Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment for carcinoma of the colon in a hemodialysis patient

Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment... Clinical Kidney Journal, 2018, 1–2 doi: 10.1093/ckj/sfy012 Exceptional Case EXCEPTIONAL CASE Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment for carcinoma of the colon in a hemodialysis patient 1,2 3 4 Emily K. Yeung , Michael A. Copland and Sharlene Gill 1 2 Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia, Monash Health, Melbourne, VIC, Australia, Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada and Department of Medicine, Division of Medical Oncology, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada Correspondence and offprint requests to: Michael A. Copland; E-mail: Michael.Copland@vch.ca ABSTRACT Type B lactic acidosis complicating malignancies is rare. Increased lactate production from abnormal metabolism of tumor tissue and extensive liver metastases impairing clearance are usual causes. Fluorouracil, commonly used as adjuvant cancer chemotherapy, is not well recognized among drugs that can lead to lactic acidosis. We report a hemodialysis patient, tumor free after surgery for colon carcinoma, developing acute severe lactic acidosis and encephalopathy. Pharmacogenetic studies failed to show common variants predisposing to the more typical patterns of fluorouracil toxicity. Routine monitoring of hemodialysis patients after fluorouracil is the only practical way to detect this potentially lethal complication. Keywords: carcinoma, fluorouracil, FOLFOX, hemodialysis, lactic acidosis Adjuvant chemotherapy with modified fluorouracil, oxaliplatin BACKGROUND and leucovorin (mFOLFOX) was started at a 20% reduced dose. Lactic acidosis, defined as pH< 7.35 and serum lactate>5 mmol/L, After dialysis he received an intravenous (IV) fluorouracil bolus may complicate malignancy if complications lead to tissue hypoxia of 320 mg/m , along with oxaliplatin and leucovorin, followed (Type A). Type B lactic acidosis in malignancy is uncommon and 2 by continuous IV infusion of 2000 mg/m over the next 46 h. results from abnormal tumor metabolism when tumor burden is Fatigue, anorexia and headache developed within 4 h and he high or from severe liver involvement from metastases leading to slept through the day. He was confused and drowsy when taken impaired clearance. Renal clearance plays only a minor role. to the hospital 32 h after starting chemotherapy. On admission Fluorouracil is commonly used in adjuvant chemotherapy for can- he was encephalopathic, with a Glasgow Coma Scale of 12. His cers. Lactic acidosis complicating its use is little recognized. neck was supple with no lateralizing neurological signs. His blood pressure was 120/60 mmHg (usual 140/90 mmHg on dialy- sis), heart rate 150 bpm, respiratory rate 38/min. He was afebrile CASE REPORT with a flat jugular venous pressure and dry mucous mem- A 59-year-old Asian male on chronic hemodialysis had success- branes. Investigations showed a hemoglobin of 144 g/L, white 9 9 ful resection of a sigmoid adenocarcinoma, stage pT3 N1c Mx. blood cell count of 20.710 /L, platelets 28610 /L, urea Received: 24.1.2018. Editorial decision: 29.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy012/4930739 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| E. K. Yeung et al. 36.5 mmol/L, creatinine 1112 mmol/L, sodium 144 mmol/L, potas- alleleic variants of key genes in fluorouracil metabolism and sium 4.6 mmol/L, chlorine 89 mmol/L and total carbon dioxide action have been studied to predict susceptibility. However, com- 11 mmol/L. Extended electrolytes were unremarkable. L-lactate monly reported variants [3] cannot comprehensively predict less was markedly elevated at 28 mmol/L with an osmolar gap of typical patterns, as evidenced by the genotype of this patient, 15.6. Blood gas showed a pH of 7.17, partial pressure of carbon who might have otherwise developed typical toxic manifesta- dioxide 29 mmHg, partial pressure of oxygen 252 on 50% oxygen tions were they not preempted by CRRT intervention. and bicarbonate 10 mmol/L. Liver