Times Not to Forget Radiotherapy When Treating Patients With Lymphoma

Charles A. Enke, MD


J Oncol Pract. 2019;15(4):167-172. 

In This Article

Relapsed or Primary Refractory Lymphoma With Prior Progression With Salvage Chemotherapy

A significant clinical challenge is the patient with primary refractory or relapsed lymphoma that does not respond to salvage chemotherapy before consideration of high-dose therapy and autologous transplantation. The prognosis for patients who experience treatment failure or do not obtain a complete response with salvage chemotherapy is poor, and frequently these patients are not considered for highdose therapy and autologous transplantation. Personal observation has shown that these lymphomas are less likely to respond to standard fractionated radiation therapy used in combination with systemic treatment. A retrospective review of patients receiving salvage radiation therapy for relapsed or refractory aggressive lymphoma treated with either palliative or curative intent demonstrated that patients treated with curative intent had a 5-year local control rate and progression-free survival rate of 66% and 34%, respectively. There was a noticeable difference in local control between patients with refractory versus relapsed disease, with 2-year local control rates of 56% and 92%, respectively. Twice-per-day radiation therapy was used in 20% of sites treated without an observed dose response when using 1.4 Gy per fraction twice per day to doses up to 36.4 Gy.[13] Their conclusion was that an alternative approach to standard radiation therapy (which might include radiation dose escalation, addition of radiosensitizers, or some combination) should be considered in patients with refractory or relapsed aggressive non-Hodgkin lymphoma. This is not an isolated observation; two decades ago, I observed progression of lymphoma while delivering standard radiation therapy in the setting of chemotherapy-refractory lymphoma. At that time, alternative radiotherapy fractionation schedules including accelerated fractionated radiation therapy (twice per day radiation therapy at doses of 1.5 to 2.0 Gy/fraction) were attempted. Radiographic responses to accelerated fractionated radiation therapy were observed in patients who initially showed in-field radiographic progression of lymphoma when standard fractionated radiation therapy was used. This was most commonly observed in patients with DLBCL. One hypothesis to explain cross-resistance to chemotherapy and radiation therapy is the cancer stem cell pathway. Cancer stem cells have been found to demonstrate various genetic and cellular adaptations that could confer resistance to both chemotherapy and radiation.[23] The mechanism of cross-resistance may vary; mantle cell lymphoma refractory to systemic therapy may respond well to palliative radiation doses of 4 Gy total.

We have considered pretransplantation accelerated fractionated radiation therapy followed by high-dose chemotherapy and autologous stem-cell transplantation as a treatment option in patients with primary refractory or relapsed refractory lymphoma who demonstrated persistent or local progression during salvage chemotherapy. How the radiation therapy is integrated into the treatment program is dependent on treatment response to salvage chemotherapy. In patients who ultimately achieve a PET complete remission after salvage chemotherapy, radiation therapy is usually administered using conventionally fractionated ISRT following hematologic recovery from autologous stem-cell transplantation. Standard doses of 36 Gy delivered in 18 to 20 fractions over 4 weeks are typically used. In presentations where salvage chemotherapy shows only a partial remission or localized progression on PET reimaging, the recommendation would include ISRT using accelerated fractionation of 1.8 Gy twice per day. Generally, the treatment volume would be the anatomic areas identified at presentation for salvage therapy on the basis of PET and other imaging. Areas of persistent disease are treated to a cumulative dose of 36 to 39.6 Gy in 20 to 22 fractions over 10 to 11 treatment days. A PET scan is usually repeated shortly after completing radiation therapy, recognizing that PET avidity within the irradiated treatment volume may be related to treatment inflammation and may not be definitive evidence of persistent disease. A favorable response should include an observed decrease in the size of the CT tumor volume after radiation therapy compared with the preradiation therapy CT tumor volume seen on PET imaging. In this case, observed PET avidity within the irradiated treatment volume is attributed to inflammation. These patients would be able to proceed to high-dose therapy with autologous transplantation. Findings of new areas of PET avidity outside of the radiation treatment volume, Deauville 5, or an infield increase in both PET avidity with a corresponding increase in the size of the PET/CT tumor volume would be considered as disease progression or persistence and generally result in termination of the plans to proceed with autologous stem-cell transplantation.