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Metabolic Abnormalities in Lymphoma
Metabolic Abnormalities in Lymphoma Fernando Cabanillas
Abstract Metabolic abnormalities occur relatively frequently in lymphoma patients undergoing chemotherapy. These abnormalities include hyperuricemia, hypercalcemia, hyperphosphatemia, hypocalcemia, hypomagnesemia, hyponatremia, and hyperkalemia. In addition, tumor lysis syndrome can result in several metabolic abnormalities, leading to potential renal failure. If these syndromes are identified promptly, they can be corrected. Guidelines for identifying metabolic abnormalities in lymphoma patients, as well as management suggestions, are presented.
Clinical Lymphoma, Vol. 3, Suppl. 1, S32-S36, 2002 Key words: Allopurinol, Chemotherapy, Hyperuricemia, Metabolic abnormalities, Rasburicase, Tumor lysis syndrome, Urine alkalinization
S32 • Clinical Lymphoma Vol 3 Suppl 1 December 2002
Lysis Syndrome 16
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1 Uric Acid Creatinine
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9 10/ 6 7a 10/ .m. 8p 10/ .m. 9a 10/ .m. 9p .m. 10/ 10 10/ a.m. 10 10/ p.m. 11 10/ a.m. 11 10/ p.m. 12 10/ a.m. 12 10/ p.m. 13 10/ a.m. 13 p.m . 10/ 15 10/ 22
Centro de Cancer Auxilio Mutuo, San Juan, Puerto Rico Submitted: Sep 23, 2002; Revised: Oct 31, 2002; Accepted: Nov 5, 2002 Address for correspondence: Fernando Cabanillas, MD, Centro de Cancer Auxilio Mutuo, PO Box 191227, San Juan, Puerto Rico 00919-1227 Fax: 713-794-5656; e-mail: [email protected]
Figure 1 Uric Acid and Creatinine in Tumor
Creatinine mg/dL
Case History #1: Multiple Metabolic Abnormalities A 20-year-old male presented with drenching night sweats, a 20-lb weight loss, and abdominal pain. A computed tomography (CT) scan done before he was referred to M. D. Anderson Cancer Center (MDACC) revealed a large mass, which on biopsy revealed Burkitt’s-like lymphoma. Nine days before admission, the patient was observed to have a calcium level of 16.8 mg/dL, uric acid of 14.1 mg/dL, and creatinine of 3.4 mg/dL. The referring physician started the patient on pamidronate, with hydration and allopurinol. At admission to MDACC, the patient was found to have an elevated lactate dehydrogenase (LDH) of 2092 mg/dL, and β2microglobulin 7.7/L. Uric acid had decreased from a baseline of 14.1 mg/dL to 12.4 mg/dL and the blood urea nitrogen (BUN)/creatinine was 16/1.6 mg/dL. There had been clear improvement in renal function with just hydration and allopurinol. Urinary output was normal. The patient’s serum calcium had decreased to 12.4 mg/dL and by the time of admission to MDACC, his phosphorus was 2.4 mg/dL. Total bilirubin, how-
0.5 0
10/
Tumor Lysis Syndrome
ever, was found to be elevated to 5.2 mg/dL. The bone marrow biopsy was negative. After 48 hours of intensive hydration, alkalinization, and allopurinol, chemotherapy was initiated with the alternating triple therapy regimen, an intensive regimen containing anthracycline. On CT scan, this patient was found to have a mass that was invading the liver, occupying most of the abdominal cavity, and obstructing the biliary tract. One week after chemotherapy was initiated, because the patient developed pain in the flanks, it was thought he was having an episode of renal colic and a CT scan was done. The tumor had improved dramatically and no evidence of nephrolithiasis was found. Figure 1 illustrates the changes in the uric acid and creatinine before and after chemotherapy was administered. Although both the uric acid and the creatinine were elevated before ther-
9/2
Even though metabolic abnormalities occur relatively often in patients under treatment for lymphoma, not much has been written about this topic except for recent studies related to the use of rasburicase, a new agent to treat the hyperuricemia associated with tumor lysis syndrome (TLS). However, these metabolic abnormalities include not only hyperuricemia, but also hypercalcemia, hyperphosphatemia, hypocalcemia, and hyperkalemia associated with TLS. In addition, hypocalcemia, hypomagnesemia, and hypophosphatemia can be frequently observed in association with the use of platinum-containing therapy, and hyponatremia often accompanies treatment with cyclophosphamide and vincristine.
Uric Acid mg/dL
Introduction
Uric acid and creatinine changes in a patient with tumor lysis syndrome. Patient was transferred to M. D. Anderson Cancer Center on the morning of October 7, and chemotherapy was started on the afternoon of October 9. Hemodialysis was initiated on October 12, and 3 sessions were given.
Fernando Cabanillas apy, by the time chemotherapy was started and following hydration and administration of allopurinol, the uric acid and creatinine levels both returned to normal. Immediately after chemotherapy was initiated, the creatinine rapidly rose to 4.2 mg/dL while the uric acid simultaneously rose but only to 8.0 mg/dL, which should not result in this degree of renal dysfunction. Renal failure has been described to occur when the conversion of xanthine to uric acid is blocked by allopurinol, thus resulting in accumulation of xanthine, which is not a very soluble substance (Figure 2). Xanthine can rapidly precipitate in the kidney tubules, leading to renal failure in the presence of a normal or slightly elevated uric acid.
Figure 2 Mechanism of Action of Allopurinol and Urate Oxidase
Hypoxanthine
Uric Acid (low solubility)
Xanthine (moderate solubility)
Xanthine Oxidase
X
Allantoin (high solubility)
Urate Oxidase (absent in humans and birds; present in fish, frogs, and rats)
Allopurinol Mechanism of action of allopurinol and urate oxidase. Allopurinol works by inhibiting the enzyme xanthine oxidase, which converts xanthine to uric acid. However, this leads to accumulation of xanthine, which is not a very soluble molecule and can lead to xanthine precipitation in the renal tubules. On the other hand, urate oxidase works by converting uric acid into allantoin, which is highly soluble.
