Correspondence Department of Haematology and Oncology, Georg August University, 37099 Göttingen, Germany

Email lorenz.truemper@med.uni-goettingen.de

Original article

Horning SJ et al. (2004) Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group Study 1484. J Clin Oncol 22: 3032–3038   PubMed

Synopsis

Background

Over the past 25 years, treatment of limited-stage diffuse aggressive non-Hodgkin's lymphoma (NHL) has moved from surgical staging and radiotherapy to primary chemotherapy with limited radiotherapy.

Objectives

To compare low-dose radiotherapy with observation in patients with NHL who had complete remission (CR) following chemotherapy, and assess whether high-dose radiotherapy allowed conversion of partial response (PR) to CR.

Design and intervention

In this randomized trial, patients over 16 years of age with stage I–II diffuse aggressive lymphoma were enrolled. Patients were excluded if they had received prior chemotherapy or radiotherapy, or undergone complete resection of lymphoma. Patients were assigned to treatment with CHOP for eight cycles, then restaged and allotted to observation or radiotherapy (30 Gy) if CR was achieved, and to radiotherapy (40 Gy) if PR was achieved. PR patients were restaged 4 weeks after the completion of radiotherapy to determine conversion to CR.

Outcome measures

The primary endpoints were disease-free survival (DFS) in patients with CR achieved with the CHOP chemotherapy regimen receiving low-dose radiotherapy, and conversion from PR to CR following high-dose radiotherapy. CR was defined as regression of all the nodes that were palpable and of radiographic disease, and PR was defined as 50% decrease in the sum of the products of the dimensions of all lesions measured. Other endpoints included time to progression, failure-free survival and overall survival.

Results

Of the 352 eligible patients (median age 59; range 19–84 years), 179 entered the observation arm, and 173 were assigned to the low-dose radiotherapy arm. CR and PR were achieved in 215 and 98 patients, respectively. There were four treatment-related deaths, because of infection (n = 2) and congestive heart failure (n = 2). Grade 4 neutropenia occurred in 128 patients, but other grade 4 toxicities (thrombocytopenia, hemorrhage, infection, cardiac, genitourinary, neurologic and gastrointestinal toxicity) were rare. In patients with CR, low-dose radiotherapy significantly improved DFS (73% vs 56% for observed patients; P = 0.05) and improved failure-free survival (75% vs 56% for observed patients; P = 0.06) at 6 years, but this was not significant. The data analyzed as intent-to-treat yielded similar results. Time to progression was increased by radiotherapy consolidation in patients who had achieved CR, but there was no difference in overall survival compared with the patients who underwent observation only. Treatment failure occurred in 17 radiotherapy patients and 31 observed patients, with relapse in initial disease sites for 3 radiotherapy patients and 15 observed patients (P = 0.06). Conversion to CR was achieved with high-dose radiotherapy in 22 of the 71 patients who had PR following induction chemotherapy, but failure-free survival, relapse rate, time to progression and overall survival did not differ between patients converting to CR and those who did not convert from PR.

Conclusion

For patients achieving CR following CHOP chemotherapy, additional radiotherapy decreased the number of relapses and improved DFS, although there was no corresponding overall survival benefit.

Commentary

For physicians treating patients with aggressive lymphoma, whether to irradiate remains an important question—even in the age of chemo-immunotherapy! Lymphoma cells have long been known to be radiosensitive, and radiation treatment alone can cure a fraction of patients with aggressive lymphoma, as demonstrated in a BNLI study, where some patients remained disease-free for more than a decade.¹ Cure rates with surgery and radiotherapy alone were disappointingly low, however, showing that even limited-stage disease in aggressive lymphoma is a manifestation of systemic disease. The fact that chemotherapy alone can cure aggressive lymphoma established systemic therapy as the gold standard treatment.²

In the nineties, radiotherapy remained a popular option in limited-stage aggressive lymphoma either as an integral part of a combination treatment regimen with reduced-intensity chemotherapy, which aimed to reduce chemotherapy-associated toxicity, or as consolidation after full-cycle chemotherapy, which aimed to improve local control. The former option involving reduced-intensity chemotherapy, pioneered by Miller et al. (SWOG),³ and followed up by the French GELA group,⁴ should probably be reserved for patients who cannot tolerate full-cycle chop chemotherapy. At 5 years' follow up, the survival curves of the SWOG trials show no advantage, and the data from the GELA trial show a significant increase in late systemic relapses, for patients receiving abbreviated combined treatment.

The latter option of consolidation following chemotherapy presented by Horning et al. (ECOG 1484 study) demonstrated lower relapse rates in patients who received radiotherapy after reaching a chemotherapy-induced complete remission, but survival rates in these patients were not superior. At its conception in the early nineties, this was a well planned and subsequently well executed trial—but the advent of rituximab has changed survival prospects for these patients dramatically.⁵

When drawing conclusions for today's clinical practice from the ECOG 1484 trial we need to consider which risk groups can be distinguished within 'early-stage' aggressive NHL, i.e. which patients are at increased risk for relapse and are likely to benefit from therapeutic measures beyond systemic therapy, and, most importantly, whether radiotherapy will play a role when rituximab is added to full-cycle chemotherapy?

Patients with low-risk disease will definitely not benefit from additional treatment since, at least for younger patients, their chance for survival after 5 years is above 90%.⁵ With excellent foresight, Horning et al. excluded these patients from their study. Bulky disease does constitute a risk factor (in addition to tumor stage) in this trial, but many bulky disease patients do not reach complete remission and may therefore not benefit from late consolidation. 'Early stage'—taken literally—denotes Ann Arbor stages I and II. However, the IPI and the WHO consensus histological classification of lymphomas and genetic studies have redefined our understanding of low- and high-risk patients and have greatly increased our ability to define clear subgroups. Understandably, this makes the interpretation of a trial conceived more than 20 years ago ever more difficult. Randomized trials examining the role of consolidation radiotherapy in patients with bulky disease and low-intermediate IPI scores after CHOP-rituximab treatment are currently underway, as are trials employing radioimmunotherapy as a consolidation in first remission instead of radiotherapy. Horning et al. have renewed the impetus to conclusively answer the old question—to irradiate or not to irradiate after successful systemic therapy?

Acknowledgments

The synopsis was written by Petra Roberts, Associate Editor, Nature Clinical Practice.

References

1. Vaughan-Hudson B et al. (1994) Clinical stage 1 non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69: 1088–1093 | PubMed | ChemPort |
2. Fisher RI et al. (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328: 1002–1006 | Article | PubMed | ISI | ChemPort |
3. Miller TP et al. (1998) Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339: 21–26 | Article | PubMed | ISI | ChemPort |
4. Reyes F et al. (2000) Superiority of the ACVBP regimen over a combined treatment with three cycles of CHOP followed by involved field radiotherapy in patients with low risk localized aggressive non-Hodgkin's lymphoma: Results of the LNH93-1 study [abstract]. Blood 96: 532a
5. Pfreundschuh M et al. (2004) First analysis of the completed Mabthera International (MInT) Trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favorable subgroup with IPI=O and no bulky disease [abstract]. Blood 104: 48a

Contact the journal about this article

Subject areas under which this article appears: Radiotherapy