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Apr 13, 2013 - (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe ...
Intern Emerg Med (2013) 8:417–423 DOI 10.1007/s11739-013-0936-8

IM - ORIGINAL

Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule Elena Magnani • Enrico Farnetti • Davide Nicoli • Bruno Casali • Luisa Savoldi • Chiara Focaccetti • Corrado Boni • Adriana Albini • Maria Banzi

Received: 13 December 2012 / Accepted: 26 March 2013 / Published online: 13 April 2013 Ó SIMI 2013

Abstract Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14?1G[A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician’s decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14?1G[A mutations.

E. Magnani  C. Boni  M. Banzi Department of Medical Oncology, Azienda Ospedaliera ASMN, IRCCS, 42123 Reggio Emilia, Italy E. Farnetti  D. Nicoli  B. Casali Laboratory of Molecular Biology, Azienda Ospedaliera ASMN, IRCCS, 42123 Reggio Emilia, Italy L. Savoldi  A. Albini (&) Research and Statistics Department, Azienda Ospedaliera ASMN, IRCCS, Viale Umberto I 50, 42123 Reggio Emilia, Italy e-mail: [email protected]; [email protected] C. Focaccetti Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy

Keywords Dihydropyrimidine dehydrogenase (DPD)  Tumors  Fluoropyrimidine chemotherapy  Toxicity  Dose reduction Abbreviations DPD Dihydropyrimidine dehydrogenase 5-FU 5-Fluorouracil ECOG Eastern Cooperative Oncology Group MTD Maximum tolerated dose

Introduction Fluoropyrimidine-based drugs are widely used in oncology for treatment of several types of common cancers, including gastrointestinal, head and neck and breast cancers [1]. 5-FU is converted to 5-fluorodeoxyuridine monophosphate, which inhibits thymidylate synthase (TS), a key enzyme that catalyzes the methylation of deoxyuridine monophosphate to deoxythymodine monophosphate. Clinical trials showed high clinical efficacy and in general good tolerability of these drugs, which are also included in combination therapies administered to cancer patients. The wide use of 5-fluorouracil (5FU), its prodrug capecitabine and derivatives (tegafur) recently highlighted the occurrence of toxic side effects (mucositis, diarrhea, neurotoxicity, hematologic and cardiac toxicity) that can be particularly serious, leading to interruption of anticancer therapy [2], and even fatality in a small percentage of patients. 5-FU is degraded through a catabolic pathway to 5-fluoro-5,6-dihydrouracil (5-FDHU); the key enzyme that regulates this metabolic step is dihydropyrimidine dehydrogenase (DPD), which catalyzes a fundamental and ratelimiting step. DPD is a ubiquitously dispersed cytosolic

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enzyme, present in many tissues [3], but with higher activity in liver and lymphocytes [4], where it acts to convert the physiologic substrate uracil (U) into 5,6-dihydrouracil (UH2). When patients that experienced 5-FU associated toxic events and their relatives were analyzed for the presence of metabolic defects that could generate reduced catabolism of 5-FU, mutations in DPD were found at higher frequencies [5–9]. The DPD gene is located on the short arm of chromosome 1, 1p22, and has been found to harbor several mutations, the most characterized of which is the IVS14?1G[A [7], resulting in the replacement of guanine 1986 (G), at the end of exon 14, with an adenine (A). This mutation does not allow the recognition of the splice site in the sequence GT at the 50 of the intron 14, causing the deletion of the entire exon 14, the loss of 165 bp and the generation of a protein with reduced or absent enzymatic activity [10–15]. The mutation of the gene coding for DPD may occur both in homozygosity and in heterozygosity and the results in the synthesis of a functionally inactive enzyme transmitted in an autosomal recessive inheritance. The homozygosity frequency of the mutated allele, calculated in a population of patients with colorectal cancer, was around 0.7 %, while in heterozygous individuals in a European population was estimated to be higher (0.5–5 %) [16, 17]. In patients harboring mutations both in homozygosity and in heterozygosity, resulting in completely inactive or only reduced activity levels, increased risk for severe toxicity in cancer patients treated with 5-FU has been observed [6, 9]. Based on a systematic review of the literature, Swen et al. [18] recommended that patients carrying a heterozygous IVS14?1G[A mutation should be receive a 5-FU drug class dose reduction of at least 50 % of the current recommended dosage, while in homozygous carriers of the same mutation should not be considered candidates for 5-FU treatment. Administration of 5-FU and its prodrugs in these patients have been found to result in high-degree gastrointestinal and hematological toxicity possibly leading to patient death. Given the wide use of fluoropyrimidines in combined cancer therapy, we decided to investigate the presence of the IVS14?1G[A DPD gene mutation in 180 patients with gastrointestinal, breast or head and neck cancers, afferent to the Oncologic Department of the IRCCS Arcispedale Santa Maria Nuova in Reggio Emilia, from April 2011 to February 2012, that were potential candidates for a first treatment with 5-FU class drugs. On the basis of the sequence analysis, the guidelines suggested by Swen were followed for patients with evident mutation. In this study, we show that those patients with heterozygous DPD, even with a dose reduction of least by 50 % according to the Swen et al. guidelines [18], showed severe gastrointestinal

