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Drug Interaction Between Complementary Herbal Medicines and Gefitinib
LETTERS
TO THE
EDITOR
Drug Interaction Between Complementary Herbal Medicines and Gefitinib To the Editor: Dear Colleagues: We would like to share with the readers of Journal of Thoracic Oncology an interesting case that we encountered. It serves as a reminder that we should ask our patients about their use of complementary medicines. A 36-yearold woman with no smoking history presented with progressive dyspnea. Computed tomography (CT) of the chest at diagnosis showed a main mass in the right lower lobe with disseminated multiple nodules and multiple interlobular septal thickening in both lungs (Fig. 1A). A needle-aspiration biopsy of the lung nodule was performed, and its histology was consistent with adenocarcinoma. A diagnosis of stage IV adenocarcinoma of lung was made, and she was treated with gefitinib 250 mg per day by mouth as the first-line chemotherapy. Within 9 weeks of gefitinib treatment, she became progressively symptomatic more short of breath. A CT scan of chest revealed progression of her disease (Fig. 1B). She was recommended to discontinue gefitinib because of progressive disease. However, she desired to continue gefitinib therapy. At that time, she informed her physician that she had simultaneously taken multiple complementary herbal medicines including ginseng, Fomes fomentarius, Inonotus obliquus, Phellinus linteus, and selenium along with gefitinib without notification. Thereafter, she discontinued all complementary herbal medicines and took only gefitinib. Her symptoms improved and a follow-up CT scan of chest obtained after 4 weeks revealed a partial response of her disease (Fig. 1C). She continued gefitinib and has been on treatment for 30 weeks with sustained response of her disease (Fig. 1D).
Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0942
942
FIGURE 1. Chest CT before and after gefitinib treatment. Initial CT scan at the level of right lower lobar bronchus revealed a speculated mass with cavitary change in the right lower lobe suggesting primary lung cancer. Multiple hematogenous metastatic nodules with or without cavitary change were seen in both lungs (A). On CT scan obtained 9 weeks after gefitinib treatment, the primary mass in the right lower lobe and pulmonary metastases in both lungs were increased (B). On CT scan obtained 4 weeks after discontinuation of herbal medicines, primary mass and hematogenous metastatic nodules were markedly decreased (C). On CT scan obtained a total of 30 weeks after gefitinib treatment, the primary mass in the right lower lobe was further decreased (D).
The CYP3A4 and CYP3A5 in the intestines and liver play primary role in the first-pass metabolism and systemic clearance of gefitinib.1 Therefore, elevated CYP3A4/A5 activity through induction by herbal medicines may result in a decrease in plasma concentrations and in total loss of therapeutic effect of gefitinib. In this case, the patient took multiple mixtures of herbal medicines including ginseng, mushrooms, and selenium. Although ginseng is one of the most widely used herbal medicine, little information is available on drug interactions. Previously a randomized trial had demonstrated that ginseng reduced the anticoagulation effects of warfarin. Because warfarin is eliminated extensively through hepatic CYP enzyme system including CYP1A2, CYP3A4, and CYP2C9, these data suggest that ginseng may induce the CYP enzyme system resulting in lower plasma concentrations of warfarin.2 In addition, an in vitro study showed that ginseng increased CYP3A4 mRNA expression in human hepatocytes.3 These findings suggest that ginseng may increase the clearance of gefitinib through CYP3A4
induction, which result in treatment failure to gefitinib. Besides ginseng, this patient took mushrooms and selenium. Although there are no reports on drug interactions with these complementary medicines, that we are aware of, the possibility of drug-interaction with these medicines and gefitinib should also be taken in consideration. To our knowledge, this is the first report of clinically relevant interaction of gefitinib with complementary herbal medicines. This case demonstrates the possibility of complementary herbal medicines causing treatment failure in a patient who was subsequently responsive to gefitinib. Physicians are encouraged to discuss the use of complementary medicines with their patients and to be aware of possible interaction with gefitinib. Sung-Wook Hwang, MD Department of Internal Medicine Seoul National University Hospital, Seoul, Korea
Hye-Suk Han, MD Kun Young Lim, MD
Journal of Thoracic Oncology • Volume 3, Number 8, August 2008
Journal of Thoracic Oncology • Volume 3, Number 8, August 2008
Ji-Youn Han, MD, PhD Research Institute and Hospital National Cancer Center, Goyang Gyeonggi, Korea
REFERENCES 1. Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98:1714 –1723. 2. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004;141:23–27. 3. Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 2003;31:533–539.
