NDT Plus (2010) 3: 271–272 doi: 10.1093/ndtplus/sfq038 Advance Access publication 28 March 2010
Case Report
A case of cetuximab-related tumour lysis syndrome Muhammad Haroon1, Whye Yan Kwong2, Brian Cantwell2 and Frank Walker1 1
Department of General Internal Medicine/Nephrology and 2Department of Medical Oncology, Waterford Regional Hospital, Waterford, Ireland Correspondence and offprint requests to: Muhammad Haroon; E-mail: [email protected]
Abstract A 60-year-old man was diagnosed with a moderately differentiated adenocarcinoma in November 2006. The computed tomography (CT), magnetic resonance imaging (MRI) and whole-body positron emission tomography–CT (PET–CT) scan showed the presence of multiple liver metastases which were confined to its right lobe. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he presented with the symptoms, signs and biochemistry suggestive of tumour lysis syndrome. Our unusual case highlights that tumour lysis syndrome can also develop in ‘low risk’ category tumours, and that clinicians should be vigilant in identifying at-risk patients.
Introduction Tumour lysis syndrome is a true oncologic emergency which consists of a constellation of a few metabolic complications—hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia. Cetuximab is a monoclonal antibody that attaches to epidermal growth factor receptors (EGFR), and it has revolutionized the treatment for colorectal carcinoma. K-ras (a G-protein) is an essential component of the EGFR signalling cascade [1]. K-ras mutations are found in 30–50% of colorectal cancers [2–4]. Such mutations occur earlier on as the colorectal adenoma progresses to carcinoma, and they have shown to predict for the lack of efficacy of such EGFR inhibitors [5]. Here, we report a case of tumour lysis syndrome induced by cetuximab. To our knowledge, there is only one other case report of tumour lysis syndrome with cetuximab use [6].
Case presentation A 60-year-old man was referred to our surgical colleagues for rectal bleeding in November 2006. He had a colonoscopy which showed a tumour few centimetres proximal to the anal verge, and the biopsy confirmed a moderately
differentiated adenocarcinoma. A computed tomography (CT) scan of thorax, abdomen and pelvis showed the presence of multiple liver metastases which were confined to its right lobe. A magnetic resonance imaging (MRI) scan of his pelvis showed a 7-cm nodular tumour which circumferentially surrounded the rectum, and the local invasion of this tumour was also noted. The whole-body positron emission tomography–CT (PET–CT) scan confirmed the same and showed no evidence of tumour dissemination to any other sites (apart from local invasion and to the right lobe of the liver). He had a successful course of palliative radiotherapy for his rectal bleeding and was started on chemotherapy with 5-fluorouracil and leucovorin on a weekly schedule for 6 weeks with a 2-week break. However, the repeat CT scans in April 2007 showed no response to this treatment. His chemotherapy was then changed to a combination of oral capecitabine plus intravenous infusions of oxaliplatin in May 2007; however, he developed significant myelosuppression and hepatotoxicity, and was taken off this regimen. In September 2007, he had a synchronous resection of his liver metastases and the resection of primary rectal tumour with colostomy. Subsequently, his chemotherapy was changed to irinotecan. Unfortunately, in January 2008, his PET scan showed an uptake at the primary tumour site and also in the right lobe of liver; this was also accompanied by the episodes of rectal bleeding. In June 2008, he had resection of local recurrence, along with local radiotherapy to his primary site. His K-ras mutation status was of wild-type, and it was decided to commence him on monoclonal form of chemotherapy. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he developed a gradually worsening nausea, feeling unwell, and lethargy. He did not seek medical attention for these complaints. He was reviewed in the outpatient clinic 10 days post-chemotherapy, and was noted to be very unwell and dehydrated; his blood tests on that day are shown in Table 1. He was urgently treated for his hyperkalaemia and was transferred to our nephrology services. The history of recent chemotherapy prompted us to request further blood biochemistry, and he was subsequently diagnosed with the tumour lysis syndrome on the basis of hyperphosphataemia (se-
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: [email protected]
