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Japanese Journal of Clinical Oncology Advance Access published online on June 11, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyp061
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© The Author (2009). Published by Oxford University Press. All rights reserved

A Phase I Study of Gemcitabine and Carboplatin in Patients with Advanced Non-small Cell Lung Cancer and a Performance Status of 2

Young Hak Kim1,2, Kaoru Kubota1, Koichi Goto1, Kiyotaka Yoh1, Seiji Niho1, Hironobu Ohmatsu1, Nagahiro Saijo1 and Yutaka Nishiwaki1

1 Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba
2 Department of Respiratory Medicine, Kyoto University Hospital, Kyoto, Japan

For reprints and all correspondence: Young Hak Kim, Department of Respiratory Medicine, Kyoto University Hospital, 54 Shogoin-Kawaharacho, sakyo-ku, Kyoto 606-8507, Japan. E-mail: ekim{at}kuhp.kyoto-u.ac.jp

Received April 16, 2009; accepted May 7, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of combination chemotherapy with gemcitabine (GEM) and carboplatin (CBDCA) in non-small cell lung cancer (NSCLC) patients with a performance status (PS) of 2.

Methods: Chemotherapy-naïve NSCLC patients with PS 2 were enrolled. Chemotherapy consisted of an escalated dose of GEM on days 1 and 8 and CBDCA on day 1 every 3 weeks. Patients were scheduled to receive GEM (mg/m2)/CBDCA (area under the curve: AUC) at four dose levels: 800/4 (level 1), 1000/4 (level 2), 1000/4.5 (level 3) and 1000/5 (level 4), respectively.

Results: Between February 2004 and August 2006, 13 patients were enrolled in this study. Dose-limiting toxicities (DLTs) were thrombocytopenia, febrile neutropenia and hyponatremia. DLTs were observed in two of six patients at dose level 1 and in three of six patients at dose level 2. Dose level 2 was thus determined to be the MTD. Among 12 evaluable patients, 7 patients had stable diseases and 5 patients had progressive diseases, and the median survival time was 3.8 months.

Conclusions: The MTD and the recommended dose for Phase II studies of this regimen were determined to be GEM 1000 mg/m2 and CBDCA AUC of 4. Additional objective measures are needed to evaluate patients’ risk and benefit in future clinical trials for PS 2 patients.

Key Words: non-small cell lung cancer • performance status 2 • gemcitabine • carboplatin • Phase I


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Platinum-based combination chemotherapy has been shown to improve survival and quality-of-life (QOL) in patients with advanced non-small cell lung cancer (NSCLC) (1,2). In the 1990s, new chemotherapeutic agents, such as gemcitabine (GEM), vinorelbine, docetaxel, paclitaxel (PTX) and irinotecan, were developed. Currently, platinum-based chemotherapy employing these new agents is accepted as the standard chemotherapy worldwide (3,4). In addition, a meta-analysis demonstrated significant longer progression-free survival of GEM and platinum combination compared with other new agents and platinum combinations (5). Thus, combination chemotherapy with GEM and platinum is now considered as one of the most active regimens for advanced NSCLC.

Like in other types of cancers, performance status (PS) has been shown to be one of the most important prognostic factors for survival in advanced NSCLC (6–8). Patients with impaired PS generally have lower response rate and shorter survival in spite of high risk for severe toxicities (9,10). Historically, clinical trials have excluded patients with Eastern Cooperative Oncology Group (ECOG) PS of 2 or worse. To date, it has not been fully elucidated whether platinum-based combination chemotherapy is feasible and effective in patients with PS 2.

Carboplatin (CBDCA), an analog of cisplatin (CDDP), has lower nephro- and gastrointestinal toxicity and has been widely used as a substitution of CDDP. Several randomized trials have shown the equivalence between GEM + CBDCA (GC) and GEM + CDDP (GP) in terms of response rate and survival (11,12). In those trials, toxicities, such as emesis, nephropathy and neuropathy were significantly mild in GC. Although recent meta-analysis disclosed slightly but significant survival advantage of CDDP (13,14), GC can be one of the treatment options, especially for patients who are not suitable to receive CDDP. In a randomized Phase III trial comparing GC with vinblastine + CDDP, GC showed better response rate and survival, and toxicities were similar between the two arms (15). Although 70% of all enrolled patients in the study had PS 2, overall response rate and median survival time (MST) were 27% and 11.6 months in GC arm. These survival data were comparable to those in patients with PS 0 or 1 who treated with platinum-based chemotherapy.