Too Restrictive Exclusion Criteria in Advanced Stage Lung Cancer Therapeutic Trials: Are We Missing the Target? To the Editor: With 965,000 new cases worldwide in 2002 in men and 387,000 new cases in women, lung cancer is the most common cancer. Because of its poor prognosis, 1.2 ⫻ 106 people died of lung cancer in that year.1 Though its incidence has stopped increasing, particularly for men, in countries where efficient tobacco control policies have been implemented, its global incidence is still on the rise.1 This dramatic situation is due to the high worldwide prevalence of tobacco smoking and the fact that most diagnoses are made at advanced stages when only palliative treatments (chemotherapy ⫾ radiotherapy) can be prescribed, surgery being the only curative treatment.1 Obviously, curbing the tobacco pandemic would be an efficient way to prevent lung cancer, but worldwide tobacco smoking is still on the rise, due to the tobacco industry’s highly efficient marketing and promotion efforts. Furthermore, even if tobacco smoking were to totally vanish, the lung cancer pandemic would last for a long time since at present, at least in developed countries, nearly one Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0943
in 2 lung cancers are diagnosed in patients who had already given up smoking.2 An efficient early detection procedure has yet to be described for this cancer,3 therefore, to improve lung cancer prognosis, it is important to try to improve treatment (chemotherapy ⫾ radiotherapy) efficacy. This can only be done through the development of more efficient treatments with the enrollment of patients in clinical trials. Unfortunately, there are currently very few patients with advanced stage lung cancer (less than 5%) enrolled in clinical trials.4 For example, in our department, a prospective study of inclusion/ noninclusion in clinical trials of patients admitted for stages IIIB and IV nonsmall cell lung cancer (NSCLC) in 2007 showed that, among 217 patients admitted for lung cancer, according to TNM staging, 123 patients with NSCLC (m/f ratio: 96/27; mean age: 61 ⫾ 12 years; 64 adenocarcinoma, 32 squamous cell carcinomas, 2 neuroendocrine carcinomas, 2 large cell carcinomas, 17 undifferentiated carcinomas, and 6 without histology) could have been enrolled in clinical trials open at time of admission. However, only 12 patients (10%) were actually included in a trial. The exclusion criteria were as follows: ⫾ symptomatic brain metastases (n ⫽ 29), common comorbidities (Charlson Comorbidity Index-CCI- ⱖ3) (n ⫽ 28), WHO PS ⱖ 2 and/or life expectancy ⬍3 months (n ⫽ 23), patient refusal or specified requirements (n ⫽ 13), technical limitation (tumor biopsy size too small for further molecular analysis, n ⫽ 9), patient transferred to another institution (n ⫽ 7), lack of organization (n ⫽ 2). Obviously, such a low percentage of included patients is not a representative sample of patients with advanced NSCLC. Low accrual rates have been observed in other clinical settings and several parameters have been suggested to be responsible: age, ethnicity, insurance status, presence of an oncology specialist, etc.4,5 In the present study, these parameters were not involved since all patients could have been included in clinical trials according to their age, clinical status, TNM staging, acceptance, etc. Our patients were mainly not included because of overly restrictive clinical trial exclusion criteria. As a result, one might question
Copyright © 2008 by the International Association for the Study of Lung Cancer
Letters to the Editor
whether the observations resulting from therapeutic protocols based on such restrictive criteria, inevitably leading to biased samples of patients, should be applied to all patients. Thus, it is suggested that, instead of studying a very exclusive subset of patients, future protocols should be targeted toward the main patient population, regardless of clinical status, but for terminally ill patients. Christelle Cle´ment-Ducheˆne, MD Charlotte Carnin, BS Yves Martinet, MD, PhD Chest Department CHU de Nancy Universite´ Henri Poincare´ France
REFERENCES 1. Fry WA, Phillips JL, Menck HR. Ten-year survey of lung cancer treatment and survival in hospitals in the United States: a national cancer database report. Cancer 1999;86: 1867–1876. 2. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking; 50 years’observations on male British doctors. Br Med J 2004;328:1507–1515. 3. McMahon PM, Christiani DC. Computed tomography screening for lung cancer. Br Med J 2007;334:271. 4. Pujol JL, Chakra M, Milleron B. Patient participation in thoracic cancer clinical trials. J Thorac Oncol 2008;3:3–5. 5. Murthy VH, Krumholz HM, Gross CP. Participation in cancer trials: race-, sex-, and age-based disparities. JAMA 2004;291:2720 –2726.
