The REAL/WHO classification of NHL includes several additional, newly identified entities not recognized by the IWF.² After consideration of cell of origin (B, T, or NK) the classification subdivides lymphomas into those derived from precursor lymphocytes versus those derived from mature lymphocytes. The classification is further refined based on immunophenotype and genetic features. These considerations have aided in defining active treatment for specific subtypes of lymphoma.

Currently, a comprehensive description of the natural history and clinical features of all NHL diagnoses recognized by the WHO classification does not exist. However, the International Lymphoma Classification Project evaluated 1403 lymphoma cases and identified the 13 most common histologic types responsible for about 90% of cases of NHL in the United States.³ The findings were as follows: diffuse large B-cell (DLBCL), 31%; follicular lymphoma (FL), 22%; small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), 6%; mantle cell lymphoma (MCL), 6%; peripheral T-cell lymphoma (PTCL), 6%; and marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue (MALT) lymphoma, 5%. The remaining subtypes each occurred in less than 2% of cases. Composite lymphomas were not included in these distribution figures. Importantly, in the United States more than 50% of cases of lymphoma are either DLBCL or FL. In a study performed by the International T-cell Lymphoma Project, PTCL–not otherwise specified (PTCL-NOS) was the most common subtype of PTCL (29.3%).⁴

Cytogenetics and Molecular Biology

Several lymphomas are associated with nonrandom chromosomal abnormalities.⁵ These abnormalities often correlate with the histologic type, immunophenotype, and clinical behavior. For example, translocation t(14:18) (q32;q21) occurs commonly in follicular lymphoma. It results in the transposition of the bcl-2 oncogene of chromosome 18 to become adjacent to the heavy chain immunoglobulin gene on chromosome 14. The bcl-2 oncogene is essential for apoptosis or programmed cell death. The t(14:18) translocation interferes with normal senescence and death of the follicular center cell and is possibly engaged in its malignant transformation. Most patients with Burkitt’s lymphoma have translocation t(8:14) or one of its variants, and c-myc is the relevant translocated oncogene. The c-myc product is an important transcription factor, and its dysregulation is probably involved in the proliferative process. Translocation t(11:14) involving bcl-1 is characteristic for recognition of mantle cell lymphoma. The gene product of bcl-1, cyclin D, is directly involved in the regulation of cell division. Rearrangement of bcl-6 has been reported in a third of patients with diffuse large-cell lymphoma. In 25% to 40% of patients with MALT lymphoma, t(11:18) has been detected and indicates an unlikely response of MALT lymphoma of the stomach to antibiotic therapy of an associated H. pylori infection.

Pathologic Diagnosis

In consideration of the clinical and histologic diversity of the lymphoid malignancies grouped together under the generic title non-Hodgkin’s lymphoma, it is crucial to obtain clear and detailed pathologic information about the biopsy specimen. An adequately processed pathologic specimen should be analyzed by a hematopathologist who is well versed in interpreting modern immunohistopathologic and molecular genetics techniques required for modern diagnosis and classification of NHL.

In Table 61-1, the more common histologies are listed by WHO classification and grouped as low grade (indolent), intermediate grade (aggressive), or high-grade (highly aggressive), a terminology that is still in clinical use.

Table 61-1 Abridged Version of the WHO Lymphoma Classification Organized by Clinical Groups

Low Grade (Indolent)

Follicular lymphoma (FL) (grades 1-2)

Small lymphocytic lymphoma (SLL)

Marginal zone lymphoma (MZL): Extranodal (MALT lymphoma)

Nodal

Splenic

Mycosis Fungoides (T-cell lymphoma of skin)

Intermediate Grade (Aggressive)

Diffuse large B-cell (including immunoblastic, and mediastinal B-cell) lymphoma (DLBCL)

Follicular lymphoma (grade III)

Mantle cell lymphoma (MCL)

T-cell lymphomas: Peripheral T-cell lymphoma (PTCL)