Associated Metabolic Abnormalities The abnormalities of uric acid and creatinine described in this case are typical of the TLS.1 There is no good definition of TLS, but for the purpose of this discussion it can be defined as the metabolic derangements produced by rapid tumor breakdown, which can occur either spontaneously from rapid tumor growth followed by spontaneous tumor cell death or as a consequence of therapy. It is characterized by hyperuricemia due to DNA breakdown, hyperkalemia because of cytosol breakdown, hyperphosphatemia because of protein breakdown, and hypocalcemia secondary to the hyperphosphatemia. As phosphate levels rise, serum calcium decreases. These derangements can result in acute renal failure secondary to urate nephropathy but also due to xanthine nephropathy.2 Also, calcium phosphate can contribute to renal failure. Cardiac dysrhythmias can occur secondary to hyperkalemia and hypocalcemia, and symptoms such as cramps can occur secondary to hypocalcemia. There can be sudden death from hyperkalemia or hypocalcemia. Tumor lysis syndrome is frequently encountered in nonHodgkin’s patients; however, it is often not clinically significant. Any time there is some degree of tumor cell death, some degree of hyperuricemia and hyperphosphatemia may be observed. However, if the TLS is not severe enough it will not result in clinically significant TLS. Several risk factors are associated with TLS (Table 1). Most important among these are the diagnostic subtypes of lymphoma. The Burkitt’s and Burkitt’s-like lymphomas are rapidly growing tumors and have a high proliferative fraction manifested by a high number of cells staining for Ki-67 antigen, which identifies the cells that are traversing through the cell cycle.3 These cell types are more prone to give rise to clinically significant TLS. Lymphoblastic lymphoma, especially when it gives rise to acute lymphoblastic leukemia, is also very likely to develop tumor lysis. Diffuse large-cell lymphoma can also be associated with TLS, but this usually occurs only when there is a high Ki-67 fraction. A very heterogeneous disorder, diffuse large-cell lymphoma has to have a rapid proliferative rate and also a significant amount of tumor burden for TLS to develop. The mantle cell lymphomas usually do not develop TLS,
however, there is a blastic variant of this disorder, mantle cell blastoid lymphoma, that could be confused with acute lymphoblastic leukemia. It can also have a high proliferative fraction and, when treated effectively, can give rise to TLS. Another predictive prognostic factor is a very high LDH,3 (≥ 2 × the normal range). Patients who already present with hyperuricemia at the time of diagnosis also are predisposed to TLS, as are those with extensive bone marrow involvement and those with renal impairment at diagnosis.3 Any patient who presents with one or more of these features should be considered at higher risk for development of clinically significant TLS. Traditional Management of Tumor Lysis Syndrome Hydration is the most important aspect of the management and prevention of TLS. Aggressive hydration should start at least 24 hours before chemotherapy. Traditionally, allopurinol has been used to counteract the hyperuricemia and this has been a fundamental aspect of management,3 although it is fraught with potentially serious problems such as nephrotoxicity.4 The
Table 1 Factors That Predict Tumor Lysis Syndrome in Lymphomas Rapidly proliferating cell types: • Burkitt’s lymphoma/leukemia • Burkitt’s-like lymphoma • Lymphoblastic lymphoma/leukemia • Diffuse large-cell lymphoma • Mantle cell blastic variant Lactate dehydrogenase ≥ 2 times over normal range Hyperuricemia at diagnosis Bulky disease Extensive marrow/blood involvement Renal impairment at diagnosis
Clinical Lymphoma Vol 3 Suppl 1 December 2002 • S33
Metabolic Abnormalities in Lymphoma modern management of TLS circumvents the use of allopurinol and its associated complications by using rasburicase. Rasburicase converts uric acid to allantoin, which is highly soluble, thereby avoiding the complications of potential renal failure. Alkalinization of the urine has also traditionally been used to treat TLS. However, this method can give rise to some problems that will be discussed later.5 Traditionally, urine is alkalinized to a pH of > 7.0. Electrolytes, uric acid, BUN, and creatinine, as well as calcium, phosphorus, LDH, and magnesium, should be monitored every 12 hours for at least the first 5 days. It is recommended that a nephrologist be consulted even before the first sign of TLS, preferably before treatment is started, to be involved early during management. Presentation of Hypercalcemia/Hypocalcemia The patient in the previous case history presented with elevated levels of serum calcium. He was treated with pamidronate, hydrated, and his urine was alkalinized. Calcium levels decreased soon after pamidronate administration. Chemotherapy was started and the calcium dropped further, resulting in the patient becoming hypocalcemic. This raises the question as to why hypocalcemia occurred in this setting. First, the patient had received pamidronate before he was referred to MDACC. Also, he was treated with cytotoxic chemotherapy. The hypercalcemia that we see in lymphoma is directly related to the activity of the tumor. The tumor appears to produce humoral substances that can give rise to hypercalcemia. If in addition to using chemotherapy to treat the tumor, which is the source of these humoral substances, we also administer pamidronate, the calci-
Figure 3 Timing of Chemotherapy in a Patient with Hyperbilirubinemia and Tumor Lysis Syndrome
6
Bilirubin mg/dL
5 4 3 2
Admitted to another hospital 5.3 5.3 5.2 4.8 4.5 Transferred 3.8 to MDACC
Add anthracycline
Chemotherapy without anthracycline
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1.8 1.4 1.4
1.2 1.2
1.1 1.1 1
10/ 6/9 9 10/ 7/9 10/ 9 8/9 9a 10/ .m. 8/9 9p 10/ . 9/9 m. 9a 10/ .m. 9/9 9p 10/ .m. 10/ 99 10/ a.m 10/ . 99 10/ p.m 11/ . 99 10/ a.m 11/ . 99 p.m 10/ 12/ . 99 10/ a.m 12/ . 99 p.m 10/ 13/ . 99 10/ a.m 13/ . 99 p.m . 10/ 15/ 99 10/ 22/ 99
1
Abbreviation: MDACC = M. D. Anderson Cancer Center Timing of chemotherapy in a patient with hyperbilirubinemia and tumor lysis syndrome. Anthracycline was postponed while other chemotherapy drugs were given in order to allow time for the bilirubin to drop, and then anthracycline was added back to the regimen.
