Radiation Therapy for Nodal Stage I-II Diffuse Large B-Cell LymphomaRichard T. Hoppe, MD Diffuse large B-cell lymphoma accounts for nearly one-third of the non-Hodgkin's lymphomas worldwide. Histologically, these lymphomas are characterized by diffuse effacement of the normal lymph node architecture by large neoplastic B cells with nuclei roughly twice the size of normal lymphocytes. The nuclei may be cleaved or multinucleated. The cells express the typical B-cell associated antigens (CD19, 20, and 22).The bcl-2 gene is rearranged in about 30% of cases, and occasional cases have a rearrangement of bcl-6. A subtype of this lymphoma is mediastinal large B-cell lymphoma. Diffuse large B-cell lymphoma presents in a broad spectrum of age. and In adults, as many as 50% of patients have stage I-II disease (involvement of a single lymph node region or multiple lymph node regions on the same side of the diaphragm).Some of these patients have involvement of a solitary extranodal site (Stage IE), such as the skin, thyroid, bone, or stomach. Others may have involvement of lymph nodes as well as an extranodal site (Stage IIE). This discussion will deal only with nodal stage I-II disease. The usual staging for patients with suspected early stage diffuse large B-cell lymphoma should include a careful physical examination with attention to the important lymphoid regions and laboratory studies to include complete blood counts, chemistry screening panel, and LDH. Radiographic studies include a chest x-ray and abdomen/pelvis or chest/abdomen/pelvis computed tomographic (CT) scan. A needle bone marrow biopsy should be performed. In addition to a stage designation, patients may be characterized according to the International Prognostic Index (IPI), which evaluates risk of death and relapse according to patient age, performance status, stage, number of extranodal sites of disease, and LDH level. More than two-thirds of patients with stage I-II disease are in the "low risk" group for relapse or death using the IPI. Historically, treatment with radiation therapy alone was used for these patients. Although results were good for treating stage I at some centers that employed high dose extended field treatment, the general results for stage II were disappointing. With the introduction of curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) for diffuse large cell lymphoma, treatment programs utilizing chemotherapy alone became popular, but relapse in initially involved sites was identified as a cause for failure in some patients. As a result, two large randomized clinical trials were conducted in the US to compare treatment with chemotherapy alone versus combined modality therapy. The SWOG 8736 trial randomized patients between CHOP chemotherapy alone (8 cycles) and CHOP chemotherapy (3 cycles) followed by involved field irradiation (40-55 Gy). Although some other related histologies were included, 75% of patients had diffuse large cell lymphoma. Patients were excluded who had masses >10 cm. Progression-free survival at five years was 64% for CHOP alone and 77% for combined modality therapy (P=0.03), and overall survivals were 72% and 82% (P=0.02). This study established combined CHOP and involved field irradiation as the treatment of choice for patients with stage I-II diffuse large cell lymphoma, excluding those with large masses. A parallel study was completed by the ECOG (EST 1484) and reported only as an abstract. Key differences in the two studies included patient eligibility (ECOG excluded patients with minimal disease but included patients with large masses), number of cycles of CHOP in the combined modality program (eight in ECOG, three in SWOG), and radiation dose (30 Gy in ECOG and 40-55 Gy in SWOG). Despite these differences, the results and conclusions were similar, with the ECOG study also demonstrating significant improvements in failure-free and disease-free survival and a borderline improvement (P=0.06) in overall survival. Based upon these studies and general consensus suggested from other large experiences, what is reasonable management for patients with nodal stage I-II diffuse large cell lymphoma? For patients with non-bulky disease, three cycles of CHOP plus involved field irradiation is reasonable. If the disease is slow to regress, up to six cycles of CHOP may be used. After a complete response (CR), radiation should be administered to the involved lymphoid region(s), but a dose of 36 Gy is probably sufficient, especially if a CR is obtained with CHOP. For patients who present with bulky disease (masses >10 cm or mediastinal masses measuring greater than one-third of the intrathoracic diameter), six to eight cycles of chemotherapy are warranted followed by involved field irradiation to 30-36 Gy if a CR was achieved with CHOP. With respect to design of the involved fields, treatment may be limited to the involved lymphoid regions (but not simply the involved node). For practical considerations, it is usually reasonable to include the ipsilateral supraclavicular area when treating the axilla, and the bilateral hilar and supraclavicular areas when treating the mediastinum. In men and post-menopausal women, the ipsilateral iliac nodes may be included in an inguinal field. Patients should undergo careful simulation and field design using a dedicated conventional or CT simulator, and treatment is generally via opposed field technique. Daily fraction size should be 1.5-2.0 Gy, depending upon the field size. Regions of concern with respect to potential toxicity include: axillary breast tissue (primarily a concern for women under thirty, who will have an increased risk of breast cancer); mediastinum (increased risk of cardiovascular disease if the coronary arteries are within the radiation fields); ovaries (function will be ablated if the iliac region is treated); and testes (generally adequate protection with specialized testicular shielding). Rare patients may not be candidates for chemotherapy treatment. In this setting, involved or slightly extended field irradiation to a dose >35 Gy may still be employed. At the Princess Margaret Hospital, patients who were younger than 60, had stage IA or limited Stage IIA disease (two adjacent sites of involvement), and no residual sites >2.5 cm had an actuarial cause-specific survival of 87% at ten years.6 For patients who were older or who had more significant residual disease (2.5-5 cm.), it was 55%. Published April 2000 |
