Invasive mediastinal staging of non-small-cell lung cancer: a clinical practice guideline

Introduction

In non-small-cell lung cancer (nsclc), invasive mediastinal staging is typically used to guide treatment decision-making. Here, we present clinical practice guideline recommendations for invasive mediastinal staging in nsclc patients who have been staged T1–4, N0–3, with no distant metastases.

Methods

Draft recommendations were formulated based on the best available evidence gathered by a systematic review and a consensus of expert opinion. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline.

Results

In general, most clinical experts agreed with the guideline, approving it for methodologic rigour. More than 80% of the surveyed practitioners gave it a high quality rating. The expert reviewers also provided written comments, with some of the suggested changes being incorporated into the final version of the guideline.

Conclusions

In the clinical practice guideline, invasive mediastinal staging of nsclc is recommended in all cases except those involving patients with normal-sized lymph nodes, negative combine positron-emission tomography and computed tomography, and peripheral clinical stage 1A tumour. When performing mediastinoscopy, 5 nodal stations (2R/L, 4R/L, and 7) should routinely be examined.     

Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: A prospective pilot study

Background: Clearance of viable tumour cells in mediastinal lymph nodes (MLN) by induction chemotherapy (IC) – so-called MLN downstaging – is an important aspect of combined-modality treatment of N2-NSCLC. Reassessment of MLN after IC by CT is far from accurate, while re-mediastinoscopy is often technically difficult. Based on our previous results with FDG-PET in the initial staging of N2 disease, we investigated whether PET after IC could be helpful in predicting MLN downstaging and therapeutic outcome.Patients and methods: Patients underwent a first PET before IC. After three cycles of platinum-based IC, a second PET was performed before locoregional therapy, either surgery or radiotherapy. PET results were correlated with pathology of the MLN when available, and with survival.Results: Fifteen surgically staged N2-NSCLC patients were prospectively included. Locoregional therapy after IC consisted of surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting MLN downstaging was 100% (six true negatives; three true positives), whereas for CT it was only 67% (two false pos; one false neg). Reassessment with PET after IC was correlated with the outcome after the entire combined modality treatment. Survival was significantly better in patients with mediastinal clearance (P = 0.01) or with a greater than 50% decrease in the Standardised Uptake Value (SUV) of the primary tumour (P = 0.03) after IC.Conclusions: Mediastinal PET after IC accurately assesses pathologic MLN downstaging in N2-NSCLC. The data suggest a possible correlation of early survival with mediastinal clearance and an important decrease of SUV in the primary tumour. Confirmation of these preliminary findings would establish PET as a useful non-invasive tool to select patients for intensive locoregional treatment after IC.     

Staging practices of primary non-small-cell lung cancer: a literature review

Lung cancer is the most frequent cause of cancer deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all cases. Stage at diagnosis is the most important indicator of survival. Various non-invasive and invasive procedures are available for NSCLC staging. However, the precise indications for performing these procedures remain controversial. There is no evidence about the level of variability in practice of imaging and invasive procedures used for NSCLC staging. Their high costs contribute to the controversy about their use. We performed a literature search on the MEDLINE database to identify studies reporting practice of staging for a nonselected group of patients with NSCLC. Only seven studies enrolling between 185 and 2,071 patients reported NSCLC staging practices. These studies were reviewed to identify patterns in practice of staging work-up and consecutive treatment. Lack of detailed reporting limits the interpretation of the results. Based on our review, future investigations should be conducted to determine the extent of variation in patterns of physician practices of NSCLC staging and their impact on the treatment practice or patient survival.     