272
M. Haroon et al.
Table 1. Serial blood biochemistry
Date
Serum creatinine (range 50–130 µmol/L)
Serum potassium (range 3.5–5.0 mmol/L)
Serum phosphate (range 0.8–1.5 mmol/L)
Serum uric acid (range 212–482 µmol/L)
Serum calcium (range 2.1–2.62 mmol/L)
27 10 10 10 11
60 1424 1351 952 124
4.2 6.2 6.5 5.1 4.1
1.12 3.54
421 2589
2.33 1.83
2.55 0.88
676 470 (baseline)
2.14 2.17
February 2009 March 2009 (11:21 am) March 2009 (15:27) March 2009 (21:51) March 2009 (9:50 am)
This table shows serial blood results, and it reveals the marked abnormalities on presentation and rapid dramatic improvement with fluid resuscitation and urine alkalization.
rum phosphate 3.54 with a normal range of 0.8– 1.5 mmol/l), hypocalcaemia (calcium 1.83 with a normal range of 2.1–2.62 mmol/l), hyperuricaemia (uric acid 2589 with normal range of 212–482 µmol/l) and hyperkalaemia (serum potassium level of 6.2 with a normal range of 3.5–5.0 mmol/l), along with acute renal failure (creatinine 1424 with a normal range of 50–130 µmol/l). Clinically, he was dehydrated and was commenced on intravenous fluids. His arterial blood gases showed metabolic acidosis (pH 7.20, bicarbonate of 10). To our surprise, even within 2 h of commencing fluids, he had massive diuresis. He had a urine output of about 7 l in the first 12 h; his intake and output were balanced with isotonic saline and bicarbonate infusion. This caused a dramatic improvement of his renal profile and uric acid levels (Table 1). The patient subjectively felt much improved and was discharged home after 48 h of his admission with normal renal profile and baseline physical status. Repeat imaging to look for any interval change of his tumour burden since the infusion of cetuximab was not done; as after about a month, our patient developed a fatal massive intracerebral haemorrhage—the cause of which remains speculative.
Discussion and conclusion Tumour lysis syndrome most often occurs after initiation of cytotoxic therapy in patients with large tumour burden, the tumour of high proliferative rate or the tumour having the high sensitivity to chemotherapy. For example, this typically can occur in patients with high-grade non-Hodgkin lymphomas (NHLs, particularly Burkitt lymphomas) and acute lymphoblastic leukaemia (ALL, particularly Burkitt ALL). In our patient, the tumour was of a low risk category for TLS; however, he had important risk factors: dehydration, pretreatment hyperuricaemia and a drug-sensitive neo-
plasm (K-ras mutation of wild-type). We are unsure about the cause of fatal intracranial haemorrhage. Though he had the background history of primary hypertension for about 10 years, it was well controlled; he was normotensive even during his inpatient stay when he was resuscitated with intravenous fluids. To the best of our knowledge, there is only one other case report of tumour lysis syndrome with cetuximab use [6]. These collected case reports highlight that TLS can also develop in ‘low risk’ category tumours, and the clinicians should be vigilant in identifying atrisk patients. It goes without saying that an ounce of prevention is worth a pound of cure. Conflict of interest statement. None declared.
