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Keywords:

  • primary chemotherapy;
  • whole brain radiotherapy;
  • nonsmall cell lung cancer;
  • brain metastasis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

This randomized pilot trial investigated whether primary chemotherapy was feasible in terms of efficacy, survival, toxicity profile, and quality of life compared with whole-brain radiotherapy (WBRT) given first in chemotherapy-naive patients nonsmall cell lung cancer (NSCLC) with synchronous brain metastasis when neurologic symptoms or signs are absent or controlled by supportive care.

METHODS.

After stratification by Eastern Cooperative Oncology Group performance status (ECOG PS) (0–1 vs 2), the number of intracranial metastases (<3 vs 3≤), and the presence of extrathoracic extracranial metastasis, eligible patients were randomized to the primary chemotherapy arm or the WBRT-first arm. World Health Organization (WHO) response criteria, National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 2.0), and the European Organization for Research and Treatment of Cancer (EORTC) C-30/LC-13 questionnaire were used.

RESULTS.

A total of 48 patients were enrolled between August 2002 and November 2005. The response rate of chemotherapy and survival outcomes in the primary chemotherapy arm were not statistically different from those in the WBRT-first arm (overall response rate, 28.0% vs 39.1%; progression-free survival, 3.6 months vs 4.4 months; overall survival, 9.1 months vs 9.9 months). There was close correlation noted between intracranial and extracranial tumor responses (k = 0.82). However, in the WBRT-first arm, grade 3 of 4 neutropenia was more frequent (79% vs 40%) during chemotherapy and 4 patients (17.4%) did not receive further chemotherapy because of early death or poor performance after WBRT. Cognitive function appeared to deteriorate during primary chemotherapy, but was also found to deteriorate after WBRT.

CONCLUSIONS.

Primary chemotherapy is more feasible and can be an appropriate option for patients with synchronous brain metastasis when neurologic symptoms or signs are absent or controlled. The role and timing of WBRT should be defined in further studies in this clinical setting. Cancer 2008. © 2008 American Cancer Society.

Brain metastasis can cause not only neurologic symptoms and cognitive difficulties but also emotional distress in cancer patients. Recently, its frequency has been reported to be rising because of improvement in imaging technology and better control of systemic disease. Among metastatic brain tumors, lung cancer is the most common primary tumor site,1, 2 and 25% to 30% of newly diagnosed nonsmall cell lung cancer (NSCLC) patients have synchronous brain metastases at the time of initial presentation.3 Traditionally, the primary treatment for brain metastasis in NSCLC patients has been whole-brain radiotherapy (WBRT), and only for a limited number of patients have surgery and/or stereotactic radiosurgery been used, whereas systemic chemotherapy has been believed to be of limited value. This was mainly because of the long-held belief that the brain is a pharmacologic sanctuary site, which has been challenged by clinical observation of contrast enhancement of the brain metastases on computed tomography (CT) and magnetic resonance imaging (MRI)4 and also by the documentation of objective tumor responses in the brain after conventional chemotherapy.5, 6 In fact, for brain lesions originating from such chemosensitive tumors as germ cell tumors or lymphoma, chemotherapy is considered to be the primary mode of treatment. Nevertheless, for NSCLC, which is believed to be less responsive to chemotherapy than the others, systemic chemotherapy had been considered only when the surgery, radiosurgery, or WBRT was deemed inappropriate or had failed.

However, recent improvement in systemic treatment for NSCLC patients, including chemotherapy and molecular-targeted therapy, made us re‒evaluate the role of systemic treatment as primary therapy for those with synchronous brain metastasis, especially when there is symptomatic systemic disease and/or there are no or mild neurologic symptoms or signs. In this randomized pilot study, we aimed to investigate whether primary chemotherapy was feasible and affected by the time of WBRT in terms of its efficacy, toxicity profile, quality of life, and survival outcomes in this clinical setting.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Eligibility Criteria

