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Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience
Original article
Annals of Oncology 16: 1817–1823, 2005 doi:10.1093/annonc/mdi369 Published online 12 September 2005
Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience K. Hotta1*, K. Matsuo2, H. Ueoka1, K. Kiura1, M. Tabata1, S. Harita3, K. Gemba4, T. Yonei5, A. Bessho6 & M. Tanimoto1 1
Received 16 March 2005; revised 4 July 2005; accepted 14 July 2005
Background: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis. 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 1.07–2.56; 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
Introduction The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because it is frequently expressed in a variety of tumours including non-small-cell lung cancer (NSCLC) [1], and elevated serum levels of EGFR have been associated with a poor prognosis [2]. Gefitinib is an orally active EGFR tyrosine kinase inhibitor [3]. Two large phase II clinical trials of gefitinib in patients with advanced NSCLC showed promising results, with objective response rates of 12% and 18.4%, median survival times of 7 and 7.6 months, and 1-year survival rates of 27% and 35%, respectively [4, 5].
*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: [email protected] K. Hotta and K. Matsuo contributed equally to this work. Ó 2005 European Society for Medical Oncology
In spite of the promising results in earlier studies [4–9], 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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Department of Medicine II, Okayama University Medical School, Okayama; 2Division of Epidemiology and Prevention, Aichi Cancer Centre Research Institute, Nagoya; 3Department of Medicine, Chugoku Central Hospital, Fukuyama; 4Department of Respiratory Medicine, Okayama Rousai Hospital, Okayama; 5Department of Respiratory Medicine, National Hospital Organisation Okayama Medical Centre, Okayama; 6Department of Medicine, National Hospital Organisation Shikoku Cancer Centre, Matsuyama, Japan
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Patients and methods Patients and gefitinib treatment
Results Characteristics of 324 patients and efficacy of gefitinib Table 1 summarises the characteristics of the 324 patients. Of these, 147 [45.4%; 95% confidence interval (CI) 39.9% to 51%] patients obtained disease stabilisation, whereas CR, PR and PD were observed in one (0.3%), 70 (21.6%) and 106
Table 1. Demographics of 324 patients Characteristic Age, years Median (range)
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.
n (%)
67 (29–92)
Gender Male
218 (67)
Female
106 (33)
ECOG PS 0–1
211 (65)
2–4
113 (35)
Histology Adenocarcinoma Squamous cell carcinoma Bronchioloalveolar carcinoma
241 (74) 56 (17) 5 (2)
Large cell carcinoma
5 (2)
Adenocarcinoma/squamous cell carcinoma
4 (1)
Others
13 (4)
Stage
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 Kaplan–Meier product-limit method. Differences between Kaplan–Meier 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
I
9 (3)
II
2 (1)
III
70 (22)
IV
179 (55)
Postoperative recurrence
64 (20)
Smoking history Yes
203 (63)
No
117 (36)
Unknown
4 (1)
Prior chemotherapy Yes
275 (85)
No
49 (15)
No. of prior chemotherapy regimens [median (range)]
1 (0–7)
Prior thoracic irradiation Yes
87 (27)
No
237 (73)
ECOG PS, Eastern Cooperative Oncology Group performance status.
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Between November 2000 and October 2003, a total of 365 Japanese patients with NSCLC were treated with gefitinib (250 mg once daily oral administration) in 12 institutions in the western part of Japan. Individual reports of patient characteristics and their detailed clinical course with gefitinib treatment were gathered from these 12 affiliate institutions of the Okayama Lung Cancer Study Group. Fifteen patients were excluded from the analysis, as they were transferred to other hospitals after the first prescription of gefitinib and the details of their treatment course were not available. Additionally, since response evaluation could not be performed in 26 patients, these patients were excluded from this analysis. Of 26 patients, 13 had early death, eight were lost to follow-up, two concurrently received other chemotherapeutic agents or radiation therapy, two did not have any evaluable lesion and one discontinued gefitinib treatment early because of patient’s refusal. Thus, a total of 324 patients were included in the analysis. Written informed consent was obtained from each patient before gefitinib treatment. In the majority of patients, gefitinib treatment was continued as long as possible until disease progression, development of unacceptable toxicity or patient’s refusal to continue treatment.
and 0.20, respectively. The association between clinicopathological factors and response to gefitinib was evaluated by v2-test. P values <0.05 were considered statistically significant.
