Original Study

Estimated Creatinine Clearance Rate Is Associated With the Treatment Effectiveness and Toxicity of Pemetrexed As Continuation Maintenance Therapy for Advanced Nonsquamous NoneSmall-Cell Lung Cancer Chung-Yu Chen,1,2 Jou-Wei Lin,2 Jenq-Wen Huang,3 Kuan-Yu Chen,1 Jin-Yuan Shih,1 Chong-Jen Yu,1 Pan-Chyr Yang1 Abstract The purpose of this study was to explore the predictive factors of the effectiveness and treatment toxicity for pemetrexed as continuation maintenance therapy in patients with advanced nonsquamous nonesmall-cell lung cancer. Patients with an estimated creatinine clearance rate (Ccr) < 60 mL/min had a significantly longer survival. However, a decrease in estimated Ccr was associated with a increased risk of Grade 3/4 neutropenia and anemia. Background: The purpose of this study was to explore the predictive factors of the effectiveness and treatment toxicity for pemetrexed as continuation maintenance therapy in patients with advanced nonsquamous nonesmall-cell lung cancer (NSCLC). Patients and Methods: Patients with advanced nonsquamous NSCLC treated with pemetrexed as continuation maintenance therapy were enrolled. The medical records were reviewed and analyzed, including data on basic characteristics, estimated creatinine clearance rate (Ccr), treatment responses, progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: A total of 124 patients were included and all had adenocarcinoma. Patients with an estimated Ccr < 60 mL/min had a significantly longer PFS and OS (P ¼ .045, and P ¼ .006, respectively). Each 10 mL/min increase in estimated Ccr was associated with an increase of 9.8% in the risk of disease progression, and an increase of 9.2% in the risk of death. In contrast, an increase of 10 mL/min in estimated Ccr was associated with a decreased risk of Grade 3/4 neutropenia by 50.9% and anemia by 42.2%. Conclusion: Estimated Ccr is helpful in predicting the effectiveness and treatment toxicities of pemetrexed maintenance therapy. Clinical Lung Cancer, Vol. 16, No. 6, e131-40 ª 2015 Elsevier Inc. All rights reserved. Keywords: Creatinine clearance rate, Maintenance therapy, Non-small cell lung cancer, Pemetrexed, Treatment effectiveness/toxicity

Introduction 1

Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan 2 Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin County, Taiwan 3 Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan Submitted: Nov 21, 2014; Revised: Jan 5, 2015; Accepted: Jan 6, 2015; Epub: Jan 10, 2015 Address for correspondence: Kuan-Yu Chen, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei 100, Taiwan Fax: 886-2-2358-2867; e-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.01.001

Lung cancer is the leading cause of cancer-related deaths worldwide. Platinum-based chemotherapy is recommended as first-line treatment for advanced nonesmall-cell lung cancer (NSCLC), which might prolong survival and improve quality of life.1 Although improvement has been achieved over the past decades, median progression-free survival (PFS) was 3 to 5 months for first-line platinum-based chemotherapy and median overall survival (OS) remained at 7 to 10 months.2,3 Many efforts were made to improve the survival benefit of first-line chemotherapy for patients with advanced NSCLC. A meta-analysis of randomized trials demonstrated that extending

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Ccr and Treatment Effectiveness/Toxicity of Pemtrexed chemotherapy could substantially improve PFS, with a modest improvement in OS and a greater rate of adverse events.4 Maintenance therapy is another strategy to improve outcomes for patients with advanced NSCLC.5-8 After achieving disease control, maintenance therapy is to prolong treatment duration at the end of initial chemotherapy,5,6 with adding either the drugs included in the induction chemotherapy regimen (continuation maintenance) or other not cross-resistant agents (switch maintenance).7,8 The treatment guidelines of the American Society of Clinical Oncology9 and European Society of Medical Oncology10 suggest maintenance therapy for patients with advanced nonsquamous NSCLC who did not have disease progression immediately after platinum-based chemotherapy. Several phase III clinical trials demonstrated that maintenance therapy might improve PFS and OS for advanced NSCLC patients with controlled disease after 4 cycles of platinum-based chemotherapy,11-15 including the maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT) trial for pemetrexed as continuation maintenance therapy. Compared with the best supportive care, pemetrexed maintenance therapy significantly improved PFS, OS, and quality of life.13-15 A good safety profile was also presented in pemetrexed maintenance therapy.16,17 Compared with studies on first-line or second-line therapy in NSCLC, few studies evaluated the predictive factors of the effectiveness of pemetrexed as maintenance therapy. Therefore, we conducted a retrospective study to explore the clinical factors potentially associated with the outcome and treatment toxicities of pemetrexed as continuation maintenance therapy for patients with advanced nonsquamous NSCLC.