The main eligibility criteria were pathologically confirmed NSCLC and clinically silent brain metastases for which surgery was not deemed appropriate or indicated either because of the number (ie, ≥3) or the location of metastatic lesions (ie, the brain metastases located in the critical area that might cause significant neurological sequel after resection). ‘Clinically silent’ brain metastasis was defined as the lesion from which patients had no or minimum neurologic symptoms or signs, which were easily controlled by supportive care only, including the administration of corticosteroids. Additional eligibility criteria were as follows: 1) ages 18 to 75 years; 2) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; 3) bidimensionally measurable lesion(s) in both intracranial and extracranial site; 4) adequate bone marrow, hepatic, and renal functions, defined as a white blood cell count ≥4000/mm3, an absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100,000/mm3, hemoglobin ≥10 mg/dL, alanine aminotransferase or aspartate aminotransferase ≤2.5 times the upper limit of normal, serum bilirubin ≤1.2 mg/dL, and serum creatinine ≤1.5 mg/dL; and 5) neither prior chemotherapy nor molecular-targeted therapy. All patients provided written informed consent approved by the Institutional Review Board of the National Cancer Center Korea. The study followed the Declaration of Helsinki and Good Clinical Practice guidelines.

Treatment Plan

After stratification according to ECOG PS (0–1 vs 2), the number of intracranial metastases (<3 vs 3≤), and the presence of extracranial extrathoracic metastasis (absence vs presence), eligible patients were randomized to 1 of 2 treatment arms: chemotherapy-first followed by WBRT or WBRT first followed by chemotherapy. Chemotherapy consisted of gemcitabine at a dose of 900 mg/m2 and vinorelbine at a dose of 25 mg/m2, which was given on Days 1 and 8 and repeated every 3 weeks.7 WBRT consisted of 30 grays (Gy) given in 10 fractions over 12 days.8 In the primary chemotherapy arm, chemotherapy was given up to 6 cycles or until disease progression, unacceptable toxicity, or patient withdrawal, followed by WBRT, which was given regardless of the development of neurologic symptoms or signs. In the WBRT-first arm, chemotherapy was initiated after at least 2 weeks of rest after the completion of WBRT, and only when ANC was ≥1500/mm3, the platelet count was ≥100,000/mm3, and all nonhematologic toxicities except alopecia recovered to grade 0 or 1. It was continued until disease progression, unacceptable toxicity or patient refusal, or for a maximum of 6 cycles.

Response and Toxicity Evaluation

A complete history and physical examination, including documentation of concomitant medications and ECOG PS, standard laboratory studies, and electrocardiogram was performed within 14 days before study entry. Chest x-ray, CT scans of the chest including the upper abdomen, MRI of the brain, and radionuclide bone scan were performed within 4 weeks before study entry. Before the commencement of chemotherapy, the same examinations performed in the baseline assessment were repeated when WBRT had been given first.

Objective tumor response was assessed according to the World Health Organization (WHO) response criteria every cycle by chest X-ray and every 2 cycles by chest CT and brain MRI.9 The intracranial tumor response was also assessed using the same diagnostic technique as in the baseline assessment and compared with that of extracranial tumors. Toxicity was graded every cycle using version 2.0 of the National Cancer Institute Common Toxicity Criteria (NCI-CTC).10

Quality-of-life (QoL) was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (version 3.0).11 An additional lung cancer module, Quality of Life Questionnaire LC13, was used.12 All of the scales and single-item measures range in scores from 0 to 100, and a high score represents a higher response level. Thus, a high score for a functional scale and the global health status represents a healthy level of functioning and high QoL, but a high score for a symptom scale or item represents high level of symptomatology. The QoL questionnaire was administered at baseline, immediately before the initiation of every cycle of chemotherapy, and at the end of study. The questionnaire was to be completed during office visits before any other evaluations or assessment of adverse events.

Progression-free survival (PFS) was defined as the interval between the date of the start of chemotherapy and the date of documented disease progression or death from any cause. Overall survival (OS) was defined as the interval between the date of randomization and the date of death because of any cause. If a patient was lost to follow-up, that patient was censored at the last date of contact.

Statistical Analysis

This was a 2-arm, open-label, prospective, single-center randomized pilot study. All patients were included in all efficacy and safety analyses. The parameters of interest were estimated and are presented with their 95% confidence intervals (95% CI) using exact binomial probabilities. All time-to-event variables were analyzed using Kaplan-Meier product-limit survival estimates. Changes in QoL scores from baseline score were evaluated using a Student t test for paired data. Data were updated as of July 15, 2007.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Between August 2002 and November 2005, a total of 48 patients were enrolled in this study and their characteristics are shown in Table 1. In the primary chemotherapy arm, all patients received WBRT after disease progression or completion of scheduled chemotherapy but none of them demonstrated progressive neurologic symptoms or signs when WBRT was initiated. In the WBRT-first arm, 4 patients (17.4%) could not receive any chemotherapy because of deterioration of performance status (2 patients) or early death (2 patients), defined as death during or within 4 weeks after the completion of WBRT, whereas the other 19 patients received the same chemotherapy according to the protocol. In the primary chemotherapy arm, after WBRT, 10 patients could not receive further chemotherapy because of deterioration of ECOG PS (7 patients) or early death (3 patients).

