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The potential palliative role and possible immune modulatory effects of low-dose total body irradiation in relapsed or chemo-resistant non-Hodgkin's lymphoma

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Abstract

In a group of 35 patients with relapsed and/or chemo-resistant non-Hodgkin's lymphoma (NHL), low-dose total body irradiation (LTBI) (+involved-field radiotherapy to bulky sites) achieved a complete remission rate of 29%, 2-years progression-free survival of 32% and a median progression-free survival of 12 months. The 2-year survival was 42% and the median survival was 17 months. Immuno-staining and flow cytometry of peripheral blood in 14 patients showed that LTBI leads to a significant increase in the percentage of CD4+ cells with a consequent significant increase in the CD4+/CD8+ ratio. High lymphocytic percent and a high percentage of CD4+ cells before LTBI were significantly correlated with longer response duration and overall survival. These data may suggest that the palliative potential of LTBI should be investigated as an alternative to chemotherapy in NHL patients. The pre-treatment percentage of lymphocytes and CD4+ cells may be used as predictors for response to LTBI.

Introduction

Patients with aggressive non-Hodgkin's lymphoma (NHL) who do not attain complete remission, or relapse after initial chemotherapy, may respond to a second line chemotherapy combination. The responses are however of short duration and long-term survival is rarely seen [8]. The same is true for the indolent subtypes where patients may repeatedly respond to different chemotherapy but the proportion responding and the duration of response decrease with each relapse [1]. The evidence that high-dose chemotherapy followed by autologous or allogeneic re-establishment of bone marrow function will prolong the duration of remissions/survival in these patients is weak, except in the subgroup of patients that have chemo-sensitive relapse and aggressive pathology [1], [8]. If such patients are not eligible for bone marrow/stem cell transplantation, treatment is therefore largely palliative.

Low-dose total body irradiation (LTBI) given as 0.1–0.25 Gy per fraction three to five fractions per week to total dose of 1.5–2 Gy, has long been used in the treatment of indolent NHL, both initially or as salvage therapy for relapsing cases [6], [11], [12]. The aggressive subtypes are thought to be less responsive, though an early phase III study comparing LTBI in a dose of 1.5 Gy to CHOP (minimum six courses) in advanced (stage III and IV) aggressive NHL, has failed to show a significant difference in outcome [9].

Data from experimental animals have established a clear stimulatory effect of LTBI on the immune system of rodents [5] and primates [7]. Human data however are still lacking. A single study in the English literature [15] and investigational data from Japan [13] pointed to changes in some immune parameters of the patients treated with LTBI though a causative relation between these changes and the clinical response has not been established.

In the National Cancer Institute, Cairo University we have therefore decided to test the efficacy and the haematological toxicity of LTBI in a feasibility study of 35 consequent NHL patients that were referred to the Radiotherapy Department between September 1998 and September 2001. To test whether LTBI is associated with a change in the various lymphocytic subsets in peripheral blood, the patients were asked whether they would participate in a para-clinical study in which blood samples would be taken before and after LTBI and tested for the various lymphocytic subsets using immuno-staining and flow cytometry. Fourteen patients consented to participate in this part of the study.

Section snippets

Patients and methods

The patients' material comprised 35 consecutive patients that represented two clinical categories namely: those who did not attain complete remission following initial chemotherapy (17 patients) and those who were in relapse (18 patients). The patients' age ranged from 24 to 67 years with a median age of 46 years. There were 22 (63%) men and 13 (27%) women. Twenty-nine (83%) had a WHO performance status of <2. According to the Working Formulation classification of pathological subtypes, 11

Results and discussion

Ten patients achieved CR (29%), while 15 patients had PR (43%), five patients had SD (14%) and five (14%) progressed while under treatment. There was no difference in response in the various pathological grade subtypes.

The whole group had a 2-years progression-free survival of 32% (±15%) and a median progression-free survival time of 12 months (±6%). None of the clinical prognostic factors studied has shown to be of significance regarding the disease-free survival apart from the response to

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