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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1553-1561 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5570 Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10
From the Division of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada; Southwest Oncology Group, San Antonio, TX; Eastern Cooperative Oncology Group, Boston, MA; and Cancer and Leukemia Group B, Chicago, IL Address reprint requests to Carmela Pepe, MD, FRCPC, Pulmonary Division, Sir Mortimer B. Davis–Jewish General Hospital, 3755 Côte Ste-Catherine Rd, Room G-203, Montréal, Québec, Canada, H3T 1E2; e-mail: carmela.pepe{at}mail.mcgill.ca
Purpose Recent trials have shown significant survival benefit from adjuvant chemotherapy for non–small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10.
Patients and Methods Pretreatment characteristics and survival were compared for 327 young ( Results Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13). Conclusion Despite elderly patients’ receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.
Lung cancer is the leading cause of cancer death in North America.1 Approximately 85% of lung cancers are of the non–small-cell lung cancer (NSCLC) type, and for patients who present with early stage NSCLC (approximately 30%), surgery is the initial treatment of choice. The 5-year survival rates after resection are approximately 55% to 65% for pathologic stage I disease, 40% to 55% for stage II, and 20% to 25% for locally advanced stage IIIA.2 Because most relapses occur at distant sites, adjuvant chemotherapy for NSCLC has been studied extensively by many groups over the last three decades.3 A meta-analysis4 of the trials conducted in the 1970s and 1980s showed that the addition of platinum-based chemotherapy to surgery resulted in a hazard ratio (HR) of 0.87 and an absolute survival benefit of 5% at 5 years. This difference did not reach statistical significance, and the results were not considered adequate for most physicians to recommend adjuvant chemotherapy for NSCLC. In 2004 and 2005, three trials evaluating modern chemotherapy regimens have survival benefits for patients with completely resected stage I-IIIA NSCLC.5-7 Absolute survival benefits at 5 years ranged from 8.6% to 15%, with overall HRs of 0.62 to 0.79. The results of these landmark studies have changed the standard of care for the management of resected early-stage NSCLC. Lung cancer is predominantly a disease of the elderly, and although the incidence of lung cancer has decreased recently in younger adults, it has increased over the years in those aged 70 years or more.8 More than 50% of lung cancer diagnoses are made in patients older than 65 years of age, and 30% to 40% in patients older than age 70.9,10 Unfortunately, despite the elderly population's being the most afflicted by lung cancer, they are the least well studied. The median age of patients with newly diagnosed lung cancer participating in clinical trials is approximately 60 years. This may be caused by the strict exclusion criteria of the studies that do not allow participation of patients with multiple comorbid conditions, or it may result from a fear of increased toxicity in the elderly population. Few randomized studies have been conducted specifically in elderly patients, and the guidelines that exist for the selection and treatment of elderly patients have been drawn largely from retrospective analyses of elderly patients who participated in trials designed primarily for younger patients. Because of concerns of increased toxicity with platinum-based doublet chemotherapy, single-agent treatments or nonplatinum doublets have been studied more extensively in the elderly population.11,12 However, the results of retrospective studies suggest that elderly patients can tolerate some platinum-based chemotherapy combinations as well as younger patients can, and that older patients may gain the same degree of clinical benefit.13,14 To date, trials specifically designed for elderly patients using platinum-based doublets have not been conducted. There have been no analyses of adjuvant chemotherapy in elderly patients with NSCLC. In view of the significant survival advantage seen in recent trials, we felt that it would be important to examine the elderly population of patients treated in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study JBR.10 to determine whether they derived the same survival benefit as did their younger counterparts and to compare chemotherapy delivery and toxicity.
