Chemotherapy for Older Patients with Newly Diagnosed, Advanced-Stage, Aggressive-Histology Non-Hodgkin Lymphoma

Age strongly influences outcomes in patients with aggressive-histology non-Hodgkin lymphoma [1]. Fewer clinical trials have tested treatment in older patients than in younger patients, and most conclusions about therapy for older patients with this disease have come from nonrandomized trials or studies in which the older patients constituted only a subset of a larger population. Several factors could account for differences in outcomes between younger and older patients with lymphoma: In brief, 1) differences in disease biology could result in more aggressive disease behavior, 2) altered pharmacokinetics and poorer host tissue tolerance may lead to a higher rate of adverse reactions, 3) comorbid illness may complicate treatment choices, and 4) the administration of less intensive chemotherapy may compromise disease control (2-6). Because half of the patients with aggressive-histology lymphoma are older than 65 years of age (7) and the proportion of older persons in the North American and European population is increasing (8), the optimal management of these patients is of considerable importance. The International Prognostic Factors Project identified age older than 60 years as an important prognostic factor in aggressive-histology lymphoma. For younger patients with aggressive-histology lymphoma, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (9) is considered standard therapy on the basis of randomized trials that compared this regimen with second-generation and third-generation regimens (10). Because the International Prognostic Factors Project and many clinical trials have used 60 years of age or older to define older patients, our review uses this age criterion. To assess the current evidence about the optimum treatment for older patients with aggressive-histology lymphoma, we conducted a systematic review designed to minimize bias and random error (11). Although several published reviews have addressed therapy for patients with lymphoma, including older patients, they have not used the methods of systematic review (3-5, 12, 13). In our systematic review, we summarize, critically appraise, and synthesize the results of randomized studies that assessed specific chemotherapy options in older patients with previously untreated, advanced-stage, aggressive-histology non-Hodgkin lymphoma. Methods Search Strategies We searched, without language restrictions (14, 15), the following databases: MEDLINE (reports published from 1966 to April 2000), EMBASE (1980 to March 2000), CANCERLIT (1983 to April 2000), Current Contents (1993 to April 2000), Best Evidence (1991 to April 2000), the Cochrane Library (issue 1, 2000), and an unpublished thesis database (UMI ProQuest [16]). Details about the search strategy are available from the authors on request. Tables of contents of hemato-oncology journals and reference lists from retrieved articles and textbooks were hand searched. Study Selection One author removed duplicate citations and citations dealing with other diseases from the MEDLINE, CANCERLIT, and EMBASE citation lists. Subsequently, two authors who were blinded to author names and institutional affiliations, journal name, publication year, and study results independently assessed the remaining citations on the basis of explicit inclusion and exclusion criteria. To be included, the study needed to be a randomized trial or an evidence-based practice guideline; the patients must have been 60 years of age or older and have had previously untreated, advanced-stage (any stage with B symptoms and stages II to IV [Ann Arbor staging system]), aggressive-histology (intermediate grade or high grade, Working Formulation [17]] non-Hodgkin lymphoma. Exclusion criteria were 1) the use of interferon, maintenance chemotherapy, or stem-cell transplantation or 2) HIV-related lymphoma. Citations were scored as yes if they met all inclusion criteria and no if they met an exclusion criterion. If citations met some of the inclusion criteria but met none of the exclusion criteria or if a clear judgment could not be rendered because of insufficient information, the citation was scored as maybe. Citations from the other databases were assessed by using the same inclusion and exclusion criteria by one author in an unblinded fashion. The printed article was retrieved if at least one reviewer judged its citation as a yes or maybe. In cases of disagreement (when only one reviewer judged a citation as no), the citation was adjudicated for eligibility by another author who was not involved in this stage of review. Abstracts were not considered because they usually provide information of a more preliminary nature. Subset analyses, although they may be misleading and require careful interpretation (18), were included if they contained data on the subset of patients 60 years of age or older. We used PC-Agree software (20) to calculate agreement coefficients (19) by