Front-line paclitaxel and topotecan chemotherapy in advanced or metastatic non-small-cell lung cancer: a phase II trial

Purpose: Based on previous experience, we combined topotecan with paclitaxel (weekly administration) in patients with non-small-cell lung cancer (NSCLC). Our primary objective was to determine the response rate and survival and our secondary objective, the safety of the regimen. Methods: From October 2003, until March 2005, 45 patients all with histologically or cytologically confirmed NSCLC were enrolled. All patients were chemotherapy and radiotherapy naive. Both agents were infused on day 1 of every week once for three consecutive weeks, every 28 days. Three infusions were considered as one course. The treatment plan was to give three courses (nine infusions) and then to evaluate the response. Topotecan (1.75 mg/m²) was infused for 30 min and paclitaxel (70 mg/m²) for 90 min; these doses had been established as the maximum tolerated dose in a previous phase I–II trial. Results: Eighteen/45 (40%) patients responded, 2 (4.4%) complete responses and 16 (35.6%) partial responses. Twenty-one (46.7%) patients had stable disease, and 6 (13.3%) disease progression. The median duration of response was 8 months and median time to tumor progression 9 months. Grade 3 and 4 neutropenia was observed in two patients (in these two patients, the dose of both drugs was reduced by 25% and G-CSF was given), grade 4 thrombocytopenia in one patient and grade 4 anemia in one patient. Conclusion: This novel combination of topotecan–paclitaxel in a weekly administration rendered a 40% response rate, with very low toxicity in stages IIIA, IIIB and IV NSCLC patients.     

Phase II trial of edatrexate plus carboplatin in metastatic non-small-cell lung cancer: a Southwest Oncology Group study

Background: Edatrexate and carboplatin are each active single agents in the treatment of non-small-cell lung cancer (NSCLC). Preclinical studies in NSCLC lines have demonstrated schedule-dependent synergy of edatrexate followed by carboplatin. In a phase I trial, we demonstrated the tolerability of this combination, the ability of ice-chip cryotherapy to ameliorate dose-limiting mucositis, and promising activity in NSCLC. This phase II trial (SWOG 9207) was undertaken to investigate the efficacy of this regimen in stage IV NSCLC. Methods: A total of 24 patients with stage IV disease were accrued to this Southwest Oncology Group (SWOG) multicenter study. Treatment consisted of edatrexate 80 mg/m² (50% dose on day 8) intravenously weekly for 5 weeks, then every other week, and carboplatin 350 mg/m² every 28 days. Results: Of the 24 patients, 23 were assessable for toxicity and response; one was ineligible for study entry. Myelosuppression was the most significant toxicity; grade 3–4 neutropenia was seen in 8/23 patients. Two patients died of neutropenic sepsis during the first cycle of therapy, in both instances associated with the presence of pleural effusions. Although mild mucositis was common, it was dose-limiting (grade 3) in only three patients. Objective response was observed in 3/23 patients (13%). The median survival time was 7 months, and 30% of patients remained alive at one year. Conclusions: This study suggests that ice-chip cryotherapy is effective in reducing the severity of mucositis typically associated with this edatrexate schedule of administration. However, unexpectedly severe myelosuppression resulted in death from neutropenic sepsis in two patients with third space fluid collections, leading to a protocol amendment to exclude such patients from study entry. Furthermore, response and median survival with this dose schedule of edatrexate and carboplatin do not appear to be improved compared to other chemotherapeutic regimens tested by SWOG in this patient population. Received: 12 August 1996 / Accepted: 8 May 1997     

Response to second-line erlotinib in an EGFR mutation-negative patient with non-small-cell lung cancer: make no assumptions

Erlotinib-an oral tyrosine kinase inhibitor (tki) of the epidermal growth factor receptor (egfr)-has commonly been used as a therapeutic option in metastatic non-small-cell lung cancer (nsclc) patients in the second- or third-line treatment setting. A mutation in the EGFR gene (EGFR M+) confers an increased response to this class of drugs. In the first-line setting, use of tkis is restricted to patients having a mutation. The importance of this biomarker has been questioned in subsequent treatment lines.Here, we report a case showing a positive response to erlotinib treatment in the second-line setting. The patient, an elderly male smoker with stage iv nsclc, had a tumour that was EGFR mutation-negative (wild-type EGFR). Based on this clinical case, we discuss the controversy concerning the need for, and impact of, testing for EGFR mutation after first-line treatment.     