Study Design JBR.10 was a phase III randomized trial of adjuvant cisplatin and vinorelbine versus observation after complete resection of stage IB or stage II NSCLC. The main goal of this study was to determine whether adjuvant postoperative chemotherapy conferred a survival benefit compared with observation alone. Accrual began in February 1994 in the NCIC CTG and ended in April 2001. The Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, and Southwest Oncology Group joined the study in 1998. Full details of the study have been reported previously.5
Study Population
Statistical Methods Dose-intensity was defined as total dose, measured in mg/m2, divided by 16, for patients who had no dose delays and for those who did not complete treatment. For patients who required dose delays, dose-intensity was calculated as the total dose divided by the number of weeks between the first and last doses of chemotherapy. Laboratory results, adverse events, and other symptoms were graded using the NCIC CTG Expanded Common Toxicity Criteria. Statistical analyses were carried out using SAS (SAS Institute, Cary, NC) and/or S-Plus (Insightful Corp, Seattle, WA)/R software.
Baseline Characteristics Of the 482 patients randomly assigned to JBR.10, 327 were young and 155 were elderly. Baseline prognostic factors for each age group for all randomly assigned patients are compared in Table 1. More young patients had a diagnosis of adenocarcinoma than did elderly (58% v 43%), and fewer young patients had squamous cell carcinoma (32% v 49%; P = .001). Performance status (PS) of 0 was more frequent among young patients (53% v 41%; P = .01). When comparing the baseline prognostic factors by age for patients randomly assigned to receive chemotherapy (Table 2), only PS remained significantly different between the young and elderly (PS 0: 57% of young v 36% of elderly patients; P = .004).
OS and DSS The Kaplan-Meier curve for OS for young versus elderly patients for all randomly assigned patients is shown in Figure 1A. The difference in OS between the groups was not statistically significant (HR for young v elderly, 0.77; 95% CI, 0.57 to 1.03; P = .08). The Kaplan-Meier curve for DSS for young versus elderly (Fig 1B) shows no significant difference (HR for young v elderly, 0.88; 95% CI, 0.63 to 1.21; P = .45). OS and DSS were further evaluated by categorizing age into four subgroups: 65 and younger, 66 to 70, 71 to 75, and more than 75 years. There were 327, 84, 48, and 23 patients in each subgroup, respectively. OSs were similar to the younger group (  65) in the elderly subgroups up to age 75, with HRs of 1.20 (95% CI, 0.83 to 1.73; P = .34) for patients 66 to 70 years old and 1.06 (95% CI, 0.65 to 1.71; P = .83) for patients 71 to 75 years old, whereas the HR was 2.41 (95% CI, 1.43 to 4.06; P < .001) for patients older than 75 years (Fig 1C). DSSs, however, were not significantly different when the younger age group was compared with the elderly subgroups with HRs of 1.21 (95% CI, 0.82 to 1.80; P = .34) for patients age 66 to 70 years, 1.03 (95% CI, 0.61 to 1.74; P = .93) for patients age 71 to 75 years, and 1.18 (95% CI, 0.55 to 2.54; P = .67) for patients older than 75 years (Fig 1D).
OS (Fig 2A and 2B) and DSS (Fig 2C and 2D) were evaluated in all elderly patients by randomized treatment group. There were 77 patients in the chemotherapy arm and 78 patients in the observation arm. Chemotherapy conferred a survival advantage over observation in elderly patients, with an HR of 0.61 (95% CI, 0.38 to 0.98; P = .04) that was similar to the treatment effect in the overall trial population (P = .41 for chemotherapy by age group interaction). This was true also for DSS (HR, 0.66; 95% CI, 0.39 to 1.13; P = .13; P = .79 for chemotherapy by age group interaction). Treatment effect was explored further in patients older than 75 years, although there were only 12 assessable patients in the chemotherapy arm and 11 in the observation arm. Chemotherapy effect in this subgroup (HR, 2.35; 95% CI, 0.84 to 6.58; P = .09) was significantly different from that of the overall trial (P = .03 for chemotherapy by age > 75 years interaction). Similar results were observed in DSS for the subgroup (HR, 7.13; 95% CI, 0.85 to 60.00; P = .04; P = .004 for chemotherapy by age > 75 years interaction).
Chemotherapy Delivery and Treatment-Related Toxicity Cisplatin and vinorelbine dose-intensity was analyzed in 213 patients (150 young and 63 elderly) who received at least one dose of adjuvant chemotherapy (Table 3). Mean dose-intensity for all patients was 18.8 mg/m2/wk for cisplatin and 12.7 mg/m2/wk for vinorelbine. Comparing young with elderly age groups, the mean dose-intensities were 18.0 versus 14.1 mg/m2/wk for cisplatin (P = .001) and 13.2 versus 9.9 mg/m2/wk for vinorelbine (P = .0004).
