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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

From the Departments of Oncology, Biostatistics, and Medicine, Mayo Clinic, Rochester, MN; St Joseph Mercy Health System, Ann Arbor, MI; Geisinger Clinic and Medical Center, Danville, PA; Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL; Mid-Dakota Clinic, Bismarck, ND; Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ; Oschner Clinic, New Orleans, LA

Address reprint requests to Aminah Jatoi, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: jatoi.aminah{at}mayo.edu

	ABSTRACT

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PURPOSE: To answer the question, "should elderly non–small-cell lung cancer patients be offered elderly-specific trials?"

PATIENTS AND METHODS: The North Central Cancer Treatment Group (NCCTG) performed a pooled analysis of elderly patients who participated in elderly-specific trials (required age 65 years) and age-unspecified trials (required age 18 years). Between 1998 and 2000, all NCCTG non–small-cell lung cancer (NSCLC) patients with incurable cancer, age 65 years, and receiving first-line chemotherapy were included. A total of 118 elderly patients participated in elderly-specific trials, and 108, in age-unspecified trials. Demographics and outcomes were compared based on trial type.

RESULTS: The median age of elderly patients in elderly-specific trials was greater: median (range): 73 years (65 to 87) and 70 years (65 to 85), respectively (P < .001), as was the percentage older than 80 years: 17% and 3%, respectively (P = .0008). Median survival times were 232 and 302 days, respectively (P = .08). After adjustment for baseline age, Eastern Cooperative Oncology Group performance score, cancer stage, and body mass index, this survival difference was not statistically significant (hazard ratio = 1.25; P = .16). Grade 3 or worse nonhematologic adverse event rates were greater in age-unspecified trials (81% v 57%, respectively; P < .001), as were grade 3 or worse hematologic events (68% v 10%, respectively; P < .001).

CONCLUSION: Elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events with no statistically significant differences in survival. It seems that elderly-specific trials are providing quality care and helping to define optimal cancer therapy in the elderly, particularly among the "oldest of the old."

	INTRODUCTION

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In 1967, the US Congress passed the Age Discrimination in Employment Act. Citing its role to "prohibit age discrimination in employment," this legislation was crucial in banning age discrimination against older Americans.¹ As recently as 2005, the US Supreme Court ruled that companies or individuals could be liable for age discrimination even when their policies could not be directly tied to age bias.² In other words, it is no longer necessary to prove discriminatory intent in court, and, as a result, the bar for winning litigation against age discrimination has been lowered. In the workplace, as well as throughout all other sectors of life in the United States, an ever-increasing sensitivity to prejudice that occurs solely on the basis of advanced age is emerging.

Should such sensitivity extend to the conduct of clinical trials in cancer patients? If elderly cancer patients are recruited to cancer clinical trials that specify advanced age as an eligibility criterion, does such an approach constitute yet another form of unjustified age discrimination, or are such trials warranted because they are helping to define optimal care for elderly cancer patients?

These questions are timely because the burden of cancer in the United States is expected to increase as a result of an aging US population. In their "Annual Report to the Nation on the Status of Cancer, 1973 to 1999, Featuring Implications of Age and Aging on US Cancer Burden," Edwards and others predicted that by 2050, the number of newly diagnosed cancer patients 85 years or older is expected to quadruple.³ Despite such projections, however, relatively little has been done to address optimal cancer therapy in the elderly.

Elderly-specific, prospective trials have been conducted, often by well-established cancer cooperative groups in the United States,^4-6 but such efforts have been met with controversy. Critics argue that elderly patients do as well as their younger counterparts and that elderly-specific trials are not necessary, citing retrospective data as proof. For example, the North Central Cancer Treatment Group (NCCTG) conducted one such retrospective study. These investigators examined 246 patients with locally advanced non–small-cell lung cancer (NSCLC).⁷ All were treated with combined-modality therapy that included chemotherapy (etoposide and cisplatin) and definitive radiation. Sixty-three of the patients in this cohort (26%) were 70 years or older. Survival was comparable between groups based on this age cutoff. Grade 4 or worse hematologic toxicity and pneumonitis were more prevalent among the elderly compared with younger patients: 81% v 62%, respectively (P = .007). The conclusions of this study were similar to those of the others that preceded it: older patients in such studies received just as much benefit from cancer therapy as their younger counterparts, in exchange for perhaps slightly increased toxicity.

