- Email: [email protected]
Gefitinib for refractory advanced non-small-cell lung cancer
the differences as well as the similarities between BSE and the CH1641 mousepassaged scrapie strain in our paper; the additional work in ovine transgenic mice described by Baron and Biacabe is important but also reveals distinct differences and does not alter the conclusions. Baron and Biacabe consider the possibility that the goat with a transmissible spongiform encephalopathy (TSE) resembling BSE might represent a previously unrecognised spontaneous TSE in this species. Considering that there is a high a priori likelihood that small ruminants have been exposed to substantial amounts of BSE infectivity, in circumstances that are experimentally sufficient to transmit infection, we think that the goat was much more likely to have been infected by BSE-contaminated material. Hugh Pennington refers to the difficulties of testing a hypothesis about a single event that occurred many years ago—ie, a “historical” hypothesis. All hypotheses of the origin of BSE have such difficulties. For a theory to be accepted, there needs to be convincing evidence that exposure to the putative source, with sufficient dosing to transmit infection, took place at the right time and place; and that there was sufficient strain similarity between the putative source and resulting infectious agent. This evidence might establish that the putative source could have been the cause—ie, would have been sufficient. Furthermore, there ideally needs to be no alternative plausible explanation that could also have been sufficient: the putative events can then be regarded as necessary and not just sufficient. Pennington also cites evidence that cattle might have been exposed to bonemeal imports from the Indian subcontinent for a much longer period than we suggest, which would increase the cumulative probability of exposure to a rare contaminant. However, we still think that the rise in the use of highprotein supplements for animal feed in the late 1960s is likely to have been the www.thelancet.com Vol 367 January 28, 2006
most important factor that led to an increased risk of exposure. We are familiar with the fall in anthrax cases after 1970, to which Pennington refers. However, imports of raw materials still amounted to tens of thousands of tonnes per year in the 1970s, and the fall in anthrax is mainly attributable to improvements in feed manufacturing practices after a scheme introduced by the UK Ministry of Agriculture, Fisheries, and Food: this scheme involved voluntary labelling of imported bonemeal to indicate that it had not been sterilised and should not be incorporated in the raw state into animal feed. Sterilisation processes needed to inactivate anthrax would not remove TSE infectivity, and a substantial risk of human TSE transmission will have persisted throughout the period when the first BSE cases are likely to have occurred. We declare that we have no conflict of interest.
*Alan Colchester, Nancy Colchester [email protected] Kent Institute of Medicine and Health Sciences, University of Kent, Canterbury CT2 7PD, UK (AC); and College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK (NC)
Gefitinib for refractory advanced non-small-cell lung cancer Nick Thatcher and colleagues (Oct 29, p 1527)1 indicate that the association between epidermal growth factor receptor (EGFR) mutation status and survival after gefitinib treatment in patients with non-small-cell lung cancer (NSCLC) is unclear. We used individual patients’ data (n=135) and Cox’s proportional hazard models to investigate factors contributing to the increase in survival seen in Asian patients with refractory advanced NSCLC in gefitinib trials.2–4 The multivariate analysis with clinical variables of sex, histology, smoking history, presence of deletions in exon 19, and presence of the L858R mutation in exon 21 of EGFR showed the following to
be contributing factors to the increase in overall survival: smoking history (hazard ratio for death 0·523, 95% CI 0·306–0·893, p=0·018; median survival 7·4 months for smokers and 24·3 months for never-smokers) and the presence of the L858R mutation (hazard ratio for death 0·534, 95% CI 0·298–0·956, p=0·035; median survival 9·3 months for patients without L858R mutation and 22·0 months for patients with the mutation). Furthermore, we found an association between smoking history and the presence of the L858R mutation by Spearman’s rank correlation test. Significantly fewer smokers than non-smokers had L858R mutations (p=0·01). There was no significant association between smoking history and the presence of deletions in exon 19 (p=0·208). Multiple regression analysis has shown that smoking is an independent variable responsible for overexpression of aldoketo reductase family 1, member B10 (AKR1B10) in NSCLC (p0·01).5 Therefore, the L858R mutation in NSCLC might be controlled by overexpression of the aldo-keto reductase family protein AKR1B10 caused by smoking. This hypothesis should be investigated to accelerate the development of new treatment strategies for NSCLC worldwide. This study was supported by the Program of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, the Focus 21 project of the New Energy and Industrial Technology Development Organization, and the Special Coordination Fund for Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology. We declare that we have no conflict of interest.
