1 Department of Oncology, Scientific Institute San Raffaele, Milan; 2 Division of Medical Oncology, Bellaria Hospital, Bologna, Italy
*Correspondence to: Dr G. L. Ceresoli, Department of Oncology, Scientific Institute San Raffaele, Via Olgettina, 60, 20123 Milano, Italy. Tel: +39-02-26432514; Fax: +39-02-26437625; Email: ceresoli.giovanni{at}hsr.it
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Abstract |
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Patients and methods: From January 2001 to May 2003, 41 consecutive NSCLC patients with measurable brain metastases were treated with gefitinib, given orally at daily dose of 250 mg. Thirty-seven patients had received previous chemotherapy and 18 patients had been treated previously with WBRT, completed at least 3 months before entering the trial.
Results: A partial response (PR) was observed in four patients (10%), with stable disease (SD) in seven cases, for an overall disease control (DC) rate (DC=PR+SD) of 27% (95% confidence interval 13% to 40%). Median duration of PR was 13.5 months. Median progression-free survival (PFS) of the whole population was 3 months. DC rate was higher in patients pre-treated with WBRT (P=0.05) and with adenocarcinoma histological type (P=0.08); adenocarcinoma patients had also a longer PFS (P=0.04). Toxicity was mild and consisted of grade 1/2 skin toxicity and diarrhoea, occurring in 24% and 10% of patients, respectively.
Conclusions: Gefitinib can be active on brain disease in NSCLC patients. Since the results of standard therapy for brain metastases in this clinical setting are particularly disappointing, gefitinib appears to be a possible new treatment option.
Key words: brain metastases, gefitinib, non-small-cell lung cancer
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Introduction |
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Brain metastases are usually associated with poor outcome, and treatment is palliative in most cases. Standard treatment options include symptomatic therapy with corticosteroids and whole-brain radiotherapy (WBRT), which lead to a median survival of 36 months [3]. Selected patients with a limited number of small lesions are candidates for surgery [4
] or stereotactic radiosurgery [5
]. Unfortunately, most patients with NSCLC metastatic to the brain either harbor or develop multiple lesions [1
].
Recent trials using platinum-based chemotherapy showed comparable response rates with intra-cranial and extra-cranial disease, suggesting that chemotherapy should be considered for patients with asymptomatic multiple brain metastases [6]. However, the efficacy of chemotherapy for the treatment of brain metastases is limited, and long-term survival remains disappointing [7
]. Although this is attributable to several factors, drug delivery to involved tissue is one of the most important issues. Penetration of chemotherapeutic drugs into the central nervous system (CNS) is limited primarily by the bloodbrain barrier (BBB) [8
].
Gefitinib (Iressa; AstraZeneca, London, UK), is an oral tyrosine kinase (TK) inhibitor of the epidermal growth factor receptor (EGFR). Phase I trials in patients with solid tumors refractory to standard chemotherapeutic agents have shown antitumor activity and good tolerability profile, with skin rash and diarrhea as dose-related toxicities [9, 10
]. Two large phase II studies conducted in pretreated patients affected by NSCLC achieved a response rate of 18.4% and 11.8%, respectively, and a symptomatic improvement in nearly 40% of cases [11
, 12
]. In all published trials, no data have been obtained on the activity of gefitinib on brain metastases. On the other hand, preclinical data [13
] and some initial case reports showing activity of gefitinib on brain metastases from NSCLC [14
17
] seem to suggest a potential role of TK inhibitors in the treatment of NSCLC patients with metastatic CNS disease.
The aim of our study was to evaluate prospectively the activity of gefitinib in a consecutive series of pretreated patients with brain metastases from NSCLC. The drug was provided by AstraZeneca within the expanded access program.
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Patients and methods |
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Eligibility criteria included age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, white blood cell count
3.5 x 109/l with absolute granulocyte count (AGC) >2.0 x 109/l, platelets
100 x 109/l, hemoglobin
9 g/dl, bilirubin <1.5-fold the upper limit of normal (ULN), prothrombin time or activated partial thromboplastin time <1.5x control, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3-fold ULN (could be elevated to 5-fold ULN in patients with known hepatic metastases) and a calculated creatinine clearance rate of >45 ml/min. Patients with an active infection or other serious concomitant disorders were ineligible.
Written informed consent was obtained from each patient before entering the study. The study was conducted after the approval of the appropriate ethical review boards. Recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.