A major limitation of generalizing this conclusion to all elderly cancer patients rests in the fact that all such retrospective analyses are derived from prospective trials designed for younger patients, and thus, in all likelihood, only the fittest of the elderly had participated. Drawing attention to this lack of adequate representation, Hutchins et al⁸ pointed out that only 39% of lung cancer patients enrolled in Southwest Oncology Group clinical trials were older than 65 years between 1993 and 1996 but that 66% of the general population fell within this age range during this period. This discrepancy suggests that the conclusion that elderly cancer patients do just as well with therapy might be flawed and that there is a very real need for elderly-specific trials.

In keeping with this philosophy, the NCCTG conducted a series of lung cancer treatment trials that mandated age 65 years as an eligibility criterion. This report describes a pooled analysis with results from only elderly NSCLC patients who participated in elderly-specific trials as well as simultaneously run, age-unspecified NCCTG trials for patients with this same malignancy. The goals of this analysis were (1) to assess whether elderly-specific trials had in fact drawn in elderly patients who were clinically distinct from elderly patients recruited to age-unspecified trials, and (2) to evaluate whether elderly-specific cancer treatment led to comparable clinical outcomes. In short, this pooled analysis explored whether clinical trials that include advanced age as an eligibility criterion are warranted and whether such trials are helping to define optimal care in elderly cancer patients.

	PATIENTS AND METHODS

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The trials that comprised this pooled analysis were all NCCTG NSCLC studies that included patients with metastatic or unresectable disease, initiated between 1998 and 2000. All had been approved by institutional review boards across the NCCTG, and this pooled analysis was approved by the Mayo Clinic institutional review board. Elderly-specific trials were defined as those requiring patient age 65 years as an eligibility criterion, whereas age-unspecified trials were defined as those in which an age of only 18 years was required. The above dates were chosen because the first elderly-specific trials were conducted during this period, and the agents tested in these trials consisted of what might be considered conventional forms of chemotherapy, as opposed to more novel agents that had not yet been approved for commercial use.

These trials consisted of 98-24-52 (an age-unspecified trial), N0026 (another age-unspecified trial), N9921 (an elderly-specific trial), and N0022 (an elderly-specific trial). (See published articles^9-11 and Perez EA, Amin BR, Hillman S, et al: Randomized phase II study of docetaxel and gemcitabine for stage IIIB/IV non-small cell lung cancer.) All required that patients have biopsy proof of NSCLC, measurable disease, adequate organ function as assessed by laboratory studies, no prior chemotherapy, no prior malignancy, no untreated symptomatic brain metastases, no concurrent major debilitating illness, and no recent surgery or radiation. Eligibility criteria are reported in each respective, published,^9-11 or submitted (Perez EA, Amin BR, Hillman S, et al: Randomized phase II study of docetaxel and gemcitabine for stage IIIB/IV non-small cell lung cancer) trial. Salient differences in eligibility criteria appear in Table 1. All four trials were available to similar patients, with the exception of the requirement of age 65 years and the allowance of an Eastern Cooperative Oncology Group performance score of 2 in the elderly-specific trials.

View larger version (12K): [in this window] [in a new window]   Fig 1. Intervals during which trials remained open are shown for each individual trial.

Several different end points were explored. First, baseline differences between elderly patients who participated in elderly-specific versus age-unspecified trials were assessed. Second, overall survival, time-to-cancer progression,¹² time-to-end of active treatment, and tumor response rates were compared based on type of trial in a univariate and multivariate fashion. Overall survival was defined as the time from trial registration to death from any cause. Time-to-cancer progression was defined as the time from trial registration to the first documented evidence of cancer progression. Any patient who died without documentation of cancer progression was censored at the time of death in the time-to-cancer progression analyses. Kaplan-Meier curves were constructed for all survival data, and log-rank tests were utilized to compare survival rates between groups. The Cox proportional hazards model was used for multivariate analyses.

Tumor response rates are reported only on the basis of confirmed responses, or those that were observed again during a 4-week reassessment. RECIST criteria were used in all trials (Perez EA, Amin BR, Hillman S, et al: Randomized phase II study of docetaxel and gemcitabine for stage IIIB/IV non-small cell lung cancer). Adverse events were reported with version 2.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Event grading.¹³ Adverse event data were summarized for each patient. If an adverse event was reported on more than one cycle, the maximum grade over the entire course of treatment was used for analysis. Differences in rates of response and adverse events were assessed with ² tests. Logistic regression models were used to evaluate differences in adverse event rates between groups after adjusting for baseline characteristics.

All the above parameters were compared first between all four trials, and then, if no outstanding individual trial differences were apparent, a comparison was made between elderly-specific and age-unspecified trials. Baseline characteristics were compared with either a rank sum test or a ² test. P values of less than .05 were considered statistically significant.