Rights were not granted to include this image in electronic media. Please refer to the printed journal
*Hisashi Moriguchi, Tae-You Kim, Chifumi Sato [email protected] Division of Decision Analysis and Technology Assessment in Health and Medicine, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan (HM); Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea (T-YK); and Tokyo Medical and Dental University, Tokyo, Japan (CS) 1
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell
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Correspondence
Correspondence
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3
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AP
Rights were not granted to include this image in electronic media. Please refer to the printed journal
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lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005; 23: 2493–501. Zhang XT, Li LY, Mu XL, et al. The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol 2005; 16: 1334–42. Chou TY, Chiu CH, Li LH, et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 2005; 11: 3750–57. Fukumoto S, Yamauchi N, Moriguchi H, et al. Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers’ non-small cell lung carcinomas. Clin Cancer Res 2005; 11: 1776–85.
Nick Thatcher and colleagues1 report that gefitinib, an epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor, failed to prolong survival in patients with non-small-cell lung cancer (NSCLC) in the Iressa Survival Evaluation in Lung Cancer study, despite promising results in phase II studies with gefitinib. Previously, Shepherd and colleagues2 reported in their BR21 study that erlotinib, an EGFR inhibitor structurally related to gefitinib, prolongs survival in previously treated NSCLC compared with placebo.2 That was the only study to have shown survival benefit of an EGFR inhibitor in patients with NSCLC. In both studies, subgroup analysis identified subsets of patients who responded well to EGFR inhibitors, namely never-smokers, women, and Asian patients.1,3 We postulate that there could be a subset of responders who might have longer survival irrespective of intervention, which might have contributed to the disparate survival benefits of gefitinib and erlotinib. In a small, exploratory study of Icelandic patients with bronchioloalveolar carcinoma, eight never-smokers had improved survival compared with 23 smokers, without use of an EGFR inhibitor. Bronchioloalveolar carcinoma is a distinct category of NSCLC that mostly affects never-smokers and
Asians. Moreover, patients with bronchioloalveolar carcinoma have a less severe clinical course than those with other types of NSCLC.4 Since BR21 did not prospectively stratify patients according to smoking status nor to whether or not they had bronchioloalveolar carcinoma, and since Thatcher and colleagues grouped the results of patients with bronchioloalveolar carcinoma with those of patients with adenocarcinoma, it is possible that disproportional enrolment of patients with bronchioloalveolar carcinoma could have contributed to the varying efficacies of EGFR inhibitors in NSCLC patients. For example, Thatcher and colleagues’ study describes 5% of patients as having bronchioloalveolar carcinoma, and about 20% of patients in each group of BR21 were categorised as having NSCLC without further classification. Overrepresentation of never-smokers with bronchioloalveolar carcinoma in the erlotinib group of BR21 could have overestimated the benefit of erlotinib. Alternatively, over-representation of smokers with bronchioloalveolar carcinoma in the gefitinib group in Thatcher and colleagues’ study could have underestimated the efficacy of gefitinib. Thus, we propose that prospective, randomised studies comparing EGFR inhibitors with placebo in neversmokers with bronchioloalveolar carcinoma could be useful to better define the therapeutic advantage conferred by such drugs in this subgroup of patients with NSCLC. Stratification of bronchioloalveolar carcinoma patients by smoking status should be considered to facilitate further development of drugs against EGFR. We declare that we have no conflict of interest.
Junji Tsurutani, Marc Ballas, Seth M Steinberg, Valgardur Egilsson, *Phillip A Dennis [email protected] Cancer Therapeutics Branch (JT, MB, PAD) and Biostatistics and Data Management Section (SMS), Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, USA; and Department of Pathology, National University Hospital, Reykjavik, Iceland (VE)
1
2
3
4
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-smallcell lung cancer. N Engl J Med 2005; 353: 123–32. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44. Breathnach OS, Ishibe N, Williams J, et al. Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung. Cancer 1999; 86: 1165–73.