References 1. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer 2001; 37: S16–S22 2. Andreyev HJ, Norman AR, Cunningham D et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 1998; 90: 675–684 3. Esteller M, González S, Risques RA et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001; 19: 299–304 4. Bazan V, Agnese V, Corsale S et al. Specific TP53 and/or Kiras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study. Ann Oncol 2005; 16: iv50–iv55 5. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to antiepidermal growth factor receptor antibody therapies. Cancer Res 2007; 67: 2643–2648 6. Krishnan G, D'Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol 2008; 26: 2406–2408 Received for publication: 1.3.10; Accepted in revised form: 2.3.10
Case Report
A case of cetuximab-related tumour lysis syndrome Muhammad Haroon1, Whye Yan Kwong2, Brian Cantwell2 and Frank Walker1 1
Department of General Internal Medicine/Nephrology and 2Department of Medical Oncology, Waterford Regional Hospital, Waterford, Ireland Correspondence and offprint requests to: Muhammad Haroon; E-mail: [email protected]
Abstract A 60-year-old man was diagnosed with a moderately differentiated adenocarcinoma in November 2006. The computed tomography (CT), magnetic resonance imaging (MRI) and whole-body positron emission tomography–CT (PET–CT) scan showed the presence of multiple liver metastases which were confined to its right lobe. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he presented with the symptoms, signs and biochemistry suggestive of tumour lysis syndrome. Our unusual case highlights that tumour lysis syndrome can also develop in ‘low risk’ category tumours, and that clinicians should be vigilant in identifying at-risk patients.
Introduction Tumour lysis syndrome is a true oncologic emergency which consists of a constellation of a few metabolic complications—hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia. Cetuximab is a monoclonal antibody that attaches to epidermal growth factor receptors (EGFR), and it has revolutionized the treatment for colorectal carcinoma. K-ras (a G-protein) is an essential component of the EGFR signalling cascade [1]. K-ras mutations are found in 30–50% of colorectal cancers [2–4]. Such mutations occur earlier on as the colorectal adenoma progresses to carcinoma, and they have shown to predict for the lack of efficacy of such EGFR inhibitors [5]. Here, we report a case of tumour lysis syndrome induced by cetuximab. To our knowledge, there is only one other case report of tumour lysis syndrome with cetuximab use [6].
Case presentation A 60-year-old man was referred to our surgical colleagues for rectal bleeding in November 2006. He had a colonoscopy which showed a tumour few centimetres proximal to the anal verge, and the biopsy confirmed a moderately
differentiated adenocarcinoma. A computed tomography (CT) scan of thorax, abdomen and pelvis showed the presence of multiple liver metastases which were confined to its right lobe. A magnetic resonance imaging (MRI) scan of his pelvis showed a 7-cm nodular tumour which circumferentially surrounded the rectum, and the local invasion of this tumour was also noted. The whole-body positron emission tomography–CT (PET–CT) scan confirmed the same and showed no evidence of tumour dissemination to any other sites (apart from local invasion and to the right lobe of the liver). He had a successful course of palliative radiotherapy for his rectal bleeding and was started on chemotherapy with 5-fluorouracil and leucovorin on a weekly schedule for 6 weeks with a 2-week break. However, the repeat CT scans in April 2007 showed no response to this treatment. His chemotherapy was then changed to a combination of oral capecitabine plus intravenous infusions of oxaliplatin in May 2007; however, he developed significant myelosuppression and hepatotoxicity, and was taken off this regimen. In September 2007, he had a synchronous resection of his liver metastases and the resection of primary rectal tumour with colostomy. Subsequently, his chemotherapy was changed to irinotecan. Unfortunately, in January 2008, his PET scan showed an uptake at the primary tumour site and also in the right lobe of liver; this was also accompanied by the episodes of rectal bleeding. In June 2008, he had resection of local recurrence, along with local radiotherapy to his primary site. His K-ras mutation status was of wild-type, and it was decided to commence him on monoclonal form of chemotherapy. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he developed a gradually worsening nausea, feeling unwell, and lethargy. He did not seek medical attention for these complaints. He was reviewed in the outpatient clinic 10 days post-chemotherapy, and was noted to be very unwell and dehydrated; his blood tests on that day are shown in Table 1. He was urgently treated for his hyperkalaemia and was transferred to our nephrology services. The history of recent chemotherapy prompted us to request further blood biochemistry, and he was subsequently diagnosed with the tumour lysis syndrome on the basis of hyperphosphataemia (se-
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: [email protected]