enzymes were unremarkable The mechanism of fluorouracil associated Type B lactic and drug screens for salicylate, acetaminophen and alcohol acidosis is unclear. Inhibition of the Kreb’s cycle by fluroace- were negative. Triglyceride was 3.22 mmol/L. His ammonia level tate, a metabolite, has been proposed, with low triglyceride as was not available. a potential risk factor [2]. This patient developed acidosis Chest X-ray, computed tomography scans of the head and despite a precautionary but unnecessary reduced dose [4]and abdomen and a lumbar puncture were all normal. Fluorouracil had a normal triglyceride level. The role of his hemodialysis was discontinued 33 h after the infusion was started. Fluids and status is uncertain, as the kidneys only play a minor role in empiric antibiotics were given, though all cultures later lactate clearance, as previously similarly reported [5]. An asso- returned negative. Seven hours after stopping fluorouracil, lac- ciated hyperammonemia could underlie his encephalopathy tate was 21.6 mmol/L despite being normotensive with a stabi- [2] but was not measured because of his unremarkable liver lized heart rate. Encephalopathy worsened and intubation was enzymes. required. Continuous renal replacement therapy (CRRT) was Pending better pharmacogenetic predictors and understand- started 12 h after admission. Lactate fell rapidly to 12.5, 6.4, 3.6 ing of pathogenesis, routine clinical monitoring and measure- mmol/L at 35 min, 6.4 h and 7 h after initiation, respectively. ments of electrolytes, acid base, lactate and ammonia in Acidosis and encephalopathy corrected in parallel and he was hemodialysis patients after fluorouracil should be implemented extubated after 24 h. He was discharged 4 days after admission. within 24 h of administration to detect this potentially lethal No mucositis, neutropenia, diarrhea, dermopathy or neuropa- but treatable complication. thy was ever noted. Fluorouracil sensitivity genotyping showed a dihydropyrimi- CONFLICT OF INTEREST STATEMENT dine dehydrogenase (DPYD) gene (NM_000110.3) cDNA change: [c.1627A>G (heterozygous)] and a thymidylate synthetase None declared. (TYMS) gene (NM_001071.2) cDNA change [c.-58_-31del (heterozygous)]. REFERENCES 1. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014; 371: DISCUSSION 2309–2319 Lactic acidosis can occur by various mechanisms [1]. While lac- 2. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional ther- tic acidosis may occur with malignancies, the acute develop- apy is associated with hyperammonaemia, lactic acidosis ment in this patient cannot be explained by complications and encephalopathy. Br J Cancer 1997; 75: 464–465 leading to tissue hypoxia (Type A) or by the malignancy itself 3. Rosmarin D, Palles C, Church D et al. Genetic markers of toxic- (Type B), as there was no tumour burden or liver disease. The ity from capecitabine and other fluorouracil-based regimens: close relation to the start of adjuvant chemotherapy with fluo- investigation in the QUASAR2 study, systemic review, and rouracil as part of the mFOLFOX regimen indicates a drug- meta-analysis. J Clin Oncol 2014; 32: 1031–1039 related Type B lactic acidosis. Fluorouracil is the most likely 4. Janus N, Thariat J, Boulanger H et al. Proposal for dosage offending agent and is rarely recognized [2]. adjustment and timing of chemotherapy in hemodialyzed Lactic acidosis has not been reported with oxaloplatin and is patients. Ann Oncol 2010; 21: 1395–1403 also not typical of fluorouracil toxicity, which are commonly 5. Ito A, Kawamoto K, Park T et al. [A case of mFOLFOX6-induced hematologic, gastrointestinal or dermatologic. As fluorouracil is lactic acidosis in a patient with colon cancer] [in Japanese]. an effective chemotherapeutic agent in cancer chemotherapy Gan To Kagaku Ryoho [Japanese Journal of Cancer and with potentially lethal toxicity, pharmacogenetic sequence and Chemotherapy] 2014; 41: 1445–1447 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy012/4930739 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment for carcinoma of the colon in a hemodialysis patient