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and hematological toxicities that resulted in hospitalization of patients and premature discontinuation of treatment.

Methods Patient selection Informed consent was obtained from a total of 180 patients that were analyzed, including 75 females (41.6 %) and 105 males (68.4 %) in accordance with the standards of the Reggio Emilia Provincial Ethical Committee, approved under protocol number 10174. All patients accessed the IRCCS Arcispedale S. Maria Nuova in Reggio Emilia (Italy) in the period between February 2011 and April 2012 and were candidates for 5-FU-based chemotherapy for the treatment of histologically diagnosed gastrointestinal (86.2 %), breast (3.9 %), head and neck (6.6 %) and other tumors (3 %) (Table 1). All patients who underwent, for the first time, 5-FU containing treatment, either intravenous or oral, and regardless to the type of chemotherapy regimen (neoadjuvant, adjuvant or metastatic), were considered eligible. Subjects that had performed multiple lines of treatment for metastatic disease and those considered not eligible to fluoropyrimidine based treatment, including patients with poor clinical condition, or with tumor characteristics not requiring chemotherapy or addressed to an alternative drug regimen, were excluded. The screening test for the deficiency of the DPD enzyme activity was generally performed before initiation of chemo- or radio/chemo-therapy. DNA was purified (Genomic DNA Purification Kit, PUREGENE) from peripheral blood mononuclear cells, collected in K3EDTA glass tubes (Vacutainer), and the region of DPYD DPD gene, including the point of the single-base substitution (end of intron 13–14 ? entire exon 14 ? first part of intron 14–15) was amplified by PCR as reported by van Kuilenburg AB et al. [16]. 5 ll of DNA served as the template for subsequent PCR reaction to amplify the segment of interest using 2 lM DPD14f forward primer (50 -TCCTCTGCAA AAATGTGAGAAGGGACC-30 —sense, 451–477) and

Table 1 Number of subjects analyzed in each sites of neoplasm and reported mutated patients Site of neoplasm

Number of patient analyzed (%)

Number with mutations IVS14?1G[A

Gastrointestinal

156 (86.6)

3

Breast Head and neck Other sites Total

7 (3.9)

0

12 (6.7)

1

5 (2.8)

0

180 (100)

4

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Fig. 1 Images of the PCR products after electrophoresis showing two patients with heterozygous IVS14?1G[A DPD mutations. The heterozygous samples are in lane 3 (left image) and lane 5 (right image), mutation positive control is in lane 9. M size markers

