Annals of Oncology 13: 480–481, 2002 Clinical case DOI: 10.1093/annonc/mdf023 © 2002 European Society for Medical Oncology Anaphylactic shock secondary to intravenous administration of folinic acid: a first report M. Benchalal 1 , E. Yahchouchy-Chouillard 2 , S. Fouere 3 & A. Fingerhut 2 * 1 Oncology and 2 Digestive Surgery Departments, Centre Hospitalier Intercommunal de Poissy-Saint Germain, Poissy Cedex; 3 Dermatology Department, Hôpital Saint-Louis, France *Correspondence to: Dr A. Fingerhut, Centre Hospitalier de Poissy- Saint Germain, 10 rue du Champ Gaillard, 78303 Poissy Cedex, France. Tel: +33-139-27-51-65; Fax: +33-139-27-44-02; E-mail: [email protected] Received 16 May 2001; accepted 5 June 2001 Background: Folates, components of the B-complex vitamins, have numerous pharmacological effects. In oncology combining folates with 5-fluorouracil (5-FU) enhances the cytotoxic effects of chemotherapy in colon cancer patients. Folic acid has been rarely involved in adverse allergic reactions. To the best of our knowledge no anaphylactic reaction secondary to folinic acid (FA) administration has ever been reported before. Patients and methods: An 80-year-old patient had adjuvant chemotherapy for colon cancer includ- ing FA and 5-FU and irinotecan as a second line agent after multiple metastases. Results: Following FA administration anaphylactic shock occurred. Diagnosis was made according to the French method of adverse reactions monitoring. Conclusion: Anaphylactic shock may be an adverse reaction of FA in patients receiving chemo- therapy for colon cancer. Key words: adverse reaction, anaphylactic shock, chemotherapy, colon cancer, folinic acid Introduction Five-fluorouracil (5-FU)-based adjuvant therapy is recom- mended for patients with resected stage III colon cancer [1]. Levamisole or folates (folic acid or FA) can be added to enhance the 5-FU efficacy. Adverse reactions to chemothera- peutic agents are common but rarely include anaphylactic shock. We report a case of such toxicity related to the adminis- tration of folinic acid (FA). To the best of our knowledge, similar events have never been reported before. Case report An 80-year-old patient was admitted for adjuvant chemotherapy after left colon resection for Dukes’ C stage adenocarcinoma. Past medical history included sideroblastic anemia and mild asthma. Bolus infusion of 5-FU (400 mg/m 2 /day) and FA (200 mg/m 2 /day) for 5 days every 4 weeks were administered from September 1999 to February 2000. Tolerance was excellent and no side effects were reported. In April 2000, increased carcinoembryonic antigen levels led to the diagnosis of multiple hepatic and pulmonary meta- stases. Second line chemotherapy included bolus infusion of irinotecan (180 mg/m 2 ) and 5-FU (400 mg/m 2 ) over 90 min, and FA (200 mg/m 2 ) over 120 min for day 1 followed by con- tinuous infusion of 5-FU (2400 mg/m 2 ) over 2 days. Anti- emetic and anticholinergic prophylaxis included ondansteron and atropin, respectively. During the first course of chemo- therapy the patient presented a nettle rash following the administration of odansteron and FA. Odansteron, incrimin- ated as the initiating factor, was withdrawn and replaced by metoclopramide and prednisone as anti-emetic agents for the next course. During the second course and just after the administration of FA, metoclopramide and prednisone the patient experienced another rash and profound hypotension requiring intravenous epinephrine. FA was withdrawn. The following FA-free courses were uneventful. An imputation method of assessing the relationships between an adverse reaction and a drug has been developed in France [2]. This method is based on the evaluation of three parameters including the chronological imputability (C), the semiological imputability (S) and the intrinsic imputability (I). According to the French imputation tables [2] the reaction was scored C3/S3/I14. The final decision table considered the drug–effect relation to be very likely, which corresponds to the highest score on the scale.
