|Year : 2018 | Volume
| Issue : 3 | Page : 282-287
Use of adjuvant chemotherapy for nonsmall cell lung cancer: Is advanced age a prognostic factor?
Ozgur Batum, Ceyda Anar, Yasemin Özdoğan, Sinem Ermin, Ufuk Yılmaz
Department of Chest Diseases, Dr. Suat Seren Chest Diseases and Thoracic Surgery Education and Research Hospital, Izmir, Turkey
|Date of Web Publication||28-Jan-2019|
Dr. Ozgur Batum
Department of Chest Diseases, Dr. Suat Seren Chest Diseases and Thoracic Surgery Education and Research Hospital, Izmir
Source of Support: None, Conflict of Interest: None
PURPOSE: In patients with nonsmall cell lung cancer (NSCLC), the effect of age on adjuvant chemotherapy (CT) after primary surgical treatment is controversial. The aim of this study was to investigate the effect of age and other clinical variables on survival in NSCLC patients who received adjuvant CT. MATERIALS AND METHODS: NSCLC patients who underwent primary resection and received adjuvant CT between January 2012 and January 2016 were included in the study. The patients were divided into two age groups: (1) patients >65 years old (older patient group) and (2) patients ≤ 65 years old (young patient group). The effects of clinical variables such as age, histology, pT stage, pN stage, pTNM stage, adjuvant thoracic radiotherapy, and recurrence status on survival were assessed using the log-rank test and multivariable Cox regression analysis. RESULTS: A total of 91 NSCLC patients who received adjuvant CT after complete resection were included in the study. The median age of the patients was 60 (36–73) years. Eighty-six percent of the patients were male. 49.4% had squamous NSCLC and 50.6% had nonsquamous NSCLC. 59% had stage I and II disease and 41% had stage III disease. The mean overall survival was 61.9 months [95% confidence interval (CI) 51.28–72.69] in the young patient group and 73.1 months (95% CI 60.24–85.94) in the older patient group . The mean disease-free survival was 47.0 months (95% CI 37.81–56.23) in the young patient group and 51.1 months (95% CI 40.68–57.17) in the older patient group (P = 0.119 and P = 0.407, respectively). Pathological stage III [heart rate (HR): 2.615, P = 0.014] and presence of recurrence (HR: 2.496, P = 0.019) were found to be independent risk factors. However, age did not show statistical significance (HR: 0.428, 95% CI 0.128–1.427, P = 0.167). CONCLUSION: In NSCLC patients who underwent complete resection and received adjuvant CT, advanced age had no prognostic effect on survival.
Keywords: Adjuvant chemotherapy, advanced age, survival
|How to cite this article:|
Batum O, Anar C, Özdoğan Y, Ermin S, Yılmaz U. Use of adjuvant chemotherapy for nonsmall cell lung cancer: Is advanced age a prognostic factor?. Indian J Cancer 2018;55:282-7
|How to cite this URL:|
Batum O, Anar C, Özdoğan Y, Ermin S, Yılmaz U. Use of adjuvant chemotherapy for nonsmall cell lung cancer: Is advanced age a prognostic factor?. Indian J Cancer [serial online] 2018 [cited 2019 Apr 26];55:282-7. Available from: http://www.indianjcancer.com/text.asp?2018/55/3/282/250886
| » Introduction|| |
The annual lung cancer incidence rate in Turkey in 2014 was 45.2 per 100,000 in men and 8.7 per 100,000 in women. The annual incidence rate of lung cancer related to aging is around 400 per 100,000 in men aged 60–79 years. Lung cancer constitutes more than 20% of the total cancer cases over the age of 60 in Turkey. In Turkey, the percentage of the population aged 65 years and more than 65 years is predicted to increase to 10.2% in the year 2023, and to 20.8% in 2050. If incidence rates continue to rise, we may expect to encounter more often with older lung cancer patients. According to the 2014 data, approximately 50% of lung cancer patients had a local or local-regional disease, and some of the patients who were operated needed systemic chemotherapy (CT).