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Table 2. Association between clinicopathological factors and response to gefitinib in 324 patients Total
CR/PR [n (%)]
NC [n (%)]
PD [n (%)]
241
61 (86)
106 (72)
74 (70)
83
10 (14)
41 (28)
32 (30)
Female
106
45 (63)
45 (31)
16 (15)
Male
218
26 (37)
102 (69)
90 (85)
Tumour histology Adenocarcinoma Others Gender
Smoking historya Yes
203
25 (36)
99 (68)
79 (75)
No
117
44 (64)
47 (32)
26 (25)
v2
P
6.517
0.038
45.5771
<0.001
29.525
<0.001
a
Smoking history was unknown in four patients. CR, complete response; PR, partial response; NC, no change (disease stabilisation); PD, progressive disease.
(32.7%) patients, respectively. Figure 1 displays overall survival stratified by response to gefitinib in a landmark analysis of patients alive at 2 months after commencing treatment. Median follow-up time of surviving patients was 11.8 months (range 2– 35.3). There was a significant difference in survival among patients achieving CR or PR (median not reached), NC (median 12.1 months), and PD (median 4.4 months) (P < 0.0001). A significant difference was also observed in progression-free survival (CR or PR: median 23.9 months; NC: median 5.4 months; and not available for PD; P < 0.0001; Figure 1). The influence of several clinicopathological factors on gefitinib sensitivity was also evaluated (Table 2). Adenocarcinoma histology affected the achievement in CR/PR more strongly than in NC or PD (proportion of adenocarcinoma histology was 86%, 72% and 70% in those with CR/PR, NC and PD). Proportions of other
two factors, gender and smoking history, also varied in association with the three response categories.
Characteristics and prognosis of patients obtaining disease stabilisation We focused on the 147 patients achieving disease stabilisation on gefitinib, in order to clarify their characteristics and prognosis. Table 3 lists the patient demographics of the 147 patients according to the duration of gefitinib treatment. Gefitinib treatment was discontinued before disease progression in 54 (37%) patients. In 30 patients discontinuation was due to adverse events (interstitial lung disease, eight patients; infection, seven; skin rash, five; nausea/vomiting, four; hepatotoxicity, three; diarrhoea, two; and fever, one), while 13 patients, discontinuation
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Figure 1. Survival stratified by response status in 324 patients receiving gefitinib treatment. (A) Overall survival (log-rank test P <0.0001). (B) Progressionfree survival (log-rank test; P <0.0001). CR, complete response; PR, partial response; NC, no change (disease stabilisation); PD, progressive disease.
1820 Table 3. Demographics of 147 patients who obtained disease stabilisation Early treatment discontinuation before PD [n (%)]
Continuous treatment until PD [n (%)]
54
93a
Age, years [median (range)]
69 (36–86)
65 (33–92)
Male
38 (70)
64 (69)
Female
16 (30)
29 (31)
0–1
31 (57)
76 (82)
2–4
23 (43)
17 (18)
Gender
ECOG PS
Histology Adenocarcinoma
36 (67)
70 (75)
Squamous cell carcinoma
13 (24)
17 (18)
Bronchioloalveolar carcinoma
1 (2)
1 (1)
Large cell carcinoma
1 (2)
2 (2)
Others
3 (5)
3 (4)
I
3 (6)
3 (3)
II
0
1 (1)
Stage
III
12 (21)
26 (28)
IV
27 (50)
41 (44)
Postoperative recurrence
12 (22)
22 (24)
Smoking history Yes
37 (69)
62 (67)
No
17 (31)
30 (33)b
Yes
47 (87)
76 (82)
No
7 (13)
17 (18)
No. of prior chemotherapy regimens [median (range)]
1 (0–5)
Prior chemotherapy
1 (0–7)
Prior thoracic irradiation Yes
22 (41)
29 (31)
No
32 (59)
64 (69)
Treatment duration, days [median (range)]
42 (5–287)
114 (37–651)
a
Sixty (64%) of 93 patients were treated until disease progression, whereas the remaining patients were still receiving gefitinib at the time of this analysis without any disease progression. b Smoking history was unknown in one patient. PD, progressive disease; ECOG PS, Eastern Cooperative Oncology Group performance status.
