- Email: [email protected]
Depressed hepatic dihydropyrimidine dehydrogenase activity and fluorouracil-related toxicities
BRIEF CLINICAL OBSERVATIONS
enex Pharmaceuticals has acknowledged in a written communication that angioedema has been reported during postmarketing experience (Cerenex Pharmaceuticals, written communication, January 7,1994). To our knowledge, none of these cases have been previously published in the medical literature. Due to the time frame of sumatriptan administration in relation to the appearance of angioedema, we believe there is an association. Clinicians should be aware of the potential for the occurrence of angioedema and be prepared to administer resuscitative agents promptly. With proper patient selection and monitoring, sumatriptan can be a useful addition to the armamentarium for treating migraine headache.
REFERENCES
Pomsium m8qA Saturn
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1. Susman JL. Sumatriptan: a new serotonin agonist for the treatment migraine headache. Am Fam Physician. 1993;47:645-647. 2. Anonymous. Injectable sumatriptan: ADR concerns. Scrip. 1992;21:1756.
of I-
6-
Manuscript
submitted January 20, 1995 and accepted June 20, 1995. -1
0
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Depressed Hepatic Dihydropyrimidine Dehydrogenase Activity and Fluorouracil-Related Toxicities
165 -I 145 125
-
-
I
105 85 85 45
:~,,:.,,,~~ -1
FranqoisStkphan, MD, Hdpital Tenon, Paris, Marie-ChristineEtienne,PharmD, Centre Antione Lacassagne, Nice, ClaudyV/allays,MD, Hdpital Tenon, Paris, Gerard Milano,PhD, Centre htione Lacassagne, Nice, FranqoisClergue,MD, Hbpital Tenon, Paris, France -Fluorouracil(5FU) is the most widely used cytotoxic drug in advanced colorectal cancer. 5F’U catabolism occurs mainly in the liver,’ and dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5FU catabolism.2 DPD is widely distributed in normal and neoplastic tissues,1 including lymphocytes. Lymphocytic DPD activity has been correlated with systemic 5FU clearance3~4 and its measurement to identify DPDdeficient patients could improve 5-m therapy by avoiding severe 5FU toxicities related to 5FLJ overexposure. Among the side effects of 5-N chemotherapy, neurotoxicity is rarely reported.2 In these cases, 5FLJ concentrations in blood and cerebrospinal fluid have never been investigated, even in patients exhibiting deficient lymphocytic-DPD activity.5,6 The tumor lysis syndrome is rarely observed in patients with solid turn~rs,~-~~and has never been reported as a consequence of 5-FU chemotherapy alone. We report a case of lethal multi-
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4
5
6
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8
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12 13
LDH mUImi
5
December
01 -1
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The In Daya Figure 1. Tie course of metabolic and electrolyte abnormalities in 43-year-old woman given 5-fluorouracil for treatment of adenocarcinoma of the cecum with multifocal hepatic metastases. Chemotherapy was administered on day 0; day -1 values are the baseline determinations the day prior to chemotherapy. LDH indicates lactic dehydrogenase. *Performance of hemodialysis.
focal encephalopathy and tumor lysis syndrome consecutive to 5-FU chemotherapy in a patient with metastatic colorectal carcinoma
CASEREPORT The patient was a 43-year-old white woman with a well-differentiated adenocarcinoma of the cecum with multifocal hepatic metastases (40% to 5O?h of 1995
The American
Journal
of Medicinea
Volume
99
685
BRIEF CLINICAL OBSERVATIONS
Figure 2. Hepatic computed tomography scan with contrast, 14 days after the first injection of 5-fluorouracil (5-FU). Large hypodense tumor of segment IV and V slightly enhanced. Density in the center of the tumor was measured at about 35 Hounsfield units (HU). Density in the center of the tumor was measured at about 60 HU 7 days after 5-FU administration.