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Anaphylactic shock secondary to intravenous administration of folinic acid: a first reportClinical case DOI: 10.1093/annonc/mdf023
Anaphylactic shock secondary to intravenous administration of
folinic acid: a first report
M. Benchalal1, E. Yahchouchy-Chouillard2, S. Fouere3 & A. Fingerhut2*
1Oncology and 2Digestive Surgery Departments, Centre Hospitalier Intercommunal de Poissy-Saint Germain, Poissy Cedex; 3Dermatology Department, Hôpital
Saint-Louis, France
*Correspondence to: Dr A. Fingerhut, Centre Hospitalier de Poissy- Saint Germain, 10 rue du Champ Gaillard, 78303 Poissy Cedex, France.
Tel: +33-139-27-51-65; Fax: +33-139-27-44-02; E-mail: [email protected]
Received 16 May 2001; accepted 5 June 2001
Background: Folates, components of the B-complex vitamins, have numerous pharmacological
effects. In oncology combining folates with 5-fluorouracil (5-FU) enhances the cytotoxic effects of
chemotherapy in colon cancer patients. Folic acid has been rarely involved in adverse allergic reactions.
To the best of our knowledge no anaphylactic reaction secondary to folinic acid (FA) administration has
ever been reported before.
Patients and methods: An 80-year-old patient had adjuvant chemotherapy for colon cancer includ-
ing FA and 5-FU and irinotecan as a second line agent after multiple metastases.
Results: Following FA administration anaphylactic shock occurred. Diagnosis was made according to
the French method of adverse reactions monitoring.
Conclusion: Anaphylactic shock may be an adverse reaction of FA in patients receiving chemo-
therapy for colon cancer.
Introduction
mended for patients with resected stage III colon cancer [1].
Levamisole or folates (folic acid or FA) can be added to
enhance the 5-FU efficacy. Adverse reactions to chemothera-
peutic agents are common but rarely include anaphylactic
shock. We report a case of such toxicity related to the adminis-
tration of folinic acid (FA). To the best of our knowledge,
similar events have never been reported before.
Case report
after left colon resection for Dukes’ C stage adenocarcinoma.
Past medical history included sideroblastic anemia and mild
asthma. Bolus infusion of 5-FU (400 mg/m2/day) and FA
(200 mg/m2/day) for 5 days every 4 weeks were administered
from September 1999 to February 2000. Tolerance was
excellent and no side effects were reported.
In April 2000, increased carcinoembryonic antigen levels
led to the diagnosis of multiple hepatic and pulmonary meta-
stases. Second line chemotherapy included bolus infusion of
irinotecan (180 mg/m2) and 5-FU (400 mg/m2) over 90 min,
and FA (200 mg/m2) over 120 min for day 1 followed by con-
tinuous infusion of 5-FU (2400 mg/m2) over 2 days. Anti-
emetic and anticholinergic prophylaxis included ondansteron
and atropin, respectively. During the first course of chemo-
therapy the patient presented a nettle rash following the
administration of odansteron and FA. Odansteron, incrimin-
ated as the initiating factor, was withdrawn and replaced by
metoclopramide and prednisone as anti-emetic agents for the
next course. During the second course and just after the
administration of FA, metoclopramide and prednisone the
patient experienced another rash and profound hypotension
requiring intravenous epinephrine. FA was withdrawn. The
following FA-free courses were uneventful.
An imputation method of assessing the relationships
between an adverse reaction and a drug has been developed in
France [2]. This method is based on the evaluation of three
parameters including the chronological imputability (C), the
semiological imputability (S) and the intrinsic imputability
(I). According to the French imputation tables [2] the reaction
was scored C3/S3/I14. The final decision table considered the
drug–effect relation to be very likely, which corresponds to
the highest score on the scale.
481
Discussion
Folates, members of the B-complex vitamins, function as a
single carbon donor in the synthesis of serine from glycine, in
the synthesis of nucleotides from purine precursors, indirectly
in the synthesis of transfer RNA and as a methyl donor to
create methylcobalamin, which is used in the re-methylation
of homocysteine to methionine [3]. Folic acid is reduced by
the liver to metabolically active 5-methyltetrahydrofolate. FA
(5-formyltetrahydrofolate) bypasses the reduction steps
required for folic acid. Folates have numerous pharmacolog-
ical effects either therapeutic as in hyperhomocysteinemia [4],
gout [5], vitiligo [6], macrocytic anemia [7] and gingivitis
[8], or preventive as in neural tube defects during pregnancy [9],
cervical dysplasia [10] and inflammatory bowel disease [11].