was due to patient’s refusal (six patients), elevation of serum tumour markers (five), detection of a second primary tumour (one) and intestinal perforation (one). Eleven patients discontinued treatment for unknown reason. Overall and progressionfree survival were longer in patients receiving gefitinib until
Discussion In this retrospective investigation, we demonstrated that (i) both overall and progression-free survival in patients obtaining NC (disease stabilisation) with gefitinib treatment were significantly longer than those in patients with PD, and (ii) overall and progression-free survival in patients with disease stabilisation receiving gefitinib until disease progression were better than those who discontinued gefitinib prior to disease progression. A benefit of continued gefitinib treatment was more evident for progression-free survival. 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
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No. of patients
disease progression than those who discontinued the treatment before disease progression. The median overall survival was 13.7 versus 7.2 months, respectively, and median progressionfree survival was 4.5 versus 3.3 months, respectively (Figure 2). These differences were marginally significant for overall survival (P = 0.080) and significant for progression-free survival (P = 0.0014). To rule out potential confounding between gefitinib administration and other factors, we conducted uni- and multivariate analysis for overall and progression-free survival (Tables 4 and 5). For overall survival, continued gefitinib treatment showed decreased risk with marginal significance [hazard ratio (HR) 0.64; 95% CI 0.39–1.06], and this was attenuated in multivariate analysis. Past smoking history and ECOG performance status showed statistically significant association in both uniand multivariate analysis. Continued gefitinib treatment showed significantly reduced risk for progression-free survival in uniand multivariate analysis. The HR in the multivariate analysis was 0.60 (95% CI 0.39–0.93; P = 0.022). Past smoking and ECOG performance status at diagnosis similarly showed strong association for progression-free survival. Regarding adverse events, continued gefitinib treatment did not significantly increase any adverse events including skin rash, diarrhoea, nausea/vomiting, liver injury, infection and interstitial lung disease.
1821
Table 4. Uni- and multivariate analysis for progression-free survival in patients who obtained disease stabilisation Univariate analysis
Multivariate analysis
HR (95% CI)
P
HR (95% CI)
P
Yes
0.51 (0.78–1.06)
0.002
0.60 (0.39–0.93)
0.022
No
1
Continued gefitinib treatment
1
ECOG PS 2–4
1.90 (1.22–2.94)
0–1
1
0.004
1.89 (1.20–2.98)
0.006
1
Smoking history Yes
1.87 (1.15–3.04)
No
1
0.011
1.98 (1.21–3.25)
0.007
1
Disease stage IV
0.79 (0.53–1.19)
Others
1
0.268
0.72 (0.48–1.10) 1
Prior chemotherapy Yes
1.27 (0.69–2.32)
No
1
0.446
Excluded
0.298
Excluded
0.040
Excluded
0.969
Excluded
Prior thoracic irradiation Yes
1.25 (0.82–1.90)
No
1
Histology Adenocarcinoma
0.63 (0.40–0.98)
Others
1
Age ‡75 years
1.01 (0.62–1.63)
<75 years
1
Multivariate model was constructed using forward stepwise methods. Threshold P values for entering and removing from the model were 0.15 and 0.20, respectively. HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
0.131
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Figure 2. Survival stratified by continuation of gefitinib in 147 patients obtaining disease stabilisation. (A) Overall survival (log-rank test, P = 0.080). (B) Progression-free survival (log-rank test, P = 0.0014).