These results suggest the potential benefit of GC in patients with PS 2; however, the optimal dose of GC has not been investigated in patients with impaired PS. Therefore, we conducted a Phase I study to determine the maximum-tolerated dose (MTD) and the recommended dose for Phase II studies of GC in advanced NSCLC patients with PS 2.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Eligibility
Patients with histologically or cytologically proven advanced NSCLC were eligible for the study. Each patient was required to meet the following criteria: (i) clinical stage IIIB or IV; (ii) ECOG PS of 2; (iii) aged 20–75 years; (iv) measurable lesion; (v) no prior chemotherapy; (vi) adequate hematological function (white blood cell ≥3500/mm3, hemoglobin ≥9.5 g/dl and platelets ≥100 000/mm3); (vii) adequate hepatic and renal function (total bilirubin ≤1.5 mg/dl, AST and ALT<100 IU/l and creatinine ≤1.5 mg/dl); (viii) PaO2 ≥60 mmHg; and (ix) written informed consent. Patients with active concomitant malignancy, radiologically apparent interstitial pneumonia or pulmonary fibrosis, serious concurrent illness (e.g. uncontrolled diabetes mellitus, hypertension, angina pectoris, myocardial infarction within 3 months after onset or severe infection), history of severe drug allergy or pregnant/lactating women were excluded. The study protocol was approved by the institutional review board of the National Cancer Center.

Treatment Schedule
This was a Phase I, dose-escalation study planned for GEM on days 1 and 8 and CBDCA on day 1 of a 21-day course. The initial dose level of GEM was 800 mg/m2 and CBDCA was an area under the concentration–time curve (AUC) of 4 mg min/ml. The actual dose of CBDCA was calculated based on Cockcroft–Gault equation (16) and Calvert formula (17) every course. CBDCA was infused over 60 min, and 60 min after the completion of CBDCA infusion, GEM was administered over 30 min. Prophylactic administration of granulocyte colony-stimulating factor (G-CSF) was not permitted. Administration of G-CSF was permitted for patients with grade 4 neutropenia and/or leukopenia and grade 3 febrile neutropenia. The administration of GEM was omitted on day 8 if patients met one of the following criteria: white blood cell <2000/mm3, neutrophil <1000/mm3, platelets <50 000/mm3 and PS ≥3. No dose modification of GEM was permitted on day 8. If dose-limiting toxicity (DLT) was observed, the dose of each drug was reduced to 80% in the next course of chemotherapy. Treatment was to be performed for at least two courses, unless unacceptable toxicity or disease progression occurred.

The DLT was defined as follows: grade 4 thrombocytopenia, grade 3 or grade 4 febrile neutropenia, grade 3 non-hematological toxicity (except for nausea/vomiting and alopecia) and omission of the treatment on day 8. Dose-escalation schedule is shown in Table 1. Initially, three patients were treated at each dose level. If DLT was not observed in any of three patients, dose escalation was made. If DLT was observed in one or two of three patients, an additional three patients were entered in the same dose level. If DLT was observed in three or more of six patients or all of the initial three patients, we considered that the dose was the MTD. If DLT was observed in one or two of six patients, dose escalation was also made. Dose escalation was decided by the toxic data only in the first course of chemotherapy.


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  		Table 1. Dose-escalation schedule

 
Baseline and Treatment Assessment
Pre-treatment evaluation consisted of complete medical history and physical examination, complete blood cell counts, blood chemistry studies, electrocardiograph, arterial blood gas analysis, chest radiography, computed tomography (CT) of the chest, CT or ultrasound study of the abdomen, CT or magnetic resonance imaging of the brain, and bone scintigraphy. Complete blood cell counts, blood chemistry studies and chest radiography were repeated every week. Creatinine clearance was estimated by the Cockcroft–Gault equation every course. Tumor response was assessed with the Response Evaluation Criteria in Solid Tumor (RECIST) criteria (18). Toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (version 2.0).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Patient Characteristics
Between February 2004 and August 2006, 13 patients were enrolled in this study. However, one patient was excluded from the analysis because of the error in dose calculation. Table 2 shows the characteristics of 12 evaluable patients. Eleven patients were male and one was female. The median age of the patients was 68 years (range, 51–72 years). There were five adenocarcinomas, four squamous cell carcinomas, two large cell carcinomas and one pleomorphic carcinoma. Stage IIIB and IV patients were five and six, respectively, and one patient was a relapse after surgical resection.


