1996;32:737–8. Kim HD, Ha KS, Woo IS, Jung YH, Han CW, Kim TJ. 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(2):204–7. Hentrich M, Schiel X, Scheidt B, Reitmeier M, Hoffmann U, Lutz L. Fatal tumor lysis syndrome after irinotecan/5-FU/folinic acid/ bevacizumab-containing therapy in a patient heavily pretreated for metastatic colon cancer. Acta Oncol. 2008;47:155–6. Krishnan G, D’Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol. 2008;26: 2406–8. Oztop I, Demirkan B, Yaren A, Tarhan O, Sengul B, Ulukus C, et al. Rapid tumor lysis syndrome in a patient with metastatic colon cancer as a complication of treatment with 5-fluorouracil/leucoverin and irinotecan. Tumori. 2004;90:514–6. Vaisban E, Braester A, Mosenzon O, Kolin M, Horn Y. Spontaneous tumor lysis syndrome in solid tumors: really a rare condition? Am J Med Sci. 2003;325(1):38–40. Patterson DJ, Dew EW, Gyorkey F, Graham DY. Niacin hepatitis. South Med J. 1983;76:239–41. Pye E, Northcote RJ, Cobbe SM. Acute hepatitis after parenteral amiodarone administration. Br Heart J. 1988;59:690–1. Huang WS, Yang CH. Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient. World J Gastroenterol. 2009;15(35):4464–6. Shiozawa K, Watanabe M, Takenaka H, Nagai H, Ishii K, Sakai K, et al. Tumor lysis syndrome after sorafenib for hepatocellular carcinoma: a case report. Hepatogastroenterology. 2010;57(101):688–90.