Table 1. Baseline Patient Characteristics
Patient characteristicsPrimary chemotherapy No. (%)Primary WBRT No. (%)P
  1. WBRT indicates whole-brain radiotherapy; ECOG, Eastern Cooperative Oncology Group; NSCLC, nonsmall-cell lung carcinoma; NOS, not otherwise specified.

Total2523 
Median age (range), y60 (41–70)62 (45–75).108
Gender   
 Male1919.319
 Female64 
ECOG performance status  1.00
 0–12522 
 201 
Histology  .104
 Adenocarcinoma2317 
 Squamous cell carcinoma04 
 Large cell carcinoma01 
 NSCLC, NOS21 
No. of intracranial metastasis  1.00
 <398 
 ≥31615 
Extracranial extrathoracic metastasis  1.00
 Absent32 
 Present2221 

Response and Survival

There was no difference in overall response rates noted between the 2 arms (Table 2). In the primary chemotherapy arm, intracranial tumor responses to chemotherapy were found to be closely correlated with extracranial tumor responses (k = 0.82) (Table 2). With a median follow-up of 40 months (range, 20–59), there were no statistically significant differences noted in PFS after chemotherapy (3.6 months in the primary chemotherapy arm vs 4.4 months in the WBRT-first arm B; log-rank P = .62) and the median survival times after the randomization (9.1 months in the primary chemotherapy arm vs 9.9 months in the WBRT-first arm; log-rank P = .61) (Fig. 1).

thumbnail image

Figure 1. Survival outcomes. (A) Progression-free survival after the initiation of chemotherapy (chemo). (B). Overall survival after randomization. WBRT indicates whole-brain radiotherapy.

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Table 2. Correlation of the Objective Tumor Response Between Intracranial and Extracranial Lesions According to WHO Response Criteria
ORRPrimary WBRT (n = 23)Primary chemotherapy
(n = 25)ExtracranialIntracranial
  1. WHO indicates World Health Organization; ORR, overall response rates; WBRT, whole-brain radiotherapy; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available.

PR9 (39.1%)7 (28.0%)6PRPR
1PRSD
SD4 (17.4%)10 (40.0%)1SDPR
9SDSD
PD6 (26.1%)8 (32.0%)1PDSD
7PDPD
NA4 (17.4%)0 (0.0%)   

Toxicity and QoL

Grade 3 or 4 neutropenia occurred more frequently in the WBRT-first arm (79% vs 40%; P = .014). The frequencies of other severe toxicities were not statistically significantly different except for alopecia and mild headache or dizziness, which was more frequent in the WBRT-first arm (Table 3).