Reports also indicate that many neuropsychiatric diseases
may be secondary to folate deficiency [3].
In oncology, thymidylate synthase is the cellular target of
the 5-FU–FA mechanism of cytotoxic action [12]. Fluoro-
deoxyuridylate, one of the 5-FU metabolites, binds to thymi-
dylate synthase in the presence of FA leading to its inhibition
via a covalent ternary complex. FA, at high doses, increases
5-FU toxicity by stabilizing the ternary complex [13, 14]. The
association of 5-FU–FA has demonstrated its clinical efficacy
in colorectal cancer, both in adjuvant and metastatic settings.
Folates are regarded as not toxic for humans [3]. However,
they may mask vitamin B12 deficiency or interfere with zinc
absorption [3]. Besides these minor and rare effects, anaphyl-
actic reactions due to ingestion or injection of folic acid have
been reported previously [15, 16]. However, to the best of our
knowledge, this case represents the first report of anaphylactic
shock involving FA.
Conclusion
FA may be a rare cause of anaphylactic shock in cancer
patients receiving 5-FU–FA chemotherapy.
References
1. Benson AB 3rd, Choti MA, Cohen AM et al. NCCN practice guide-
lines for colorectal cancer. Oncology 2000; 14: 203–212.
2. Moore N, Biour M, Paux G et al. Adverse drug reaction monitoring:
doing it the French way. Lancet 1985; 2: 1056–1058.
3. Kelly GS. Folates: supplemental forms and therapeutic applications.
Altern Med Rev 1998; 3: 208–220.
4. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—
the effects of betaine in the treatment of patients not responsive to
pyridoxine. N Engl J Med 1983; 309: 448–453.
5. Lewis AS, Murphy L, McCalla C et al. Inhibition of mammalian
xanthine oxidase by folate compounds and amethopterin. J Biol
Chem 1984; 259: 12–15.
6. Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and vitamin B12
in vitiligo: a nutritional approach. Cutis 1992; 50: 39–42.
7. De Michelis AG, Rabbia F, Sacchetta AC, Chiandussi L. The calcium
salt of folinic acid for the treatment of deficiency anemia. Minerva
Med 1991; 82: 97–100.
8. Vogel RI, Fink RA, Schneider LC et al. The effect of folic acid on
gingival health. J Periodontol 1976; 47: 667–668.
9. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid
exposure and risk of occurrent neural tube defects. JAMA 1993; 269:
1257–1261.
10. Liu T, Soong SJ, Wilson NP et al. A case-control study of nutritional
factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev
1993; 2: 525–530.
11. Lashner BA, Heidenreich PA, Su GL et al. Effect of folate supple-
mentation on the incidence of dysplasia and cancer in chronic ulcera-
tive colitis. A case-control study. Gastroenterology 1989; 97: 255–259.
12. Etienne MC, Guillot T, Milano G. Critical factors for optimizing the
5-fluorouracil–folinic acid association in cancer chemotherapy. Ann
Oncol 1996; 7: 283–289.
13. Machover D, Goldschmidt E, Chollet P et al. Treatment of advanced
colorectal and gastric adenocarcinomas with 5-fluorouracil and high-
dose folinic acid. J Clin Oncol 1986; 4: 685–696.
14. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and
deoxyinosine on the activity and site of action of 5-fluorouracil.
Cancer Res 1981; 41: 3288–3295.
15. Dykewicz MS, Orfan NA, Sun W. In vitro demonstration of IgE anti-
body to folate-albumin in anaphylaxis from folate acid. J Allergy Clin
Immunol 2000; 106: 386–389.
16. Woodliff HJ, Davis RE. Allergy to folic acid. Med J Aust 1966;
1: 351–352.
