Bulky disease and RIT?
"... experiments in demonstrating an adverse impact of tumor size on antibody penetration, though the implications of this finding for treatment remain
In a phase I study of I-131-labeled anti-B cell antibodies, we found that patients with tumor burdens less than 500 cc in volume were more likely to achieve a favorable
bio-distribution than patients with tumor burdens greater than 500 cc (p <.0001)8 (a favorable
bio-distribution was rigorously defined in this study to mean every assessable tumor site received more radiation than any of the critical normal organs).
Splenomegaly seems to exert a similar adverse effect on antibody
bio-distributions. In our phase I bio-distribution study, we found that only 2 of 16 patients with significant splenomegaly achieved a favorable
bio-distribution compared to 17 of 22 with normal spleens and 5 of 5 splenectomized patients.8 We have assumed that the deleterious effect of splenomegaly on antibody
bio-distributions is due to the entrapment of anti-B cell antibodies by large numbers of resident CD20-expressing B-cells in the spleen.
The trapping of I-131-anti-CD20 antibodies in the spleen limits the availability of I-131-anti-CD20 antibody to other tumor sites, for example lymph nodes. Other clinical investigators have also reported splenic trapping of therapeutic antibodies, although this phenomenon can be partially circumvented by preinfusion of a large dose of unlabeled cold antibody prior to the radiolabeled antibody.6,7,22
Despite the unfavorable influence of large tumor burdens and splenomegaly on antibody penetration into tumor sites, it has been shown that even patients with these unfavorable characteristics can achieve sufficient concentrations of radioimmunoconjugates in tumor sites to attain meaningful clinical benefit, though the chances of achieving a remission, particularly a complete remission, are diminished compared to those of patients with smaller tumor burdens and normal spleen sizes.12
We have shown that patients with bulky disease can achieve better antibody
bio-distributions if they are treated with a combined approach which includes initial
cyto-reduction with chemotherapy or splenectomy to debulk the tumor prior to I-131-anti-CD20 antibody therapy.9"
Radioimmunotherapy of non-Hodgkin’s lymphomas - http://www.haematologica.it/free/press.pdf
OLIVER W. PRESS Division of
Medical Oncology, University of Washington Medical Center, Fred
Hutchinson Cancer Research Center, Seattle, USA
Study to Treat Relapsed Follicular Non-Hodgkin’s Lymphoma With Radiation and Bexxar
RATIONALE: "Total dose delivered and tumor size are important predictors of local control in the treatment of low-grade NHL. The basic principle is that larger nodal masses require increased doses of EBRT to achieve local control.
Radioimmunotherapy (RIT) seems to share this same characteristic. Review of the published literature on both Bexxar and Zevalin reveals that one of the most important predictors of treatment failure is nodal volume and its apparent relationship to dose delivered by RIT.
The best tumor dosimetry for RIT is from Dr. Wiseman et al reporting on the dosimetry of Zevalin (11418315). He showed that tumors ≥15 cm3 received only 1082 cGy with Zevalin, whereas the average dose delivered in tumors <15 cm3 was 4763 cGy. (~4x the dose)
Recently, Gokhale et al (16111589) published their experience with Zevalin at Cleveland Clinic and showed a significant correlation with pretreatment tumor volume and response to therapy. In their experience, tumors ≥5 cm had an 83% rate of local recurrence versus 28% for tumors <5 cm.
This dosing paradox (bigger masses, which require more dose, receive less with RIT) may be diminished by the delivery of additional EBRT. This is the hypothesis that underlies the pilot study.
The dosimetric data available for Bexxar is more heterogeneous but confirms the observations seen with Zevalin. In patients previously untreated for low-grade NHL, Koral et al (12621015) showed an increased likelihood of achieving a complete response (CR) if tumor doses were >650 cGy.
Previous work by these same authors showed a trend for larger tumor volumes receiving less dose (10994741). The most compelling data for this relationship comes from the clinical trials done using Bexxar. Both in the pivotal trial (11579112) and the recently published trial treating naïve patients (15689582), tumor volume was a significant predictor of response to Bexxar. In the pivotal trial, smaller tumor burden was the only factor predicting longer duration of response.
Whereas EBRT might be able to provide reliable radiation dose, the use of Bexxar may provide the therapeutic equivalent of CLI, which would permit the use of true involved field radiotherapy. Investigators have previously noted that increased EBRT field size is associated with increased short-term and long-term toxicity. The toxicities associated with the treatment of radiotherapy are related to the site treated, but do not necessarily include the dose limiting toxicity of Bexxar, which is primarily hematologic and transient. As the toxicity of RT and Bexxar may not overlap, the combination of both may allow an increase in in the therapeutic window for both radiotherapy and Bexxar therapy."