After 16 Years: Watch and Wait’ No Different than Immediate Therapy for Favorable Histology Lymphoma 

Abstsract & Commentary 

Synopsis: Currently, there is no curative treatment for advanced-stage, low-grade non-Hodgkin’s lymphoma, and there remains a question of when to initiate treatment in the asymptomatic patient. In the current report from the British National Lymphoma Investigation, a long-term analysis of immediate (with single-agent oral chlorambucil) vs watchful waiting is reported. As has been previously reported from other series, there was no survival difference between those who received initial chemotherapy and those who were only started at a time of clinical progression. Almost 20% of those who were in the watchful-waiting arm had not required chemotherapy after 10 years on study, and for those 70 years and older, the actuarial chance of not needing chemotherapy was 40%. Source: Ardeshna KM, et al. Lancet. 2003;362:516-522.

For patients with asymptomatic low-grade lymphomas (stage III or IV), there remains a question about the merits of immediate vs delayed treatment. Accordingly, in 1981 a multi-institutional UK study, the British National Lymphoma Investigation (BNLI) was initiated, and for approximately 10 years patients were randomly assigned to either immediate treatment (chlorambucil, 10 mg, administered orally daily) or watchful waiting. In the latter group, chlorambucil was administered when lymphoma progression necessitated treatment. Of the 309 randomized patients enrolled, 158 were to receive immediate treatment and 151 were to be observed without initial treatment. In both groups, local radiotherapy was permitted to symptomatic nodes.

As of the writing of this report, the median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the 2 groups (median overall survival for the immediate treatment was 5.9 years (range, 0-17.8) and for the observation 6.7 years (0.5-18.9) (P = 0.84). The median cause-specific survival was 9 (0.5-17.8) 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) of less than 20 mm/hr, and stage III disease conferred significant advantages in both overall and cause-specific survival. 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 at 10 years (with nonlymphoma deaths censured) was 19% (40% if older than 70 years).

Comment by William B. Ershler, MD

Although aggressive treatment regimens have been used, including combinations like CHOP or even more aggressive chemotherapy followed by stem cell rescue, there remains little evidence that advanced-stage, low-grade lymphoma can be cured by such treatments. Thus, in asymptomatic patients, the question of whether there is any advantage to immediate treatment was appropriately raised over 2 decades ago, and this and several other reports have addressed the question.1-3 The BNLI project represents an advance because of its larger sample size and longer duration of follow-up. Nonetheless, the findings have all been consistent: There does not appear to be any benefit in immediate rather than delayed treatment in selected patients with low-grade lymphomas. The long-term follow-up provided by the current series is particularly valuable because of the indolent nature of the disease and the possibility that delays in therapy may, in some way, influence late recurrences and treatment responsiveness.

When the cohort that was randomized to watchful waiting was examined in the context of age at presentation, it is notable that for those older than 70, the chance of not needing chemotherapy was 40% after 10 years on study. Thus, for asymptomatic patients in this group, a strong case can be made for delaying treatment until clinical progression is evident inasmuch as this strategy quite possibly could prevent unnecessary treatment in a significant number of patients.

Of course, it is always possible that new and more effective treatments will prove better than single-agent chlorambucil, even though CHOP and similar regimens have failed to do so. Yet, a recent pilot study with CHOP plus rituximab has shown encouraging results, with more than 50% of patients not having progressed during a median follow-up period of 5 years.4 In fact, rituximab alone was also recently shown to produce a response rate of 73% and a "molecular" remission in 57%.5 The current role of rituximab in asymptomatic patients with low-grade lymphoma is a matter of active investigation, and exactly when to initiate treatment will become a critical question in this research.

Dr. Ershler is INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.

References

1. Brice P, et al. J Clin Oncol. 1997;15:1110-1117.

2. O’ Brien ME, et al. QJM. 1991;80:651-660.

3. Young RC, et al. Semin Hematol. 1988;25 (Suppl 2): 11-16.

4. Czuczman MS. Semin Oncol. 2002;29 (Suppl 6):11-17.

5. Solal-Celigny P. Anti Cancer Drugs. 2001; 12 (Suppl 2):511-514.