Elderly patients received fewer doses of cisplatin compared with young patients (fewer than five doses, 49% v 27%; five to seven doses, 19% v 21%; all eight doses, 32% v 51%; P = .006). Similarly, elderly patients received fewer vinorelbine doses (< 10 doses, 71% v 51%; 10 to 15 doses, 29% v 47%; all 16 doses, 0% v 3%; P = .014). More elderly patients discontinued chemotherapy treatment due to refusal compared with younger patients (40% v 23%; P = .01). Toxicity by age group is shown in Table 4. Among 26 toxicity outcomes evaluated, none was significantly different between the young and elderly. Hematologic toxicities were similar, with anemia and neutropenia common in both age groups, and there was no difference in hematopoietic growth factor usage by age group (P = .20). Nausea, anorexia, and neuropathy were reported somewhat more frequently by young patients, but this may have been due to younger patients’ having received more chemotherapy. There was no difference in hospitalization by age group (P = .86), and there was only one treatment-related death in each age group. Cause of death for each age group by treatment arm is shown in Table A1 (Appendix, online only). More elderly patients had non–disease-related deaths than did young patients (P = .13).
Elderly patients older than 65 years of age now comprise more than half of the lung cancer population overall, yet few studies designed specifically for the elderly have been performed. Furthermore, studies that have addressed therapy for older patients have focused mainly on the treatment of advanced disease. Approximately one third of patients with NSCLC present with early-stage cancers that are amenable to surgical resection and are, therefore, potentially curable. Reports of the feasibility of surgery in elderly patients (> 70 years) with early-stage tumors show that operative procedures can be performed safely with OS results that are similar to those seen in younger patients.15-17 Perioperative mortality of 3% and morbidity of 10% were seen in one series of patients age 70 years or older,16 and no mortality was reported in another series of 40 patients older than 80 years, although nonlethal postoperative complications approached 20%.17 Careful selection of elderly patients for lung cancer surgery is necessary, but age alone does not appear to be a contraindication to surgery. Until recently, observation alone after complete resection was the standard of care for stages I to III NSCLC. However, one large international trial that allowed any of four cisplatin-based doublets18 and two other trials, including JBR.10, that administered cisplatin and vinorelbine5,7 have shown that a brief course of adjuvant chemotherapy can result in significant improvement in both disease-free survival and OS. The Cancer and Leukemia Group B trial that administered four adjuvant cycles of carboplatin and paclitaxel was initially reported as a study with positive results,6 but a recent update now shows that OS was not significantly prolonged, although the difference in disease-free survival remains significant.19 At this time, it is unknown whether the elderly population derives equal benefit without suffering increased toxicity compared with younger patients. Since combined-modality therapy consisting of surgery and adjuvant chemotherapy is potentially curative, it is important that elderly patients not be denied access to such treatment solely on the basis of age. For that reason, we felt that it was important to examine the effect of age on outcome, treatment delivery, and toxicity in the North American Intergroup JBR.10 trial.