	RESULTS

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Baseline Characteristics
A total of 118 patients participated in the elderly-specific trials, and 108 elderly patients participated in the age-unspecified trials. This latter number represents 45% of all patients who were treated on the age-unspecified trials. The median age of both these cohorts was 73 years (range, 65 to 87 years) and 70 years (range, 65 to 85 years), respectively (P < .001). Seventeen percent of patients on the elderly-specific trials were 80 years old, compared with only 3% in the age-unspecified trials (P = .0008). Figure 2 shows a graph of the age distribution based on type of trial. Other baseline differences are presented in Table 3. Of note, Eastern Cooperative Group performance score was statistically different between groups with the less favorable characteristics observed in patients who participated in the elderly-specific trials. These differences in performance score may in part be explained by the fact that the two elderly-specific trials allowed entry to patients with a performance score of 2, whereas the age-unspecified trials restricted entry to patients with performance scores of 0 and 1. Body mass index (BMI) was not statistically different between groups, but a trend suggested lower BMI’s among elderly patients who participated in elderly-specific trials: median (range): 26.7 (15.5 to 43.9) and 25.8 (16.5 to 41.6) in age-unspecified and elderly-specific trials, respectively (P = .07).

View larger version (12K): [in this window] [in a new window]   Fig 2. Gray bars denote elderly-specific trials on which a greater proportion of the "oldest of the old" were recruited.

View larger version (9K): [in this window] [in a new window]   Fig 3. Median survival times in age-unspecified and elderly-specific trials were 302 and 232 days, respectively.

Of parenthetical note, among the patients who were 80 years or older, the majority participated in elderly-specific trials, as mentioned. These 22 patients had a median survival of 5.4 months, and median time-to-cancer-progression of 3.9 months. Two manifested a tumor response. Nineteen patients had an Eastern Cooperative Oncology Group performance score of 2, and all had been recruited onto the elderly-specific trials, as mentioned. Within this subgroup, median survival was 6.2 months, and median time-to-cancer-progression was 3.8 months. One patient manifested a tumor response. No grade 5 event (death) occurred in either of these groups.

Adverse Events
In general, the incidence and severity of adverse events were worse among the elderly patients who participated in the age-unspecified trials. When rates of nonhematologic adverse events were tabulated regardless of attribution, the percentage of patients who experienced any grade 5 event (death) in age-unspecified and elderly-specified trials was 9% in both groups (P = .86). Although to our knowledge, physician attribution of adverse events to study drug has never been validated, it seems that in the elderly-specific trials, three deaths were attributed to study drug by the treating oncologist ("possibly," "probably," or "definitely" related), whereas none were in the age-unspecified trials.

The percentages of patients with grade 4 or worse nonhematologic events were 25% and 20%, respectively in age-unspecified and elderly-specific trials (P = .44). The percentages of patients with grade 4 or worse hematologic events were 30% and 3%, respectively (P < .001). Similarly, grade 3 or worse nonhematologic events were observed in 81% and 57% of patients, respectively (P < .001), and grade 3 or worse hematologic events were observed in 68% and 10% of patients, respectively (P < .001; See Table 4). When adverse events were reported on the basis of attribution, those that were directly attributable to the study drugs occurred at slightly decreased rates, but comparisons between groups yielded the same statistically significant findings. When logistic regression models were used to adjust for other clinical variables, all adverse event end points that were statistically significant in the univariate setting remained so. In summary, although the frequency of catastrophic adverse events was not statistically different between groups, overall, the frequency of severe adverse events was more pronounced among patients who participated in age-unspecified trials, and many of these adverse events centered on hematologic toxicity.

	DISCUSSION

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Another important observation is that these elderly-specific trials recruited far older patients, the so-called "oldest of the old." This observation is particularly notable when one considers that between most of 1998 and 2000, there was considerable overlap in opportunities to recruit patients onto either elderly-specific or age-unspecified trials within the NCCTG. Although we have no way of truly proving this possibility, the fact that the "oldest of the old" were recruited onto elderly trials and less so onto age-unspecified trials may suggest that elderly-specific trials were attracting elderly patients who might not have otherwise participated in clinical trials. When we looked at recruitment rates of the "oldest of the old" in two other NCCTG age-unspecified studies that were conducted before the initiation of our elderly-specific trials and that were not included in this pooled analysis, less than 2% of patients were more than 80 years of age.^15,16 In contrast, the fact that the two elderly-specific trials analyzed here did include a sizable older population of patients suggests that such trials are definitely attracting and serving the "oldest of the old." It remains unclear whether this recruitment of the "oldest of the old" is a reflection of physician bias, patient bias, or rational clinical judgment, but the inclusion of these patients into clinical trials provides an opportunity to explore these issues.