Anaphylactic shock secondary to intravenous administration of
folinic acid: a first report
M. Benchalal1, E. Yahchouchy-Chouillard2, S. Fouere3 & A. Fingerhut2*
1Oncology and 2Digestive Surgery Departments, Centre Hospitalier Intercommunal de Poissy-Saint Germain, Poissy Cedex; 3Dermatology Department, Hôpital
Saint-Louis, France
*Correspondence to: Dr A. Fingerhut, Centre Hospitalier de Poissy- Saint Germain, 10 rue du Champ Gaillard, 78303 Poissy Cedex, France.
Tel: +33-139-27-51-65; Fax: +33-139-27-44-02; E-mail: [email protected]
Received 16 May 2001; accepted 5 June 2001
Background: Folates, components of the B-complex vitamins, have numerous pharmacological
effects. In oncology combining folates with 5-fluorouracil (5-FU) enhances the cytotoxic effects of
chemotherapy in colon cancer patients. Folic acid has been rarely involved in adverse allergic reactions.
To the best of our knowledge no anaphylactic reaction secondary to folinic acid (FA) administration has
ever been reported before.
Patients and methods: An 80-year-old patient had adjuvant chemotherapy for colon cancer includ-
ing FA and 5-FU and irinotecan as a second line agent after multiple metastases.
Results: Following FA administration anaphylactic shock occurred. Diagnosis was made according to
the French method of adverse reactions monitoring.
Conclusion: Anaphylactic shock may be an adverse reaction of FA in patients receiving chemo-
therapy for colon cancer.
Introduction
mended for patients with resected stage III colon cancer [1].
Levamisole or folates (folic acid or FA) can be added to
enhance the 5-FU efficacy. Adverse reactions to chemothera-
peutic agents are common but rarely include anaphylactic
shock. We report a case of such toxicity related to the adminis-
tration of folinic acid (FA). To the best of our knowledge,
similar events have never been reported before.
Case report
after left colon resection for Dukes’ C stage adenocarcinoma.
Past medical history included sideroblastic anemia and mild
asthma. Bolus infusion of 5-FU (400 mg/m2/day) and FA
(200 mg/m2/day) for 5 days every 4 weeks were administered
from September 1999 to February 2000. Tolerance was
excellent and no side effects were reported.
In April 2000, increased carcinoembryonic antigen levels
led to the diagnosis of multiple hepatic and pulmonary meta-
stases. Second line chemotherapy included bolus infusion of
irinotecan (180 mg/m2) and 5-FU (400 mg/m2) over 90 min,
and FA (200 mg/m2) over 120 min for day 1 followed by con-
tinuous infusion of 5-FU (2400 mg/m2) over 2 days. Anti-
emetic and anticholinergic prophylaxis included ondansteron
and atropin, respectively. During the first course of chemo-
therapy the patient presented a nettle rash following the
administration of odansteron and FA. Odansteron, incrimin-
ated as the initiating factor, was withdrawn and replaced by
metoclopramide and prednisone as anti-emetic agents for the
next course. During the second course and just after the
administration of FA, metoclopramide and prednisone the
patient experienced another rash and profound hypotension
requiring intravenous epinephrine. FA was withdrawn. The
following FA-free courses were uneventful.
An imputation method of assessing the relationships
between an adverse reaction and a drug has been developed in
France [2]. This method is based on the evaluation of three
parameters including the chronological imputability (C), the
semiological imputability (S) and the intrinsic imputability
(I). According to the French imputation tables [2] the reaction
was scored C3/S3/I14. The final decision table considered the
drug–effect relation to be very likely, which corresponds to
the highest score on the scale.
481
Discussion
Folates, members of the B-complex vitamins, function as a
single carbon donor in the synthesis of serine from glycine, in
the synthesis of nucleotides from purine precursors, indirectly
in the synthesis of transfer RNA and as a methyl donor to
create methylcobalamin, which is used in the re-methylation
of homocysteine to methionine [3]. Folic acid is reduced by
the liver to metabolically active 5-methyltetrahydrofolate. FA
(5-formyltetrahydrofolate) bypasses the reduction steps
required for folic acid. Folates have numerous pharmacolog-
ical effects either therapeutic as in hyperhomocysteinemia [4],
gout [5], vitiligo [6], macrocytic anemia [7] and gingivitis
[8], or preventive as in neural tube defects during pregnancy [9],
cervical dysplasia [10] and inflammatory bowel disease [11].