liver mass) and biopsy-proven metastatic colonic adenocarcinoma. She was admitted for a first course of chemotherapy 2 weeks after colectomy. Pretreatment blood urea nitrogen, serum creatinine, and electrolyte levels were normal, but those of liver enzymes and bilirubin were markedly elevated (aspartate transaminase 256 mU/mL; alkaline phosphatase 2,730 mU/mL; bilirubin 162 pmol/L). The chemotherapy, initiated on day 0, consisted of a 2day treatment comprising folinic acid (500 mg/m2 2-hour IV infusion plus 125 mg orally) and 5F’U (2 g/m2 24-hour continuous IV in-
fusion). On day 2, the patient rapidly fell into a stuporous coma and suffered a general seizure. Simultaneously, the patient became o&uric. Urinalysis revealed uric acid crystals consistent with the diagnosis of acute uric acid nephropathy; other causes of acute renal failure were excluded. The time course of metabolic and electrolyte abnormalities is shown in Figure 1, suggesting the occurrence of tumor lysis syndrome. The hepatic computed tomography (CT) scan confirmed the presence of tumor lysis syndrome, with a density in the center of the tumor of 60 Hounsfield units (HU) on day 7, and 35 HU on day 14, suggestive of central necrosis (Figure 2). Etiologic assessment of coma revealed no hepatic encephalopathy, lactic acidosis, hypoglycemia, or major hyponatremia. Cerebrospmal fluid was sterile. Toxic screen was negative. CT scan of the head revealed only a moderate cerebral edema. Magnetic resonance imaging of the brain obtained on day 14 was consistent with demyelination in cerebellar white matter, right and left internal capsules, thalami, and periventricular white matter, compatible with 5-F’Urelated neurotoxicity (Figure 3).5J1 Other 5FU toxic reactions included mild leukopenia (leukocyte count 3.9 x log/L), and thrombocytopenia (platelet count 81 X log/L) on day 6, and moderate gastrointestinal bleeding on day 8. 5-F’LJ concentrations in plasma and cerebrospinal fluid were measured by high performance liquid chro matography as described by Christophidis et all2
Figure 3. A. Brain magnetic resonance imaging (MRI) scan obtained 2 weeks after the beginning of the chemotherapy, showing bilateral increased signal intensity in cerebellar white matter on T2ureighted transversal slice CR?/TE= 1,8OO/lOO). These cerebellar abnormalities were enhanced after contrast, in Tlvveighted spin echo sequences. B. Spin echo T2weighted brain MRI scan obtained 2 weeks after the beginning of chemotherapy. Similar high signal was present in the right and left internal capsule, thalami (arrows) and in periientricular white matter. 686
December
1995
The American
Journal
of Medicine@
Volume
99
Pharmacokinetic investigations demonstrated very high and prolonged 5FU concentrations in plasma and cerebrospinal fluid on day 10 and day 15 (Table). Charcoal hemoperfusion initiated on day 15 reduced 5FU concentrations in plasma and cerebrospinal fluid (Table) without any harmful effects. DPD activity (radioenzymatic assay according to Harris et all was very depressed in the liver (nonneoplastic liver biopsy ob tained under ultrasound guidance, snap frozen, and stored in liquid nitrogen), although normal in blood lymphocytes (Table). Neurotoxicity persisted, and the patient died on day 60.