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um level can decrease further than the drop seen with chemotherapy alone. In the presence of TLS, the phosphorus level rises, which causes the calcium to drop even further. This patient developed tetany, manifested by the presence of Chvostek’s sign. At that point, it was decided to administer aluminum hydroxide and calcium gluconate. Eventually, the phosphorus dropped and the calcium normalized. Hypercalcemia in lymphoma is usually associated with either Hodgkin’s disease, where the incidence ranges from 1.6%-5.4%, or with B-cell non-Hodgkin’s lymphomas, particularly the aggressive histological types where the incidence ranges from 5%-10%.6 It has become clear that the etiology of hypercalcemia is not usually due to parathormone (PTH) or PTH-like hormone. The most common cause of hypercalcemia in 22 non-Hodgkin’s lymphoma cases studied at MDACC was elevation of calcitriol.6 It is not clear whether this molecule is directly produced by the tumor cells or whether the tumor cells produce some cytokine, which in turn stimulates other cells in the body, perhaps the macrophages, to produce 1-α-hydroxylase, which in turn metabolizes 1,25 (OH)-D3 to calcitriol, as in the case of sarcoidosis. Use of Alkali Therapy Most clinicians feel that alkalinization of the urine is mandatory because uric acid is more soluble at a high pH, so precipitation of uric acid in the renal tubules would thereby be avoided. However, a study done in 1977 showed that alkalinization did not improve the abnormalities induced by hyperuricemia.5 Even though intuitively alkalinization seems logical, there is no scientific proof in the literature that this approach is effective. Furthermore, in the presence of hyperphosphatemia and hypocalcemia, the use of intravenous (I.V.) alkalinization therapy might aggravate manifestations of hypocalcemia such as tetany. It could also increase the risk for calcium phosphate deposition in the kidneys. It is not totally clear whether alkalinization of the urine should be done in every case. Use of Anthracyclines in Patients with Hyperbilirubinemia Another frequent metabolic problem is hyperbilirubinemia in lymphoma patients who require anthracycline therapy. Anthracyclines are eliminated through the biliary system, so hyperbilirubinemia can interfere with their metabolism, resulting in serious toxicity. There are 2 options in this case: the insertion of a biliary catheter to decompress the biliary tract and correct the hyperbilirubinemia, or the initiation of chemotherapy without anthracycline until the bilirubin levels decrease sufficiently, followed by the introduction of anthracycline. Each of these 2 alternatives has both advantages and disadvantages. The disadvantage of the first option is that it might take several days for the bilirubin to drop to normal levels. In addition, there is a risk of infection with the introduction of a catheter. The second option has the disadvantage that, by withholding anthracyclines, which are very active agents in nonHodgkin’s lymphoma, response to chemotherapy might be compromised. However, patients whose tumors have a very high proliferative fraction usually tend to respond quickly, and re-
Fernando Cabanillas spond well, to alkylating agents. Whenever possible, it is preferable to temporarily withhold the anthracycline. This approach is depicted in Figure 3. For the patient in the previous case history, 2 days after chemotherapy began and bilirubin levels had decreased, treatment with anthracycline was initiated. The patient responded with a complete remission, which has continued for > 2 years.
Table 2 Case History #2: How Do You Treat This Patient’s Metabolic Problem? • 32-year-old Puerto Rican male with history of recurrent Hodgkin’s disease was treated with 2 courses of ASHAP regimen (doxorubicin/methylprednisolone/high-dose cytarabine/platinum) and achieved a complete response. • Developed facial numbness after second course of ASHAP. • While flying to Houston developed muscle cramps, tremors in hands and legs. • Physical exam: positive Chvostek's sign. • Serum calcium = 7.0 mg/dL, serum phosphorus = 2.9 mg/dL, albumin = 3.9 g/dL, magnesium = 0.8 mg/dL • Serum uric acid = 7.2 mg/dL, creatinine serum = 1.2 mg/dL, Na = 144 mEq/L/day, K = 3.5 mEq/L/day, Cl = 100 mEq/day, serum CO2 = 32 mEq/L
Conclusions Renal failure following clinically significant TLS can occur in the absence of severe hyperuricemia. This is due to xanthine deposition in the renal tubules. Hypercalcemia can also contribute to the renal failure because it leads to dehydration and calcium phosphate renal tubular deposition. Rigorous monitoring of metabolic changes is critical and should be done every 12 hours for the first 3 days. All complications related to TLS are fully reversible. If bisphosphonates are used, tumor-related hypercalcemia can rapidly turn into symptomatic hypocalcemia, because once the antitumor response to chemotherapy starts, the hypercalcemia is rapidly corrected and the hyperphosphatemia secondary to TLS can then cause a drop in the calcium level. This calcium decrease is aggravated by the prolonged action of bisphosphonates. Therefore, the use of bisphosphonates should be avoided whenever possible, especially if TLS is expected to occur.