Study design and treatment
In this study, consecutive NSCLC patients with brain metastases received gefitinib at the daily dose of 250 mg given until disease progression, unacceptable toxicity or refusal. Baseline evaluation included a complete history and physical examination, a complete blood cell count and serum chemistry analysis, urinalysis, and a total-body CT scan. Brain metastases were assessed with contrast-enhanced CT or MRI of the brain. All baseline imaging procedures were performed in the 4 weeks before study entry. After trial inclusion, toxicity and disease-related symptom assessment were performed every 28 days. Toxic effects were assessed according to the National Cancer Institute Common Toxicity Criteria [18]. Symptom assessment was performed by the physician and no questionnaire was used. Side-effects and safety were evaluated clinically and serum creatinine, electrolyte, alkaline phosphatase, bilirubin, AST, ALT, calcium and protein levels were assessed. Patients were evaluated for response according to the RECIST (Response Evaluation Criteria In Solid Tumors) criteria [19
]. Patients with a rapid clinical progression before radiologic re-assessment were considered to have progressive disease (PD). Patients in which a complete response (CR), partial response (PR) or stable disease (SD) was measured were considered as having achieved disease control (DC).
Tumor response was assessed by CT scan every 2 months, with a confirmatory evaluation to be repeated in responding patients at least 4 weeks after the initial determination of response. Brain metastases response was assessed at the same time as extra-cranial evaluation (±10 days) using the same diagnostic technique performed in baseline assessment.
Statistical considerations
Forty patients were to be enrolled onto the study, as calculated according to the method described by Gehan [20]. This was to ensure that if the drug had a <20% DC rate, the study could be terminated with a maximal error of 5% in estimation of the true response rate. Response to treatment was evaluated according to the intention-to-treat principle. Confidence limits (95% CI) of response rates were estimated. Progression-free survival (PFS) was defined as the period from the first day of treatment to the date of first evidence of disease progression or last follow-up. Overall survival (OS) was calculated from the first day of therapy until death or last follow-up. Actuarial survival curves were generated using the method of Kaplan and Meier.
Response rates were analyzed according to the following variables: age (less than median value versus greater than median value), gender, ECOG PS (0 versus 1 versus 2), histology (adenocarcinoma including bronchiolar-alveolar carcinoma (BAC) versus non-adenocarcinoma), number of metastatic sites apart from CNS (01 versus >1), previous systemic treatment (none/one versus more than one lines of chemotherapy), previous platinum-based chemotherapy (yes versus no) and previous WBRT (yes versus no). All parameters were analyzed as categorical variables. Spearman's test was used to compare percentages in subsets of patients through univariate analysis. Multivariate analysis was performed using a logistic regression model. The impact of these variables on PFS and OS was evaluated by univariate analysis using the log-rank test. The independent value of variables was assessed in multivariate analysis using the Cox proportional hazard regression model with an estimate of hazard ratios (HR). All probability values were two-sided.
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Results |
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Activity and efficacy measures
All patients were evaluated for response, both in brain and extracranial disease sites. No case of mixed response (i.e. CNS response and extracranial progression, or vice versa) was observed. Among the 41 patients enrolled, we registered four PRs (10%) (Figure 1). Median duration of response was 13.5 months (range 315). Seven patients had SD (17%) with a median duration of 4 months (range 311), for an overall DC rate of 27% (95% CI 13% to 40%). Two patients were not evaluable for response. In one case a PR was observed at extracranial sites (lung and pleura) with symptom improvement, but brain metastases were not evaluated due to sudden death as a result of pulmonary embolism at 4 months. This patient was considered as having disease progression according to the intention-to-treat principle. The other patient refused any further radiological assessment after baseline evaluation; he is alive and well at 13 months, and still on treatment. In statistical analysis, this patient was not considered a responder, but was included in the group of patients achieving DC. Including this patient, the DC rate was 29% (95% CI 15% to 43%). Overall, disease-related symptoms improved in 32%, remained stable in 32% and worsened in 36% of patients. Nine patients had neurological symptoms at trial inclusion, despite the administration of steroids; an improvement occurred in four cases. All responding patients showed rapid tumor regression, which was evidenced at first post-baseline assessment. In particular, one radio-naïve patient showed an impressive response after 4 weeks of treatment (Figure 1
); tumor regression was confirmed at 2 and 4 months.
|
At a median follow-up of 11 months, 11 patients are still alive and five patients are free of disease progression and still on treatment (at >3, >3, >8, >13 and >14 months, respectively). One patient died at 4 months, while in PR at extracranial sites, due to massive pulmonary embolism. Figure 2A and B shows the actuarial survival curves for the entire population. Median PFS was 3 months (range 0 to >14). PFS was significantly related to adenocarcinoma histology in multivariate analysis (P=0.04; HR 2.3; 95% CI 1.05.1), and age <62 years had borderline significance (P=0.09; HR 2.0; 95% CI 0.94.7). PFS was longer in patients previously submitted to WBRT (4 months compared with 2 months in non-irradiated patients), but this difference was not significant (P=0.17; HR 1.9; 95% CI 0.84.6). Median OS was 5 months (range 0 to >24) and was related to PS (P=0.01; HR 2.2; 95% CI 1.24.0). Patients with PS 0 had a median OS of 8 months, compared with 4 months and 1 month for patients with PS 1 and 2, respectively. Furthermore, patients with less than two sites of metastatic disease, apart from CNS, survived significantly longer in comparison with patients with an higher metastatic burden (7.5 compared with 2 months, respectively) (P=0.03; HR 3.0; 95% CI 1.18.0).
