1 Department of Medicine II, Okayama University Medical School, Okayama; 2 Division of Epidemiology and Prevention, Aichi Cancer Centre Research Institute, Nagoya; 3 Department of Medicine, Chugoku Central Hospital, Fukuyama; 4 Department of Respiratory Medicine, Okayama Rousai Hospital, Okayama; 5 Department of Respiratory Medicine, National Hospital Organisation Okayama Medical Centre, Okayama; 6 Department of Medicine, National Hospital Organisation Shikoku Cancer Centre, Matsuyama, Japan
* Correspondence to: Dr K. Hotta, Department of Medicine II, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama, 700-8558, Japan. Tel: +81-86-235-7227; Fax: +81-86-232-8226; E-mail: khotta{at}md.okayama-u.ac.jp
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Abstract |
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Patients and methods: We reviewed the clinical records of 365 Japanese patients with NSCLC who received gefitinib (250 mg/day).
Results: Of 324 (89%) patients assessable for response, 147 (45%) obtained disease stabilisation and 71 (22%) patients achieved an objective response. Overall survival in patients obtaining disease stabilisation was significantly longer than in patients with progressive disease (median survival time 12.1 versus 4.4 months; P <0.0001). In patients obtaining disease stabilisation, those who continued gefitinib treatment until disease progression tended to have longer overall and progression-free survival compared with those discontinuing gefitinib treatment (1-year survival rate 52.1% versus 36.6%, P = 0.08; 1-year progression-free survival rate 31.8% versus 5.2%, P = 0.001). Multivariate analysis showed discontinuing gefitinib was an independent risk factor for progression-free survival (hazard ratio 1.66; 95% confidence interval 1.072.56; P = 0.022) but not for overall survival.
Conclusions: Our findings indicate the importance of achieving disease stabilisation with gefitinib treatment and continued gefitinib treatment in Japanese patients with disease stabilisation, although further studies are required to confirm these findings.
Key words: disease stabilisation, gefitinib, non-small-cell lung cancer, survival
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Introduction |
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In spite of the promising results in earlier studies [49
], a recent phase III trial failed to demonstrate the survival benefit of gefitinib over best supportive care alone in relapsed patients with NSCLC [10
]. In the subgroup analysis, patients of Oriental origin showed a survival benefit of gefitinib. Of these, those who obtained objective responses might especially benefit from gefitinib treatment in terms of survival. However, there have been no reports investigating the prognosis of patients obtaining disease stabilisation with gefitinib treatment. Furthermore, the impact of continued gefinitib treatment until obvious disease progression on survival has not been fully evaluated in patients who have obtained disease stabilisation. The aims of this retrospective investigation are (i) to investigate the survival outcome of Japanese patients with NSCLC who achieved disease stabilisation with gefitinib treatment compared with patients whose disease progressed, and (ii) to clarify effect of continued usage of gefitinib on prognosis in patients obtaining disease stabilisation.
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Patients and methods |
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Response and toxicity assessment
Tumour response was assessed as complete response (CR), partial response (PR), no change (NC; disease stabilisation) or progressive disease (PD) according to the World Health Organisation (WHO) criteria [11]. CR was defined as the disappearance of disease at all sites, and PR was defined as a reduction of at least 50% in the sum of the products of the two largest perpendicular diameters of all measurable lesions, without progression in any other sites. NC was defined as a decrease of <50% or an increase of <25% in the sum of the products of the two largest perpendicular diameters of all measurable lesions for at least 4 weeks. PD was defined as an increase of
25% in the sum of the products of the two largest perpendicular diameters of all measurable lesions or the appearance of a new lesion. Tumour markers were not used to assess response. The first assessment of tumour response was generally performed 4 weeks after initiation of treatment. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
Statistics
Statistical analyses were conducted with the STATA version 8 software (College Station, TX, USA). Overall survival time was defined as the duration from initiation of gefitinib treatment to the time of death from any cause or to the date the patient was last known to be alive. Progression-free survival time was defined as duration from initiation of gefitinib treatment until the day of documented relapse. Overall and progression-free survival curves were constructed using the KaplanMeier product-limit method. Differences between KaplanMeier curves were evaluated by log-rank test. To evaluate the impact of continued gefitinib usage on survival, gefinitib usage was treated as a time-dependent covariate throughout the analyses [12]. Observed survival time for patients who discontinued gefitinib due to any reason other than PD were divided into two periods: on drug and off drug. A landmark method [13
] was applied at 2-month time point from initiation of gefinitib in non-adjusted analysis as described in a previous report [14
]. Proportional hazard regression models were applied to evaluate potential impact of confounders (age, stage, histology, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, prior thoracic radiotherapy, prior chemotherapy and continued gefitinb treatment). Multivariate models were built using forward/backward stepwise method using threshold P value for entering and removing from the model as 0.15 and 0.20, respectively. The association between clinicopathological factors and response to gefitinib was evaluated by
2-test. P values <0.05 were considered statistically significant.