Patients and Methods Patients From September 2009 to September 2012, patients with stage IIIB or IV nonsquamous NSCLC treated with pemetrexed as continuation maintenance therapy and with Eastern Cooperative Oncology Group Performance Status of 0 to 1 were included. These patients were recruited from National Taiwan University Hospital and National Taiwan University Hospital Yunlin Branch. All patients had received 4 to 6 cycles of pemetrexed with platinum as first-line chemotherapy without disease progression. The doublet regimens were pemetrexed (500 mg/m2) with cisplatin (60-75 mg/m2) or carboplatin (Area under the curve 4-6) on day 1 every 3 weeks. The patients received pemetrexed 500 mg/m2 intravenously every 3 weeks as continuation maintenance therapy. The medical records were reviewed and data on age, sex, smoking status, comorbidities, disease stages, metastatic sites, cisplatin or carboplatin use, previous or concurrent palliative radiotherapy, treatment responses to first-line chemotherapy and maintenance therapy, survival, and chemotherapy-related hematologic, hepatic, and renal toxicities were analyzed. Disease stages were determined according to the seventh version of the tumor, node, metastases staging system for lung cancer of the International Association for the Study of Lung Cancer.18 The reasons for treatment discontinuation during the follow-up period were recorded.

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The estimated creatinine clearance rate (Ccr) was calculated using the CockcrofteGault formula at the first dose of pemetrexed maintenance therapy. According to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative guideline for evaluation, classification, and stratification of chronic kidney disease19 and the BIRMA (Belgian Renal Insufficiency and Anticancer Medications) study,20 a creatinine level > 1.2 mg/dL,20 or an estimated creatinine clearance < 60 mL/min19,20 is a sign of renal insufficiency. Therefore, the cutoff value for categorizing serum creatinine as < 1.2 or  1.2 mg/dL and for categorizing estimated Ccr as < 60 or  60 mL/min was used.

Evaluation of Treatment Effectiveness and Toxicities Chest radiography was performed every 2 to 4 weeks, and chest computed tomography scans were undertaken every 2 to 3 months as routine clinical practice, and as needed to confirm the treatment response. Treatment response was defined as the best response recorded during the period from the start of the treatment to the time of disease progression or treatment discontinuation. The treatment responses were evaluated according to the Response Evaluation Criteria in Solid Tumors21 and defined as complete remission (CR), partial response (PR), stable disease (SD), and progressive disease. Response rate was defined as the percentage of patients who achieved CR or PR. Information on survival was obtained through active follow-up based on verification of the patients’ vital status. The definition of PFS was defined as the time period from the date of beginning pemetrexed maintenance therapy to the date of objectively determined disease progression. Patients who had not experienced disease progression but discontinued treatment because of unacceptable adverse events, decision of the patient or physician, or died were censored. OS was defined as the time period from the date of beginning pemetrexed maintenance therapy to the date of death or the last follow-up. Patients were followed until July 31, 2013. Any Grade 3 to 4 hematologic, hepatic, or renal toxicities that occurred during the period of pemetrexed maintenance therapy were recorded, and if the patients discontinued pemetrexed maintenance therapy because of intolerable adverse effects. The adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.22

Statistical Analysis Continuous variables are expressed as median with ranges, and categorical variables as a percentage of the group from which they were derived. The proportions of variables between groups were compared using Pearson c2 test or Fisher exact test. KaplaneMeier curves were plotted for the subgroups of clinical factors, and the log-rank test was used to determine statistical significance. A Cox regression model was used for covariate analysis to determine the hazard ratio (HR) of clinical factors and survival. A P value < .05 was considered significant. Multivariate analysis using a logistic regression model was performed with variables with a P value < .05 in univariate analysis. All analyses were performed using SPSS software (version 16, SPSS Institute, Chicago, IL).

Chung-Yu Chen et al Table 1 Patient Demographic Characteristics, Treatment Outcomes, and Toxicities Characteristic

Value

Median Age (Range), Years

64 (31-87)

Male Sex

70 (56.5)

Ever or Current Cigarette Smoking Adenocarcinoma

Table 1 Continued Characteristic Creatinine

Value 5 (4.0)

AST

9 (7.3)

ALT

7 (5.6)

48 (38.7) 124 (100)

Disease Stage IIIB

6 (4.8)

IV

118 (95.2)

Values are n (%) except where otherwise noted. Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; Ccr ¼ creatinine clearance rate; COPD ¼ chronic obstructive pulmonary disease; HBV ¼ hepatitis B virus; HCV ¼ hepatitis C virus; OS ¼ overall survival; PFS ¼ progression-free survival. a A total of 13 patients were still receiving pemetrexed maintenance therapy as of the last followup date in this study.