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Abstract

Clinical Kidney Journal, 2018, 1–2 doi: 10.1093/ckj/sfy012 Exceptional Case EXCEPTIONAL CASE Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment for carcinoma of the colon in a hemodialysis patient 1,2 3 4 Emily K. Yeung , Michael A. Copland and Sharlene Gill 1 2 Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia, Monash Health, Melbourne, VIC, Australia, Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada and Department of Medicine, Division of Medical Oncology, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada Correspondence and offprint requests to: Michael A. Copland; E-mail: Michael.Copland@vch.ca ABSTRACT Type B lactic acidosis complicating malignancies is rare. Increased lactate production from abnormal metabolism of tumor tissue and extensive liver metastases impairing clearance are usual causes. Fluorouracil, commonly used as adjuvant cancer chemotherapy, is not well recognized among drugs that can lead to lactic acidosis. We report a hemodialysis patient, tumor free after surgery for colon carcinoma, developing acute severe lactic acidosis and encephalopathy. Pharmacogenetic studies failed to show common variants predisposing to the more typical patterns of fluorouracil toxicity. Routine monitoring of hemodialysis patients after fluorouracil is the only practical way to detect this potentially lethal complication. Keywords: carcinoma, fluorouracil, FOLFOX, hemodialysis, lactic acidosis Adjuvant chemotherapy with modified fluorouracil, oxaliplatin BACKGROUND and leucovorin (mFOLFOX) was started at a 20% reduced dose. Lactic acidosis, defined as pH< 7.35 and serum lactate>5 mmol/L, After dialysis he received an intravenous (IV) fluorouracil bolus may complicate malignancy if complications lead to tissue hypoxia of 320 mg/m , along with oxaliplatin and leucovorin, followed (Type A). Type B lactic acidosis in malignancy is uncommon and 2 by continuous IV infusion of 2000 mg/m over the next 46 h. results from abnormal tumor metabolism when tumor burden is Fatigue, anorexia and headache developed within 4 h and he high or from severe liver involvement from metastases leading to slept through the day. He was confused and drowsy when taken impaired clearance. Renal clearance plays only a minor role. to the hospital 32 h after starting chemotherapy. On admission Fluorouracil is commonly used in adjuvant chemotherapy for can- he was encephalopathic, with a Glasgow Coma Scale of 12. His cers. Lactic acidosis complicating its use is little recognized. neck was supple with no lateralizing neurological signs. His blood pressure was 120/60 mmHg (usual 140/90 mmHg on dialy- sis), heart rate 150 bpm, respiratory rate 38/min. He was afebrile CASE REPORT with a flat jugular venous pressure and dry mucous mem- A 59-year-old Asian male on chronic hemodialysis had success- branes. Investigations showed a hemoglobin of 144 g/L, white 9 9 ful resection of a sigmoid adenocarcinoma, stage pT3 N1c Mx. blood cell count of 20.710 /L, platelets 28610 /L, urea Received: 24.1.2018. Editorial decision: 29.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy012/4930739 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| E. K. Yeung et al. 36.5 mmol/L, creatinine 1112 mmol/L, sodium 144 mmol/L, potas- alleleic variants of key genes in fluorouracil metabolism and sium 4.6 mmol/L, chlorine 89 mmol/L and total carbon dioxide action have been studied to predict susceptibility. However, com- 11 mmol/L. Extended electrolytes were unremarkable. L-lactate monly reported variants [3] cannot comprehensively predict less was markedly elevated at 28 mmol/L with an osmolar gap of typical patterns, as evidenced by the genotype of this patient, 15.6. Blood gas showed a pH of 7.17, partial pressure of carbon who might have otherwise developed typical toxic manifesta- dioxide 29 mmHg, partial pressure of oxygen 252 on 50% oxygen tions were they not preempted by CRRT intervention. and bicarbonate 10 mmol/L. Liver enzymes were unremarkable The mechanism of fluorouracil associated Type B lactic and drug screens for