1822 Table 5. Uni- and multivariate analysis for overall survival in patients who obtained disease stabilisation Univariate analysis HR (95% CI)
Multivariate analysis P
HR (95% CI)
P
Continued gefitinib treatment Yes
0.64 (0.39–1.06)
No
1
0.083
0.91 (0.53–1.54)
0.698
1
ECOG PS 2–4
2.17 (1.20–3.93)
0–1
1
0.011
2.44 (1.30–4.58)
0.006
1
Smoking history 3.61 (2.17–5.98)
No
1
<0.001
3.95 (2.32–6.71)
<0.001
1
Disease stage IV
0.87 (0.53–1.41)
Others
1
0.563
0.66 (0.39–1.11)
0.117
1
Prior chemotherapy Yes
1.95 (0.84–4.53)
No
1
0.118
1.96 (0.83–4.66)
0.126
1
Prior thoracic irradiation Yes
1.39 (0.85–2.28)
No
1
0.193
Excluded
0.300
Excluded
0.624
Excluded
Histology Adenocarcinoma
0.75 (0.43–1.30)
Others
1
Age ‡75 years
0.86 (0.47–1.58)
<75 years
1
Multivariate model was constructed using forward stepwise methods. Threshold P values for entering and removing from the model were 0.15 and 0.20, respectively. HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
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
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Yes
1823
Acknowledgements We wish to thank Drs Atsuko Ogino, Shigeki Umemura, Keiichi Fujiwara, Toshiyuki Kozuki, Toshiaki Okada, Akiko Hisamoto (Okayama University Medical School), Shoichi Kuyama (Chugoku Central Hospital), Yoshihiko Segawa, Naoyuki Nogami (National Shikoku Cancer Center Hospital), Tadashi Maeda, Keisuke Aoe, Hideki Katayama (National Sanyo Hospital), Tomonori Moritaka, Takushi Kitajima (Ehime Prefectural Central Hospital), Keisuke Sugimoto (National Fukuyama Hospital), Takuo Shibayama, Nagio Takigawa (National MinamiOkayama Hospital), Keisuke Matsuo, (Okayama Red-Cross Hospital), Haruhito Kamei (Sumitomo Besshi Hospital) and Hiroaki Miyamoto (Okayama City Hospital) for their support, data provision and comments on the analysis.
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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.
Annals of Oncology 16: 1817–1823, 2005 doi:10.1093/annonc/mdi369 Published online 12 September 2005
Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience K. Hotta1*, K. Matsuo2, H. Ueoka1, K. Kiura1, M. Tabata1, S. Harita3, K. Gemba4, T. Yonei5, A. Bessho6 & M. Tanimoto1 1
Received 16 March 2005; revised 4 July 2005; accepted 14 July 2005
Background: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis. 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 1.07–2.56; 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
Introduction The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because it is frequently expressed in a variety of tumours including non-small-cell lung cancer (NSCLC) [1], and elevated serum levels of EGFR have been associated with a poor prognosis [2]. Gefitinib is an orally active EGFR tyrosine kinase inhibitor [3]. Two large phase II clinical trials of gefitinib in patients with advanced NSCLC showed promising results, with objective response rates of 12% and 18.4%, median survival times of 7 and 7.6 months, and 1-year survival rates of 27% and 35%, respectively [4, 5].
*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: [email protected] K. Hotta and K. Matsuo contributed equally to this work. Ó 2005 European Society for Medical Oncology
In spite of the promising results in earlier studies [4–9], 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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Department of Medicine II, Okayama University Medical School, Okayama; 2Division of Epidemiology and Prevention, Aichi Cancer Centre Research Institute, Nagoya; 3Department of Medicine, Chugoku Central Hospital, Fukuyama; 4Department of Respiratory Medicine, Okayama Rousai Hospital, Okayama; 5Department of Respiratory Medicine, National Hospital Organisation Okayama Medical Centre, Okayama; 6Department of Medicine, National Hospital Organisation Shikoku Cancer Centre, Matsuyama, Japan
1818
Patients and methods Patients and gefitinib treatment
Results Characteristics of 324 patients and efficacy of gefitinib Table 1 summarises the characteristics of the 324 patients. Of these, 147 [45.4%; 95% confidence interval (CI) 39.9% to 51%] patients obtained disease stabilisation, whereas CR, PR and PD were observed in one (0.3%), 70 (21.6%) and 106
Table 1. Demographics of 324 patients Characteristic Age, years Median (range)
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.