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Discussion |
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In our series of 41 consecutive cases, we registered an interesting activity of gefitinib in this heavily pretreated group of patients. Four major responses in brain metastases (10%) were observed, both in previously irradiated and non-irradiated patients; overall, nearly 30% of patients appeared to achieve DC as a result of the treatment. All responding patients showed rapid tumor regression that was evidenced at the first post-baseline assessment. Neurological status improvement was also observed in four of nine symptomatic patients. These findings confirm previous case reports of activity of gefitinib on brain metastases from NSCLC [1417
]. The efficacy of single-agent or combination chemotherapy in disseminated NSCLC with brain metastases remains unsatisfactory [7
, 21
]; this is commonly attributed to the presence of the BBB, which allows only relatively low concentrations of most cytotoxic agents in the normal CNS. However, the protective role of the BBB is limited to normal brain and micro-metastatic disease, while in overt metastatic disease it may already be disrupted by the presence of brain metastases and/or previous radiotherapy [7
, 8
]. In fact, in experimental models, BBB functions begin to fail with metastatic lesions of a few millimeters [22
]. Gefitinib has low molecular weight and excellent cell penetration [23
]; however, preclinical data showed only a low distribution of 14C-radiolabeled drug to the CNS, as assessed by quantitative whole-body autoradiography 2 h after oral dosing during peak concentrations in non-tumor-bearing rats (data on file at AstraZeneca). Recently, a study in mice has shown therapeutic activity of gefitinib in intracranial tumors overexpressing EGFR; oral administration of high-dose gefitinib (50100 mg/kg/day during weekdays for 3 weeks) had marked efficacy, resulting in increased survival and nearly complete inhibition of receptor phosphorylation with minimal systemic and neurological toxicity [13
]. No pharmacokinetic and clinical data on the ability of gefitinib to cross the BBB in patients have been published so far, and no conclusion can be drawn about this issue in humans.
In our study, gefitinib proved effective both in WBRT-pretreated and WBRT-naïve subjects, with three PRs and 10 cases of DC in patients pretreated with radiotherapy, and one PR and two cases of DC in patients not previously brain-irradiated. DC was significantly higher in irradiated patients in univariate and multivariate analyses. Moreover, we observed in these patients a trend towards better PFS. Whether these observations could be due to changes in BBB permeability induced by WBRT or simply to a selection bias of patients with a more indolent disease course is difficult to ascertain. Median time from the end of WBRT to gefitinib administration was 7 months. Data on duration of BBB disruption after radiotherapy are extremely heterogeneous in clinical studies and experimental models [8
], varying from hours to years. On the other hand, several authors have suggested that the DC achieved with gefitinib could be a function of an intrinsically more indolent tumor biology (e.g. in adenocarcinoma or in BAC) [11
, 12
]. Furthermore, preclinical data on erlotinib, another orally active EGFR TK- inhibitor, suggest that exposure to multiple chemotherapeutic agents may result in some cell lines becoming more dependent on the EGFR signaling pathway and thus more sensitive to EGFR inhibitors [24
]. This could be also the case in WBRT-pretreated patients, in which radio-resistant clones could have developed increased sensitivity to gefitinib. Interestingly, cellular resistance to ionizing radiation has been shown to be casually associated with functional expression of EGFR in experimental models [25
].
Adenocarcinoma was found to be a favorable prognostic factor for response in the IDEAL 1 and IDEAL 2 trials [11, 12
]; our series confirmed these data, but were lacking statistical significance, probably due to the small sample size of the study population. Nevertheless, we observed a longer PFS in adenocarcinoma cases. The higher activity of gefitinib in this histotype could be of importance in NSCLC patients with brain metastases, as adenocarcinoma is highly represented in this subset of patients [3
].
Treatment was well tolerated, with mild diarrhea and skin toxicity, confirming the favorable adverse event profile of gefitinib in heavily pretreated NSCLC patients.
In conclusion, our observations suggest that gefitinib, at the standard dose of 250 mg/day, can be active on brain disease in NSCLC patients. Since the results of standard therapy for brain metastases in this clinical setting are particularly disappointing, gefitinib appears to be a possible new treatment option. To assess the role of this compound better, we have planned a new trial in asymptomatic radio-naïve patients with brain metastases from NSCLC who have relapsed following previous chemotherapy.
Received for publication December 20, 2003. Revision received March 8, 2004. Accepted for publication March 9, 2004.
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