An evaluation of screening for lung cancer in Niigata Prefecture, Japan: a population-based case-control study.

Although an annual screening programme for lung cancer has been carried out widely in Japan since 1987, there is insufficient evidence to confirm its efficacy in terms of reducing mortality. In order to evaluate the efficacy of the lung cancer screening which has been widely carried out in Japan since 1987, a case-control study was conducted in Niigata Prefecture, Japan. In the study area, chest X-ray examinations for all participants and sputum cytology for high-risk participants were offered annually. Case subjects, who had died from lung cancer (174), and control subjects matched by sex, year of birth, residence and smoking status (801), who had been alive at the time of diagnosis of the corresponding case, were selected from the National Health Insurance holders. Screening histories of the subjects were compared between cases and matched controls for the identical calendar period before the time of diagnosis of the cases. The odds ratio of death from lung cancer for those screened within 12 months vs those not screened was 0.401 (95% CI: 0.272-0.591) with adjustment by smoking index. Our results suggest that annual lung cancer screening might reduce mortality from lung cancer by approximately 60%.     

Detecting mediastinal lymph node metastases in non-small-cell lung cancer using a combination of technetium-99m tetrofosmin chest single photon emission computed tomography and chest computed tomography

The staging of non-small-cell lung cancer (NSCLC) to detect mediastinal lymph node (MLN) metastases is very important for determining the therapeutic strategy.

Methods: Thirty-four patients with proven NSCLC were enrolled in this study. All patients underwent chest computed tomography (CT) and technetium-99m (Tc-99m) tetrofosmin chest single photon emission computed tomography (SPECT) preoperative staging. Mediastinal lymph node metastases were determined on the basis of postoperative pathologic findings to compare the diagnostic accuracy of chest CT with that of Tc-99m tetrofosmin chest SPECT.

Results: Tc-99m tetrofosmin chest SPECT showed a diagnostic accuracy rate of 85.3% in detecting MLN metastases. Chest CT had an accuracy rate of 73.5%. If either Tc-99m tetrofosmin chest SPECT or chest CT with positive findings was considered as positive findings, the sensitivity was 94.7%. If either Tc-99m tetrofosmin chest SPECT or chest CT with negative findings was considered as negative, the specificity was 93.3%.

Conclusion: Tc-99m tetrofosmin chest SPECT was more accurate than chest CT in detecting MLN metastases in NSCLC patients. In addition, the combined use of Tc-99m tetrofosmin chest SPECT and chest CT could significantly increase the sensitivity and specificity compared with the single use of either Tc-99m tetrofosmin chest SPECT or chest CT.     

Carboplatin and docetaxel in advanced non-small-cell lung cancer: results of a multicenter phase II study

Background To evaluate the efficacy of carboplatin and docetaxel combination in patients with advanced non-small-cell lung cancer.Methods In a phase II study, patients with inoperable stage IIIB or stage IV non-small-cell lung cancer (ECOG performance status of 0 or 1) were treated with the combination of carboplatin AUC 5 mg/ml·min and docetaxel 80 mg/m² administered once every 3 weeks.Results A total of 45 patients were accrued to the study. The median age was 62 years and adenocarcinoma was the most common histology. Patients received a median of four cycles of chemotherapy. The objective response rate was 29% with a median survival of 11.9 months among evaluable patients. The 1-year survival rate was 47%. Febrile neutropenia (17%) was the most common hematological toxicity associated with the regimen whereas grade 3 fatigue (4%) was the major nonhematological toxicity.Conclusions The combination of carboplatin plus docetaxel is well tolerated and is effective for the treatment of patients with previously untreated advanced or metastatic non-small-cell lung cancer.This work was supported in part by Aventis Pharmaceuticals Inc.     

Metadherin regulates proliferation and metastasis via actin cytoskeletal remodelling in non-small cell lung cancer

Background:

Metaderin (MTDH) protein is a novel component part of tight junction complex. The aim of this study was to investigate the correlation between MTDH and prognosis of patients and to explore the role of MTDH on NSCLC development and metastasis.