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  		Table 2. Characteristics of evaluable patients (n = 12)

 
Dose Escalation
At the dose level 1, DLT was observed in two of the first three patients: one experienced grade 3 hyponatremia and the other experienced grade 3 febrile neutropenia. Thereafter, we amended the protocol, and grade 3 hyponatremia was excluded from DLT criteria after that. Another three patients were treated at the same dose. Since these patients did not show any additional DLT, the dosage was then escalated to the next step. At the dose level 2, DLT was observed in two of the first three patients: one experienced grade 3 nausea/vomiting and omission on day 8 and the other experienced grade 3 febrile neutropenia and anorexia. Therefore, another three patients were assigned to receive the treatment at the same dose. Out of those three patients, one patient developed grade 4 febrile neutropenia and grade 3 anorexia. Thus, DLT was observed in three of six patients at the dose level 2. As a result, the dose level 2 (GEM, 1000 mg/m2 and CBDCA, AUC of 4) was determined to be the MTD.

Toxicity
The worst grades for each patient in the first cycle are listed in Table 3. Grade 3/4 leukopenia or neutropenia was observed in one patient at level 1 and two patients at level 2. Febrile neutropenia was observed in one patient at level 1 and two patients at level 2. Two patients had grade 3/4 anemia at level 1 and one patient required red blood cell transfusion. No grade 3/4 anemia occurred at level 2. Thrombocytopenia was the principal toxicity of this combination chemotherapy. At level 1, grade 3/4 thrombocytopenias were observed in three patients, and two patients received platelet transfusion. At level 2, two patients experienced grade 3/4 thrombocytopenia requiring no platelet transfusions. Non-hematologic toxicities were generally mild at level 1, however, one patient experienced grade 3 nausea/vomiting and omission of day 8 at level 2. This patient also presented grade 3 hyperbilirubinemia suspected to be drug-induced hepatitis, and died 16 days after the start of the treatment. The worst value of his laboratory data was 6.6 mg/dl in total bilirubin on day 12, 40 IU/l in AST on day 7 and 103 IU/l in ALT on day 7. He had a past history of drug-induced hepatitis related to aspirin. The excluded patient was administered GEM at 800 mg/body. Despite the dose was approximately two-thirds of the planned dose, he experienced grade 3 nausea/vomiting and the treatment was discontinued. The median number of administered cycle was 1. The actual administered cycles were one in seven patients, two in one patient, three in two patients and four in two patients. The reasons for the discontinuation in seven patients who terminated the treatment at one cycle were toxicity for three patients, patient refusal for two patients, treatment delay for one patient and both toxicity and disease progression was for one patient.


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  		Table 3. Toxicities during the first cycle

 
Anti-tumor Activity
There were seven stable diseases and five progressive diseases (PD). No partial or complete response was observed (Table 4). Four patients received second-line chemotherapy after GC: docetaxel for two patients and gefitinib for two patients. One patient received gefitinib experienced partial response; however, remaining three patients had PD also in the second-line treatment. The MST was 3.8 months (Fig. 1).


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  		Table 4. Drug delivery and anti-tumor efficacy

 

Figure 1
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  		Figure 1. Kaplan–Meier curve of overall survival. Median overall survival time was 3.8 months.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
This is the first PS 2-specific Phase I study of GC in Japanese patients, and the MTD and recommended dose were determined to be GEM 1000 mg/m2 and CBDCA AUC of 4.

The recommended dose of CBDCA was lower than other studies conducted in the USA (19,20). With respect to the dose of CBDCA, the method of measuring serum creatinine values is critical. In Japan, most institutions use the enzymatic method, whereas the Jaffe method remains the mainstream in the USA (21). According to the study comparing these two methods, serum creatinine values are higher in the Jaffe method than in the enzymatic method by ~0.2 mg/dl (21). Therefore, at the same AUC, higher CBDCA dose is administered in Japan than in the USA. Incidentally, based on the Calvert formula, a difference of 0.2 mg/dl of creatinine leads to the difference of AUC = 1. In short, the AUC = 4 in Japan roughly corresponds to the AUC = 5 in the USA. For global clinical trials, the difference of methods for measurement of laboratory data also should be paid attention to.

PS is one of the most powerful and reliable prognostic factors in advanced NSCLC (6–8), and a worse PS is characterized by lower response rate to chemotherapy and shorter survival (9,10). Median survival of patients with PS 2 is substantially shorter than that of patients with PS 0 or 1. Moreover, patients with PS 2 are at higher risk for severe toxicity than those with better PS. According to the population-based surveys, up to 30–40% of all advanced NSCLC is characterized PS 2 (22,23). Namely, patients with PS 2 constitute a distinctive, non-trivial subgroup in NSCLC. However, little attention has been paid to this special patient population until recently.