Table 3. Worst NCI-CTC Grade Toxicities Noted per Patient
Adverse effectPrimary chemotherapy (n = 25)Primary WBRT (n = 19)
Grade 0Grade 1Grade 2Grade 3Grade 4Grade 0Grade 1Grade 2Grade 3Grade 4
  1. NCI-CTC indicates National Cancer Institute Common Toxicity Criteria; WBRT, whole-brain radiotherapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Hematologic Toxicities, No. (%)
Leukopenia3 (12)10 (40)7 (28)5 (20)0 (0)2 (11)1 (5)7 (37)7 (37)2 (11)
Neutropenia6 (24)2 (8)7 (28)9 (36)1 (4)2 (11)1 (5)1 (5)11 (57)4 (21)
Anemia0 (0)19 (76)5 (20)0 (0)1 (4)0 (0)8 (42)9 (47)2 (11)0 (0)
Thrombocytopenia11 (44)12 (48)2 (8)0 (0)0 (0)9 (47)9 (47)1 (5)0 (0)0 (0)
Nonhematologic Toxicities, No. (%)
Alopecia6 (24)18 (72)1 (4)0 (0)0 (0)0 (0)4 (21)15 (79)0 (0)0 (0)
Anorexia0 (0)16 (64)8 (32)1 (4)0 (0)0 (0)5 (26)12 (63)2 (11)0 (0)
Nausea10 (40)12 (48)2 (8)1 (4)0 (0)5 (0)11 (58)3 (16)0 (0)(0)
Vomiting20 (80)3 (12)2(8)0 (0)0 (0)13 (68)5 (26)1 (5)0 (0)0 (0)
Constipation10 (40)9 (36)6 (24)0 (0)0 (0)6 (32)8 (42)5 (26)0 (0)0 (0)
Diarrhea23 (92)2 (8)0 (0)0 (0)0 (0)11 (58)7 (27)1 (5)0 (0)0 (0)
Dysphagia23 (92)2 (8)0 (0)0 (0)0 (0)14 (74)5 (26)0 (0)0 (0)0 (0)
Mucositis16 (64)8 (32)1 (4)0 (0)0 (0)8 (42)6 (32)5 (26)0 (0)0 (0)
Fatigue0 (0)18 (72)7 (28)0 (0)0 (0)1 (5)7 (37)11 (58)0 (0)0 (0)
Elevated AST/ALT8 (32)11 (44)6 (24)0 (0)0 (0)9 (47)6 (32)3 (16)1 (5)0 (0)
Febrile neutropenia25 (100)0 (0)0 (0)0 (0)0 (0)18 (95)0 (0)0 (0)1 (5)0 (0)
Headache12 (48)12 (48)1 (4)0 (0)0 (0)7 (37)10 (53)2 (11)0 (0)0 (0)
Dizziness15 (60)9 (36)1 (94)0 (0)0 (0)5 (26)13 (68)1 (5)0 (0)0 (0)
Pneumonitis25 (100)0 (0)0 (0)0 (0)0 (0)18 (95)0 (0)0 (0)1 (5)0 (0)
Radiation dermatitis25 (100)0 (0)0 (0)0 (0)0 (0)13 (68)4 (21)2 (11)0 (0)0 (0)

To evaluate the impact of the primary chemotherapy versus the WBRT-first treatment plan, we assessed the QoL parameters in 33 patients, starting from the 16th patient onward, using the EORTC questionnaire C30 and L13. At baseline, before the initiation of either chemotherapy or WBRT, global health status was found to be most impaired in both groups, although statistically not different, with mean scores of 58 and 65, respectively. The function scores or symptom scores were also statistically not different between the 2 groups. After WBRT, global health status was found to be statistically significantly impaired, with a decreased mean score of 48 from 65, and physical and cognitive function were also more impaired. Of interest, as chemotherapy proceeded, cognitive function in the primary chemotherapy arm became impaired, whereas that in the WBRT-first arm rather improved slightly from the most impaired score immediately after WBRT. The changes are shown in Figure 2.

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Figure 2. The change of mean scores for the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire C30 and LC13 by treatment group. (A) Global Quality of Life. (B) Cognitive Functional Scale. (C) Physical Functional Scale. (D) Role Functional Scale. (E) Fatigue Symptom Scale. (F) Dyspnea Symptom Scale. (G) Appetite Symptom Scale. (H) Nausea/Vomiting Symptom Scale. WBRT indicates whole-brain radiotherapy; chemo, chemotherapy.

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Salvage Therapy on Progression

Of the 25 patients randomized to the primary chemotherapy arm, 15 (60.0%) received further salvage chemotherapy after the frontline gemcitabine/vinorelbine therapy and WBRT. Regimens used in the salvage second-line setting included irinotecan plus cisplatin (n = 6 patients), paclitaxel plus cisplatin (n = 2 patients), docetaxel plus capecitabine (n = 2 patients), docetaxel plus cisplatin (n = 1 patient), single-agent docetaxel (n = 2 patients), and gefitinib (n = 2 patients). Of the 23 patients in the WBRT-first arm, 19 (82.6%) received gemcitabine/vinorelbine therapy as first-line chemotherapy per protocol and 12 (52.3%) received further salvage chemotherapy. Regimens used in salvage second-line setting included irinotecan plus cisplatin (n = 4 patients), paclitaxel plus cisplatin (n = 1 patient), docetaxel plus cisplatin (n = 2 patients), docetaxel plus capecitabine (n = 1 patient), and gefitinib (n = 4 patients). Of interest, none of the patients in either group demonstrated a deterioration in neurologic signs or symptoms during the chemotherapy follow-up period. No patient required any surgical resection or stereotactic radiosurgery during this period.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Advances in neuroimaging techniques and its routine use as initial staging evaluation tools not only increased the incidence of NSCLC patients with brain metastasis13 but also forced clinicians to face a new dilemma with regard to the choice of initial treatment for the patients who have ‘clinically silent’ brain metastasis. In this randomized clinical trial, although closed prematurely because of slow patient accrual, we clearly demonstrated that those patients with minimum or no neurologic symptoms or signs from brain metastases could be treated with systemic chemotherapy alone as an initial treatment without jeopardizing their clinical outcome parameters. Rather, our data suggest that NSCLC patients with brain metastases might benefit from primary chemotherapy in terms of toxicity and QoL parameters when compared with the conventional a WBRT-first approach.