Along similar lines, it is also important to note that the elderly-specific trials accrued quickly, especially if one considers that the age requirement prompted these trials to focus on a restrictive patient population. As suggested by Figure 1, these trials tended to open and close at a relatively expeditious rate compared to age-unspecified trials. This observation suggests once again that elderly-specific trials are valued by patients and health care providers, and that by accruing patients rapidly, they are helping to define optimal care for this population of patients.

Two aspects of this pooled analysis require further comment. First, the NCCTG trials in this pooled analysis did not assess comorbidity extensively. Future elderly-specific studies may assess comorbidity to assess its impact on outcome. Second, admittedly, the study agents tested in each trial may account in part for the observed outcomes. One might argue that a logical approach might be to utilize such gentler regimens for a wider population of NSCLC patients. The roughly comparable survival data observed in this pooled analysis—coupled with the comparable survival data observed in the younger patients who participated in the age-unspecified trials included in this pooled analysis (not reported here but also corroborated by our findings)—suggest these regimens might merit further testing in other NSCLC patients. It is important to point out that the impetus for designing the elderly-specific trials was in fact the need to focus on a gentler approach tailored to the needs of elderly lung cancer patients. Although the conclusions of this pooled analysis justify continued pursuit of elderly trials, they also suggest that such approaches might be expanded to include younger debilitated patients with NSCLC.

In summary, this pooled analysis suggests that elderly patients who participated in elderly-specific trials attained roughly comparable survival advantages and yet suffered lower rates of adverse events. Participation in elderly-specific trials does not appear to compromise clinical outcomes. At the same time, such trials are attracting the "oldest of the old" more readily than age-unspecified trials. This report suggests that elderly-specific trials are providing quality care to elderly cancer patients and are helping to define optimal care, particularly among the "oldest of the old."

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. U.S. Equal Employment Opportunity Commission Web site. http://www.eeoc.gov/policy/adea.html

2. Greenhouse L: Supreme court removes hurdle to age bias suits. New York Times, March 31, 2005, section A, page 1

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4. Langer CJ: Elderly patients with lung cancer: Biases and evidence. Curr Treat Options Oncol 3:85-102, 2002[Medline]

5. Hainsworth JD, Carell D, Drengler RL, et al: Weekly combination chemotherapy with docetaxel and gemcitabine as first-line treatment for elderly patients and patients with poor performance status who have extensive stage small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial. Cancer 100:2437-2441, 2004[CrossRef][Medline]

6. 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[Abstract/Free Full Text]

7. Schild SE, Stella PJ, Geyer SM, et al: The outcome of combined modality therapy for stage III non-small cell lung cancer in the elderly. J Clin Oncol 21:3201-2306, 2003[Abstract/Free Full Text]

8. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999[Abstract/Free Full Text]

9. Ma CX, Nair S, Thomas S, et al: Randomized phase II trial of three schedule of pemetrexed and gemcitabine as front-line therapy for advanced non small cell lung cancer. J Clin Oncol 23:5929-5937, 2005[Abstract/Free Full Text]

10. Jatoi A, Stella PJ, Hillman S, et al: Weekly carboplatin and paclitaxel in elderly non-small cell lung cancer patients ( 65 years of age): A phase II North Central Cancer Treatment Group study. Am J Clin Oncol 26:441-447, 2003[Medline]

11. Kanard A, Jatoi A, Castillo R, et al: Oral vinorelbine for the treatment of metastatic non-small cell lung cancer in elderly patients: A phase II trial of efficacy and toxicity. Lung Cancer 43:345-353, 2004[CrossRef][Medline]

12. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

13. http://ctep.cancer.gov/reporting/ctc.html

14. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non-small cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003[Abstract/Free Full Text]

15. Colon-Otero G, Niedringhaus RD, Hillman SH, et al: A phase II trial of edetrexate, vinblastine, adriamycin, cisplatin, and filgrastin in patients with non-small cell carcinoma of the lungs: A North Central Cancer Treatment Group trial. Am J Clin Oncol 24:551-555, 2001[CrossRef][Medline]

16. Marks RS, Graham DL, Sloan JA, et al: A phase II study of dolastatin 15 analogue LU 103793 in the treatment of advanced non-small cell lung cancer. Am J Clin Oncol 26:336-337, 2003[CrossRef][Medline]

Submitted August 10, 2005; accepted September 29, 2005.

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