Non-Hodgkin's Lymphomas are divided into low grade and high grade and are pathologically divided by type. They are CD20 positive and CD15/30 negative. The major histopathologic types are:
NHL prognostic indicators include the International Prognostic Indicator for DLBC and FL-IPI for follicular lymphomas. The IPI consists of points for each of the following criteria:
The index is constructed by awarding points for each unfavorable, i.e. age > 60, abnormal LDH, poorer performance status, advanced stage and presence of more than one site. The five year overall survival is a function of the sum of points.
| OS5 yr | Risk Group |
|---|---|
| 73% (R-CHOP 83%) | Low (IPI= 0-1) |
| 51% (R-CHOP 61%) | Low Intermediate (2) |
| 43% (R-CHOP 53%) | High Intermediate (3) |
| 26% (R-CHOP 36%) | High (4-5) |
The workup includes a comprehensive history and physical exam with emphasis on node bearing areas, Waldeyer's Ring and liver and spleen for enlargement. The history should assess for B signs (fevers, chills, night sweats, unexplained weight loss).
Imaging studies include diagnostic quality CT and PET scan. These studies are important before treatment is initiated as they will be used to determine the extent of pre-treatment disease for consolidation radiation and response to therapy. They are also important in defining the stage of disease, which in turn sets the treatment course.
NHL is frequently treated with cardiotoxic chemotherapy, including Adriamycin or epirubicin. A MUGA scan should be obtained to insure cardiac function.
Laboratory studies. The LDH is a component of the IPI. Uric acid should be assessed to determine the need for pre-emptive management of tumor lysis syndrome. CBC/diff/platelets, and chemistries should be obtained.
Other laboratory studies include HBV, and a pregnancy test in women who could become pregnant. If future fertility is desired, a discussion on options available should be held prior to commencing treatment.
The work up for NHL includes obtaining a tissue diagnosis. A fine needle aspirate and core needle biopsy are not adequate to confirm diagnosis. The pathologist will usually require enough tissue for architecture. This means that an excisional biopsy is important. FLow cytometry and immunochemistry work up is important. A bone marrow biopsy may be omitted if PET imaging is negative in DLBCL. In FL, NK/T and Mantle Cell, a bone marrow biopsy should be done. In Burkitt's Lymphoma, a lumbar puncture should be performed.
Finally, the IPI should be calculated and recorded. There are a number of IPI scoring systems available. The most commonly used awards a point for each of the following:
Points are scored as follows:
| Points | Risk category |
|---|---|
| 0 - 1 | Low |
| 2 | Low intermediate |
| 3 | High intermediate |
| 4-5 | High |
For early stage disease (Stage I/II) chemotherapy with R-CHOP is the initial treatment of choice. This should be followed with radiation therapy to the involved site. For advanced disease Chemotherapy is used with radiation for limited Stage III disease, bulky disease or persistent PET positive disease and skeletal disease.
For non-bulky Stage I/II disease, generally 3 cycles of R-CHOP are used followed by consolidative radiation. Up to 6 cycles may be used. If there is bulky disease, then 6 cycles of R-CHOP should be used. After initial R-CHOP, all positive studies should be repeated. If the PET-CT is positive, the site should be rebiopsied before altering the treatment course.
If there is a complete response, then complete planned radiotherapy course. For less than complete response (ie partial response), complete radiotherapy course but increase the radiation dose. If there is progressive disease, proceed to stem cell transplant or second line chemotherapy. Consideration of palliative radiotherapy may also be an option.
The data supporting the use of radiotherapy in DLBCL includes the ECOG 1484 trial published in 2004. (Horning et al, JCO 2004;22:3032) This work included Stage I/II aggressive diffuse lymphomas with DLBCL accounting for about 80%. It included bulky Stage I disease, (> 10 cm) Stage IE and Stage II disease. 8 cycles of CHOP (pre-retuximab era) were given. If there was a CR by CT, then patients were randomized to observation or 30 Gy of radiation therapy. All partial responders received 40 Gy. The primary endpoint was disease free survival with a 20% threshold to claim success. This study was a very high threshold. It was not powered to detect a survival benefit.
The ECOG 1484 trial not only met its 20% threshold for improved DFS, but it also demonstrated trend toward a survival benefit.
The MDACC published a retrospective analysis of 327 patients in 2010 (Phan et al, JCO 2010;28:4170). Patients got 6-8 cycles of R-CHOP. Patients were Stage I/II (37%) and Stage III/IV (63%). Those who had a CR received radiation therapy at the treating physician's discretion. The radiation doses were 30 - 40 Gy, when radiation was given. There was a clear and convincing benefit to adding radiation therapy with a HR of 0.32. There was also a survival benefit in favor or radiation therapy with a HR of 0.19.
A Phase III trial of radiation dose was reported in 2011 with an examination of 640 sites of agressive Non-Hodgkin's Lymphoma, 82% with DLBCL, 675 Stage I/II, 73% post-chemotherapy consolidation radiation. Patients were randomized to 30 Gy in 15 fractions (2 Gy/fraction) or 40-45 Gy in 20-23 fractions. There was no significant difference between 30 Gy adn 40-45 Gy at 5.6 years median follow up. Note that this study was not without problems: it included patients which were treated with RT alone or with palliative/salvage radiation. The chemotherapy data was not gathered, most were treated without rituximab, and finally, no functional imaging (PET) was used to determine chemotherapy response. (Lowry et al, Radiotherapy and Oncology, 2011;100:86 )
For Stage I-II DLBCL:
For Stage III-IV DLBCL:
Note: the ECOG 1484 validated 30 Gy only in a NEGATIVE PET (CR).
This review demonstrated a role for radiation therapy in extranodal disease. Radiation therapy improved event free survival for skeletal involvement with a HR of 0.3, p=0.001. ( Held, et al,JCO 2013;31:4115).
This study looked at R-CHOP x 6 cycles + two addtional rituximab cycles and radiation therapy for bulky or extranodal disease. It also compared an amended arm without radiation therapy. Radiation improved EFS, PFS and OS. (Held, et al, JCO 2014;32:1112)