n (%)
67 (29–92)
Gender Male
218 (67)
Female
106 (33)
ECOG PS 0–1
211 (65)
2–4
113 (35)
Histology Adenocarcinoma Squamous cell carcinoma Bronchioloalveolar carcinoma
241 (74) 56 (17) 5 (2)
Large cell carcinoma
5 (2)
Adenocarcinoma/squamous cell carcinoma
4 (1)
Others
13 (4)
Stage
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 Kaplan–Meier product-limit method. Differences between Kaplan–Meier 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
I
9 (3)
II
2 (1)
III
70 (22)
IV
179 (55)
Postoperative recurrence
64 (20)
Smoking history Yes
203 (63)
No
117 (36)
Unknown
4 (1)
Prior chemotherapy Yes
275 (85)
No
49 (15)
No. of prior chemotherapy regimens [median (range)]
1 (0–7)
Prior thoracic irradiation Yes
87 (27)
No
237 (73)
ECOG PS, Eastern Cooperative Oncology Group performance status.
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Between November 2000 and October 2003, a total of 365 Japanese patients with NSCLC were treated with gefitinib (250 mg once daily oral administration) in 12 institutions in the western part of Japan. Individual reports of patient characteristics and their detailed clinical course with gefitinib treatment were gathered from these 12 affiliate institutions of the Okayama Lung Cancer Study Group. Fifteen patients were excluded from the analysis, as they were transferred to other hospitals after the first prescription of gefitinib and the details of their treatment course were not available. Additionally, since response evaluation could not be performed in 26 patients, these patients were excluded from this analysis. Of 26 patients, 13 had early death, eight were lost to follow-up, two concurrently received other chemotherapeutic agents or radiation therapy, two did not have any evaluable lesion and one discontinued gefitinib treatment early because of patient’s refusal. Thus, a total of 324 patients were included in the analysis. Written informed consent was obtained from each patient before gefitinib treatment. In the majority of patients, gefitinib treatment was continued as long as possible until disease progression, development of unacceptable toxicity or patient’s refusal to continue treatment.
and 0.20, respectively. The association between clinicopathological factors and response to gefitinib was evaluated by v2-test. P values <0.05 were considered statistically significant.
1819
Table 2. Association between clinicopathological factors and response to gefitinib in 324 patients Total
CR/PR [n (%)]
NC [n (%)]
PD [n (%)]
241
61 (86)
106 (72)
74 (70)
83
10 (14)
41 (28)
32 (30)
Female
106
45 (63)
45 (31)
16 (15)
Male
218
26 (37)
102 (69)
90 (85)
Tumour histology Adenocarcinoma Others Gender
Smoking historya Yes
203
25 (36)
99 (68)
79 (75)
No
117
44 (64)
47 (32)
26 (25)
v2
P
6.517
0.038
45.5771
<0.001
29.525
<0.001
a
Smoking history was unknown in four patients. CR, complete response; PR, partial response; NC, no change (disease stabilisation); PD, progressive disease.
(32.7%) patients, respectively. Figure 1 displays overall survival stratified by response to gefitinib in a landmark analysis of patients alive at 2 months after commencing treatment. Median follow-up time of surviving patients was 11.8 months (range 2– 35.3). There was a significant difference in survival among patients achieving CR or PR (median not reached), NC (median 12.1 months), and PD (median 4.4 months) (P < 0.0001). A significant difference was also observed in progression-free survival (CR or PR: median 23.9 months; NC: median 5.4 months; and not available for PD; P < 0.0001; Figure 1). The influence of several clinicopathological factors on gefitinib sensitivity was also evaluated (Table 2). Adenocarcinoma histology affected the achievement in CR/PR more strongly than in NC or PD (proportion of adenocarcinoma histology was 86%, 72% and 70% in those with CR/PR, NC and PD). Proportions of other
two factors, gender and smoking history, also varied in association with the three response categories.