Metabolic Abnormalities Unrelated to Tumor Lysis Syndrome Case History #2: Hypocalcemia A 32-year-old male from Puerto Rico with a history of recurrent Hodgkin’s disease was treated with salvage ASHAP (doxorubicin/methylprednisolone/high-dose cytarabine/platinum). After 2 rounds of ASHAP, the patient achieved a complete remission of his recurrent Hodgkin’s disease. However, after the second course of ASHAP, the patient noticed that he had developed some facial numbness. While he was traveling to MDACC for a bone marrow transplant, he developed muscle cramps in the airplane and tremors in the hands and legs. When the patient arrived at MDACC, he had a very positive Chvostek’s sign. His calcium was 7.0 mg/dL, with phosphorus of 2.9 mg/dL. Albumin was normal, so the hypocalcemia was not related to hypoalbuminemia. The magnesium was low at 0.8 mg/dL. Uric acid, creatinine, and electrolytes were essentially normal (Table 2). Hypocalcemia Secondary to Platinum The patient in the above case history developed hypocalcemia secondary to platinum. Since platinum is a drug used so commonly in conjunction with cytarabine for the management of lymphoma, physicians should be aware of this potential complication. Hypocalcemia is clinically manifested by muscle
cramps or tetany; in lymphoma, it usually results from hypomagnesemia that occurs because of renal tubular loss secondary to platinum nephrotoxicity. However, it is not necessarily associated with an elevated creatinine. The nephrotoxicity of platinum can result in renal tubular dysfunction, which is independent from the renal failure that you see frequently with platinum. Magnesium appears to be a necessary molecule for PTH function, although hypocalcemia can also be due to impaired secretion of PTH or inappropriate levels of PTH for the degree of hypocalcemia.7 The PTH levels can be normal, but if the magnesium level is low, PTH might not be capable of exerting its effect. If magnesium replacement is used, it usually results in rapid correction of the hypocalcemia seen in these patients. It is recommended for a magnesium level < 1.6 that I.V. magnesium sulfate 24-36 mEq (≤ 56 mEq) be used. To avoid hypotension, administration should not exceed 16 mEq/hour. In patients with magnesium levels 1.6-1.8 mg/dL, hypocalcemia is generally not an issue. For prophylaxis, magnesium oxide given by mouth, 500-1000 mg twice a day, is recommended. Hypophosphatemia Although it is not as common in lymphoma patients as hypocalcemia and hypomagnesemia, hypophosphatemia can also result from the use of platinum-based regimens.8 Hypophosphatemia occurs as a result of renal tubular dysfunction, with consequent urinary loss of phosphate. This condition is seen in patients treated with cisplatinum and does not necessarily occur in the presence of renal failure. When it is secondary to renal phosphate loss induced by platinum, hypophosphatemia frequently coexists with hypocalcemia, hypomagnesemia, and hypokalemia. The clinical consequences can be quite serious.8 Severe hypophosphatemia can lead to rhabdomyolysis, ileus, respiratory failure, cardiac dysfunction, metabolic encephalopathy, and coma. Decrease in intracellular adenosine triphosphate can result in hemolysis, thrombocytopenia, and impaired phagocytosis. If there is no other comorbid illness to explain the hypophosphatemia, one has to assume that it is due to renal wastage of phosphorus. Treatment depends on the severity. If the hypophosphatemia is moderate (1-2.5), potassium phosphate or sodium phosphate 0.08-0.16 mmol/kg I.V. every 4-6 hours should be
Clinical Lymphoma Vol 3 Suppl 1 December 2002 • S35
Metabolic Abnormalities in Lymphoma given. If it is very severe (< 1.0), then 0.25 mmol/kg I.V. over 46 hours is recommended. Intravenous administration can be discontinued when the serum phosphorus concentration is > 2 mg/dL. Simultaneous oral supplementation might also be necessary to prevent severe hypocalcemia, and maintenance with oral phosphate might be needed to prevent recurrence of the hypophosphatemia. Diarrhea can complicate oral supplementation. Oral phosphate can be given in the form of skim milk, which has a high content of elemental phosphorus (0.9-1 mg/mL), or sodium/potassium phosphate tablets in doses of 2-3 g/day.8
A problem the clinician frequently faces is the patient who develops hyponatremia following therapy with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone). If the patient is responding well to this regimen, one would hesitate to discontinue it because of hyponatremia. In those cases, prophylactic administration of demeclocycline at 150 mg every 6 hours before initiating subsequent chemotherapy courses can be used cautiously. Also, fluid restriction before administering the chemotherapy is recommended.
Conclusion Hyponatremia Hyponatremia is commonly seen as a consequence of inappropriate antidiuretic hormone (ADH) secretion,8 secondary to cyclophosphamide or ifosfamide. Both of these drugs can produce inappropriate ADH secretion. Vincristine will have the same effect. The presence of central nervous system metastasis from lymphoma, as well as pulmonary disorders including pneumonia or pulmonary metastasis, can produce inappropriate ADH secretion. It is not an uncommon problem. A more uncommon cause of hyponatremia is severe hyperproteinemia as seen in myeloma or macroglobulinemia. The hyperproteinemia causes a decrease in sodium concentration in whole plasma. Because there is no change in the concentration of sodium in plasma water, tonicity remains normal, and no treatment is necessary. Manifestations of hyponatremia are drowsiness and seizures. Low serum osmolality and high urine osmolality are present. These features should be present, and edema should be absent, before one can conclude that the diagnosis is a symptom of inappropriate ADH secretion (SIADH). In the asymptomatic patient, management should consist of fluid restriction. Demeclocycline 150 or 300 mg by mouth 4 times daily can be used if fluid restriction is not enough, but it should be used with caution because of its nephrotoxic effects. Correction of the underlying abnormality usually results in resolution of the SIADH. In severely symptomatic patients, hypertonic saline with or without furosemide I.V. should be administered.9,10
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The management of patients with lymphoma can be associated with multiple metabolic abnormalities, and the clinician should be aware of these. Abnormalities such as hyperuricemia can be easily prevented with the use of urate oxidase. Other abnomalities, such as hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, and hyponatremia, can be corrected if identified promptly.
References 1. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol 1993; 13:273280. 2. Potter JL, Silvidi AA. Xanthine lithiasis, nephrocalcinosis, and renal failure in a leukemia patient treated with allopurinol. Clin Chem 1987; 33:23142316. 3. Gerdes J, Dallenbach F, Lennert K, et al. Growth fractions in malignant non-Hodgkin’s lymphomas (NHL) as determined in situ with the monoclonal antibody Ki-67. Hematol Oncol 1984; 2:365-371. 4. Paller MS. Drug-induced nephropathies. Med Clin North Am 1990; 74:909917. 5. Conger JD, Falk SA. Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest 1977; 59:786-793. 6. Seymour JF, Gagel R, Hagemeister FB, et al. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin’s lymphoma. Ann Int Med 1994; 121:633-640. 7. Bringhurst F, Demay M, Kronenberg H.Williams Textbook of Endocrinology. 9th ed. St. Louis, MO: W. B. Saunders; 1998. 8. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin 2001; 17:503-529. 9. Sorensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238:97-110. 10. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342:15811589.