COMMENTS The combination of acute renal failme, hyperuricemia, hypocalcemia, and hyperphosphatemia shortly after initiation of chemotherapy strongly suggested a clinical diagnosis of acute tumor lysis syndrome.7-10 The hepatic CT scan corroborates this statement by showing an increase of central necrosis. A spontaneous tumor lysis syndrome with hyperuricemic renal failure has been reported in a patient with metsstatic adenocarcinoma of gastrointestinal tract origin7 Rapid tumor lysis of hepatic metsstases with transient hepatic abnormalities from colorectal cancer has been previously suggested in patients receiving 5FIJ plus N-phosphonacetyl-Laspartate (PAIA).15 Our patient may have experienced some degree of spontaneous tumor necrosis, but the temporal relationship between the tumor necrosis and the onset of chemotherapy is probably in favor of chemotherapy-induced acute tumor lysis syndrome rather than spontaneous tumor necrosis. Moreover, chemotoxicity may be accentuated in our patient with prolonged and very high serum concentrations of 5FU modulated by folinic acid. In our patient, central neurotoxicity was associated with high concentrations of 5FU in blood and cerebrospinal fluid. The possibility of a paraneoplastic cerebellar degeneration could be raised, but the patient had never suffered from ataxia before therapy, and the abrupt onset of neurologic disorders concomitant with 5FIJ administration made this diagnosis quite unlikely. Previous reports have suggested that neurotoxicity seems to be attributable to marked and prolonged exposure to 5-F’U in the cerebrospinal fluid.5 It has been reported that cancer patients with clinical evidence of hepatic metsstases exhibited lower 5-FU plasma clearance than patients without liver metastases.16 Decreased uracil metabolism (5FU catabolism follows that of uracil) is also observed in patients with impaired liver function.17 The overexposure to 5-FU observed in our patient was dramatic, with a terminal half-life >3 days as compared with 10 to 15 minutes in normal cancer patients. This phenomenon could be explained by the combination of the depressed DPD activity in the nonneoplastic
TABLE Temporal Course of Concentrations of 5-FU and DPD in a 43-Year-Old Woman With Adenocarcinoma of the Cecum and Multifocal Hepatic Metastases Days After the Start of Chemotherapy Day 10 Day 15. Day 32 5-FU concentrations Plasma CSF DPD activity Lymphocytes+ Live9
6.02 4.35
2.43/0.98 2.20/1.14
ND ND
NI NI
0.4O/NI NIflI
0.35 0.09
Concentrations of 5-FU reported as umol/L and DPD activity as nmol/min/mg protein. ‘Data for Day 15 reported for before charcoal hemoperfusion fCHP)/lZ hours after CHP. +Compare with levels from 185 unselected cancer patients not previously treated with 5-W: DPD activity measured in blood lymphocytes ranged between 0.06 and 0.56 nmoL/min/mg of protein (mean = 0.22).13 *Compare with 16 consecutive patients with laparotomy for nonmalignant disease (who can be considered as a control set of patients): DPD activity measured in liver ranged between 0.10 and 0.26 nmoL/min/mg of protein (mean = 0.19).r4 5-FU = 5fluorouracil; DPD = dihydropyrimidine dehydrogenase; CSF = cere brospinal fluid; ND = concentration not detectable (~0.07 umol/L); NI = not investigated.
liver tissue (approximately half the activity of a control group of patients, Table); the presence of metastases from colon adenocarcinoma involving 40% to 50% of the liver mass, since it has been demonstrated that DPD activity in colon tumors is about 100 times lower than that in liver’; and the concomitant renal failme. However, it might be suggested that the massive accumulation of unchanged 5FU could have been cleared to a large extent by the kidneys, as, in the case of DPD deficiency, more than 8% of the 5 FU administered is excreted in the urine.5 The coexistence of renal failure in the present case accentuates the delayed elimination of 5FU observed. In contrast, lymphocytic DPD activity was within the normal range (Table). The discrepancy observed between hepatic and lymphocytic DPD activity in this patient draws attention to the fact that normal DPD determination in lymphocytes may not be a reliable predictor of life-threatening systemic 5FU overexposure in cases of disease-related liver impairment.