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Results |
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Discussion |
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The survival impact of disease stabilisation during treatment with molecular targeted drugs has aroused a great deal of interest. In a randomised phase III study comparing erlotinib with placebo in patients with relapsed NSCLC, a significant survival benefit was demonstrated with erlotinib treatment compared with placebo [15]. Furthermore, subgroup analysis in patients who did not obtain objective response demonstrated that those treated with erlotinib had longer survival compared with those receiving placebo [15
]. Our results suggest that patients obtaining disease stabilisation with gefitinib also have longer survival compared with those having PD. However, to the best of our knowledge there have been no previous reports demonstrating this effect with gefitinib treatment. Accordingly, further confirmation of these data is warranted.
There have been no definitive data regarding the impact of continued gefinitib treatment on survival in patients obtaining disease stabilisation. In addition, optimal duration of gefitinib treatment still remains an issue of debate. Effectiveness of continued treatment with cytotoxic agents in patients who achieved disease stablisation has not been verified. In a phase III trial conducted in the UK, 308 patients were allocated to receive either three or six cycles of a combination of mitomycin, vinblastine and cisplatin [16]. Since the majority of patients failed to have a major response, or became intolerant of chemotherapy by the third or fourth cycle, survival and response rates were similar in both groups. Thus, effectiveness of maintenance chemotherapy has not yet been established, and current guidelines from the American Society of Clinical Oncology recommend that stopping chemotherapy after three to four cycles in patients who are not responding to chemotherapy is quite reasonable [17
].
In our study, both uni- and multivariate analysis revealed that continued gefitinib treatment after disease stabilisation had a significant impact on progression-free survival but not on overall survival. To our knowledge, this is the first report demonstrating the benefit of continued gefitinib treatment. Our results indicate that prognosis may be improved without any excessive toxicities when gefitinib treatment is continued until disease progression compared with discontinuation before disease progression. As gefitinib has a mechanism of action distinct from conventional cytotoxic agents [18], survival impact of continued treatment of gefitinib may differ from cytotoxic agents.
The recent Iressa Survival Evaluation in Lung cancer (ISEL) trial was conducted to compare gefitinib monotherapy with best supportive care alone in patients with advanced NSCLC who had failed one or more lines of chemotherapy. This trial showed no overall survival benefit; however, it also suggested that patients of Oriental origin have survival benefit of gefitinib according to a subgroup analysis [10]. Additionally, the activity of gefitinib differed between Japanese and non-Japanese patients in the phase II monotherapy trial [4
]. Thus, the effectiveness of continued gefitinib treatment on survival in our Japanese cohort might also be influenced by ethnic difference. However, even if this is so, it is unlikely to be associated with the ethnic difference in incidence of EGFR mutations, since the incidence of EGFR mutations is itself rare in NSCLC patients with NC or PD [19
]. As another major limitation, our analysis was based on a retrospective review with an unplanned analysis. Reasons for not continuing on therapy are not necessarily equally or randomly distributed among patients with disease stabilisation. Another problem was the lack of a uniform procedure for patient follow-up. Thus, our conclusions should be interpreted cautiously, although our results raise a critical point that needs to be evaluated in future studies.
Several clinical studies have demonstrated a certain correlation between efficacy of tyrosine kinase inhibitors and skin toxicity in patients with NSCLC [20]. However, we failed to find its positive association; those who received continuous gefitinib treatment did not develop skin rash more frequently, in spite of their significant survival advantage, compared with those who discontinued gefitinib before disease progression. Additionally, there was no association between efficacy and skin toxicity in the IDEAL trials [4
, 5
]. All these observation suggest that this issue is still controversial.
We used the WHO response criteria through this analysis, although new guidelines for evaluating tumour response, the Response Evaluation Criteria in Solid Tumours (RECIST) guidelines, have been recently adopted by many organisations. Watanabe et al. [21] showed that there is no difference between the RECIST guidelines and WHO response criteria in terms of validity in relation to tumour volume and inter-criteria reproducibility in NSCLC patients. Therefore, we consider that our results may be consistent if RECIST guidelines are applied to our analysis.
In conclusion, our data suggest that both overall and progression-free survival in patients obtaining disease stabilisation are significantly better than those with PD. In addition, survival is better in patients receiving gefitinib until disease progression than those who discontinued the treatment before disease progression. Further investigation is needed to confirm the importance of obtaining disease stabilisation and continued gefitinib treatment on survival.
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Acknowledgements |
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Notes |
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Received for publication March 16, 2005. Revision received July 4, 2005. Accepted for publication July 14, 2005.
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References |
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