The guidelines from the American Society of Clinical Oncology support the single use of third-generation non-platinum agents for patients with PS 2 (24). This recommendation is mainly based on the results of Phase III trials comparing single-agent chemotherapy with best supportive care alone, in which good tolerability and significant survival benefit or improvement of QOL with single-agent chemotherapy have been demonstrated (25–28). However, PS 2 patients accounted for a small proportion of patients in those trials and any conclusive evidence cannot be drawn for the treatment of patients with PS 2. At present, available data from PS 2-specific clinical trials are quite limited. In this context, no consensus has been developed on the standard chemotherapy in patients with PS 2.

The role of adding platinum to third-generation single agents is still unclear. Recently, the Norwegian Lung Cancer Study Group reported the results of a retrospective study that compared the outcome of patients with PS 2 to that of patients with PS 0 or 1 who had participated in randomized trials comparing two third-generation, CBDCA-based regimens (29). According to the retrospective study, although MST of patients with PS 2 was significantly shorter than that of patients with PS 0 or 1 (4.5 vs. 8.9 months; P < 0.01), toxicity was acceptable for patients with PS 2 and they achieved better symptom improvement compared with patients with PS 0 or 1. ECOG conducted the first PS 2-specific randomized trial (19). In the randomized Phase II trial, two platinum-based chemotherapy regimens, PTX + CBDCA (PC) and GP, have been compared, and both regimens were proved feasible with acceptable toxicity. However, survival time was quite limited in both treatment arms: MST was 6.2 months for PC and 6.9 months for GP, respectively. A Greece Group performed a randomized Phase II trial comparing non-platinum single-agent chemotherapy with CBDCA-based chemotherapy (30). In the study, patients were randomly assigned to either GC or GEM alone and MST was 6.7 months for GC and 4.8 months for GEM alone, respectively (P = 0.49), whereas neutropenia (P = 0.007) and thrombocytopenia (P < 0.001) were more common in GC arm. In contrast, according to a subgroup analysis of the Cancer and Leukemia Group B study 9730 comparing PC with PTX alone, patients with PS 2 (107 patients, 18% of the population) achieved significantly better survival when they were treated with PC than those treated with PTX alone (20). Thus, the role of platinum-based chemotherapy for patients with PS 2 is still controversial.

The results could vary even between PS 2-specific trials due to two major reasons. First, determining PS score is inevitably subjective, there is considerable inter-observer variation even between healthcare professionals (31). Second, there can be significant heterogeneity in the PS 2 patient population: the reasons for impaired PS may be due to tumor-related (such as pain, fatigue and weight loss), to pre-existing co-morbidities (such as chronic obstructive pulmonary disease, cardiovascular disease and age-related decline in functional status) or both, furthermore (32). There is a clear need for a more objective classification system that takes into account the individual effects of disease-related symptoms and co-morbidities. The common co-morbidity scales are the Cumulative Illness Rating Scale-Geriatric (CIRS-G) and the Charlson scale. Their prognostic impacts have been validated prospectively (33,34). Moreover, they are more objective than PS. Although our study did not, all future studies for PS 2 patients should use such co-morbidity scales to stratify patients more accurately.

Recently, molecular-targeted agents, especially epidermal growth factor receptor tyrosine kinase inhibitors such as gefitinib or erlotinib, have been tested in clinical trials for patients with poor PS. Inoue et al. (35) conducted a Phase II trial of gefitinib in patients with NSCLC whose tumor harboring EGFR gene mutation. In the study, all patients were not feasible for cytotoxic chemotherapy due to poor PS: 26 of 29 patients were PS 2–4. Overall response rate and MST were 66% and 6.5 months, respectively. In addition, PS improvement rate was 79%, and no treatment-related deaths were observed. These excellent results strongly suggest that stratification with molecular status should be required in the future trial of PS 2 or more.