Abstract Metabolic abnormalities occur relatively frequently in lymphoma patients undergoing chemotherapy. These abnormalities include hyperuricemia, hypercalcemia, hyperphosphatemia, hypocalcemia, hypomagnesemia, hyponatremia, and hyperkalemia. In addition, tumor lysis syndrome can result in several metabolic abnormalities, leading to potential renal failure. If these syndromes are identified promptly, they can be corrected. Guidelines for identifying metabolic abnormalities in lymphoma patients, as well as management suggestions, are presented.
Clinical Lymphoma, Vol. 3, Suppl. 1, S32-S36, 2002 Key words: Allopurinol, Chemotherapy, Hyperuricemia, Metabolic abnormalities, Rasburicase, Tumor lysis syndrome, Urine alkalinization
S32 • Clinical Lymphoma Vol 3 Suppl 1 December 2002
Lysis Syndrome 16
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Centro de Cancer Auxilio Mutuo, San Juan, Puerto Rico Submitted: Sep 23, 2002; Revised: Oct 31, 2002; Accepted: Nov 5, 2002 Address for correspondence: Fernando Cabanillas, MD, Centro de Cancer Auxilio Mutuo, PO Box 191227, San Juan, Puerto Rico 00919-1227 Fax: 713-794-5656; e-mail: [email protected]
Figure 1 Uric Acid and Creatinine in Tumor
Creatinine mg/dL
Case History #1: Multiple Metabolic Abnormalities A 20-year-old male presented with drenching night sweats, a 20-lb weight loss, and abdominal pain. A computed tomography (CT) scan done before he was referred to M. D. Anderson Cancer Center (MDACC) revealed a large mass, which on biopsy revealed Burkitt’s-like lymphoma. Nine days before admission, the patient was observed to have a calcium level of 16.8 mg/dL, uric acid of 14.1 mg/dL, and creatinine of 3.4 mg/dL. The referring physician started the patient on pamidronate, with hydration and allopurinol. At admission to MDACC, the patient was found to have an elevated lactate dehydrogenase (LDH) of 2092 mg/dL, and β2microglobulin 7.7/L. Uric acid had decreased from a baseline of 14.1 mg/dL to 12.4 mg/dL and the blood urea nitrogen (BUN)/creatinine was 16/1.6 mg/dL. There had been clear improvement in renal function with just hydration and allopurinol. Urinary output was normal. The patient’s serum calcium had decreased to 12.4 mg/dL and by the time of admission to MDACC, his phosphorus was 2.4 mg/dL. Total bilirubin, how-
0.5 0
10/
Tumor Lysis Syndrome
ever, was found to be elevated to 5.2 mg/dL. The bone marrow biopsy was negative. After 48 hours of intensive hydration, alkalinization, and allopurinol, chemotherapy was initiated with the alternating triple therapy regimen, an intensive regimen containing anthracycline. On CT scan, this patient was found to have a mass that was invading the liver, occupying most of the abdominal cavity, and obstructing the biliary tract. One week after chemotherapy was initiated, because the patient developed pain in the flanks, it was thought he was having an episode of renal colic and a CT scan was done. The tumor had improved dramatically and no evidence of nephrolithiasis was found. Figure 1 illustrates the changes in the uric acid and creatinine before and after chemotherapy was administered. Although both the uric acid and the creatinine were elevated before ther-
9/2
Even though metabolic abnormalities occur relatively often in patients under treatment for lymphoma, not much has been written about this topic except for recent studies related to the use of rasburicase, a new agent to treat the hyperuricemia associated with tumor lysis syndrome (TLS). However, these metabolic abnormalities include not only hyperuricemia, but also hypercalcemia, hyperphosphatemia, hypocalcemia, and hyperkalemia associated with TLS. In addition, hypocalcemia, hypomagnesemia, and hypophosphatemia can be frequently observed in association with the use of platinum-containing therapy, and hyponatremia often accompanies treatment with cyclophosphamide and vincristine.
Uric Acid mg/dL
Introduction
Uric acid and creatinine changes in a patient with tumor lysis syndrome. Patient was transferred to M. D. Anderson Cancer Center on the morning of October 7, and chemotherapy was started on the afternoon of October 9. Hemodialysis was initiated on October 12, and 3 sessions were given.
Fernando Cabanillas apy, by the time chemotherapy was started and following hydration and administration of allopurinol, the uric acid and creatinine levels both returned to normal. Immediately after chemotherapy was initiated, the creatinine rapidly rose to 4.2 mg/dL while the uric acid simultaneously rose but only to 8.0 mg/dL, which should not result in this degree of renal dysfunction. Renal failure has been described to occur when the conversion of xanthine to uric acid is blocked by allopurinol, thus resulting in accumulation of xanthine, which is not a very soluble substance (Figure 2). Xanthine can rapidly precipitate in the kidney tubules, leading to renal failure in the presence of a normal or slightly elevated uric acid.
Figure 2 Mechanism of Action of Allopurinol and Urate Oxidase
Hypoxanthine
Uric Acid (low solubility)
Xanthine (moderate solubility)
Xanthine Oxidase
X
Allantoin (high solubility)
Urate Oxidase (absent in humans and birds; present in fish, frogs, and rats)
Allopurinol Mechanism of action of allopurinol and urate oxidase. Allopurinol works by inhibiting the enzyme xanthine oxidase, which converts xanthine to uric acid. However, this leads to accumulation of xanthine, which is not a very soluble molecule and can lead to xanthine precipitation in the renal tubules. On the other hand, urate oxidase works by converting uric acid into allantoin, which is highly soluble.