Angiocentric

Angioimmunoblastic

NK lymphoma

Anaplastic large cell lymphoma (ALCL)

High Grade (Highly Aggressive)

Lymphoblastic lymphoma

Burkitt’s lymphoma

High-grade B-cell, Burkitt’s-like

Staging and Prognostic Factors

Although histology is the predominant determinant of prognosis in this diverse group of lymphoid malignancies, stage remains important for selection of treatment strategy and predicting prognosis in each histologic category. The Ann Arbor Staging Classification system, developed originally for Hodgkin’s disease, has also been used for NHL. The staging system is described in Chapter 60, Hodgkin’s Disease, and reflects the number of sites of involvement and their relation to the diaphragm, existence of B symptoms, and the presence of extranodal disease. In NHL, most patients are assigned to a stage based on physical examination, imaging studies, and bone marrow biopsy. The Ann Arbor staging system is considered by many to be inadequate for NHL, a shortfall that has led to the incorporation of other prognostic factors to define initial therapy.

The International Prognostic Index

In addition to stage, other important prognostic factors have been identified in patients with NHL.⁶ They frequently include patient parameters such as age, performance status, and tumor burden indicators such as bulk, number of involved sites, presence of extranodal disease, and lactate dehydrogenase (LDH) level.

An international team developed a prognostic model to predict outcomes of patients with aggressive NHL ⁶ (Table 61-2). The International Prognostic Index (IPI) identified five significant risk factors predictive of overall survival: age (<60 years versus >60 years), serum LDH (normal versus elevated), performance status (0 or 1 versus 2 to 4), stage (I or II versus III or IV), and number of extranodal sites involved (0 or 1 versus 2 to 4). These features were incorporated into a model that identified four groups of patients with significantly different outcomes following treatment. Risk groups were determined by the sum of adverse risk factors: low (0 to 1 factor), low-intermediate (2 factors), high-intermediate (3 factors), and high (4 to 5 factors). The predicted 5-year survival rates for these groups were 73%, 51%, 43%, and 26%, respectively. When only patients younger than 60 were evaluated, stage, performance status, and LDH levels remained significant for poor prognosis (age-adjusted IPI).

Table 61-2 International Prognostic Index for Aggressive NHL

All Patients

Age > 60 years

Serum LDH above normal

ECOG performance status > 2

Ann Arbor clinical stage III or IV

Number of involved extranodal sites > 1

	IPI Score	5-Year Survival (%)
Low-risk	0-1	73
Low-intermediate	2	51
High-intermediate	3	43
High-risk	4-5	26
Patients ≤ 60 years
Serum LDH above normal
ECOG performance > 2
Ann Arbor stage III or IV

	Age-Adjusted IPI Score	5-Year Survival (%)
Low-risk	0	83
Low-intermediate	1	69
High-intermediate	2	46
High-risk	3	32

Patients With Early-Stage (I-II) Disease
Age > 60
Serum LDH above normal
Stage II disease
ECOG performance status ≤2

Modified IPI Score	10-Year Survival (%)
0	90
1-2	56
3	48

After validation by several centers, the major cooperative groups have accepted this index for the design of new protocols. The model is simple to apply, reproducible, and predicts outcome even after patients have achieved complete response. Although originally designed for patients with untreated aggressive lymphomas, it has been shown to be predictive after relapse for patients undergoing salvage therapy with or without high-dose therapy and stem cell support.

For follicular lymphoma, the Follicular Lymphoma International Prognostic Index (FLIPI) has been shown to be a valuable prognostic tool.⁷ It is depicted in Table 61-3.

Table 61-3 The International Prognostic Index for Follicular Lymphoma⁴

Age	≤60 years
Ann Arbor stage	III-IV
Hemoglobin level	<12 g/dL
Serum LDH level	>ULN (upper limit of normal)
Number of nodal sites	>5
Risk Group According to FLIPI Chart	Number of Factors
Low	0-1
Intermediate	2
High	≤3

FLIPI, Follicular Lymphoma International Prognostic Index.