272
M. Haroon et al.
Table 1. Serial blood biochemistry
Date
Serum creatinine (range 50–130 µmol/L)
Serum potassium (range 3.5–5.0 mmol/L)
Serum phosphate (range 0.8–1.5 mmol/L)
Serum uric acid (range 212–482 µmol/L)
Serum calcium (range 2.1–2.62 mmol/L)
27 10 10 10 11
60 1424 1351 952 124
4.2 6.2 6.5 5.1 4.1
1.12 3.54
421 2589
2.33 1.83
2.55 0.88
676 470 (baseline)
2.14 2.17
February 2009 March 2009 (11:21 am) March 2009 (15:27) March 2009 (21:51) March 2009 (9:50 am)
This table shows serial blood results, and it reveals the marked abnormalities on presentation and rapid dramatic improvement with fluid resuscitation and urine alkalization.
rum phosphate 3.54 with a normal range of 0.8– 1.5 mmol/l), hypocalcaemia (calcium 1.83 with a normal range of 2.1–2.62 mmol/l), hyperuricaemia (uric acid 2589 with normal range of 212–482 µmol/l) and hyperkalaemia (serum potassium level of 6.2 with a normal range of 3.5–5.0 mmol/l), along with acute renal failure (creatinine 1424 with a normal range of 50–130 µmol/l). Clinically, he was dehydrated and was commenced on intravenous fluids. His arterial blood gases showed metabolic acidosis (pH 7.20, bicarbonate of 10). To our surprise, even within 2 h of commencing fluids, he had massive diuresis. He had a urine output of about 7 l in the first 12 h; his intake and output were balanced with isotonic saline and bicarbonate infusion. This caused a dramatic improvement of his renal profile and uric acid levels (Table 1). The patient subjectively felt much improved and was discharged home after 48 h of his admission with normal renal profile and baseline physical status. Repeat imaging to look for any interval change of his tumour burden since the infusion of cetuximab was not done; as after about a month, our patient developed a fatal massive intracerebral haemorrhage—the cause of which remains speculative.
Discussion and conclusion Tumour lysis syndrome most often occurs after initiation of cytotoxic therapy in patients with large tumour burden, the tumour of high proliferative rate or the tumour having the high sensitivity to chemotherapy. For example, this typically can occur in patients with high-grade non-Hodgkin lymphomas (NHLs, particularly Burkitt lymphomas) and acute lymphoblastic leukaemia (ALL, particularly Burkitt ALL). In our patient, the tumour was of a low risk category for TLS; however, he had important risk factors: dehydration, pretreatment hyperuricaemia and a drug-sensitive neo-
plasm (K-ras mutation of wild-type). We are unsure about the cause of fatal intracranial haemorrhage. Though he had the background history of primary hypertension for about 10 years, it was well controlled; he was normotensive even during his inpatient stay when he was resuscitated with intravenous fluids. To the best of our knowledge, there is only one other case report of tumour lysis syndrome with cetuximab use [6]. These collected case reports highlight that TLS can also develop in ‘low risk’ category tumours, and the clinicians should be vigilant in identifying atrisk patients. It goes without saying that an ounce of prevention is worth a pound of cure. Conflict of interest statement. None declared.
References 1. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer 2001; 37: S16–S22 2. Andreyev HJ, Norman AR, Cunningham D et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 1998; 90: 675–684 3. Esteller M, González S, Risques RA et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001; 19: 299–304 4. Bazan V, Agnese V, Corsale S et al. Specific TP53 and/or Kiras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study. Ann Oncol 2005; 16: iv50–iv55 5. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to antiepidermal growth factor receptor antibody therapies. Cancer Res 2007; 67: 2643–2648 6. Krishnan G, D'Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol 2008; 26: 2406–2408 Received for publication: 1.3.10; Accepted in revised form: 2.3.10