Associated Metabolic Abnormalities The abnormalities of uric acid and creatinine described in this case are typical of the TLS.1 There is no good definition of TLS, but for the purpose of this discussion it can be defined as the metabolic derangements produced by rapid tumor breakdown, which can occur either spontaneously from rapid tumor growth followed by spontaneous tumor cell death or as a consequence of therapy. It is characterized by hyperuricemia due to DNA breakdown, hyperkalemia because of cytosol breakdown, hyperphosphatemia because of protein breakdown, and hypocalcemia secondary to the hyperphosphatemia. As phosphate levels rise, serum calcium decreases. These derangements can result in acute renal failure secondary to urate nephropathy but also due to xanthine nephropathy.2 Also, calcium phosphate can contribute to renal failure. Cardiac dysrhythmias can occur secondary to hyperkalemia and hypocalcemia, and symptoms such as cramps can occur secondary to hypocalcemia. There can be sudden death from hyperkalemia or hypocalcemia. Tumor lysis syndrome is frequently encountered in nonHodgkin’s patients; however, it is often not clinically significant. Any time there is some degree of tumor cell death, some degree of hyperuricemia and hyperphosphatemia may be observed. However, if the TLS is not severe enough it will not result in clinically significant TLS. Several risk factors are associated with TLS (Table 1). Most important among these are the diagnostic subtypes of lymphoma. The Burkitt’s and Burkitt’s-like lymphomas are rapidly growing tumors and have a high proliferative fraction manifested by a high number of cells staining for Ki-67 antigen, which identifies the cells that are traversing through the cell cycle.3 These cell types are more prone to give rise to clinically significant TLS. Lymphoblastic lymphoma, especially when it gives rise to acute lymphoblastic leukemia, is also very likely to develop tumor lysis. Diffuse large-cell lymphoma can also be associated with TLS, but this usually occurs only when there is a high Ki-67 fraction. A very heterogeneous disorder, diffuse large-cell lymphoma has to have a rapid proliferative rate and also a significant amount of tumor burden for TLS to develop. The mantle cell lymphomas usually do not develop TLS,
however, there is a blastic variant of this disorder, mantle cell blastoid lymphoma, that could be confused with acute lymphoblastic leukemia. It can also have a high proliferative fraction and, when treated effectively, can give rise to TLS. Another predictive prognostic factor is a very high LDH,3 (≥ 2 × the normal range). Patients who already present with hyperuricemia at the time of diagnosis also are predisposed to TLS, as are those with extensive bone marrow involvement and those with renal impairment at diagnosis.3 Any patient who presents with one or more of these features should be considered at higher risk for development of clinically significant TLS. Traditional Management of Tumor Lysis Syndrome Hydration is the most important aspect of the management and prevention of TLS. Aggressive hydration should start at least 24 hours before chemotherapy. Traditionally, allopurinol has been used to counteract the hyperuricemia and this has been a fundamental aspect of management,3 although it is fraught with potentially serious problems such as nephrotoxicity.4 The
Table 1 Factors That Predict Tumor Lysis Syndrome in Lymphomas Rapidly proliferating cell types: • Burkitt’s lymphoma/leukemia • Burkitt’s-like lymphoma • Lymphoblastic lymphoma/leukemia • Diffuse large-cell lymphoma • Mantle cell blastic variant Lactate dehydrogenase ≥ 2 times over normal range Hyperuricemia at diagnosis Bulky disease Extensive marrow/blood involvement Renal impairment at diagnosis
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Metabolic Abnormalities in Lymphoma modern management of TLS circumvents the use of allopurinol and its associated complications by using rasburicase. Rasburicase converts uric acid to allantoin, which is highly soluble, thereby avoiding the complications of potential renal failure. Alkalinization of the urine has also traditionally been used to treat TLS. However, this method can give rise to some problems that will be discussed later.5 Traditionally, urine is alkalinized to a pH of > 7.0. Electrolytes, uric acid, BUN, and creatinine, as well as calcium, phosphorus, LDH, and magnesium, should be monitored every 12 hours for at least the first 5 days. It is recommended that a nephrologist be consulted even before the first sign of TLS, preferably before treatment is started, to be involved early during management. Presentation of Hypercalcemia/Hypocalcemia The patient in the previous case history presented with elevated levels of serum calcium. He was treated with pamidronate, hydrated, and his urine was alkalinized. Calcium levels decreased soon after pamidronate administration. Chemotherapy was started and the calcium dropped further, resulting in the patient becoming hypocalcemic. This raises the question as to why hypocalcemia occurred in this setting. First, the patient had received pamidronate before he was referred to MDACC. Also, he was treated with cytotoxic chemotherapy. The hypercalcemia that we see in lymphoma is directly related to the activity of the tumor. The tumor appears to produce humoral substances that can give rise to hypercalcemia. If in addition to using chemotherapy to treat the tumor, which is the source of these humoral substances, we also administer pamidronate, the calci-
Figure 3 Timing of Chemotherapy in a Patient with Hyperbilirubinemia and Tumor Lysis Syndrome
6
Bilirubin mg/dL
5 4 3 2
Admitted to another hospital 5.3 5.3 5.2 4.8 4.5 Transferred 3.8 to MDACC
Add anthracycline
Chemotherapy without anthracycline
2.2
1.8 1.4 1.4
1.2 1.2
1.1 1.1 1
10/ 6/9 9 10/ 7/9 10/ 9 8/9 9a 10/ .m. 8/9 9p 10/ . 9/9 m. 9a 10/ .m. 9/9 9p 10/ .m. 10/ 99 10/ a.m 10/ . 99 10/ p.m 11/ . 99 10/ a.m 11/ . 99 p.m 10/ 12/ . 99 10/ a.m 12/ . 99 p.m 10/ 13/ . 99 10/ a.m 13/ . 99 p.m . 10/ 15/ 99 10/ 22/ 99
1
Abbreviation: MDACC = M. D. Anderson Cancer Center Timing of chemotherapy in a patient with hyperbilirubinemia and tumor lysis syndrome. Anthracycline was postponed while other chemotherapy drugs were given in order to allow time for the bilirubin to drop, and then anthracycline was added back to the regimen.