Essential workup studies for staging and IPI based on National Comprehensive Cancer Network (NCCN) guidelines ⁸ are detailed in Table 61-4.

Table 61-4 Essential Workup of Patients With Non-Hodgkin’s Lymphomas

In Selected Cases

Neck CT

Head CT or MRI

HIV testing

Determination of ejection fraction: MUGA scan or echocardiogram

Lumbar puncture, if: paranasal sinus, testicular, parameningeal, periorbital, CNS, paravertebral, bone marrow involvement or HIV positive

Discussion of fertility issues and sperm banking

Response Criteria

The International Working Group (IWG) published the guidelines for response criteria for lymphoma in 1999. These criteria are based on the reduction in size of the enlarged lymph nodes as measured by computed tomography (CT) scan, and the extent of bone marrow involvement, determined by bone marrow aspirate and biopsy.⁹ These guidelines were revised in 2007 by the International Harmonization Project to incorporate immunohistochemistry (IHC) flow cytometry and 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans in the definition of response. The category “complete response uncertain” (CRu) was essentially eliminated because residual masses were defined as a partial response (PR) or a complete response (CR) based on the result of the PET scan.¹⁰ Using the revised system, response is categorized as CR, PR, stable disease (SD), and relapsed disease or progressive disease (PD). However, the application of PET to responses is limited to histologies where there is reliable FDG uptake in active tumor. Response criteria for lymphoma are summarized in Table 61-5.

Table 61-5 Revised Response Criteria for Lymphoma (Including PET)*

Common Lymphomas and the Role of Radiation Therapy

There are certain types of lymphomas that are more likely to require radiation oncology attention. Table 61-6 lists the types of HL and NHL most likely to benefit from radiation therapy.

Table 61-6 Indications for Radiotherapy in the Treatment of Non-Hodgkin’s Lymphomas

Radiation Alone—Potentially Curative	Radiation Is Effective for Palliation and Local Control
Follicular lymphoma Stage I-II Stage III (rarely used) Extranodal marginal zone (MALT) lymphoma Stage IE-IIE Nodal marginal zone lymphoma Stage I-II Mycosis fungoides Stage IA, IB, IIA Anaplastic large cell lymphoma of skin Stage IE

Highly sensitive:

Follicular lymphoma

Mantle cell lymphoma

Small lymphocytic lymphoma/CLL

Marginal zone lymphoma

Mycosis fungoides

Moderately sensitive:

Diffuse large cell lymphoma

Radiation Is Part of a Potentially Curable Combined Modality Program

Diffuse large B-cell lymphoma

Stage I-II

Primary mediastinal lymphoma

Stage I-II

Peripheral T-cell lymphoma

Stage I-II

Extranodal NK/T-cell lymphoma-nasal type

Primary CNS lymphoma

In high-dose therapy programs for diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma

Low-Grade Lymphomas

Follicular Lymphomas

Follicular lymphoma (FL) is the most common type of lymphoma in the United States. FL of different grades constitutes as much as 35% of adult NHL; the incidence is apparently lower in other parts of the world. This is a disease of adults, with a median age of 59 years and a male-to-female ratio of 1 : 1.7. Follicular lymphoma, particularly grade 1 or 2, is indolent in nature, with a median survival of 8 to 10 years reported in selected populations. Reproducible distinction between grade 1 and grade 2 is difficult and of questionable significance. Recently, the WHO has recommended that these two grades be combined as “Grade 1-2.”