REFERENCES 1. Ho DH, Towsend L, Luna MA, Bodey GP. Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5fluorouracil as a substrate. Anticancer Res. 1986;6:781-784. 2. Grem JL. Fluorinated pyrimidines. In: Chabner BA, Collins JM. eds. Cancer Chemotherapy: Principles and Practices. Philadelphia: JB Lippincott; 1990; 180-224. 3. Harris BE, Song R, Soong S-J, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5fluorouracil by protracted continuous infusion. Cancer Res. 1990;50:197-201. 4. Flemming RA, Milan0 G, Thyss A, et al. Correlation between dihydropyrimidine
December 1995 The American Journal of Medicine@ Volume 99
687
dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res. 1992;52: 2899-2902. 5. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe Sfluorouracilinduced toxicity. J Clin Invest 1988;81:47-51. 6. Harris BE, Carpenter JT, Diasio RB. Severe 5fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991;68:499-501. 7. Crittenden DR, Ackerman GL. Hyperuricemic acute renal failure in disseminated carcinoma. Arch Intern Med. 1977;137:97-99. 8. Vogelzang NJ, Nelimark RA, Nath KA. Tumor lysis syndrome after induction chemotherapy of small-cell bronchogenic carcinoma. JAMA. 1983;249: 513-514. 9. Stark ME, Dyer MCD, Coonley CJ. Fatal acute tumor lysis syndrome with metastatic breast carcinoma. Cancer. 1987;60:762-764. 10. Barton JC. Tumor lysis syndrome in nonhematopoietic neoplasm. Cancer. 1989;64:738-740. 11. Hook CC, Kimmel DW, Kvols LK, et al. Multtfocal inflammatory leukoencephalopathy with Muorouracil and levamisole. Ann Neurof. 1992;31:262-267. 12. Christophidis N, Mihaly G, Vadja F, Louis W. Comparison of liquid- and gas-
688
December
1995
The American
Journal
of Medicine@
Volume
liquid chromatographic assays of 5-fluorouracil in plasma. Clin Chem. 1979;25: 83-86. 13. Etienne MC, Lagrange JL, Dassonville 0, et al. A population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994;12: 2248-2253. 14. Etienne MC, Bourgeon A, Renee N, et al. Analyse cornparke de I’actitit6 dihydropyrimidine deshydrogdnase (DPD) mesurke au niveau des lymphocytes et du tissu hepatique. Bull Cancer (Paris). 1994;81:48&489. Abstract. 15. Kemeny N, Seiter K, Martin D, et al. A new syndrome: ascites, hyperbilirb binemia, and hypoalbuminemia after biochemical modulation of fluorouracil with NphosphonacetyCL-aspartate (PALA). Ann Intern Med. 1991; 115:94&951. 16. Floyd RA, Hornbeck CL, Byfield JE, et al. Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intel1 Clin Pharm. 1982;16:665-667. 17. Creasey WA, Koutras GA, Calabresi P. The metabolism of uracil-2-14C and granulocyte response to endotoxin as indicators of the toxicity produced in patients receiving 5-fluorouracil. Clin Pharmacol Ther. 1967;8:273-282. Manuscript submitted September 27, 1994 and accepted in revised form May 12, 1995.
99
enex Pharmaceuticals has acknowledged in a written communication that angioedema has been reported during postmarketing experience (Cerenex Pharmaceuticals, written communication, January 7,1994). To our knowledge, none of these cases have been previously published in the medical literature. Due to the time frame of sumatriptan administration in relation to the appearance of angioedema, we believe there is an association. Clinicians should be aware of the potential for the occurrence of angioedema and be prepared to administer resuscitative agents promptly. With proper patient selection and monitoring, sumatriptan can be a useful addition to the armamentarium for treating migraine headache.
REFERENCES
Pomsium m8qA Saturn
ufk*eldlngll00mlgrum 15i.0
1-
-
F' -6
12!.5 I( A0
-
7,s ; 5.02.5 -
0.0 -1’ lo10
1
’
’
0
’
1
’
I
’
2345678
9 Ptmsphanu
CddummgtdLSmum --
11
12
13
94rum
mgidL
----r
8
d
12
I1
10
-16,5 16,5 -14,5
9-
8-
1. Susman JL. Sumatriptan: a new serotonin agonist for the treatment migraine headache. Am Fam Physician. 1993;47:645-647. 2. Anonymous. Injectable sumatriptan: ADR concerns. Scrip. 1992;21:1756.