Reports also indicate that many neuropsychiatric diseases
may be secondary to folate deficiency [3].
In oncology, thymidylate synthase is the cellular target of
the 5-FU–FA mechanism of cytotoxic action [12]. Fluoro-
deoxyuridylate, one of the 5-FU metabolites, binds to thymi-
dylate synthase in the presence of FA leading to its inhibition
via a covalent ternary complex. FA, at high doses, increases
5-FU toxicity by stabilizing the ternary complex [13, 14]. The
association of 5-FU–FA has demonstrated its clinical efficacy
in colorectal cancer, both in adjuvant and metastatic settings.
Folates are regarded as not toxic for humans [3]. However,
they may mask vitamin B12 deficiency or interfere with zinc
absorption [3]. Besides these minor and rare effects, anaphyl-
actic reactions due to ingestion or injection of folic acid have
been reported previously [15, 16]. However, to the best of our
knowledge, this case represents the first report of anaphylactic
shock involving FA.
Conclusion
FA may be a rare cause of anaphylactic shock in cancer
patients receiving 5-FU–FA chemotherapy.
References
1. Benson AB 3rd, Choti MA, Cohen AM et al. NCCN practice guide-
lines for colorectal cancer. Oncology 2000; 14: 203–212.
2. Moore N, Biour M, Paux G et al. Adverse drug reaction monitoring:
doing it the French way. Lancet 1985; 2: 1056–1058.
3. Kelly GS. Folates: supplemental forms and therapeutic applications.
Altern Med Rev 1998; 3: 208–220.
4. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—
the effects of betaine in the treatment of patients not responsive to
pyridoxine. N Engl J Med 1983; 309: 448–453.
5. Lewis AS, Murphy L, McCalla C et al. Inhibition of mammalian
xanthine oxidase by folate compounds and amethopterin. J Biol
Chem 1984; 259: 12–15.
6. Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and vitamin B12
in vitiligo: a nutritional approach. Cutis 1992; 50: 39–42.
7. De Michelis AG, Rabbia F, Sacchetta AC, Chiandussi L. The calcium
salt of folinic acid for the treatment of deficiency anemia. Minerva
Med 1991; 82: 97–100.
8. Vogel RI, Fink RA, Schneider LC et al. The effect of folic acid on
gingival health. J Periodontol 1976; 47: 667–668.
9. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid
exposure and risk of occurrent neural tube defects. JAMA 1993; 269:
1257–1261.
10. Liu T, Soong SJ, Wilson NP et al. A case-control study of nutritional
factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev
1993; 2: 525–530.
11. Lashner BA, Heidenreich PA, Su GL et al. Effect of folate supple-
mentation on the incidence of dysplasia and cancer in chronic ulcera-
tive colitis. A case-control study. Gastroenterology 1989; 97: 255–259.
12. Etienne MC, Guillot T, Milano G. Critical factors for optimizing the
5-fluorouracil–folinic acid association in cancer chemotherapy. Ann
Oncol 1996; 7: 283–289.
13. Machover D, Goldschmidt E, Chollet P et al. Treatment of advanced
colorectal and gastric adenocarcinomas with 5-fluorouracil and high-
dose folinic acid. J Clin Oncol 1986; 4: 685–696.
14. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and
deoxyinosine on the activity and site of action of 5-fluorouracil.
Cancer Res 1981; 41: 3288–3295.
15. Dykewicz MS, Orfan NA, Sun W. In vitro demonstration of IgE anti-
body to folate-albumin in anaphylaxis from folate acid. J Allergy Clin
Immunol 2000; 106: 386–389.
16. Woodliff HJ, Davis RE. Allergy to folic acid. Med J Aust 1966;
1: 351–352.
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