2 lM DPD14r reverse primer (50 -TCACCAACTTATGC CAATTCTC-30 —antisense, 762–783) under the following cycling conditions: 1 min denaturation at 94 °C, 35 cycles of 30 s at 94 °C, 30 s at 60 °C, and 30 s at 72 °C, followed by a final elongation for 3 min at 72 °C. The presence of the mutation was detected through the use of sensitivity to specific restriction endonuclease (tail: 50 -ACGT.-30 – 30 -mTGCA-50 ) and 2.5 % agarose gel electrophoresis (Fig. 1) [9–11]. Digestion was performed at 65 °C for 2 h. Only 4 patients out of the 180 were found positive in heterozygosity for the specific mutation (2.2 %, in line with the previous estimates). One patient was not treated with chemotherapy based on the clinician’s decision. The other three patients with the IVS14?1G[A mutation had three different types of tumors and were treated with reduced doses of 5-FU according to specific guidelines, combined with carboplatin, irinotecan, or oxaliplatin (Table 2). The remaining 176 patients were treated, intravenously or orally, with fluoropyrimidines (5-FU or capecitabine) in single or combined chemotherapy. Monitoring of toxicity All patients were monitored during and after the administration of therapy and all the adverse reactions registered. Reduction in 5-FU dosage at first administration was performed in a patient-specific manner, based on the results of DPD testing, characteristics and prognosis of disease, age and clinical conditions of patients and according to the recent guidelines proposed by Swen et al. [18]. It is of note that even if the mutational status was similar among the patients the therapy they received were differently reduced in 5-FU dosage according to the illness progression and therapy needed: in subjects with advanced or metastatic disease or with a worst prognosis the lowest reduction of 5-FU dosage was applied. After each cycle of chemotherapy, adverse reactions were recorded, reporting the corresponding degrees of toxicity, in agreement with the standard criteria NCI-

Common Toxicity Criteria, particularly focusing on grades 3–4 reactions and on 2–3 weeks delayed grade 2 reactions. It has been reported in the literature that 100 % of DPDdeficient patients manifest their impaired drug metabolism with hematological (neutropenia G3–4) and gastrointestinal (mucositis G3, vomiting G3–4, diarrhea G3–4) adverse effects. The correlation between treatment with 5-FU and adverse reactions was analyzed. The clinical and pathological staging system for cancer used was the American Joint Committee on Cancer (AJCC), also known as the TNM system [19].

Results In a wild-type patient population, who express normal DPD activity, incidence of adverse drug reactions reported with fluoropyrimidine drugs, during the standard therapy, is about 22 % due to wide interindividual variability in activity [8, 19]. We collected data coherent with the previous literature both for general population incidence of side effects and for DPD mutated patients and here we describe the cases of three cancer patients found positive for DPD heterozygous mutation and that were treated with reduced doses of 5-FU according to recent guidelines [18] and a fourth for which the decision was not to administer a 5-FU-based regimen. Case 1 was a 43-year-old Caucasian male, body weight 67 kg, height 180 cm and body mass index 1.85 20.87. No relevant concomitant illness in his medical history. The patient had Eastern Cooperative Oncology Group (ECOG) Performance Status 0, and underwent treatment for a pT1N1/16-M0 colon cancer after a left hemicolectomy. He received an adjuvant regimen with XELOX with capecitabine reduced to 50 % of standard dosage (capecitabine 1,000 mg/m2 for 14 days every 21 days and oxaliplatin 130 mg/m2). Nineteen days after first administration, hospitalization was required for G4 diarrhea (30 stools per day), G4 febrile neutropenia, and G3 thrombocytopenia. In

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123

M

M

M

M

Case 1

Case 2

Case 3

Case 4

66

68

71

43

Age (years)

0

1

0

0

PS1

Mismatch repair gene mutation

Hypertension, hypercholesterolemy, dyspnoea

Past myocardial heart failure

None

Co-morbidities

Colon cancer T1N0M0

Head and neck cancer T2N1M1

Colon cancer T1N1M0

Colon cancer T1N1M0

Neoplasm type TNM

No chemotherapy treatment

leucovorin 100 mg/m2

5 FU 3,400 mg/m

Not applicable

60 % ? growth factors 50 % 2

Initially 0 %

oxaliplatin 85 mg/m2

67 %

Folfox-1 line regimen with:

capecitabine 500 mg/m2 9 2/day for 14 days

oxaliplatin 130 mg/m

Xelox—adjuvant regimen with:

Anemia G2 Not applicable

Febrile neutropenia G4

Mucositis G3

Sepsis

Thrombocytopenia G3

Febrile neutropenia G4

Abdominal pain G3

Vomiting G3

Thrombocytopenia G3

capecitabine 500 mg/m2 9 2/day for 14 days

Diarrhea G4

Toxicity after chemotherapy

Febrile neutropenia G4

50 %

FP reduction2

oxaliplatin 130 mg/m2

Xelox—adjuvant regimen with:

Chemotherapy type

2

1

Fluoropyrimidine reduction when compared with standard dose

ECOG Performance Status (PS)

0 Asymptomatic (fully active, able to carry on all predisease activities without restriction), 1 symptomatic but completely ambulatory (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work), 2 symptomatic \50 % time in bed during the day (ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50 % of waking hours), 3 symptomatic [50 % time in bed, but not bedbound (capable of only limited self-care, confined to bed or chair 50 % or more of waking hours), 4 Bedbound (completely disabled. Cannot carry on any self-care. totally confined to bed or chair), 5 death

Sex

Heterozygous cases

Table 2 Characteristics of the heterozygous subjects identified and toxicity following fluoropyrimidine therapy

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view of the adjuvant regimen and the marked toxicity, despite the young age of the patient, the clinical team decided for a permanent discontinuation of chemotherapy. Case 2 was a 71-year-old Caucasian male, body weight 52 kg, height 165 cm and body mass index 1.56 19.1. He had in 1986 (26 years earlier) a myocardial heart failure without subsequent recurrence and no other relevant concomitant illness in medical history. His ECOG Performance Status was 0. The patient underwent adjuvant treatment for a pT1-N1/39-M0 colon cancer following a right hemicolectomy. Owing to toxicity manifested by the patient in case 1 and age of present subject, he was addressed to an adjuvant regimen treatment with XELOX with a fluropyrimidine reduction of 67 % (capecitabine 800 mg/m2 for 14 days every 21 days combined with oxaliplatin 130 mg/m2). After only 1 day of treatment, the patient required hospitalization for acute gastrointestinal toxicity (G3 vomiting and G3 abdominal pain). In view of the adjuvant regimen and of the marked toxicity, the clinical team decided for a permanent discontinuation of chemotherapy. Case 3 was a 68-year-old Caucasian male, body weight 70 kg, height 175 cm and body mass index 1.75 22.87. He was treated with first-line chemotherapy for a metastatic maxillary sinus carcinoma with involvement of retro-ocular region and right pulmonary lymphangitis. His medical history was positive for hypertension and hypercholesterolemia. His ECOG Performance Status was 1. Because of this patient’s severe dyspnea, requiring an urgent need to start chemotherapy, the physician decided to start chemotherapy before notification of the DPD mutation results. Therefore, the patient received a complete chemotherapeutic treatment composed of carboplatin AUC 4 i.v., 5-FU 3,000 mg/m2 i.c. for 46 h ? 400 mg/m2 i.v. bolus and leucovorin i.v. 200 mg total, every 21 days. After 15 days of the initiation of chemotherapy, the patient was hospitalized for G4 febrile neutropenia, G3 thrombocytopenia, severe G3 E. coli sepsis and extensive G3 ulceration of the palate with candidiasis. After the patient’s complete recovery, notwithstanding the confirmation of DPD mutational status, and in consequence of an impressive partial response to the first treatment, the decision was taken for an additional cycle of chemotherapy; however, with the 5-FU dose reduced by 60 % as compared to the previous standard dose administered (1500 mg/m2, without bolus). Precautionary growth factors were also administered at the same time. The patient tolerated the therapy fairly well and did not exhibit toxicity. In view of this result, the physicians decided to try to run the third cycle of chemotherapy increasing the dose of 5-FU to 2,000 mg/m2 in bolus administration but without growth factors. After 14 days, patient required hospitalization for treatment of G4 febrile neutropenia and