using quadratic weights in which partial credit was given for partial agreement (for example, yes-maybe vs. yes-no). To assess the reliability of our eligibility criteria, we used to quantify the agreement between reviewers beyond the degree of agreement that would be expected by chance alone. The interobserver was calculated for the two independent reviewers' scores (yes, maybe, no) of the blinded citations. The intraobserver was calculated for each of the two independent reviewers on the basis of 20 citations from MEDLINE that were randomly selected by using a random-numbers table. According to convention, we considered an acceptable to be 0.60 or higher (19). Assessment of Study Quality Methodologic quality was assessed by using a validated instrument for scoring the quality of randomized, controlled trials [21]. The quality scores ranged from 0, which represents poor quality, to 5, which represents the best quality. A score was determined on the basis of whether 1) the randomization method was described, 2) the study was double-blinded, and 3) withdrawn participants were adequately described. The score was not used to determine study inclusion or quantitative weighting of results. We established that the study evidence needed to address clinically important outcomes, such as overall survival, any measure of the disease-control period (for example, time to treatment failure), or quality of life; reporting of response rates alone was insufficient. The conclusions about eligibility were based on the full reports of primary studies that described overall survival and any measure of disease control. Determination of whether to combine (pool) the results of the studies was based on the study sample, treatment regimens, and reported outcomes. Results Retrieved Articles The search strategy resulted in a total of 289 citations in MEDLINE, 106 in CANCERLIT, and 391 in EMBASE. After one author initially screened the citations, two blinded reviewers independently assessed a total of 385 citations for eligibility. The interobserver assessing the agreement beyond chance alone for the blinded databases was 0.83, and the intraobserver values for each of the blinded assessors were 0.60 and 0.80. Table 1 summarizes the reasons for study exclusion. Of 76 total entries found by searching the Current Contents database, none represented additional eligible studies. Likewise, searching the other databases revealed no reports. Table 1. Reasons for Study Exclusion Data Synthesis Twelve full-length reports of randomized trials were examined and are summarized in Tables 2 and 3. Three studies (22-24) received a quality score of 3, 8 studies (25-32) received a score of 2, and 1 study [33] received a score of 1. Studies were grouped into one of three categories according to whether the study compared 1) regimens that differed only in the specific anthracycline agent used [22, 25-27], 2) a fractionated chemotherapy schedule with the standard schedule for the same chemotherapy [28], or 3) regimens that differed by some other criteria (23, 24, 29-33). The age criterion differed among these 12 randomized studies, with the minimum age for older patients ranging between 60 and 70 years. Because of differences in the hypotheses tested, the heterogeneity of the inclusion criteria for age, and the variety of chemotherapy regimens used, we considered statistical pooling of these data to be inappropriate. Table 2. Randomized Trials of Chemotherapy: Patients and Therapy Table 3. Randomized Trials of Chemotherapy: Results Comparisons Testing Regimens with Anthracycline Substitution We examined four full reports in which regimens were compared to test the substitution of the anthracycline component (Tables 2 and 3). Sonneveld and colleagues (22) randomly allocated 148 patients at least 60 years of age to receive CHOP or a similar regimen that substituted mitoxantrone for doxorubicin (CNOP). In this study, which received a quality score of 3, the researchers analyzed the results on an intention-to-treat basis; sample-size calculations were reported, and the groups were balanced at baseline. The minimum cardiac ejection fraction required was at least 0.40, which is lower than that allowed in other studies. In contrast to the standard treatment cycle for CHOPfull-dose administration every 3 weeksthe treatments in this trial were administered at weekly intervals for 4 weeks (9). In comparison with patients receiving CNOP, patients receiving CHOP had a superior median and 3-year overall survival, but no difference was detected in the rate of 3-year disease-free survival. The overall toxicity did not differ among patients 60 to 70 years of age, patients 70 to 75 years of age, and those older than 75 years of age. These results favoring doxorubicin are consistent with those seen in younger patients (34). Aviles and coworkers (25) randomly assigned 169 patients to one of two regimens containing dose-escalated anthracycline: One group received cyclophosphamide, epirubicin, vincristine,