Internet-based eye care As recognised by Sajeesh Kumar and Kanagasingam Yogesan (Oct 8, p 3244),1 some of the obstacles to the expansion of teleophthalmology are organisational not technological. However, other issues also need to be considered. Clinicians who provide the input (diagnosis, advice on clinical management or on improving clinical or surgical skills) need to be (1) fully aware of the competencies and resources of the local providers, (2) experts in the disorders likely to be found in the catchment population, and (3) able to understand what is affordable and acceptable to patients. Deficiencies in any of these areas can result in inappropriate advice, or input that cannot be implemented. Perhaps this gives a clue to what is probably the major obstacle to the widespread use of telemedicine, and specifically teleophthalmology: the lack of compelling evidence—medical and economic—that its use will improve routine medical care in a cost-effective way that cannot otherwise be provided. This problem is particularly pertinent to low-income and middle-income countries where sparse resources must be used wisely. Screening via teleophthalmology could represent a different challenge and an opportunity. Preterm babies are at risk of developing the potentially blinding disorder retinopathy of prematurity (ROP). Owing to high levels of www.thelancet.com Vol 367 January 28, 2006
most important factor that led to an increased risk of exposure. We are familiar with the fall in anthrax cases after 1970, to which Pennington refers. However, imports of raw materials still amounted to tens of thousands of tonnes per year in the 1970s, and the fall in anthrax is mainly attributable to improvements in feed manufacturing practices after a scheme introduced by the UK Ministry of Agriculture, Fisheries, and Food: this scheme involved voluntary labelling of imported bonemeal to indicate that it had not been sterilised and should not be incorporated in the raw state into animal feed. Sterilisation processes needed to inactivate anthrax would not remove TSE infectivity, and a substantial risk of human TSE transmission will have persisted throughout the period when the first BSE cases are likely to have occurred. We declare that we have no conflict of interest.
*Alan Colchester, Nancy Colchester [email protected] Kent Institute of Medicine and Health Sciences, University of Kent, Canterbury CT2 7PD, UK (AC); and College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK (NC)
Gefitinib for refractory advanced non-small-cell lung cancer Nick Thatcher and colleagues (Oct 29, p 1527)1 indicate that the association between epidermal growth factor receptor (EGFR) mutation status and survival after gefitinib treatment in patients with non-small-cell lung cancer (NSCLC) is unclear. We used individual patients’ data (n=135) and Cox’s proportional hazard models to investigate factors contributing to the increase in survival seen in Asian patients with refractory advanced NSCLC in gefitinib trials.2–4 The multivariate analysis with clinical variables of sex, histology, smoking history, presence of deletions in exon 19, and presence of the L858R mutation in exon 21 of EGFR showed the following to
be contributing factors to the increase in overall survival: smoking history (hazard ratio for death 0·523, 95% CI 0·306–0·893, p=0·018; median survival 7·4 months for smokers and 24·3 months for never-smokers) and the presence of the L858R mutation (hazard ratio for death 0·534, 95% CI 0·298–0·956, p=0·035; median survival 9·3 months for patients without L858R mutation and 22·0 months for patients with the mutation). Furthermore, we found an association between smoking history and the presence of the L858R mutation by Spearman’s rank correlation test. Significantly fewer smokers than non-smokers had L858R mutations (p=0·01). There was no significant association between smoking history and the presence of deletions in exon 19 (p=0·208). Multiple regression analysis has shown that smoking is an independent variable responsible for overexpression of aldoketo reductase family 1, member B10 (AKR1B10) in NSCLC (p0·01).5 Therefore, the L858R mutation in NSCLC might be controlled by overexpression of the aldo-keto reductase family protein AKR1B10 caused by smoking. This hypothesis should be investigated to accelerate the development of new treatment strategies for NSCLC worldwide. This study was supported by the Program of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, the Focus 21 project of the New Energy and Industrial Technology Development Organization, and the Special Coordination Fund for Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology. We declare that we have no conflict of interest.
Rights were not granted to include this image in electronic media. Please refer to the printed journal
*Hisashi Moriguchi, Tae-You Kim, Chifumi Sato [email protected] Division of Decision Analysis and Technology Assessment in Health and Medicine, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan (HM); Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea (T-YK); and Tokyo Medical and Dental University, Tokyo, Japan (CS) 1
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell
299
Science Photo Library
Correspondence
Correspondence
2
3
4
5
AP
Rights were not granted to include this image in electronic media. Please refer to the printed journal
300
lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005; 23: 2493–501. Zhang XT, Li LY, Mu XL, et al. The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol 2005; 16: 1334–42. Chou TY, Chiu CH, Li LH, et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 2005; 11: 3750–57. Fukumoto S, Yamauchi N, Moriguchi H, et al. Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers’ non-small cell lung carcinomas. Clin Cancer Res 2005; 11: 1776–85.