Characteristics and prognosis of patients obtaining disease stabilisation We focused on the 147 patients achieving disease stabilisation on gefitinib, in order to clarify their characteristics and prognosis. Table 3 lists the patient demographics of the 147 patients according to the duration of gefitinib treatment. Gefitinib treatment was discontinued before disease progression in 54 (37%) patients. In 30 patients discontinuation was due to adverse events (interstitial lung disease, eight patients; infection, seven; skin rash, five; nausea/vomiting, four; hepatotoxicity, three; diarrhoea, two; and fever, one), while 13 patients, discontinuation
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Figure 1. Survival stratified by response status in 324 patients receiving gefitinib treatment. (A) Overall survival (log-rank test P <0.0001). (B) Progressionfree survival (log-rank test; P <0.0001). CR, complete response; PR, partial response; NC, no change (disease stabilisation); PD, progressive disease.
1820 Table 3. Demographics of 147 patients who obtained disease stabilisation Early treatment discontinuation before PD [n (%)]
Continuous treatment until PD [n (%)]
54
93a
Age, years [median (range)]
69 (36–86)
65 (33–92)
Male
38 (70)
64 (69)
Female
16 (30)
29 (31)
0–1
31 (57)
76 (82)
2–4
23 (43)
17 (18)
Gender
ECOG PS
Histology Adenocarcinoma
36 (67)
70 (75)
Squamous cell carcinoma
13 (24)
17 (18)
Bronchioloalveolar carcinoma
1 (2)
1 (1)
Large cell carcinoma
1 (2)
2 (2)
Others
3 (5)
3 (4)
I
3 (6)
3 (3)
II
0
1 (1)
Stage
III
12 (21)
26 (28)
IV
27 (50)
41 (44)
Postoperative recurrence
12 (22)
22 (24)
Smoking history Yes
37 (69)
62 (67)
No
17 (31)
30 (33)b
Yes
47 (87)
76 (82)
No
7 (13)
17 (18)
No. of prior chemotherapy regimens [median (range)]
1 (0–5)
Prior chemotherapy
1 (0–7)
Prior thoracic irradiation Yes
22 (41)
29 (31)
No
32 (59)
64 (69)
Treatment duration, days [median (range)]
42 (5–287)
114 (37–651)
a
Sixty (64%) of 93 patients were treated until disease progression, whereas the remaining patients were still receiving gefitinib at the time of this analysis without any disease progression. b Smoking history was unknown in one patient. PD, progressive disease; ECOG PS, Eastern Cooperative Oncology Group performance status.
was due to patient’s refusal (six patients), elevation of serum tumour markers (five), detection of a second primary tumour (one) and intestinal perforation (one). Eleven patients discontinued treatment for unknown reason. Overall and progressionfree survival were longer in patients receiving gefitinib until
Discussion In this retrospective investigation, we demonstrated that (i) both overall and progression-free survival in patients obtaining NC (disease stabilisation) with gefitinib treatment were significantly longer than those in patients with PD, and (ii) overall and progression-free survival in patients with disease stabilisation receiving gefitinib until disease progression were better than those who discontinued gefitinib prior to disease progression. A benefit of continued gefitinib treatment was more evident for progression-free survival. 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
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No. of patients
disease progression than those who discontinued the treatment before disease progression. The median overall survival was 13.7 versus 7.2 months, respectively, and median progressionfree survival was 4.5 versus 3.3 months, respectively (Figure 2). These differences were marginally significant for overall survival (P = 0.080) and significant for progression-free survival (P = 0.0014). To rule out potential confounding between gefitinib administration and other factors, we conducted uni- and multivariate analysis for overall and progression-free survival (Tables 4 and 5). For overall survival, continued gefitinib treatment showed decreased risk with marginal significance [hazard ratio (HR) 0.64; 95% CI 0.39–1.06], and this was attenuated in multivariate analysis. Past smoking history and ECOG performance status showed statistically significant association in both uniand multivariate analysis. Continued gefitinib treatment showed significantly reduced risk for progression-free survival in uniand multivariate analysis. The HR in the multivariate analysis was 0.60 (95% CI 0.39–0.93; P = 0.022). Past smoking and ECOG performance status at diagnosis similarly showed strong association for progression-free survival. Regarding adverse events, continued gefitinib treatment did not significantly increase any adverse events including skin rash, diarrhoea, nausea/vomiting, liver injury, infection and interstitial lung disease.
