Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial

Summary: Background: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma. Methods: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed. Findings: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5·9 [range 0–17·8] years and for observation 6·7 [0·5–18·9] years, p=0·84; median cause-specific survival 9 [0–17·8] years and 9·1 [0·67–18·9] years, respectively p=0·44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0·0001, 0·03, and 0·03, respectively) and cause-specific survival (p=0·002, 0·008, and 0·001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years). Interpretation: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.