Zoledronic Acid and Survival in Patients with Metastatic Bone Disease From Lung Cancer and Elevated Markers of Osteoclast Activity: A Novel Molecular Mechanism To the Editor: Dear Sir, I read with great interest the paper by Hirsh et al.1 Disclosure: The author declares no conflict of interest. Address for correspondence: Hamid Namazi, PhD, Chamran hospital, Shiraz, Iran. E-mail: [email protected] Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0943
943
TO THE
EDITOR
Drug Interaction Between Complementary Herbal Medicines and Gefitinib To the Editor: Dear Colleagues: We would like to share with the readers of Journal of Thoracic Oncology an interesting case that we encountered. It serves as a reminder that we should ask our patients about their use of complementary medicines. A 36-yearold woman with no smoking history presented with progressive dyspnea. Computed tomography (CT) of the chest at diagnosis showed a main mass in the right lower lobe with disseminated multiple nodules and multiple interlobular septal thickening in both lungs (Fig. 1A). A needle-aspiration biopsy of the lung nodule was performed, and its histology was consistent with adenocarcinoma. A diagnosis of stage IV adenocarcinoma of lung was made, and she was treated with gefitinib 250 mg per day by mouth as the first-line chemotherapy. Within 9 weeks of gefitinib treatment, she became progressively symptomatic more short of breath. A CT scan of chest revealed progression of her disease (Fig. 1B). She was recommended to discontinue gefitinib because of progressive disease. However, she desired to continue gefitinib therapy. At that time, she informed her physician that she had simultaneously taken multiple complementary herbal medicines including ginseng, Fomes fomentarius, Inonotus obliquus, Phellinus linteus, and selenium along with gefitinib without notification. Thereafter, she discontinued all complementary herbal medicines and took only gefitinib. Her symptoms improved and a follow-up CT scan of chest obtained after 4 weeks revealed a partial response of her disease (Fig. 1C). She continued gefitinib and has been on treatment for 30 weeks with sustained response of her disease (Fig. 1D).
Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0942
942
FIGURE 1. Chest CT before and after gefitinib treatment. Initial CT scan at the level of right lower lobar bronchus revealed a speculated mass with cavitary change in the right lower lobe suggesting primary lung cancer. Multiple hematogenous metastatic nodules with or without cavitary change were seen in both lungs (A). On CT scan obtained 9 weeks after gefitinib treatment, the primary mass in the right lower lobe and pulmonary metastases in both lungs were increased (B). On CT scan obtained 4 weeks after discontinuation of herbal medicines, primary mass and hematogenous metastatic nodules were markedly decreased (C). On CT scan obtained a total of 30 weeks after gefitinib treatment, the primary mass in the right lower lobe was further decreased (D).
The CYP3A4 and CYP3A5 in the intestines and liver play primary role in the first-pass metabolism and systemic clearance of gefitinib.1 Therefore, elevated CYP3A4/A5 activity through induction by herbal medicines may result in a decrease in plasma concentrations and in total loss of therapeutic effect of gefitinib. In this case, the patient took multiple mixtures of herbal medicines including ginseng, mushrooms, and selenium. Although ginseng is one of the most widely used herbal medicine, little information is available on drug interactions. Previously a randomized trial had demonstrated that ginseng reduced the anticoagulation effects of warfarin. Because warfarin is eliminated extensively through hepatic CYP enzyme system including CYP1A2, CYP3A4, and CYP2C9, these data suggest that ginseng may induce the CYP enzyme system resulting in lower plasma concentrations of warfarin.2 In addition, an in vitro study showed that ginseng increased CYP3A4 mRNA expression in human hepatocytes.3 These findings suggest that ginseng may increase the clearance of gefitinib through CYP3A4
induction, which result in treatment failure to gefitinib. Besides ginseng, this patient took mushrooms and selenium. Although there are no reports on drug interactions with these complementary medicines, that we are aware of, the possibility of drug-interaction with these medicines and gefitinib should also be taken in consideration. To our knowledge, this is the first report of clinically relevant interaction of gefitinib with complementary herbal medicines. This case demonstrates the possibility of complementary herbal medicines causing treatment failure in a patient who was subsequently responsive to gefitinib. Physicians are encouraged to discuss the use of complementary medicines with their patients and to be aware of possible interaction with gefitinib. Sung-Wook Hwang, MD Department of Internal Medicine Seoul National University Hospital, Seoul, Korea
Hye-Suk Han, MD Kun Young Lim, MD
Journal of Thoracic Oncology • Volume 3, Number 8, August 2008
Journal of Thoracic Oncology • Volume 3, Number 8, August 2008
Ji-Youn Han, MD, PhD Research Institute and Hospital National Cancer Center, Goyang Gyeonggi, Korea
REFERENCES 1. Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98:1714 –1723. 2. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004;141:23–27. 3. Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 2003;31:533–539.