The disease involves predominantly lymph nodes, although the bone marrow is involved in approximately 40% of patients. Of particular interest to the radiation oncologist is that about 20% of FL patients present with localized (stage I and stage II) disease and are largely curable with radiation therapy.¹¹ Although patients with advanced-stage disease may have an indolent course, there is no curative treatment, and there is an inexorable relapse rate of 15% to 20% per year. In many patients, follicular lymphomas¹² eventually evolve into aggressive lymphomas manifested by histologic transformation to diffuse-pattern and large-cell morphology, clinical progression, and abnormal cytogenetic findings in addition to t(14;18).¹² Diffuse large-cell lymphomas that evolve from follicular lymphomas lack the curability of diffuse large-cell lymphomas. A recent study disclosed a transformation risk of 28% in 10 years.¹² The median survival after transformation was only 1.2 years.

Most patients with FL present with an advanced stage of the disease (III-IV). Their treatment is primarily with systemic chemotherapy and/or immunotherapy (rituximab, an anti-CD20 antibody), and patients with low-burden asymptomatic disease are frequently managed with expectant observation.

The standard treatment for patients with localized stages (I and II) is regional or involved-field radiotherapy. Results from large series of patients with stage I and II indolent lymphomas who were treated with radiotherapy alone are summarized in Table 61-7. It should be noted that in past series, no clear distinction was made between early stages of follicular lymphomas and the less frequent currently recognized low-grade histologies of marginal zone and small lymphocytic lymphoma (SLL). Additionally, patients in series from more than 2 decades ago were staged less meticulously than today, and it is estimated that a significant number of them would be upstaged with current imaging technology (such as PET).

Table 61-7 Radiotherapy Alone for Stage I and II Indolent Lymphomas

The report from Stanford ⁵ of patients with stage I and II low-grade follicular lymphoma with long-term follow-up indicated that a substantial number of patients in this category have, indeed, been “cured” by radiotherapy. The median follow-up was 7.7 years, and observation has been maintained for up to 31 years. The median survival after radiotherapy was 14 years. The actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. Freedom from relapse (FFR) at 5, 10, 15, and 20 years was 55%, 44%, 40%, and 37%, respectively. Only 5 of 47 patients who reached 10 years without a relapse developed a late recurrence. There was no significant FFR difference between stage I and stage II or between nodal or extranodal disease. The survival of patients irradiated after the age of 60 years was significantly shorter than the survival of younger patients, but the decrease of survival in this age group was strongly affected by death from other causes.

Most relapses in early-stage patients occur in unirradiated sites during the first 5 to 6 years following therapy.¹⁴ In the Stanford series, administration of radiotherapy to nodal sites on both sides of the diaphragm was associated with a significantly better FFR compared with more localized treatment but did not translate into a clear survival benefit.¹¹ Similar experience was reported from M.D. Anderson.¹⁵ In the absence of a clear survival benefit for total lymphoid irradiation in this setting, the common involvement of mesenteric nodes that may require whole abdominal irradiation, and in consideration of the fact that almost half the patients will eventually require chemotherapy for relapse, a limited field is preferred. Involved or regional field irradiation for these patients is currently the standard of care.

The optimal radiation dose for indolent lymphoma has not been determined in a prospective study. However, most current radiotherapy series for stage I and II indolent lymphomas usually employ 30 to 40 Gy, and in-field recurrences have been uncommon. Data from the Princess Margaret Hospital showed in-field disease control in 78% of patients treated with doses of less than 25 Gy and 91% control with doses greater than 25 Gy.¹⁶ At M.D. Anderson, excellent local control was achieved with 30 Gy to lesions smaller than 3 cm.¹⁰ A recent (as yet unpublished) prospectively randomized British study showed that 24 Gy provide response and local control rates similar to those obtained with 40 to 45 Gy.¹⁷ At Memorial Sloan-Kettering Cancer Center (MSKCC), a dose of 24 to 36 Gy to involved sites (36 Gy, if bulky) is the standard of care.