Methods:

Relative mRNA expression was evaluated by quantitative real-time PCR, and protein expression was detected using immunohistochemistry staining. The role of MTDH in cancer cell proliferation, migration and invasion was studied by modulation of MTDH expression in NSCLC cell lines. These functions of MTDH were further confirmed in vivo.

Results:

In NSCLC, low MTDH protein expression was correlated with lymph node metastasis, TNM stage and decreased OS (P=0.001, 0.011 and 0.013, respectively). Overexpression of MTDH reduced anchorage-independent and -dependent growth through arresting cell cycle, inhibited migration and invasion in vitro and further suppressed tumorigenesis, tumour growth and metastasis in vivo. Knockdown of MTDH expression increased cell invasiveness. MTDH overexpression reversed pro-metastatic actin cytoskeleton remodelling and inhibited EMT, supporting that MTDH has a key role on cancer proliferation and metastasis.

Conclusions:

MTDH has an important role in NSCLC proliferation and metastasis and provides potential in predicting metastasis and prognosis for patients with NSCLC.     

Finding needles in a haystack: annual low-dose computed tomography screening reduces lung cancer mortality in a high-risk group

Evaluation of: Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5), 395–409 (2011).

Lung cancer is a global health issue. Compared with other common malignancies, the prognosis is poor as many patients present with advanced disease. The National Lung Screening Trial (NLST) aimed to identify and treat early lung cancers using annual low-dose computed tomography (CT) screening in a high-risk group. When compared with chest x-ray screening, low-dose CT screening reduced lung cancer mortality by 20%; the NLST is the first lung cancer screening trial to demonstrate such a mortality benefit. However, we must wait for cost–effectiveness data from the NLST, as well as the results of ongoing European studies comparing low-dose CT with observation alone, before firm conclusions can be drawn regarding the overall benefits of introducing a CT screening program to clinical practice.     

Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapy: a multicenter phase II trial

Purpose: To investigate the activity of docetaxel and granulocyte colony-stimulating factor support (G-CSF) in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with cisplatin. Patients and methods: A total of 60 patients with locoregional and metastatic NSCLC who had relapsed or progressed after first-line treatment with cisplatin-based regimens were enrolled into the trial. Docetaxel at 100 mg/m² was given as a 1-h infusion with G-CSF (rhG-CSF given s.c. at 150 μg/m²) support from day 2 to day 8 every 3 weeks; all patients received premedication with corticosteroids. Results: In all, 1 (1.6%) and 14 (23.3%) patients achieved a complete response (CR) and a partial response (PR), respectively, for an overall response rate of 25% (95% CI 14.0–35.9%); stable disease (SD) and progressive disease (PD) were documented in 18 (30%) and 27 (45%) patients, respectively. The median duration of response was 20 weeks and the median time to tumor progression was 28 weeks. The median overall survival was 32 weeks and the 1-year survival rate was 23%. A total of 263 courses were given at a median of 3 cycles/patient. Grade 3 and 4 neutropenia occurred in 11 (18%) and 14 (23%) patients, respectively, with 18 (30%) patients requiring hospitalization for neutropenic fever; 1 patient died of sepsis. Grade 2 peripheral neuropathy occurred in 9 patients (15%) and grade 3 asthenia, in 4 (7%). Other toxicities were mild. Conclusions: Docetaxel has considerable single-agent activity in patients with NSCLC who have relapsed or progressed after first-line chemotherapy with cisplatin-based regimens. Received: 17 June 1998 / Accepted: 17 August 1998     

Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review

Increased understanding of the genetic aetiology of advanced non-small-cell lung cancer (aNSCLC) has facilitated personalised therapies that target specific molecular aberrations associated with the disease. Biopsy samples for mutation testing may be taken from primary or metastatic sites, depending on which sample is most accessible, and upon differing diagnostic practices between territories. However, the mutation status concordance between primary tumours and corresponding metastases is the subject of debate. This review aims to ascertain whether molecular diagnostic testing of either the primary or metastatic tumours is equally suitable to determine patient eligibility for targeted therapies. A literature search was performed to identify articles reporting studies of mutations in matched primary and metastatic aNSCLC tumour samples. Clinical results of mutation status concordance between matched primary and metastatic tumour samples from patients with aNSCLC were collated. Articles included in this review (N =26) all reported mutation status data from matched primary and metastatic tumour samples obtained from adult patients with aNSCLC. Generally, substantial concordance was observed between primary and metastatic tumours in terms of EGFR, KRAS, BRAF, p16 and p53 mutations. However, some level of discordance was seen in most studies; mutation testing methodologies appeared to play a key role in this, along with underlying tumour heterogeneity. Substantial concordance in mutation status observed between primary and metastatic tumour sites suggests that diagnostic testing of either tumour type may be suitable to determine a patient’s eligibility for personalised therapies. As with all diagnostic testing, highly sensitive and appropriately validated mutation analysis methodologies are desirable to ensure accuracy. Additional work is also required to define how much discordance is clinically significant given natural tumour heterogeneity. The ability of both primary and metastatic tumour sites to accurately reflect the tumour mutation status will allow more patients to receive therapies personalised to their disease.     

An exploratory comparative analysis of tyrosine kinase inhibitors or docetaxel in second-line treatment of EGFR wild-type non-small-cell lung cancer: a retrospective real-world practice review at a single tertiary care centre

Background

Treatment for advanced non-small-cell lung cancer (nsclc), especially in patients with wild-type EGFR, remains limited. Recently, erlotinib, a tyrosine kinase inhibitor (tki) targeting EGFR mutation, was approved as second-line treatment in EGFR wild-type nsclc. Despite evidence of better overall survival (os) with chemotherapy than with tki in second-line treatment, data on the use of tki in the real-life clinical setting remain limited. The present practice review of tki use for second- and third-line treatment in EGFR wild-type nsclc also compares clinical outcomes for tki and single-agent docetaxel as second-line treatment.

Methods

Our retrospective cohort study included patients with EGFR wild-type nsclc treated at the Jewish General Hospital (Montreal, QC) between 2003 and 2013. Patients received a tki (erlotinib or gefitinib) in the second and third line or docetaxel in the second line. For each group, we determined os, disease control rate, progression-free survival (pfs), and event-free survival (efs).

Results

The tki group included 145 patients, with 92 receiving second-line treatment. In the control group, 53 patients received docetaxel as second-line therapy. In the tki group, os was 6.0 months; pfs, 2.7 months; and efs, 3.0 months. Comparing second-line treatments, os was 5.3 and 5.0 months respectively (p = 0.88), pfs was 2.5 and 1.8 months respectively (p = 0.041), and efs was 3.0 and 1.7 months respectively (p = 0.009).

Conclusions

In our study cohort, second-line therapy for EGFR wild-type nsclc with tki (compared with docetaxel) was associated with statistically better pfs and efs and noninferior os. Those findings raise the question of whether efs should also be considered when choosing second-line treatment in this patient population.     

Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy

Several studies in the past have shown appreciably higher lung cancer risk estimates associated with smoking exposure among men than among women, while more recent studies in the USA report just the opposite. To evaluate this topic in a European population we conducted a case-control study of lung cancer in three German and three Italian centres. Personal interviews and standardized questionnaires were used to obtain detailed life-long smoking and occupational histories from 3723 male and 900 female cases and 4075 male and 1094 female controls. Lung cancer risk comparing ever-smokers with never-smokers was higher among men (odds ratios (OR) adjusted for age and centre = 16.1, 95% confidence interval (CI) 12.8-20.3) than among women (OR = 4.2, CI 3.5-5.1). Because the smoking habits of women were different from men, we conducted more detailed analyses using comparable levels of smoking exposure. After restriction to smokers and adjustment for other smoking variables, risk estimates did not differ appreciably between genders. The analysis of duration of smoking (0-19, 20-39, 40+ years) adjusted for cigarette consumption and time since quitting smoking revealed similar risk estimates in men (OR = 1.0, 3.3 [CI 2.6-4.2], 4.1 [CI 3.1-5.6]) and women (OR = 1.0, 2.7 [CI 1.7-4.1], 3.3 [CI 1.9-5.8]). The same was true of the analysis of average or cumulative smoking consumption, and also of analyses stratified by different histological types. We conclude that for comparable exposure to tobacco smoke, the risk of lung cancer is comparable in women and men.     