of I-
6-
Manuscript
submitted January 20, 1995 and accepted June 20, 1995. -1
0
1
2
3
Urm t8trop
4
5
6
7
8
9
10
Cmaini~
m~lO9 ml Swum
11
172.5 12 13
mghO0 ml &rum 10
Depressed Hepatic Dihydropyrimidine Dehydrogenase Activity and Fluorouracil-Related Toxicities
165 -I 145 125
-
-
I
105 85 85 45
:~,,:.,,,~~ -1
FranqoisStkphan, MD, Hdpital Tenon, Paris, Marie-ChristineEtienne,PharmD, Centre Antione Lacassagne, Nice, ClaudyV/allays,MD, Hdpital Tenon, Paris, Gerard Milano,PhD, Centre htione Lacassagne, Nice, FranqoisClergue,MD, Hbpital Tenon, Paris, France -Fluorouracil(5FU) is the most widely used cytotoxic drug in advanced colorectal cancer. 5F’U catabolism occurs mainly in the liver,’ and dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5FU catabolism.2 DPD is widely distributed in normal and neoplastic tissues,1 including lymphocytes. Lymphocytic DPD activity has been correlated with systemic 5FU clearance3~4 and its measurement to identify DPDdeficient patients could improve 5-m therapy by avoiding severe 5FU toxicities related to 5FLJ overexposure. Among the side effects of 5-N chemotherapy, neurotoxicity is rarely reported.2 In these cases, 5FLJ concentrations in blood and cerebrospinal fluid have never been investigated, even in patients exhibiting deficient lymphocytic-DPD activity.5,6 The tumor lysis syndrome is rarely observed in patients with solid turn~rs,~-~~and has never been reported as a consequence of 5-FU chemotherapy alone. We report a case of lethal multi-
0
1
2
3
4
5
6
7
8
9
10
11
12 13
LDH mUImi
5
December
01 -1
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’
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’
’
’
’
’
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The In Daya Figure 1. Tie course of metabolic and electrolyte abnormalities in 43-year-old woman given 5-fluorouracil for treatment of adenocarcinoma of the cecum with multifocal hepatic metastases. Chemotherapy was administered on day 0; day -1 values are the baseline determinations the day prior to chemotherapy. LDH indicates lactic dehydrogenase. *Performance of hemodialysis.
focal encephalopathy and tumor lysis syndrome consecutive to 5-FU chemotherapy in a patient with metastatic colorectal carcinoma
CASEREPORT The patient was a 43-year-old white woman with a well-differentiated adenocarcinoma of the cecum with multifocal hepatic metastases (40% to 5O?h of 1995
The American
Journal
of Medicinea
Volume
99
685
BRIEF CLINICAL OBSERVATIONS
Figure 2. Hepatic computed tomography scan with contrast, 14 days after the first injection of 5-fluorouracil (5-FU). Large hypodense tumor of segment IV and V slightly enhanced. Density in the center of the tumor was measured at about 35 Hounsfield units (HU). Density in the center of the tumor was measured at about 60 HU 7 days after 5-FU administration.
liver mass) and biopsy-proven metastatic colonic adenocarcinoma. She was admitted for a first course of chemotherapy 2 weeks after colectomy. Pretreatment blood urea nitrogen, serum creatinine, and electrolyte levels were normal, but those of liver enzymes and bilirubin were markedly elevated (aspartate transaminase 256 mU/mL; alkaline phosphatase 2,730 mU/mL; bilirubin 162 pmol/L). The chemotherapy, initiated on day 0, consisted of a 2day treatment comprising folinic acid (500 mg/m2 2-hour IV infusion plus 125 mg orally) and 5F’U (2 g/m2 24-hour continuous IV in-
fusion). On day 2, the patient rapidly fell into a stuporous coma and suffered a general seizure. Simultaneously, the patient became o&uric. Urinalysis revealed uric acid crystals consistent with the diagnosis of acute uric acid nephropathy; other causes of acute renal failure were excluded. The time course of metabolic and electrolyte abnormalities is shown in Figure 1, suggesting the occurrence of tumor lysis syndrome. The hepatic computed tomography (CT) scan confirmed the presence of tumor lysis syndrome, with a density in the center of the tumor of 60 Hounsfield units (HU) on day 7, and 35 HU on day 14, suggestive of central necrosis (Figure 2). Etiologic assessment of coma revealed no hepatic encephalopathy, lactic acidosis, hypoglycemia, or major hyponatremia. Cerebrospmal fluid was sterile. Toxic screen was negative. CT scan of the head revealed only a moderate cerebral edema. Magnetic resonance imaging of the brain obtained on day 14 was consistent with demyelination in cerebellar white matter, right and left internal capsules, thalami, and periventricular white matter, compatible with 5-F’Urelated neurotoxicity (Figure 3).5J1 Other 5FU toxic reactions included mild leukopenia (leukocyte count 3.9 x log/L), and thrombocytopenia (platelet count 81 X log/L) on day 6, and moderate gastrointestinal bleeding on day 8. 5-F’LJ concentrations in plasma and cerebrospinal fluid were measured by high performance liquid chro matography as described by Christophidis et all2
Figure 3. A. Brain magnetic resonance imaging (MRI) scan obtained 2 weeks after the beginning of the chemotherapy, showing bilateral increased signal intensity in cerebellar white matter on T2ureighted transversal slice CR?/TE= 1,8OO/lOO). These cerebellar abnormalities were enhanced after contrast, in Tlvveighted spin echo sequences. B. Spin echo T2weighted brain MRI scan obtained 2 weeks after the beginning of chemotherapy. Similar high signal was present in the right and left internal capsule, thalami (arrows) and in periientricular white matter. 686
December
1995
The American
Journal
of Medicine@
Volume
99
Pharmacokinetic investigations demonstrated very high and prolonged 5FU concentrations in plasma and cerebrospinal fluid on day 10 and day 15 (Table). Charcoal hemoperfusion initiated on day 15 reduced 5FU concentrations in plasma and cerebrospinal fluid (Table) without any harmful effects. DPD activity (radioenzymatic assay according to Harris et all was very depressed in the liver (nonneoplastic liver biopsy ob tained under ultrasound guidance, snap frozen, and stored in liquid nitrogen), although normal in blood lymphocytes (Table). Neurotoxicity persisted, and the patient died on day 60.