1821
Table 4. Uni- and multivariate analysis for progression-free survival in patients who obtained disease stabilisation Univariate analysis
Multivariate analysis
HR (95% CI)
P
HR (95% CI)
P
Yes
0.51 (0.78–1.06)
0.002
0.60 (0.39–0.93)
0.022
No
1
Continued gefitinib treatment
1
ECOG PS 2–4
1.90 (1.22–2.94)
0–1
1
0.004
1.89 (1.20–2.98)
0.006
1
Smoking history Yes
1.87 (1.15–3.04)
No
1
0.011
1.98 (1.21–3.25)
0.007
1
Disease stage IV
0.79 (0.53–1.19)
Others
1
0.268
0.72 (0.48–1.10) 1
Prior chemotherapy Yes
1.27 (0.69–2.32)
No
1
0.446
Excluded
0.298
Excluded
0.040
Excluded
0.969
Excluded
Prior thoracic irradiation Yes
1.25 (0.82–1.90)
No
1
Histology Adenocarcinoma
0.63 (0.40–0.98)
Others
1
Age ‡75 years
1.01 (0.62–1.63)
<75 years
1
Multivariate model was constructed using forward stepwise methods. Threshold P values for entering and removing from the model were 0.15 and 0.20, respectively. HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
0.131
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Figure 2. Survival stratified by continuation of gefitinib in 147 patients obtaining disease stabilisation. (A) Overall survival (log-rank test, P = 0.080). (B) Progression-free survival (log-rank test, P = 0.0014).
1822 Table 5. Uni- and multivariate analysis for overall survival in patients who obtained disease stabilisation Univariate analysis HR (95% CI)
Multivariate analysis P
HR (95% CI)
P
Continued gefitinib treatment Yes
0.64 (0.39–1.06)
No
1
0.083
0.91 (0.53–1.54)
0.698
1
ECOG PS 2–4
2.17 (1.20–3.93)
0–1
1
0.011
2.44 (1.30–4.58)
0.006
1
Smoking history 3.61 (2.17–5.98)
No
1
<0.001
3.95 (2.32–6.71)
<0.001
1
Disease stage IV
0.87 (0.53–1.41)
Others
1
0.563
0.66 (0.39–1.11)
0.117
1
Prior chemotherapy Yes
1.95 (0.84–4.53)
No
1
0.118
1.96 (0.83–4.66)
0.126
1
Prior thoracic irradiation Yes
1.39 (0.85–2.28)
No
1
0.193
Excluded
0.300
Excluded
0.624
Excluded
Histology Adenocarcinoma
0.75 (0.43–1.30)
Others
1
Age ‡75 years
0.86 (0.47–1.58)
<75 years
1
Multivariate model was constructed using forward stepwise methods. Threshold P values for entering and removing from the model were 0.15 and 0.20, respectively. HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.
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
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Yes
1823
Acknowledgements We wish to thank Drs Atsuko Ogino, Shigeki Umemura, Keiichi Fujiwara, Toshiyuki Kozuki, Toshiaki Okada, Akiko Hisamoto (Okayama University Medical School), Shoichi Kuyama (Chugoku Central Hospital), Yoshihiko Segawa, Naoyuki Nogami (National Shikoku Cancer Center Hospital), Tadashi Maeda, Keisuke Aoe, Hideki Katayama (National Sanyo Hospital), Tomonori Moritaka, Takushi Kitajima (Ehime Prefectural Central Hospital), Keisuke Sugimoto (National Fukuyama Hospital), Takuo Shibayama, Nagio Takigawa (National MinamiOkayama Hospital), Keisuke Matsuo, (Okayama Red-Cross Hospital), Haruhito Kamei (Sumitomo Besshi Hospital) and Hiroaki Miyamoto (Okayama City Hospital) for their support, data provision and comments on the analysis.
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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.