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um level can decrease further than the drop seen with chemotherapy alone. In the presence of TLS, the phosphorus level rises, which causes the calcium to drop even further. This patient developed tetany, manifested by the presence of Chvostek’s sign. At that point, it was decided to administer aluminum hydroxide and calcium gluconate. Eventually, the phosphorus dropped and the calcium normalized. Hypercalcemia in lymphoma is usually associated with either Hodgkin’s disease, where the incidence ranges from 1.6%-5.4%, or with B-cell non-Hodgkin’s lymphomas, particularly the aggressive histological types where the incidence ranges from 5%-10%.6 It has become clear that the etiology of hypercalcemia is not usually due to parathormone (PTH) or PTH-like hormone. The most common cause of hypercalcemia in 22 non-Hodgkin’s lymphoma cases studied at MDACC was elevation of calcitriol.6 It is not clear whether this molecule is directly produced by the tumor cells or whether the tumor cells produce some cytokine, which in turn stimulates other cells in the body, perhaps the macrophages, to produce 1-α-hydroxylase, which in turn metabolizes 1,25 (OH)-D3 to calcitriol, as in the case of sarcoidosis. Use of Alkali Therapy Most clinicians feel that alkalinization of the urine is mandatory because uric acid is more soluble at a high pH, so precipitation of uric acid in the renal tubules would thereby be avoided. However, a study done in 1977 showed that alkalinization did not improve the abnormalities induced by hyperuricemia.5 Even though intuitively alkalinization seems logical, there is no scientific proof in the literature that this approach is effective. Furthermore, in the presence of hyperphosphatemia and hypocalcemia, the use of intravenous (I.V.) alkalinization therapy might aggravate manifestations of hypocalcemia such as tetany. It could also increase the risk for calcium phosphate deposition in the kidneys. It is not totally clear whether alkalinization of the urine should be done in every case. Use of Anthracyclines in Patients with Hyperbilirubinemia Another frequent metabolic problem is hyperbilirubinemia in lymphoma patients who require anthracycline therapy. Anthracyclines are eliminated through the biliary system, so hyperbilirubinemia can interfere with their metabolism, resulting in serious toxicity. There are 2 options in this case: the insertion of a biliary catheter to decompress the biliary tract and correct the hyperbilirubinemia, or the initiation of chemotherapy without anthracycline until the bilirubin levels decrease sufficiently, followed by the introduction of anthracycline. Each of these 2 alternatives has both advantages and disadvantages. The disadvantage of the first option is that it might take several days for the bilirubin to drop to normal levels. In addition, there is a risk of infection with the introduction of a catheter. The second option has the disadvantage that, by withholding anthracyclines, which are very active agents in nonHodgkin’s lymphoma, response to chemotherapy might be compromised. However, patients whose tumors have a very high proliferative fraction usually tend to respond quickly, and re-
Fernando Cabanillas spond well, to alkylating agents. Whenever possible, it is preferable to temporarily withhold the anthracycline. This approach is depicted in Figure 3. For the patient in the previous case history, 2 days after chemotherapy began and bilirubin levels had decreased, treatment with anthracycline was initiated. The patient responded with a complete remission, which has continued for > 2 years.
Table 2 Case History #2: How Do You Treat This Patient’s Metabolic Problem? • 32-year-old Puerto Rican male with history of recurrent Hodgkin’s disease was treated with 2 courses of ASHAP regimen (doxorubicin/methylprednisolone/high-dose cytarabine/platinum) and achieved a complete response. • Developed facial numbness after second course of ASHAP. • While flying to Houston developed muscle cramps, tremors in hands and legs. • Physical exam: positive Chvostek's sign. • Serum calcium = 7.0 mg/dL, serum phosphorus = 2.9 mg/dL, albumin = 3.9 g/dL, magnesium = 0.8 mg/dL • Serum uric acid = 7.2 mg/dL, creatinine serum = 1.2 mg/dL, Na = 144 mEq/L/day, K = 3.5 mEq/L/day, Cl = 100 mEq/day, serum CO2 = 32 mEq/L
Conclusions Renal failure following clinically significant TLS can occur in the absence of severe hyperuricemia. This is due to xanthine deposition in the renal tubules. Hypercalcemia can also contribute to the renal failure because it leads to dehydration and calcium phosphate renal tubular deposition. Rigorous monitoring of metabolic changes is critical and should be done every 12 hours for the first 3 days. All complications related to TLS are fully reversible. If bisphosphonates are used, tumor-related hypercalcemia can rapidly turn into symptomatic hypocalcemia, because once the antitumor response to chemotherapy starts, the hypercalcemia is rapidly corrected and the hyperphosphatemia secondary to TLS can then cause a drop in the calcium level. This calcium decrease is aggravated by the prolonged action of bisphosphonates. Therefore, the use of bisphosphonates should be avoided whenever possible, especially if TLS is expected to occur.