COMMENTS The combination of acute renal failme, hyperuricemia, hypocalcemia, and hyperphosphatemia shortly after initiation of chemotherapy strongly suggested a clinical diagnosis of acute tumor lysis syndrome.7-10 The hepatic CT scan corroborates this statement by showing an increase of central necrosis. A spontaneous tumor lysis syndrome with hyperuricemic renal failure has been reported in a patient with metsstatic adenocarcinoma of gastrointestinal tract origin7 Rapid tumor lysis of hepatic metsstases with transient hepatic abnormalities from colorectal cancer has been previously suggested in patients receiving 5FIJ plus N-phosphonacetyl-Laspartate (PAIA).15 Our patient may have experienced some degree of spontaneous tumor necrosis, but the temporal relationship between the tumor necrosis and the onset of chemotherapy is probably in favor of chemotherapy-induced acute tumor lysis syndrome rather than spontaneous tumor necrosis. Moreover, chemotoxicity may be accentuated in our patient with prolonged and very high serum concentrations of 5FU modulated by folinic acid. In our patient, central neurotoxicity was associated with high concentrations of 5FU in blood and cerebrospinal fluid. The possibility of a paraneoplastic cerebellar degeneration could be raised, but the patient had never suffered from ataxia before therapy, and the abrupt onset of neurologic disorders concomitant with 5FIJ administration made this diagnosis quite unlikely. Previous reports have suggested that neurotoxicity seems to be attributable to marked and prolonged exposure to 5-F’U in the cerebrospinal fluid.5 It has been reported that cancer patients with clinical evidence of hepatic metsstases exhibited lower 5-FU plasma clearance than patients without liver metastases.16 Decreased uracil metabolism (5FU catabolism follows that of uracil) is also observed in patients with impaired liver function.17 The overexposure to 5-FU observed in our patient was dramatic, with a terminal half-life >3 days as compared with 10 to 15 minutes in normal cancer patients. This phenomenon could be explained by the combination of the depressed DPD activity in the nonneoplastic
TABLE Temporal Course of Concentrations of 5-FU and DPD in a 43-Year-Old Woman With Adenocarcinoma of the Cecum and Multifocal Hepatic Metastases Days After the Start of Chemotherapy Day 10 Day 15. Day 32 5-FU concentrations Plasma CSF DPD activity Lymphocytes+ Live9
6.02 4.35
2.43/0.98 2.20/1.14
ND ND
NI NI
0.4O/NI NIflI
0.35 0.09
Concentrations of 5-FU reported as umol/L and DPD activity as nmol/min/mg protein. ‘Data for Day 15 reported for before charcoal hemoperfusion fCHP)/lZ hours after CHP. +Compare with levels from 185 unselected cancer patients not previously treated with 5-W: DPD activity measured in blood lymphocytes ranged between 0.06 and 0.56 nmoL/min/mg of protein (mean = 0.22).13 *Compare with 16 consecutive patients with laparotomy for nonmalignant disease (who can be considered as a control set of patients): DPD activity measured in liver ranged between 0.10 and 0.26 nmoL/min/mg of protein (mean = 0.19).r4 5-FU = 5fluorouracil; DPD = dihydropyrimidine dehydrogenase; CSF = cere brospinal fluid; ND = concentration not detectable (~0.07 umol/L); NI = not investigated.