In resected early-stage nonsmall-cell lung cancer (NSCLC) patients, the 5-year survival rate is 77% for stage I disease and 23% for stage IIIa. Local-regional recurrence or distant metastasis shortens total life expectancy and disease-free life expectancy. Adjuvant CT administered after surgical treatment in patients with stage II–IIIa NSCLC reduces recurrence rate and also improves total life expectancy and disease-free life expectancy. While adjuvant CT is not administered for stage Ia disease, the role of adjuvant CT in stage Ib disease is still a matter of debate. In general, adjuvant CT provides an improvement of 10–15% in 5-year survival rate in NSCLC patients undergoing complete resection. However, quality of life may deteriorate or deaths due to treatment may occur in non-well-selected cases.,, Comorbid diseases in advanced age patients may increase the severity of CT side effects., For this reason, in many studies, advanced age and type and severity of comorbid diseases are considered as the exclusion criteria for treatment.,,,
Discussions continue on how to use adjuvant CT in elderly patients with NSCLC. In a meta-analysis involving 3324 patients, it was shown that platinum-based adjuvant CT reduced mortality rate in stage II–IIIa NSCLC, but advanced age was associated with a higher risk of toxicity. Other studies indicate that adjuvant CT can be given in elderly patients.,,
The primary purpose of this study was to investigate the effects of age on survival and myelosuppression in NSCLC patients who received adjuvant CT after complete resection. The secondary goal was to determine the association of other clinical variables with survival.
| » Materials and Methods|| |
The patients who were followed in the Oncology Polyclinic of Dr. Suat Seren Chest Diseases and Thoracic Surgery Education and Research Hospital and who underwent primary surgical resection due to NSCLC between January 2012 and January 2016 were examined for the study inclusion criteria.
The study inclusion criteria were:
- Having a histological diagnosis of NSCLC
- Having complete resection
- Having Eastern Cooperative Oncology Group (ECOG) PS 0-1
- Receiving adjuvant CT (adjuvant radiotherapy was not an obstacle to inclusion in the study).
The study exclusion criteria were:
- Having noncomplete resection
- Having synchronous tumor
- Receiving neoadjuvant chemotherapy or chemoradiotherapy.
Pathologic tumor–node–metastasis (TNM) staging was performed according to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM Staging Manual. Performance status was determined according to the criteria of the ECOG. Complete resection was defined as an absence of both macroscopic and microscopic residual cancer, especially in the resection margins (bronchial, vascular, and any other margins with close proximity to the tumor).
The patients who underwent primary surgery and adjuvant chemotherapy ± radiotherapy were followed by thorax and upper abdominal computed tomography and blood tests. These examinations were performed once every 3 months for the first year, once every 6 months for the second year, and once every one year for the following years. New local complaints of the patients were also assessed.
Overall survival (OS) was defined as the time from the moment of operation until death due to any reason. Disease-free survival (DFS) was defined as the time from the moment of operation until disease recurrence and death. The recurrence occurring in primary tumor loci was defined as local recurrence. The recurrence occurring in regional lymph nodes was defined as regional recurrence. The metastasis occurring in the opposite hemithorax and extrapulmonary organs was defined as distant recurrence. Chemotherapy-induced myelosuppression was assessed according to the “Common toxicity criteria for adverse events 3.0.”
The patients were divided into two age groups: (1) patients >65 years old (older patient group) and (2) patients ≤65 years old (young patient group). The groups were compared using the Chi-square test in terms of gender, tumor histology, differentiation degree, pT stage, pN stage, pTNM stage, chemotherapy regimen, number of cycles, adjuvant thoracic radiotherapy (TRT), and recurrence status. The Kaplan–Meier method was used for survival analysis according to age groups. The OS and DFS differences between the groups were evaluated using the log-rank test. A value of P < 0.05 was considered statistically significant. The effects of clinical variables such as histology (squamous cell vs nonsquamous cell), pT stage (pT1-2 vs pT3-4), pN stage (N0 vs N1 + 2), pathologic stage (stage I + II vs stage IIIa + IIIb), recurrence (yes vs no), age group (≤65 years vs >65 years), and adjuvant TRT (yes/no) on survival were assessed using the log-rank test. Variables with P < 0.25 in the log-rank test were included in the multivariate Backward Cox regression analysis.
| » Results|| |
Ninety-one NSCLC patients who received adjuvant CT after complete resection between 2012 and 2016 were included in the study. The median age of the patients was 60 (36–73) years. The distribution of clinical characteristics of the patients according to the groups is shown in [Table 1].