salicylate, acetaminophen and alcohol acidosis is unclear. Inhibition of the Kreb’s cycle by fluroace- were negative. Triglyceride was 3.22 mmol/L. His ammonia level tate, a metabolite, has been proposed, with low triglyceride as was not available. a potential risk factor [2]. This patient developed acidosis Chest X-ray, computed tomography scans of the head and despite a precautionary but unnecessary reduced dose [4]and abdomen and a lumbar puncture were all normal. Fluorouracil had a normal triglyceride level. The role of his hemodialysis was discontinued 33 h after the infusion was started. Fluids and status is uncertain, as the kidneys only play a minor role in empiric antibiotics were given, though all cultures later lactate clearance, as previously similarly reported [5]. An asso- returned negative. Seven hours after stopping fluorouracil, lac- ciated hyperammonemia could underlie his encephalopathy tate was 21.6 mmol/L despite being normotensive with a stabi- [2] but was not measured because of his unremarkable liver lized heart rate. Encephalopathy worsened and intubation was enzymes. required. Continuous renal replacement therapy (CRRT) was Pending better pharmacogenetic predictors and understand- started 12 h after admission. Lactate fell rapidly to 12.5, 6.4, 3.6 ing of pathogenesis, routine clinical monitoring and measure- mmol/L at 35 min, 6.4 h and 7 h after initiation, respectively. ments of electrolytes, acid base, lactate and ammonia in Acidosis and encephalopathy corrected in parallel and he was hemodialysis patients after fluorouracil should be implemented extubated after 24 h. He was discharged 4 days after admission. within 24 h of administration to detect this potentially lethal No mucositis, neutropenia, diarrhea, dermopathy or neuropa- but treatable complication. thy was ever noted. Fluorouracil sensitivity genotyping showed a dihydropyrimi- CONFLICT OF INTEREST STATEMENT dine dehydrogenase (DPYD) gene (NM_000110.3) cDNA change: [c.1627A>G (heterozygous)] and a thymidylate synthetase None declared. (TYMS) gene (NM_001071.2) cDNA change [c.-58_-31del (heterozygous)]. REFERENCES 1. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014; 371: DISCUSSION 2309–2319 Lactic acidosis can occur by various mechanisms [1]. While lac- 2. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional ther- tic acidosis may occur with malignancies, the acute develop- apy is associated with hyperammonaemia, lactic acidosis ment in this patient cannot be explained by complications and encephalopathy. Br J Cancer 1997; 75: 464–465 leading to tissue hypoxia (Type A) or by the malignancy itself 3. Rosmarin D, Palles C, Church D et al. Genetic markers of toxic- (Type B), as there was no tumour burden or liver disease. The ity from capecitabine and other fluorouracil-based regimens: close relation to the start of adjuvant chemotherapy with fluo- investigation in the QUASAR2 study, systemic review, and rouracil as part of the mFOLFOX regimen indicates a drug- meta-analysis. J Clin Oncol 2014; 32: 1031–1039 related Type B lactic acidosis. Fluorouracil is the most likely 4. Janus N, Thariat J, Boulanger H et al. Proposal for dosage offending agent and is rarely recognized [2]. adjustment and timing of chemotherapy in hemodialyzed Lactic acidosis has not been reported with oxaloplatin and is patients. Ann Oncol 2010; 21: 1395–1403 also not typical of fluorouracil toxicity, which are commonly 5. Ito A, Kawamoto K, Park T et al. [A case of mFOLFOX6-induced hematologic, gastrointestinal or dermatologic. As fluorouracil is lactic acidosis in a patient with colon cancer] [in Japanese]. an effective chemotherapeutic agent in cancer chemotherapy Gan To Kagaku Ryoho [Japanese Journal of Cancer and with potentially lethal toxicity, pharmacogenetic sequence and Chemotherapy] 2014; 41: 1445–1447 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy012/4930739 by Ed 'DeepDyve' Gillespie user on 12 July 2018

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Clinical Kidney JournalOxford University Press

Published: Mar 12, 2018

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