Too Restrictive Exclusion Criteria in Advanced Stage Lung Cancer Therapeutic Trials: Are We Missing the Target? To the Editor: With 965,000 new cases worldwide in 2002 in men and 387,000 new cases in women, lung cancer is the most common cancer. Because of its poor prognosis, 1.2 ⫻ 106 people died of lung cancer in that year.1 Though its incidence has stopped increasing, particularly for men, in countries where efficient tobacco control policies have been implemented, its global incidence is still on the rise.1 This dramatic situation is due to the high worldwide prevalence of tobacco smoking and the fact that most diagnoses are made at advanced stages when only palliative treatments (chemotherapy ⫾ radiotherapy) can be prescribed, surgery being the only curative treatment.1 Obviously, curbing the tobacco pandemic would be an efficient way to prevent lung cancer, but worldwide tobacco smoking is still on the rise, due to the tobacco industry’s highly efficient marketing and promotion efforts. Furthermore, even if tobacco smoking were to totally vanish, the lung cancer pandemic would last for a long time since at present, at least in developed countries, nearly one Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0943
in 2 lung cancers are diagnosed in patients who had already given up smoking.2 An efficient early detection procedure has yet to be described for this cancer,3 therefore, to improve lung cancer prognosis, it is important to try to improve treatment (chemotherapy ⫾ radiotherapy) efficacy. This can only be done through the development of more efficient treatments with the enrollment of patients in clinical trials. Unfortunately, there are currently very few patients with advanced stage lung cancer (less than 5%) enrolled in clinical trials.4 For example, in our department, a prospective study of inclusion/ noninclusion in clinical trials of patients admitted for stages IIIB and IV nonsmall cell lung cancer (NSCLC) in 2007 showed that, among 217 patients admitted for lung cancer, according to TNM staging, 123 patients with NSCLC (m/f ratio: 96/27; mean age: 61 ⫾ 12 years; 64 adenocarcinoma, 32 squamous cell carcinomas, 2 neuroendocrine carcinomas, 2 large cell carcinomas, 17 undifferentiated carcinomas, and 6 without histology) could have been enrolled in clinical trials open at time of admission. However, only 12 patients (10%) were actually included in a trial. The exclusion criteria were as follows: ⫾ symptomatic brain metastases (n ⫽ 29), common comorbidities (Charlson Comorbidity Index-CCI- ⱖ3) (n ⫽ 28), WHO PS ⱖ 2 and/or life expectancy ⬍3 months (n ⫽ 23), patient refusal or specified requirements (n ⫽ 13), technical limitation (tumor biopsy size too small for further molecular analysis, n ⫽ 9), patient transferred to another institution (n ⫽ 7), lack of organization (n ⫽ 2). Obviously, such a low percentage of included patients is not a representative sample of patients with advanced NSCLC. Low accrual rates have been observed in other clinical settings and several parameters have been suggested to be responsible: age, ethnicity, insurance status, presence of an oncology specialist, etc.4,5 In the present study, these parameters were not involved since all patients could have been included in clinical trials according to their age, clinical status, TNM staging, acceptance, etc. Our patients were mainly not included because of overly restrictive clinical trial exclusion criteria. As a result, one might question
Copyright © 2008 by the International Association for the Study of Lung Cancer
Letters to the Editor
whether the observations resulting from therapeutic protocols based on such restrictive criteria, inevitably leading to biased samples of patients, should be applied to all patients. Thus, it is suggested that, instead of studying a very exclusive subset of patients, future protocols should be targeted toward the main patient population, regardless of clinical status, but for terminally ill patients. Christelle Cle´ment-Ducheˆne, MD Charlotte Carnin, BS Yves Martinet, MD, PhD Chest Department CHU de Nancy Universite´ Henri Poincare´ France
REFERENCES 1. Fry WA, Phillips JL, Menck HR. Ten-year survey of lung cancer treatment and survival in hospitals in the United States: a national cancer database report. Cancer 1999;86: 1867–1876. 2. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking; 50 years’observations on male British doctors. Br Med J 2004;328:1507–1515. 3. McMahon PM, Christiani DC. Computed tomography screening for lung cancer. Br Med J 2007;334:271. 4. Pujol JL, Chakra M, Milleron B. Patient participation in thoracic cancer clinical trials. J Thorac Oncol 2008;3:3–5. 5. Murthy VH, Krumholz HM, Gross CP. Participation in cancer trials: race-, sex-, and age-based disparities. JAMA 2004;291:2720 –2726.
Zoledronic Acid and Survival in Patients with Metastatic Bone Disease From Lung Cancer and Elevated Markers of Osteoclast Activity: A Novel Molecular Mechanism To the Editor: Dear Sir, I read with great interest the paper by Hirsh et al.1 Disclosure: The author declares no conflict of interest. Address for correspondence: Hamid Namazi, PhD, Chamran hospital, Shiraz, Iran. E-mail: [email protected] Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0308-0943
943