The mean OS was 61.9 months [95% confidence interval (CI) 51.28–72.69] in the young patient group and 73.1 months (95% CI 60.24–85.94) in the older patient group (P = 0.119) [Figure 1]a. The mean DFS was 47.0 months (95% CI 37.81–56.23) in the young patient group and 51.1 months (95% CI 40.68–57.17) in the older patient group (P = 0.407) [Figure 1]b.
In the young patient group, the rate of grade 1–2 neutropenia was 77%, and the rate of grade 3–4 neutropenia was 22%. In the older patient group, the rate of grade 1–2 neutropenia was 90%, and the rate of grade 3–4 neutropenia was 10%. There was no statistically significant difference between the two age groups in terms of chemotherapy-induced myelosuppression [Table 2].
|Table 2: The distribution of myelosuppression toxicity according to age groups|
Click here to view
There was no significant difference in survival between the two age groups according to other variables (histology, pT stage, pN stage, pathologic stage, presence of recurrence, and adjuvant TRT) [Table 3]. The pT, stage, pN, recurrence, age, and adjuvant TRT variables were included in the multivariate Cox regression analysis. The multivariate Cox regression analysis did not find statistical significance for pT (HR: 1.442, 95% CI 0.595–3.494, P = 0.18), pN (HR: 1.405, 95% CI 0.532–3.711, P = 0.492), adjuvant TRT (HR: 1.418, 95% CI 0.632–3.178, P = 0.397), and age (HR: 0.428, 95% CI 0.128–1.427, P = 0.167), but showed that pathologic stage III (HR: 2.615, 95% CI 1.212–5.617, P = 0.014) and presence of recurrence (HR: 2.496, 95% CI 1.165–5.368, P = 0.019) increased the risk of mortality [Table 4]. The mean overall survival was 68.989 months (95% CI 60.365_77.613) in stage 1-2 patients and 50.631 months (95% CI 36.213_65.050) in stage 3 patients. OS was significantly longer in stage 1-2 patients as expected (p:006) [Figure 2]. Similary, OS was significantly longer in patients without recurrence. The mean overall survival was 70.014 months (95% CI 61.486_78.182) in patients without recurrence and 49.754 months (95% CI 35.885_63.623) (p:009) [Figure 3].
| » Discussion|| |
In our retrospective study, when the age of 65 was considered as the cut-off value, the survival time and incidence of myelosuppression obtained with adjuvant CT in NSCLC patients undergoing complete resection did not differ between the two age groups. However, locally advanced stage and presence of recurrence were determined as factors affecting survival.
The 5-year OS rates obtained with only primary surgical treatment in patients with stage I, II, and IIIa NSCLC were, respectively, 67, 34, and 13%.,,, However, the 5-year DFS rates were lower than these values. Recurrence occurs via systemic metastasis in 35% of patients undergoing surgery., Controlling of systemic disease with an effective adjuvant systemic CT can increase life expectancy.
Many randomized controlled trials and meta-analyses showed that adjuvant CT prolonged survival time in NSCLC patients with completely resected N1 and N2 disease. According to the results of meta-analyses, an increase of 5.4% was achieved in the 5-year survival rate for N1 disease.,,,, However, while adjuvant CT increases the 5-year survival rate, it should not cause morbidity and mortality due to treatment-related toxicity. In cases of metastatic lung cancer, the performance status, age, and weight loss are important criteria in selecting patients for CT. Patient selection for CT in patients undergoing thoracotomy and resection becomes more important. The patient must be given a sufficient period of time to improve the adverse effects of resection. Age is an important patient selection criterion after resection.