In this study, we determined the MTD and the recommended dose of GC in Japanese patients with PS 2. Response rate and overall survival of the regimen were disappointing. However, some previous studies clearly support the use of platinum agent in PS 2 patients (19,20). Future clinical trials for PS 2 patients should use more objective criterion such as co-morbidity scales in addition to PS in order to measure patients’ risk more accurately. Such studies may reveal that which patients should be treated and not be treated with platinum-based chemotherapy among PS 2 patients.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This study was supported in part by a Grant-in Aid for Cancer Research from the Japanese Ministry of Health and Welfare.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
1 Souquet PJ, Chauvin F, Boissel JP, Cellerino R, Cormier Y, Ganz PA, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet (1993) 342:19–21.[CrossRef][Web of Science][Medline]

2 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ (1995) 311:899–909.[Abstract/Free Full Text]

3 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med (2002) 346:92–8.[Abstract/Free Full Text]

4 Bunn PA Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why? J Clin Oncol (2002) 20:23–33S.

5 Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer (2005) 47:69–80.[CrossRef][Web of Science][Medline]

6 Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst (1980) 65:25–32.[Web of Science][Medline]

7 Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol (1991) 9:1618–26.[Abstract]

8 Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress. Chest (2002) 122:1037–57.[Abstract/Free Full Text]

9 Gridelli C, Ardizzoni A, Le Chevalier T, Manegold C, Perrone F, Thatcher N, et al. Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Ann Oncol (2004) 15:419–26.[Abstract/Free Full Text]

10 Gridelli C, Maione P, Rossi A, Guerriero C, Ferrara C, Del Gaizo F, et al. Chemotherapy of advanced NSCLC in special patient population. Ann Oncol17 Suppl (2006) 5:v72–8.

11 Mazzanti P, Massacesi C, Rocchi MB, Mattioli R, Lippe P, Trivisonne R, et al. Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer (2003) 41:81–9.[Web of Science][Medline]

12 Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, et al. Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer (2003) 41:321–31.[CrossRef][Web of Science][Medline]

13 Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol (2004) 22:3852–9.[Abstract/Free Full Text]

14 Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst (2007) 99:847–57.[Abstract/Free Full Text]

15 Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer (2002) 37:9–14.[CrossRef][Web of Science][Medline]

16 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[Web of Science][Medline]

17 Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol (1989) 7:1748–56.[Abstract]

18 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.[Abstract/Free Full Text]

19 Langer C, Li S, Schiller J, Tester W, Rapoport BL, Johnson DH, et al. Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol (2007) 25:418–23.[Abstract/Free Full Text]

20 Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol (2005) 23:190–6.[Abstract/Free Full Text]

21 Ando Y, Minami H, Saka H, Ando M, Sakai S, Shimokata K. Adjustment of creatinine clearance improves accuracy of Calvert's formula for carboplatin dosing. Br J Cancer (1997) 76:1067–71.[Web of Science][Medline]

22 Buccheri G, Ferrigno D, Tamburini M. Karnofsky and ECOG performance status scoring in lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J Cancer (1996) 32A:1135–41.[CrossRef]

23 Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20 561 cases. Ann Oncol (2002) 13:1087–93.[Abstract/Free Full Text]

24 Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol (2004) 22:330–53.[Free Full Text]

25 The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst (1999) 91:66–72.[Abstract/Free Full Text]

26 Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst (2000) 92:1074–80.[Abstract/Free Full Text]

27 Roszkowski K, Pluzanska A, Krzakowski M, Smith AP, Saigi E, Aasebo U, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer (2000) 27:145–57.[CrossRef][Web of Science][Medline]

28 Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer—a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer (2000) 83:447–53.[CrossRef][Web of Science][Medline]

29 Helbekkmo N, Aasebo U, Sundstrom SH, von Plessen C, Brunsvig PF, Bremnes RM, Norwegian Lung Cancer Study Group. Treatment outcome in performance status 2 advanced NSCLC patients administered platinum-based combination chemotherapy. Lung Cancer (2008) 62:253–60.[CrossRef][Web of Science][Medline]

30 Kosmidis PA, Dimopoulos MA, Syrigos K, Nicolaides C, Aravantinos G, Boukovinas I, et al. Gemcitabine versus gemcitabine-carboplatin for patients with advanced non-small cell lung cancer and a performance status of 2: a prospective randomized phase II study of the Hellenic Cooperative Oncology Group. J Thorac Oncol (2007) 2:135–40.[Web of Science][Medline]

31 Taylor AE, Olver IN, Sivanthan T, Chi M, Purnell C. Observer error in grading performance status in cancer patients. Support Care Cancer (1999) 7:332–5.[CrossRef][Web of Science][Medline]

32 Gebbia V, Galetta D, De Marinis F. Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials. Ann Oncol (2005) 16(Suppl 4):iv123–31.[Free Full Text]

33 Firat S, Byhardt RW, Gore E. Comorbidity and Karnofksy performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys (2002) 54:357–64.[CrossRef][Web of Science][Medline]

34 Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol (2000) 18:2529–36.[Abstract/Free Full Text]

35 Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol (2009) 27:1394–400.[Abstract/Free Full Text]


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