Long-term survival of surgically staged IIIA-N2 non-small-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience.

BACKGROUND: The aim of this study was to analyse the outcome of surgically staged IIIA-N2 non-small-cell lung cancer (NSCLC) treated with induction chemotherapy followed by surgical exploration. METHODS: Univariate and multivariate analyses were carried out on a prospective cohort of 131 mediastinoscopy-proven IIIA-N2 NSCLC patients. Three preoperative cycles of vindesine-ifosfamide-cisplatin (VIP) were given. Patients with at least stable disease (SD) were considered for surgery, or radical radiotherapy in selected cases. RESULTS: The response rate after VIP was 54% (95% confidence interval 45% to 63%) and was important for the final outcome. The median and 5-year survival for the total group were 24 months and 21% (38 months and 30% in responders), respectively. Involvement of subcarinal nodes at diagnosis was the most important prognostic factor (P=0.022). Seventy-five patients were considered for surgery. Downstaging occurred in 34 of 70 resection specimens, with a pathological complete response in six. Median and 5-year survival in the surgical cohort were 45 months and 35%, respectively. Surgery was rewarding both in patients with a response and in those with SD, although the complete resection rate was significantly lower in the latter. On multivariate analysis, favourable prognostic factors were low pathological T-stage (P=0.001) and downstaging of mediastinal nodes in the resection specimen (P=0.008). CONCLUSIONS: VIP induction chemotherapy followed by surgical exploration was rewarding in mediastinoscopy-proven stage IIIA-N2 NSCLC, both in cases of response and SD, despite a lower complete resection rate in the latter. Patients with subcarinal nodes at diagnosis (5-year survival 8.5%) or without nodal downstaging at post-induction surgery (13.7%) might preferably be treated with a non-surgical approach.     

Intra-patient variability of tumor volume and tumor motion during conventionally fractionated radiotherapy for locally advanced non-small-cell lung cancer: a prospective clinical study

PURPOSE: The aim of this study was to investigate the change in tumor volume, motion, and breathing frequency during a course of radiotherapy, for locally advanced non-small-cell lung cancer. METHODS AND MATERIALS: A total of 23 patients underwent computed tomography-positron emission tomography (CT-PET) and respiration correlated CT scans before treatment, which was repeated in the first and second weeks after the start of radiotherapy. Patients were treated with an accelerated fractionation schedule, 1.8 Gy twice a day, with a total tumor dose depending on preset dose constraints for the lungs and spinal cord. RESULTS: A striking heterogeneity of tumor volume changes was observed at all time points. In some patients the volume decreased >30% (3/23), whereas in others the volume increased >30% (4/24); but for the majority of patients (16/23), the tumor volume changed only slightly (<30%). No significant changes in average tumor motion or breathing frequencies were observed during treatment. Although a number of changes in individual tumor motion were seen, only in 1 patient would this have led to an increase of the internal margin >1 mm in 1 direction, 1 week after the start of treatment, and in 3 patients for 1 direction, 2 weeks after the start of the treatment. CONCLUSION: In this patients in this study, a large variability in changes in tumor volume was observed. This underscores the need for repeated imaging during the course of radiotherapy. However, the changes in tumor motion are small, which indicates that repeated respiration correlated CT does not appear to be necessary.     

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study

Purpose We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). Methods Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m² and 30 mg/m², respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m² was conducted and primary objective in the phase II portion was response rate. Results The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m² because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C _max and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. Conclusion These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.