Although there was no statistically significant difference in the number of patients constituting the young and older patient groups in our study, there was a difference in terms of absolute values. The small number of patients might create this result. However, it might also be due to hesitations to administer adjuvant CT in elderly patients in daily practice. Despite the fact that the distribution of stage III patients was equally balanced in the study group, there was a statistically insignificant difference in the application of adjuvant radiotherapy in the young patient group. Cisplatin-based CT regimens were found to be similar in both groups. The number of cycles of adjuvant CT is planned as 4 in patients who can tolerate it. In our study group, there was no significant difference in reaching the planned number of CT cycles between the two age groups.
In our study, there was no significant difference in both OS and DFS between the two age groups. The National Cancer Institute of Canada Clinical Trials Group JBR.10 (NCIC-CTG JBR.10) trial concerning adjuvant CT involved in 327 young (≤65 years) and 155 elderly (>65 years) NSCLC patients. The subgroup analysis of this study indicated that OS was similar between younger patients and elderly subgroup before 75 years age. The LACE study showed that there was no significant difference in either OS or event-free survival between old age group (≥70 years), middle-age group (65–69 years), and younger age group (<65 years). The Adjuvant Navelbine International Trialist Association (ANITA) trial found that the median age of the patients was 59 years and that the 5-year survival rate increased in adjuvant CT group. In a study by Rodriguez et al., patients over 70 years of age undergoing lobectomy received less adjuvant CT than younger patients. In the same study, the multivariate analysis of preoperative and postoperative factors determined that only age was an independent determinant of CT use. In another study involving 2897 stage IB–III NSCLC patients who received adjuvant CT after surgical resection, it was reported that the risk of death was similarly reduced in both younger patients (HR: 0.79; 95% CI: 0.72–0.86) and patients over 70 years of age (HR: 0.79; 95% CI: 0.72–0.86).
Although adjuvant CT improves survival in patients with completely resected NSCLC, it is also associated with potentially adverse events. In a recent study, it has been reported that the increased mortality risk is higher in patients older than 70 years, especially ECOG ≥2, with higher comorbidity scores and a prolonged length of stay postoperatively as different from our study. So, the authors concluded that careful selection should be applied before the decision on the use of CT.
Severe hematologic adverse events occurred in a small proportion of patients in the study. These events did not prevent patients from taking maintenance CT. Although it was thought that elderly patients would develop more serious side effects, there was no significant difference when compared to young patients. However, in a study of Wisnivesky et al. involving older patients receiving postoperative adjuvant chemotherapy for resected stages II–IIIa lung cancer, adjuvant CT was associated with an increased rate of serious adverse events (odds ratio 2.0, 95% CI 1.5–2.6). In the JBR.10 trial, the rate of neutropenia was 88% and the rate of febrile neutropenia was 7%. In the Adjuvant Navelbine International Trialist Association (ANITA) trial, the rates of neutropenia and febrile neutropenia were 92 and 9%, respectively. In another study, the rate of grade 3–4 neutropenia was 40%. In our study, while the rates of grade 1–2 neutropenia and grade 3–4 neutropenia were, respectively, 77 and 22% in the young patient group and 90 and 10% in the older patient group. The rates of neutropenia and febrile neutropenia were similar for both groups.
In our study, clinical variables such as histology, pT stage, pN stage, pathologic stage, presence of recurrence, and adjuvant TRT except for age had no effect on survival. However, the multiple regression analysis revealed that pathologic stage III and presence of recurrence doubled mortality risk. A recently published study indicated that adjuvant CT was an independent prognostic factor in patients over 75 years old with completely resected stage IB–IIIa NSCLC and also emphasized that gender and stage were other prognostic factors.
Our study has some limitations. Firstly, the number of patients was small. Secondly, it was a retrospective study. The fact that it was a single-centered study and that the same CT regimen was mostly preferred can be considered as advantages of the study.
In conclusion, young and older NSCLC patients receiving adjuvant CT had similar survival times. There was no significant difference between side effects when similar benefit was achieved.
