Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin’s or Hodgkin’s lymphoma

Abstract

Purpose

In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma.

Methods and materials

Patients had Hodgkin’s or non-Hodgkin’s lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions.

Results

Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields.

Conclusion

Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

Introduction

The treatment of patients with a relapse of Hodgkin’s or non-Hodgkin’s lymphoma after systemic chemotherapy has been substantially altered by the availability of bone marrow transplantation (BMT) 1, 2. High-dose chemotherapy with BMT is now considered the standard approach for patients with refractory or relapsed Hodgkin’s disease, as well as relapsed or refractory non-Hodgkin’s lymphoma. Despite its efficacy, however, tumor recurrence remains the main cause of failure after BMT, and most recurrences occur in sites known to have contained disease before initiating BMT 3, 4. Because of this pattern of relapse, many centers have used involved-field radiation to sites containing disease in conjunction with BMT, with the radiation given either before or after the BMT regimen 5, 6. Some nonrandomized series have shown improved disease control in the areas irradiated 3, 7 and/or improved disease-free survival 8, 9.

We have previously evaluated the use of post-BMT involved-field radiotherapy (RT) in patients with both Hodgkin’s and non-Hodgkin’s lymphoma (10). In that experience, we observed that locoregional RT after BMT could be successfully completed in most patients, even those who underwent total body irradiation (TBI). However, patients with poor hematologic recovery after BMT had increased toxicity from the locoregional therapy, and in-field control was worse in patients who had disease progression before the start of locoregional RT (p = 0.04). On the basis of this experience, we chose to evaluate the use of involved-field RT incorporated into the pretransplant regimen. The merits and disadvantages of RT before BMT have been summarized by Constine and Rapoport (11). Patients in a minimal disease state after pretransplant cytoreductive therapy have a better prognosis than patients with residual bulky disease; a lower disease burden at BMT is also associated with lower rates of treatment-related toxicity 8, 9, 12. Finally, engrafted stem cells are not exposed to the myelosuppressive and potential leukemogenic effects of radiation.