liver tissue (approximately half the activity of a control group of patients, Table); the presence of metastases from colon adenocarcinoma involving 40% to 50% of the liver mass, since it has been demonstrated that DPD activity in colon tumors is about 100 times lower than that in liver’; and the concomitant renal failme. However, it might be suggested that the massive accumulation of unchanged 5FU could have been cleared to a large extent by the kidneys, as, in the case of DPD deficiency, more than 8% of the 5 FU administered is excreted in the urine.5 The coexistence of renal failure in the present case accentuates the delayed elimination of 5FU observed. In contrast, lymphocytic DPD activity was within the normal range (Table). The discrepancy observed between hepatic and lymphocytic DPD activity in this patient draws attention to the fact that normal DPD determination in lymphocytes may not be a reliable predictor of life-threatening systemic 5FU overexposure in cases of disease-related liver impairment.
REFERENCES 1. Ho DH, Towsend L, Luna MA, Bodey GP. Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5fluorouracil as a substrate. Anticancer Res. 1986;6:781-784. 2. Grem JL. Fluorinated pyrimidines. In: Chabner BA, Collins JM. eds. Cancer Chemotherapy: Principles and Practices. Philadelphia: JB Lippincott; 1990; 180-224. 3. Harris BE, Song R, Soong S-J, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5fluorouracil by protracted continuous infusion. Cancer Res. 1990;50:197-201. 4. Flemming RA, Milan0 G, Thyss A, et al. Correlation between dihydropyrimidine
December 1995 The American Journal of Medicine@ Volume 99
687
dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res. 1992;52: 2899-2902. 5. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe Sfluorouracilinduced toxicity. J Clin Invest 1988;81:47-51. 6. Harris BE, Carpenter JT, Diasio RB. Severe 5fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991;68:499-501. 7. Crittenden DR, Ackerman GL. Hyperuricemic acute renal failure in disseminated carcinoma. Arch Intern Med. 1977;137:97-99. 8. Vogelzang NJ, Nelimark RA, Nath KA. Tumor lysis syndrome after induction chemotherapy of small-cell bronchogenic carcinoma. JAMA. 1983;249: 513-514. 9. Stark ME, Dyer MCD, Coonley CJ. Fatal acute tumor lysis syndrome with metastatic breast carcinoma. Cancer. 1987;60:762-764. 10. Barton JC. Tumor lysis syndrome in nonhematopoietic neoplasm. Cancer. 1989;64:738-740. 11. Hook CC, Kimmel DW, Kvols LK, et al. Multtfocal inflammatory leukoencephalopathy with Muorouracil and levamisole. Ann Neurof. 1992;31:262-267. 12. Christophidis N, Mihaly G, Vadja F, Louis W. Comparison of liquid- and gas-
688
December
1995
The American
Journal
of Medicine@
Volume
liquid chromatographic assays of 5-fluorouracil in plasma. Clin Chem. 1979;25: 83-86. 13. Etienne MC, Lagrange JL, Dassonville 0, et al. A population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994;12: 2248-2253. 14. Etienne MC, Bourgeon A, Renee N, et al. Analyse cornparke de I’actitit6 dihydropyrimidine deshydrogdnase (DPD) mesurke au niveau des lymphocytes et du tissu hepatique. Bull Cancer (Paris). 1994;81:48&489. Abstract. 15. Kemeny N, Seiter K, Martin D, et al. A new syndrome: ascites, hyperbilirb binemia, and hypoalbuminemia after biochemical modulation of fluorouracil with NphosphonacetyCL-aspartate (PALA). Ann Intern Med. 1991; 115:94&951. 16. Floyd RA, Hornbeck CL, Byfield JE, et al. Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intel1 Clin Pharm. 1982;16:665-667. 17. Creasey WA, Koutras GA, Calabresi P. The metabolism of uracil-2-14C and granulocyte response to endotoxin as indicators of the toxicity produced in patients receiving 5-fluorouracil. Clin Pharmacol Ther. 1967;8:273-282. Manuscript submitted September 27, 1994 and accepted in revised form May 12, 1995.
99