A trial of 635 patients, aged 61 to 69 years, with stage III and stage IV disease, elevated lactate dehydrogenase (LDH), or performance status of 2 to 4, randomly assigned patients to receive CHOP or ACVBP. With a median follow-up of 68 months, patients who received ACVBP had superior EFS and OS (EFS = 39% vs. 29% at 5 years, P = .005 and OS = 46% vs. 38% at 5 years, P = .036).[Level of evidence: 1iiA] Two prospective randomized trials that compared CHOP with CNOP for patients aged 60 years and older with diffuse large cell lymphoma showed a significant advantage for CHOP in terms of disease-free survival and OS.;[Level of evidence: 1iiA] Two other randomized trials of patients aged 70 years and older confirm the superiority of CHOP over other less toxic regimens in progression-free survival and OS.;[Level of evidence: 1iiA] Although infusion regimens have been proposed, a randomized trial of infusional CHOP versus standard CHOP therapy showed no improvement in relapse-free survival or OS.[Level of evidence: 1iiA] As SWOG-9349 did, clinical trials continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, and combining new drugs with new mechanisms of action.[14,20,21,22]
An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:
- Age (?60 years vs. >60 years).
- Serum LDH (normal vs. elevated).
- Performance status (0 or 1 vs. 2-4).
- Stage (stage I or stage II vs. stage III or stage IV).
- Extranodal site involvement (0 or 1 vs. 2-4).
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. Patients at high risk of relapse may be considered for clinical trials. Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[25,26]
Several randomized prospective trials evaluated the role of autologous bone marrow transplantation (BMT) or stem cell transplantation consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[27,28,29,30,31,32,33,34];[Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series. Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[28,34] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients. Whether autologous BMT, or peripheral stem cell transplantation, or allogeneic BMT have definitive roles in the treatment of high-risk patients in first remission awaits the results of ongoing randomized trials such as SWOG-S0016, for example, that employed R-CHOP or other rituximab-based chemotherapy regimens.