Metabolic Abnormalities Unrelated to Tumor Lysis Syndrome Case History #2: Hypocalcemia A 32-year-old male from Puerto Rico with a history of recurrent Hodgkin’s disease was treated with salvage ASHAP (doxorubicin/methylprednisolone/high-dose cytarabine/platinum). After 2 rounds of ASHAP, the patient achieved a complete remission of his recurrent Hodgkin’s disease. However, after the second course of ASHAP, the patient noticed that he had developed some facial numbness. While he was traveling to MDACC for a bone marrow transplant, he developed muscle cramps in the airplane and tremors in the hands and legs. When the patient arrived at MDACC, he had a very positive Chvostek’s sign. His calcium was 7.0 mg/dL, with phosphorus of 2.9 mg/dL. Albumin was normal, so the hypocalcemia was not related to hypoalbuminemia. The magnesium was low at 0.8 mg/dL. Uric acid, creatinine, and electrolytes were essentially normal (Table 2). Hypocalcemia Secondary to Platinum The patient in the above case history developed hypocalcemia secondary to platinum. Since platinum is a drug used so commonly in conjunction with cytarabine for the management of lymphoma, physicians should be aware of this potential complication. Hypocalcemia is clinically manifested by muscle
cramps or tetany; in lymphoma, it usually results from hypomagnesemia that occurs because of renal tubular loss secondary to platinum nephrotoxicity. However, it is not necessarily associated with an elevated creatinine. The nephrotoxicity of platinum can result in renal tubular dysfunction, which is independent from the renal failure that you see frequently with platinum. Magnesium appears to be a necessary molecule for PTH function, although hypocalcemia can also be due to impaired secretion of PTH or inappropriate levels of PTH for the degree of hypocalcemia.7 The PTH levels can be normal, but if the magnesium level is low, PTH might not be capable of exerting its effect. If magnesium replacement is used, it usually results in rapid correction of the hypocalcemia seen in these patients. It is recommended for a magnesium level < 1.6 that I.V. magnesium sulfate 24-36 mEq (≤ 56 mEq) be used. To avoid hypotension, administration should not exceed 16 mEq/hour. In patients with magnesium levels 1.6-1.8 mg/dL, hypocalcemia is generally not an issue. For prophylaxis, magnesium oxide given by mouth, 500-1000 mg twice a day, is recommended. Hypophosphatemia Although it is not as common in lymphoma patients as hypocalcemia and hypomagnesemia, hypophosphatemia can also result from the use of platinum-based regimens.8 Hypophosphatemia occurs as a result of renal tubular dysfunction, with consequent urinary loss of phosphate. This condition is seen in patients treated with cisplatinum and does not necessarily occur in the presence of renal failure. When it is secondary to renal phosphate loss induced by platinum, hypophosphatemia frequently coexists with hypocalcemia, hypomagnesemia, and hypokalemia. The clinical consequences can be quite serious.8 Severe hypophosphatemia can lead to rhabdomyolysis, ileus, respiratory failure, cardiac dysfunction, metabolic encephalopathy, and coma. Decrease in intracellular adenosine triphosphate can result in hemolysis, thrombocytopenia, and impaired phagocytosis. If there is no other comorbid illness to explain the hypophosphatemia, one has to assume that it is due to renal wastage of phosphorus. Treatment depends on the severity. If the hypophosphatemia is moderate (1-2.5), potassium phosphate or sodium phosphate 0.08-0.16 mmol/kg I.V. every 4-6 hours should be
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Metabolic Abnormalities in Lymphoma given. If it is very severe (< 1.0), then 0.25 mmol/kg I.V. over 46 hours is recommended. Intravenous administration can be discontinued when the serum phosphorus concentration is > 2 mg/dL. Simultaneous oral supplementation might also be necessary to prevent severe hypocalcemia, and maintenance with oral phosphate might be needed to prevent recurrence of the hypophosphatemia. Diarrhea can complicate oral supplementation. Oral phosphate can be given in the form of skim milk, which has a high content of elemental phosphorus (0.9-1 mg/mL), or sodium/potassium phosphate tablets in doses of 2-3 g/day.8
A problem the clinician frequently faces is the patient who develops hyponatremia following therapy with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone). If the patient is responding well to this regimen, one would hesitate to discontinue it because of hyponatremia. In those cases, prophylactic administration of demeclocycline at 150 mg every 6 hours before initiating subsequent chemotherapy courses can be used cautiously. Also, fluid restriction before administering the chemotherapy is recommended.
Conclusion Hyponatremia Hyponatremia is commonly seen as a consequence of inappropriate antidiuretic hormone (ADH) secretion,8 secondary to cyclophosphamide or ifosfamide. Both of these drugs can produce inappropriate ADH secretion. Vincristine will have the same effect. The presence of central nervous system metastasis from lymphoma, as well as pulmonary disorders including pneumonia or pulmonary metastasis, can produce inappropriate ADH secretion. It is not an uncommon problem. A more uncommon cause of hyponatremia is severe hyperproteinemia as seen in myeloma or macroglobulinemia. The hyperproteinemia causes a decrease in sodium concentration in whole plasma. Because there is no change in the concentration of sodium in plasma water, tonicity remains normal, and no treatment is necessary. Manifestations of hyponatremia are drowsiness and seizures. Low serum osmolality and high urine osmolality are present. These features should be present, and edema should be absent, before one can conclude that the diagnosis is a symptom of inappropriate ADH secretion (SIADH). In the asymptomatic patient, management should consist of fluid restriction. Demeclocycline 150 or 300 mg by mouth 4 times daily can be used if fluid restriction is not enough, but it should be used with caution because of its nephrotoxic effects. Correction of the underlying abnormality usually results in resolution of the SIADH. In severely symptomatic patients, hypertonic saline with or without furosemide I.V. should be administered.9,10
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The management of patients with lymphoma can be associated with multiple metabolic abnormalities, and the clinician should be aware of these. Abnormalities such as hyperuricemia can be easily prevented with the use of urate oxidase. Other abnomalities, such as hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, and hyponatremia, can be corrected if identified promptly.
References 1. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol 1993; 13:273280. 2. Potter JL, Silvidi AA. Xanthine lithiasis, nephrocalcinosis, and renal failure in a leukemia patient treated with allopurinol. Clin Chem 1987; 33:23142316. 3. Gerdes J, Dallenbach F, Lennert K, et al. Growth fractions in malignant non-Hodgkin’s lymphomas (NHL) as determined in situ with the monoclonal antibody Ki-67. Hematol Oncol 1984; 2:365-371. 4. Paller MS. Drug-induced nephropathies. Med Clin North Am 1990; 74:909917. 5. Conger JD, Falk SA. Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest 1977; 59:786-793. 6. Seymour JF, Gagel R, Hagemeister FB, et al. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin’s lymphoma. Ann Int Med 1994; 121:633-640. 7. Bringhurst F, Demay M, Kronenberg H.Williams Textbook of Endocrinology. 9th ed. St. Louis, MO: W. B. Saunders; 1998. 8. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin 2001; 17:503-529. 9. Sorensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238:97-110. 10. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342:15811589.