Furthermore, current study data also suggest that both primary and delayed WBRT adversely affect the clinical outcome of those patients with brain metastases. Traditionally, WBRT has been recommended for all patients with metastatic brain lesions, regardless of neurologic signs or symptoms. As shown in this prospectively collected dataset and also by our clinical practices, nearly all patients experience deterioration in PS after WBRT, which in turn results in compromised further systemic treatment. In our study, 4 patients (17.4%) in the WBRT-first arm could not receive any chemotherapy because of deterioration of PS and/or death, and 10 patients (40.0%) in the primary chemotherapy arm could not receive further systemic treatment because of the same reason after WBRT.

Conversely, all patients participating in this study received WBRT per protocol. This may in part explain why no patient required additional treatment such as surgical resection or stereotactic radiosurgery for the brain lesions while on the study and thereafter. It should also be noted that none of the patients in the primary chemotherapy arm had worsening of neurologic symptoms or signs while receiving therapy even when there was progression of the brain lesions documented by radiologic imaging techniques.

In the current study, QoL data should be interpreted with some precautionary remarks because it was based on the unbalanced open-label study outcome and a small sample size. Nevertheless, there were statistically significant changes in the scores indicating deterioration of QoL parameters after WBRT was given first. Taken together with the finding that WBRT resulted in a significant increase in chemotherapy-related grade 3 or 4 neutropenia,14 one may reserve the WBRT for future use as long as the brain metastases are controlled with systemic chemotherapy. This appears to be a quite reasonable approach when the recent advances in systemic chemotherapy and molecular-targeted therapy are taken into consideration, which has been shown to improve both overall survival and QoL of lung cancer patients.15–20

In fact, while this trial was still actively accruing patients, we had 4 separate phase 2 primary chemotherapy trials running sequentially,21–23 which accrued a total of 187 NSCLC patients. Among those, 32 patients had brain metastases and were initially treated with chemotherapy alone without WBRT. The eligibility criteria were basically the same as the current randomized trial, although the chemotherapy regimens were different for each trial. Their median survival time of 10.6 months is quite similar to the results of the current study (9.1 months in the primary chemotherapy arm vs 9.9 months in the WBRT-first arm), although it tended to be shorter than the result for the patients without brain metastasis (10.6 months vs 15.7 months; log-rank P = .089). Of interest, of the 32 patients with brain metastases who were enrolled in those primary chemotherapy trials, 9 (28%) did not receive WBRT at all during their disease course and their cause of death was progressive systemic disease rather than the progression of metastatic brain lesions. Their survival outcome was not different from the result of the other 23 patients who received WBRT (median survival time, 11.3 months vs 9.8 months; log-rank P = .345). As we gained more clinical experience, it became apparent that WBRT was not always necessary for patients with asymptomatic brain metastases, and also it became hard to keep randomizing the patients to the WBRT-first arm. We therefore decided to close this randomized clinical trial and report the data herein.

In the current study and also in our competing studies, we observed that the response of the intracranial lesions correlated very closely with that of the extracranial lesions, which suggests that at least the clinically silent metastatic brain lesions can be treated as 1 of systemic manifestation of the disease. It also suggests that more effective chemotherapeutic agents should enhance the intracranial tumor responses. Because such molecular-targeted agents as epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors demonstrated very high response rates in a selected subset of patients,24–26 one may use them as primary therapy instead of chemotherapy for those patients with specific biologic markers (ie, EGFR gene mutation) or clinical characteristics (ie, never-smoker adenocarcinoma), which should be investigated further.

Based on the results of current study, we conclude that primary chemotherapy for brain metastases is feasible and advisable, more so than primary WBRT, for NSCLC patients who present with clinically silent brain metastasis. There is no reason to believe otherwise that the same principle would be applicable to the management of other types of cancer provided there are reasonably effective systemic treatment regimens available.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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