Nick Thatcher and colleagues1 report that gefitinib, an epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor, failed to prolong survival in patients with non-small-cell lung cancer (NSCLC) in the Iressa Survival Evaluation in Lung Cancer study, despite promising results in phase II studies with gefitinib. Previously, Shepherd and colleagues2 reported in their BR21 study that erlotinib, an EGFR inhibitor structurally related to gefitinib, prolongs survival in previously treated NSCLC compared with placebo.2 That was the only study to have shown survival benefit of an EGFR inhibitor in patients with NSCLC. In both studies, subgroup analysis identified subsets of patients who responded well to EGFR inhibitors, namely never-smokers, women, and Asian patients.1,3 We postulate that there could be a subset of responders who might have longer survival irrespective of intervention, which might have contributed to the disparate survival benefits of gefitinib and erlotinib. In a small, exploratory study of Icelandic patients with bronchioloalveolar carcinoma, eight never-smokers had improved survival compared with 23 smokers, without use of an EGFR inhibitor. Bronchioloalveolar carcinoma is a distinct category of NSCLC that mostly affects never-smokers and
Asians. Moreover, patients with bronchioloalveolar carcinoma have a less severe clinical course than those with other types of NSCLC.4 Since BR21 did not prospectively stratify patients according to smoking status nor to whether or not they had bronchioloalveolar carcinoma, and since Thatcher and colleagues grouped the results of patients with bronchioloalveolar carcinoma with those of patients with adenocarcinoma, it is possible that disproportional enrolment of patients with bronchioloalveolar carcinoma could have contributed to the varying efficacies of EGFR inhibitors in NSCLC patients. For example, Thatcher and colleagues’ study describes 5% of patients as having bronchioloalveolar carcinoma, and about 20% of patients in each group of BR21 were categorised as having NSCLC without further classification. Overrepresentation of never-smokers with bronchioloalveolar carcinoma in the erlotinib group of BR21 could have overestimated the benefit of erlotinib. Alternatively, over-representation of smokers with bronchioloalveolar carcinoma in the gefitinib group in Thatcher and colleagues’ study could have underestimated the efficacy of gefitinib. Thus, we propose that prospective, randomised studies comparing EGFR inhibitors with placebo in neversmokers with bronchioloalveolar carcinoma could be useful to better define the therapeutic advantage conferred by such drugs in this subgroup of patients with NSCLC. Stratification of bronchioloalveolar carcinoma patients by smoking status should be considered to facilitate further development of drugs against EGFR. We declare that we have no conflict of interest.
Junji Tsurutani, Marc Ballas, Seth M Steinberg, Valgardur Egilsson, *Phillip A Dennis [email protected] Cancer Therapeutics Branch (JT, MB, PAD) and Biostatistics and Data Management Section (SMS), Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, USA; and Department of Pathology, National University Hospital, Reykjavik, Iceland (VE)
1
2
3
4
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-smallcell lung cancer. N Engl J Med 2005; 353: 123–32. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44. Breathnach OS, Ishibe N, Williams J, et al. Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung. Cancer 1999; 86: 1165–73.
Internet-based eye care As recognised by Sajeesh Kumar and Kanagasingam Yogesan (Oct 8, p 3244),1 some of the obstacles to the expansion of teleophthalmology are organisational not technological. However, other issues also need to be considered. Clinicians who provide the input (diagnosis, advice on clinical management or on improving clinical or surgical skills) need to be (1) fully aware of the competencies and resources of the local providers, (2) experts in the disorders likely to be found in the catchment population, and (3) able to understand what is affordable and acceptable to patients. Deficiencies in any of these areas can result in inappropriate advice, or input that cannot be implemented. Perhaps this gives a clue to what is probably the major obstacle to the widespread use of telemedicine, and specifically teleophthalmology: the lack of compelling evidence—medical and economic—that its use will improve routine medical care in a cost-effective way that cannot otherwise be provided. This problem is particularly pertinent to low-income and middle-income countries where sparse resources must be used wisely. Screening via teleophthalmology could represent a different challenge and an opportunity. Preterm babies are at risk of developing the potentially blinding disorder retinopathy of prematurity (ROP). Owing to high levels of www.thelancet.com Vol 367 January 28, 2006