When all randomly assigned patients in both arms were compared, no significant differences could be detected in OS or DSS between younger ( Our exploratory subgroup analyses of the elderly group (66 to 70, 71 to 75, and > 75 years) showed that in patients up to 75 years of age, OS was similar to that of younger patients, although this was not the case in patients older than 75 years. However, DSS was similar for all age groups, including patients older than 75 years. A possible explanation for this lies in the observation that patients older than 75 years had proportionately more deaths that were unrelated to lung cancer or its treatment compared with the other subgroups. Overall, 21.1% of deaths (15 of 71) in patients older than 65 years resulted from nonmalignant causes versus 11.9% (15 of 126) in young patients and in patients older than 75 years, this rose to 50.0% (eight of 16). The results seen in the group older than 75 years must be interpreted with caution in view of the small size of this cohort. An analysis of chemotherapy compliance for all patients in JBR.10 has been reported previously.20 In this analysis, we have shown that the elderly patients received significantly lower dose-intensity than did younger patients. Our analysis of toxicity by age does not suggest that this resulted from significantly increased toxicity in the elderly patients. We postulate that both the elderly patients and their physicians may have been less willing to tolerate even modest degrees of toxicity, particularly at a time when the benefits of adjuvant chemotherapy were unproven. This is supported by the greater rate of refusal to continue chemotherapy seen in elderly patients compared with the young. The poorer PS of the elderly patients may also have contributed to the decreased compliance. However, it is important to emphasize that decreased adherence to the treatment protocol did not influence the clinical benefit of the adjuvant treatment received by the elderly patients, at least up to 75 years of age. Siu et al21 reported similar results in their analysis of elderly patients treated with chemotherapy and radiotherapy for limited-stage small-cell lung cancer. Response and survival rates were similar for patients younger than 70 years of age compared with those 70 years and older. However, just as in this analysis of JBR.10, the elderly patients received significantly less chemotherapy, even though toxicity was comparable between the two age groups. As was the case in this analysis of JBR.10, patients age 76 to 80 years with small-cell lung cancer in the Siu analysis had poorer overall survival. Chemotherapy treatment in elderly patients presents specific challenges. Comorbid illnesses such as cardiac, renal, or hepatic dysfunction may lead to reduced clearance of drugs and an increased risk of toxicity. In the setting of advanced NSCLC, studies designed specifically for the elderly have focused on single-agent therapy or nonplatinum combinations.11,12 Elderly-specific randomized trials have not been conducted to assess the tolerability of platinum-based doublet chemotherapy. Retrospective analyses have suggested that elderly patients can tolerate such treatment, although one study demonstrated an increase in mortality with increasing age after starting platinum-based chemotherapy.22 Cisplatin and carboplatin have been administered in doublet chemotherapy regimens in elderly patients and with modified schedules, with mixed results.13,23 In the absence of randomized controlled trials of platinum-based treatment specifically designed for elderly patients in the advanced disease setting, no firm conclusions can be drawn. It is unlikely that specific trials of adjuvant therapy comparing modified chemotherapy regimens or platinum- versus nonplatinum-based chemotherapy will be designed for elderly patients, and so extrapolations will have to be made from prospective trials in the advanced setting or from other retrospective analyses of age in the previously reported unrestricted adjuvant trials. There is, however, one trial of adjuvant single-agent vinorelbine currently open in Europe for patients who could not tolerate platinum-based chemotherapy. This study may include a larger proportion of elderly patients, and so the results are awaited with interest. In summary, this analysis shows that, despite receiving less total chemotherapy than did younger patients, elderly patients derive a similar survival benefit from adjuvant chemotherapy and with an acceptable toxicity profile. Although these fit elderly patients in JBR.10 may not be representative of all older lung cancer patients, adjuvant chemotherapy should not be withheld from elderly patients purely on the basis of age; however, the population of patients older than 75 years requires further study. Now that the benefit of adjuvant chemotherapy for NSCLC has been proven, it may also be of interest to study the perception of elderly patients with respect to such treatment and to determine their views on the cost (in terms of toxicity) -benefit ratio that would be required for them to accept adjuvant treatment.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Frances A. Shepherd, Pierre Fabre Research Funds: Frances A. Shepherd, GlaxoSmithKline; Lesley Seymour, GlaxoSmithKline Testimony: N/A Other: N/A
