Stage I and II, Follicular Grade 1 and 2 Non-Hodgkin's Lymphoma

There are a number of questions regarding RT and follicular grade 1 and 2 NHL. Is follicular grade 1 and 2 NHL curative with RT alone? (Yes.) What is the frequency of recurrence after 10 years? (Only approximately 10%.) A Patients with early-stage disease are curable with local regional irradiation. The updated series from Stanford University details the results of RT in 177 patients treated from 1961 to 1994. Out of 177 patients, 73 were stage I and 104 had stage II disease. Staging laparotomy was performed in 25% of patients and 20% of patients had extranodal presentations. Total nodal irradiation (TLI)and subtotal nodal irradiation were given to 41 patients, and involved-field or extended-field irradiation was delivered to 133 patients. Staging laparotomy and TLI were used in the early years of the study. Histology was follicular grade 1 in 57% of cases and follicular grade 2 to 3 in 43% of patients. The median follow-up was 7.7 years. The 10-year, 15-year, and 20-year survivals were 64%, 44%, and 35%, respectively. The 10-year, 15-year, and 20-year disease-free survivals were 44%, 40%, and 37%, respectively. Only 5 of 47 patients in remission for 10 years or longer have relapsed at longer intervals. This study demonstrates that a substantial percentage of patients with early-stage follicular small cleaved cell NHL never have recurrence of disease following local regional irradiation. All the series demonstrate greater than a 40% freedom from treatment failure at 10 years. Median survival ranges from 13 to 16 years in the studies. Prognostic factors for relapse were analyzed. Age in all studies was a significant adverse factor for relapse. Although most studies use age under and over 60, the British National Lymphoma Investigation (BNLI) study found no difference in relapse for patients in their 50s or 60s and only age 70 or greater was an adverse factor.  Other significant but less important prognostic factors for increasing recurrence risk include extranodal disease, female gender, and stage II disease. There appears to be little difference in outcome between follicular grade 1 and follicular grade 2 disease.

On multivariant analysis, for patients with stage I to II disease, there is no evidence that the use of extended-field or TLI provided for a survival advantage compared with involved-field or regional irradiation in the Stanford study. There are concerns for increased toxicity with larger RT fields and the possibility that subsequent treatment, if needed, will be compromised as more than 50% of stage I to II patients eventually develop a recurrence and require more aggressive treatment. In addition, there is a high conversion rate of follicular small cleaved cell NHL to a more aggressive histology over time, requiring treatment with chemotherapy.  Prior treatment with TLI may compromise marrow reserve and limit subsequent multiagent chemotherapy given either for recurrent indolent NHL or for NHL transformed to a more aggressive histology. Also, there appears to be an increased risk of late complications including second cancers with large-field irradiation. [ref: 281]There are no large prospective or randomized studies evaluating the dose and field size of RT for patients with stage I to II follicular small cleaved cell NHL. However, most centers use radiation doses between 30 and 40 Gy, and either involved-field irradiation or regional fields. Current recommendations include the use of regional RT fields. This consists of irradiating the involved nodal region plus one additional uninvolved region on each side of the involved nodes. For example, the treatment field for lymphoma of the inguinal nodes would include the ipsilateral femoral, inguinal, and external iliac nodes. The treatment of a stage I lymphoma of the right supraclavicular nodes would include the ipsilateral axilla, supraclavicular, and cervical nodes. The cervical, supraclavicular, oropharyngeal, and nasopharyngeal nodes would be irradiated in patients with involvement of Waldeyer's ring. The recommended dose for patients with follicular small cleaved cell NHL is 3000 to 3600 cGy, with a boost to areas of initial involvement to 36 to 40 Gy. When there is a possibility of significant morbidity from treatment, such as long-term xerostomia from irradiation of the salivary glands, lower doses to the uninvolved nodal areas are recommended (i.e., 25 to 30 Gy).

The role of combination chemotherapy in the management of early-stage follicular lymphoma is unclear. At least three randomized studies conducted in the 1970s failed to demonstrate that non-adriamycin-containing combination chemotherapy regimens plus RT were superior to
RT alone. A more recent BNLI study randomized 148 patients to receive either RT alone or RT plus chlorambucil chemotherapy. There were no differences in freedom from recurrence or survival between the groups. A single-arm study of 91 stage I and II patients treated at the M. D. Anderson Cancer Center with cyclophosphamide, vincristine, and prednisone (COP) or cyclophosphamide, doxorubicin, vincristine, and prednisone-bleomycin (CHOP-Bleo) chemotherapy in addition to RT demonstrated an improved freedom from recurrence compared with historic controls but no overall survival differences. In part, the choice of therapy may lie in the careful assessment of prognostic factors. Most patients with Ann Arbor clinical stage I or II follicular small cleaved cell and follicular mixed lymphomas should have a good prognosis following local regional RT alone. For patients whose prognosis is less certain, such as patients with stage II disease with multiple sites of involvement or bulky nodes, or patients with follicular large cell histology, chemotherapy followed by involved-field irradiation may provide more durable remissions.
Cancer. Princ&Pract Onc DeVita. 6th Ed. 2001