Metastatic Site Pleural effusion

46 (37.1)

Bone

46 (37.1)

Results

Lung to lung

34 (27.4)

Clinical Characteristics

Brain

29 (23.4)

Liver Palliative Radiotherapy

7 (5.6) 28 (22.6)

Platinum in First-Line Chemotherapy Cisplatin

91 (73.4)

Carboplatin

32 (25.8)

Cisplatin/Carboplatin

1 (0.8)

Comorbidities Cardiovascular disease

30 (24.2)

COPD/asthma

17 (13.7)

Diabetes mellitus

15 (12.1)

Other malignancies

11 (8.9)

HBV/HCV infection Median Estimated Ccr (Range), mL/min

8 (6.5) 65.8 (20.5-229.5)

Treatment Response to First-Line Chemotherapy PR

82 (66.1)

SD

42 (33.9)

Median Maintenance Treatment Cycles (Range)

6 (1-36)

Median PFS (Months)

3.9

Median OS (Months)

19.6

Best Treatment Response PR

22 (17.8)

SD

36 (29.0)

PD

66 (53.2)

Reason for Discontinuationa Disease progression

96 (77.4)

Intolerable toxicities

10 (8.1)

Death

From September 2009 to September 2012, 227 patients with advanced nonsquamous NSCLC received pemetrexed with platinum as first-line treatment, and 191 completed 4 to 6 cycles of chemotherapy. A total of 149 patients had controlled disease, and 124 of them who started pemetrexed maintenance therapy were included. The patient demographic characteristics are shown in Table 1. The median age was 64 years old. Most patients were male (70 patients [56.5%]), never-smokers (76 patients [61.3%]), stage IV disease (118 patients [95.2%]). All patients had lung adenocarcinoma. The median estimated Ccr was 65.8 mL/min. For the firstline chemotherapy regimen, 91 patients (73.4%) received cisplatin, 32 (25.8%) received carboplatin, and 1 received cisplatin at first and then shifted to carboplatin. Before starting pemetrexed maintenance therapy, 82 patients (66.1%) had PR.

5 (4.0)

Treatment Effectiveness, Outcomes, and TreatmentRelated Toxicities The median number of treatment cycles was 6. The best treatment response was PR in 22 patients (17.8%) and SD in 36 (29.0%). The median PFS was 3.9 months, and OS was 19.6 months (Table 1). The most common reason for treatment discontinuation was disease progression (n ¼ 96; 77.4%), followed by intolerable adverse effects (n ¼ 10; 8.1%; 6 patients had fatigue, 1 had pancytopenia, 1 had neutropenic fever, 1 had hepatitis, and 1 had edema) and death (n ¼ 5; 4.0%; Table 1). Thirteen patients were still receiving pemetrexed maintenance therapy at the last follow-up date. In terms of Grade 3/4 hematologic, renal, and hepatic toxicities, 5 patients (4.0%) developed neutropenia, 10 (8.1%) had anemia, and 4 (3.2%) had thrombocytopenia. Five patients (4.0%) had increased creatinine level, 9 (7.3%) had increased aspartate aminotransferase level, and 7 (5.6%) had increased level of alanine aminotransferase (Table 1).

Grade 3/4 Toxicities

Clinical Factors Associated With Treatment Effectiveness

Hematologic Neutropenia Anemia Thrombocytopenia Nonhematologic

5 (4.0) 10 (8.1) 4 (3.2)

In univariate analysis (Table 2), we found that elderly patients (aged  70 vs. < 70 years, median PFS: 7.9 vs. 3.7 months; P ¼ .005; Figure 1A), and patients with a higher serum creatinine level ( 1.2 vs. < 1.2 mg/dL, median PFS: 16.7 vs. 4.0 months; P ¼ .004; Figure 1B) had a significantly longer PFS. In multivariate

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Ccr and Treatment Effectiveness/Toxicity of Pemtrexed Table 2 Univariate Analysis for Median Progression-Free Survival and Overall Survival PFS, Months

P

OS, Months

P

70 (n ¼ 44)

7.9

.005

25.4

.369