Conception and design: Timothy L. Winton, Robert B. Livingston, David H. Johnson, James R. Rigas, Frances A. Shepherd Financial support: N/A Administrative support: Lesley Seymour Provision of study materials or patients: Timothy L. Winton, Robert B. Livingston, David H. Johnson, James R. Rigas, Frances A. Shepherd Collection and assembly of data: Baktiar Hasan, Lesley Seymour, Barbara Graham, James R. Rigas, Keyue Ding, Frances A. Shepherd Data analysis and interpretation: Carmela Pepe, Baktiar Hasan, Timothy L. Winton, Lesley Seymour, Barbara Graham, Keyue Ding, Frances A. Shepherd Manuscript writing: Carmela Pepe, Baktiar Hasan, Lesley Seymour, David H. Johnson, Keyue Ding, Frances A. Shepherd Final approval of manuscript: Carmela Pepe, Baktiar Hasan, Timothy L. Winton, Lesley Seymour, Barbara Graham, Robert B. Livingston, David H. Johnson, James R. Rigas, Keyue Ding, Frances A. Shepherd Other: Carmela Pepe
published online ahead of print at www.jco.org on March 19, 2007. C.P. and B.H. contributed equally to this work. Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Supported in part by a grant from GlaxoSmithKline (then Burroughs Wellcome). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:1710-1717, 1997[CrossRef][Medline] 3. Visbal AL, Leighl NB, Feld R, et al: Adjuvant chemotherapy for early-stage non-small cell lung cancer. Chest 128:2933-2943, 2005[CrossRef][Medline] 4. 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 311:899-909, 1995 5. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005 6. Strauss GM, Herndon J, Maddaus MA, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non–small-cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 22:621s, 2004 (suppl; abstr 7019) 7. Douillard JY, Rosell R, Delena M, et al: ANITA: Phase III adjuvant vinorelbine and cisplatin versus observation in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients—Final results after 70-month median follow-up, On behalf of the Adjuvant Navelbine International Trialists Association. J Clin Oncol 23:624s, 2005 (suppl; abstr 7013) 8. Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review 1975-2000. http://seer.cancer.gov/csr/1975_2000 9. Bunn PA Jr, Lilenbaum R: Chemotherapy for elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 95:341-343, 2003 10. Montella M, Gridelli C, Crispo A, et al: Has lung cancer in the elderly different characteristics at presentation? Oncol Rep 9:1093-1096, 2002[Medline] 11. Gridelli C, Shepherd FA: Chemotherapy for elderly patients with non–small-cell lung cancer: A review of the evidence. Chest 128:947-957, 2005[CrossRef][Medline] 12. Gridelli C, Aapro M, Ardizzoni A, et al: Treatment of advanced non–small-cell lung cancer in the elderly: Results of an international expert panel. J Clin Oncol 23:3125-3137, 2005 13. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002 14. Rocha Lima CM, Herndon JE II, Kosty M, et al: Therapy choices among older patients with lung carcinoma: An evaluation of two trials of the Cancer and Leukemia Group B. Cancer 94:181-187, 2002[CrossRef][Medline] 15. Yamamoto K, Padilla Alarcon J, Calvo Medina V, et al: Surgical results of stage I non-small cell lung cancer: Comparison between elderly and younger patients. Eur J Cardiothorac Surg 23:21-25, 2003 16. Conti B, Brega Massone PP, Lequaglie C, et al: Major surgery in lung cancer in elderly patients? Risk factors analysis and long-term results. Minerva Chir 57:317-321, 2002[Medline] 17. Matsuoka H, Okada M, Sakamoto T, et al: Complications and outcomes after pulmonary resection for cancer in patients 80 to 89 years of age. Eur J Cardiothorac Surg 28:380-383, 2005 18. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004 19. Strauss GM, Herndon JE, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 24:365s, 2006 (suppl; abstr 7007) 20. Alam N, Shepherd FA, Winton T, 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 47:385-394, 2005[CrossRef][Medline] 21. Siu LL, Shepherd FA, Murray N, et al: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14:821-828, 1996 22. Rinaldi M, De Marinis F, Ardizzoni A, et al: Correlation between age and prognosis in patients with advanced non small cell lung cancer treated with cisplatin containing chemotherapy: A retrospective multicentre study. Ann Oncol 5:58, 1994 (suppl 8) 23. Hensing TA, Peterman AH, Schell MJ, et al: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98:779-788, 2003[CrossRef][Medline] Submitted October 25, 2006; accepted January 12, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test was used to assess associations between categoric variables; Kaplan-Meier curves were used to estimate the distributions of time-to-event outcomes, and the Cox regression model was used to correlate the age groups, other baseline factors, and study treatment to the time to event outcomes (OS and DSS); whereas analysis of variance was used to compare continuous variables between age groups. Age was further categorized into four age groups (
