Cigarette smoking during irinotecan therapy: Effects on pharmacokinetics and neutropenia

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2007

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Presenter: De Jong, F.A.
Presenter's Affiliation: Erasmus University Medical Center, Rotterdam, the Netherlands
Type of Session: Scientific

Background

  • Irinotectan is known for its broad spectrum of anti-tumor activity and its narrow therapeutic window.
  • After irinotecan treatment, the occurrence of late onset diarrhea and neutropenia remain unpredictable in any given patient. These symptoms have been related to the rate of clearance of the drug's active metabolite, SN-38.
  • Irintoecan is typically dosed using a patient's body surface area; however this has not helped decrease significant variability in the occurrence of toxicities.
  • UGT1A is an enzyme that has been implicated in the detoxification of the toxic metabolite SN-38.
  • Genetic variations in this enzyme may explain why certain patients experience severe toxicities following irinotecan treatment.
  • Cytochrome P450 enzymes in the liver, such as CYP3A, are important for the detoxification of many drugs and substances.
  • The level of CYP3A expression may determine which patients best respond to certain drugs, and which patients experience side effects when the same dosage is administered.
  • The inter and intrapatient variation in toxicity after irinotecan treatment is also related to the concurrent use of medications that can increase or decrease the levels of CYP3A.
  • Exposure to cigarette smoke can affect the expression of cytochrome P450 enzymes and has been demonstrated to affect the levels and clearances of a number of different medications.

Materials and Methods

  • This study was designed as a retrospective analysis of prospectively obtained data on 202 patients treated with irinotecan.
  • All patients received irinotecan on a three week schedule.
  • The study sought to explore the effects of smoking on the pharmacokinetic profile of irinotecan and its active metabolite SN-38 as well as on the risk of toxicities.
  • Irinotecan dose varied between 175-350 mg/m2, although some study patients received 600 mg fixed dose. Pharmacokinetic parameters for the first course of irinotecan treatment were available.
  • Patients were excluded from the study if they were receiving other medications that could cause a clinically relevant induction or inhibition of the CYP3A or UGT1A enzymes.
  • Smoking status was determined based on medical files, and records were available from 190 of the 202 patients.
  • Patients were either classified as smokers or non-smokers (former smokers were placed in the non-smoker category). Patients who had stopped smoking within 4 weeks of the initiation of treatment were excluded from this study.
  • Toxicity analysis was limited to the subset of patients who received 350mg/m2 or 600 mg.
  • In particular, the occurrence of leukopenia, neutropenia and delayed type diarrhea were explored, and this data was available in 134 patients.
  • Genotyping data of the UGT1A enzyme was available for 128 patients.

Results

  • 49 patients were identified as smokers (26%) and 141 as non-smokers (74%).
  • Smokers were younger than non-smokers (median age of 49 compared to 56, p = 0.001)
  • UGT1A genotype did not vary significantly between smokers and non-smokers.
  • Smokers had a 15% lower dose normalized exposure to irinotecan (p = 0.001).
  • Smokers had a 40% lower dose normalized exposure to SN-38 (p < 0.001)
  • Smokers experienced significantly lower rates of both grade 3 or 4 leukopenia (9% vs. 32%, p = 0.006) and grade 3 or 4 neutropenia (6% compared to 38%, p < 0.001) when compared to non-smokers.
  • Although smokers had a lower risk of grade 3 or 4 delayed type diarrhea than non-smokers, this was not statistically significant (6% vs. 15%, p = 0.149)

Author's Conclusions

  • Smoking lowers the exposure to both irinotecan and its active metabolite SN-38.
  • Consequently, smoking lowers the incidence of exposure related neutropenia (OR 0.10).
  • The incidence of delayed type diarrhea appears lower in smokers as well (OR 0.34, p = N.S.)
  • Smoking affects key enzymes/transporters involved in the metabolism of irinotecan, probably CYP3A and UGT1A, but the exact mechanism has not yet been elucidated.
  • Given the lower exposure to irinotecan and SN-38 and the lower incidence of exposure related toxicity, it seems reasonable to hypothesize that smoking causes a negative effect of the therapeutic efficacy of irinotecan.

Clinical/Scientific Implications

  • The authors presented a well performed retrospective analysis of prospectively obtained data. This line of inquiry is very interesting, and the study design was narrow enough to properly asses the effect of cigarette smoking on the pharmacokinetic profile of irinotecan and its metabolite SN-38 as well as the risk of toxicity following administration.
  • Further investigation with regards to the effect of cigarette smoking on survival outcomes in patients treated with this drug would be interesting; however, the authors were unable to perform the necessary analyses to answer this question because many of the patients studied were enrolled in phase I trials.
  • Given these results, smoking status should be prospectively stratified in any further trials utilizing irinotecan.
  • Similar lines of inquiry into the effect of cigarette smoking on the metabolism of other chemotherapeutics would likely be equally informative; however, because there are so many different variables (age, race, gender, genetic polymorphisms and concurrent medication usage) the relative importance of cigarette smoking in patients receiving cancer treatment may never be fully understood.

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