Financial support and sponsorship
No financial support and sponsorship.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Alam N, Shepherd FA, Winton T, Graham B, Johnson D, Livingston R, et al
. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature. Lung Cancer 2005;47:385-94.
Republic of Turkey Ministry of Health, Turkey Cancer Statistics, Ankara, 2017.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-80.
Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899-909.
Edwards BK, Howe HL, Ries LA, Thun MJ, Rosenberg HM, Yancik R, et al
. Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002;94:2766-92.
Owonikoko TK, Ragin CC, Belani CP, Oton AB, Gooding WE, Taioli E, et al
. Lung cancer in elderly patients: An analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25:5570-7.
Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: Race-, sex-, and age-based disparities. JAMA 2004;291:2720-6.
Jennens RR, Giles GG, Fox RM. Increasing under representation of elderly patients with advanced colorectal or non-small-cell lung cancer in chemotherapy trials. Intern Med J 2006;36:216-20.
Jatoi A, Hillman S, Stella P, Green E, Adjei A, Nair S, et al
. Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005;23:9113-9.
Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Under representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061-7.
Wisnivesky JP, Smith CB, Packer S, Strauss GM, Lurslurchachai L, Federman A, et al
. Survival and risk of adverse events in older patients receiving postoperative adjuvant chemotherapy for resected stages II-IIIA lung cancer: Observational cohort study. BMJ 2011;343:d4013.
Pepe C, Hasan B, Winton TL, Seymour L, Graham B, Livingston RB, et al
. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 2007;25:1553-61.
Ganti AK, Williams CD, Gajra A, Kelley MJ. Effect of age on the efficacy of adjuvant chemotherapy for resected non-small cell lung cancer. Cancer 2015;121:2578-85.
Früh M, Rolland E, Pignon JP, Seymour L, Ding K, Tribodet H, et al
. Pooled analysis of the effect of age on adjuvant cisplatin-based chemotherapy for completely resected non-small-cell lung cancer. J Clin Oncol 2008;26:3573-81.
Le Chevalier T. Adjuvant chemotherapy for resectable non-small cell lung cancer: Where is it going? Ann Oncol 2010;21:196-8.
Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-7.
Van Rens MT, de la Rivière AB, Elbers HR ve ark. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA. Chest 2000;117:374-9.
Naruke T, Tsuchiya R, Kondo H ve ark. Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: The Japanese experience. Ann Thorac Surg 2001;71:1759-64.
Pairolero PC, Williams DE, Bergstralh EJ ve ark. Postsurgical stage I bronchogenic carcinoma: Morbid implications of recurrent disease. Ann Thorac Surg 1984;38:331-8.
Cerfolio RJ, Bryant AS. Survival of patients with true pathological stage I non-small cell lung cancer. Ann Thorac Surg 2009;88:917-22.
Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd
ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e278S-e313S.
Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al
. Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9.
Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, et al
. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;2:CD011430.
Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, Astudillo J, et al
. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010;28:3138-45.
Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, et al
. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 2006;7:719-27.
Rodriguez KA, Guitron J, Hanseman DJ, Williams V, Starnes SL. Adjuvant chemotherapy and age-related biases in non-small cell lung cancer. Ann Thorac Surg 2012;94:1810-4.
Morgensztern D, Samson PS, Waqar SN, Devarakonda S, Robinson CG, Govindan R, et al
. Early Mortality in Patients Undergoing Adjuvant Chemotherapy for Non–Small Cell Lung Cancer. J Thorac Oncol 2018;13:543-9.
Bouchard N, Laberge F, Raby B, Martin S, Lacasse Y. Adjuvant chemotherapy in resected lung cancer: Two-year experience in a university hospital. Can Respir J 2008;15:270-4.
Yamanashi K, Okumura N, Yamamoto Y, Takahashi A, Nakashima T, Matsuoka T, et al
. Adjuvant chemotherapy for elderly patients with non-small-cell lung cancer. Asian Cardiovasc Thorac Ann 2017;25:371-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]