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G2 anemia that brought clinicians to finally interrupt the 5-FU-based regimen and continued treatment without fluoropyrimidines. Case 4 was a 66-year-old Caucasian male, body weight 70 kg, height 160 cm and body mass index 1.73 27.34. He had no relevant concomitant illness in his medical history although he also showed microsatellite instability indicating mismatch repair gene mutations. The patient had Eastern Cooperative Oncology Group (ECOG) Performance Status 0. Physician decided that because of DPD heterozygous genotype and presence of microsatellite instability that is associated with better prognosis, patient did not receive adjuvant treatment for his pT1-N0/22-M0 colon cancer after left hemicolectomy.

Discussion Given the improvements in survival of oncology patients, control of therapy-induced toxicity has now become a major issue, leading to calls for increased awareness and cooperation [19, 20] and for improvements in onco-pharmacovigilance [21]. One major point is identification of patients at risk for toxicity, including those individuals with mutations in metabolic enzymes involved in drug metabolism, constituting an example of pharmacogenomics, one of the most interesting and current topics in the field of clinically applied molecular research. We pursued the molecular evaluation of DPD, a key enzyme in fluoropyrimidine metabolism, and in our patients found a frequency of IVS14?1G[A mutations at 2.2 %, in the range (0.5–5 %) previously described for Caucasian populations [16]. The analysis of toxicity showed that the patients with the mutation, even if treated with lower doses of 5-FU according to the guidelines published by Swen et al. [18], all experienced significant toxicities G3 and G4 of gastrointestinal and hematological origin after treatment that in all cases resulted in the patients’ hospitalization and premature discontinuation of chemotherapy with fluoropyrimidines [22, 23]. Furthermore, it is important to note that in our heterozygous patients, toxicities occurred early during the first cycle of chemotherapy in agreement with the data reported in literature describing that toxicities in patients with DPD activity deficits occur early during treatment due to drug accumulation in tissues [24]. DPD screening prior to 5-FU-based therapy is one of the key point for protection from fluoropyrimidines derived toxicities. Although agreement on methods for detection of mutations is still lacking [25], several DPD variants have been isolated [5] all contributing to enzyme reduced activity. The different contribution given by specific mutations to the toxicities experienced by patients also depends on

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disease type, patient characteristics, concomitant treatments [22] and geographical distribution [25]. Therefore, the hypothesis of a common dose reduction (50 %) for all mutated patients, as suggested by recent guidelines [18], does not seem feasible to protect from severe toxicity events. We feel necessary to set-up a pharmacokinetic study to better determine how to treat this class of patients with DPD mutations and to identify the maximum tolerated dose (MTD) for each patient with a DPD enzyme deficiency. This would permit the possibility to customize fluoropyrimidine-based therapies, tailoring it for the specific patient requirements and characteristics, constituting a clinically valid example of pharmacogenomics. This will also allow us to avoid that patients, due to wide interindividual variability in enzyme activity, receive an over- or under-estimated dose of drug. There is general agreement that continuous monitoring of 5-FU blood levels during administration combined with appropriate dose adjustments may represent a more rational approach for 5-FU dosing, therefore allowing the early identification of patients with a reduced capacity to metabolize 5-FU and avoiding the administration of toxicity-generating drugs. The important gains in terms of health care costs will be the reduction in hospitalization or death for severe complications and the possibility for the patients to maintain their treatment regimens due to a simple and economic screening test (10 USD$ for each patient). Acknowledgments We thank all the Patients involved in the study, at the Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico of Reggio Emilia that have made this project possible. The authors also thank Professor Douglas Noonan (University of Insubria, Varese) that provided medical writing assistance and Loretta Fornaciari for laboratory technical support. We acknowledge AIRC (Assciazione Italiana Ricerca sul Cancro) to AA. Multimedica Onlus Italy and the MIUR Grande Progetto Strategico GPS DM28938 for support.

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