Several prospective randomized trials failed to demonstrate that the use of radiation followed by chemotherapy was superior to radiation alone in early-stage indolent lymphoma. The rare histology of early-stage nodal marginal zone lymphoma is treated (as is FL) with involved-field radiotherapy (IFRT) alone.⁸

Marginal Zone Lymphomas

Marginal zone lymphomas (MZLs) constitute 7% to 8% of all B-cell lymphomas. When MZLs involve the nodes, they are called monocytoid B-cell lymphomas. When they involve extranodal sites (mucosa-associated lymphoid tissue), they are called MALT lymphomas. These are tumors of adults, most in the sixth to eighth decade of life, with a 1.5 : 1 male predominance.

Marginal zone lymphomas are characterized by cellular heterogeneity, including marginal zone (centrocyte-like) cells, monocytoid B cells, small lymphocytes, and plasma cells. In epithelial tissue, the marginal zone cells typically infiltrate the epithelium, forming lymphoepithelial lesions.

The immunophenotype of MZLs helps distinguish them from other neoplastic proliferations of small lymphoid cells. Although positive for pan–B-cell antigens and expressing surface immunoglobulin, they are negative for both CD5 (unlike small lymphocytic and mantle cell) and CD10 (unlike follicle center cells).

The MALT lymphomas have been identified in many extranodal sites, most commonly in the stomach but also in salivary glands, Waldeyer’s ring, large and small intestine, thyroid, eye (orbit and conjunctiva), lung, breast, and skin. Some of these sites do not have mucous membranes but contain columnar epithelium, which may be the common feature. Most of these lymphomas are limited to the involved site at diagnosis, with occasional involvement of adjacent lymph nodes. The clinical course is indolent, even in patients with advanced-stage disease.

There is considerable evidence to suggest that MALT lymphoma develops as a result of prolonged antigenic stimulation and in some situations may depend on continuous stimulation. MALT lymphoma may develop in the thyroid gland of patients with Hashimoto’s thyroiditis and in salivary glands of patients with Sjögren syndrome. As noted earlier, H. pylori infection of the stomach has been shown to be the etiologic factor in many patients with MALT lymphoma of the stomach, and lymphoma regression has been documented following eradication of H. pylori with antibiotics. For patents with MALT lymphoma of the stomach and evidence for active H. pylori presence in the stomach, omeprazole with antibiotics is the first line of lymphoma eradication treatment.

Approximately 30% to 50% of patients with H. pylori–positive gastric MALT lymphoma (GML) will show persistent or progressing lymphoma even after eradication of H. pylori with antibiotic therapy. Even in complete responders, almost 15% will relapse within 3 years, suggesting that about half of patients with GML will eventually be considered for additional therapies.¹⁸ Most of those will still have disease limited to the stomach. In these patients and in those who present with no evidence of H. pylori infection, IFRT with relatively low radiation dose is the treatment of choice.⁸

Several institutions reported excellent results using IFRT of the stomach in H. pylori–independent GML patients who either failed antibiotic therapy or had no evidence for H. pylori infection.¹⁸^–²² A recent update of the MSKCC experience included 51 patients with GML (stage I, 39; stage II, 10; stage IV, 2) who were either H. pylori–negative (30) or remained with persistent lymphoma after antibiotic therapies and adequate observation (21).¹⁹ All patients were treated with radiation to the stomach and perigastric nodes; the median total dose was 30 Gy in 4 weeks. All patients had regular follow-up endoscopic evaluations and biopsies, and 49 of 51 (96%) patients obtained a biopsy-proven complete response. Of three patients who relapsed, two were salvaged. Three patients died of other malignancies; all second tumors developed outside the radiation field. At a median follow-up of 4 years, freedom from treatment failure, overall survival and cause-specific survival were 89%, 83%, and 100%, respectively. Treatment was well tolerated, with no significant acute or chronic side effects. The experience from Toronto and Boston using the same radiation treatment approach was equally successful,²⁰^–²² supporting the notion that modest-dose IFRT is the treatment of choice for patients with persistent GML who have exhausted the antibiotic therapy approach or are unlikely to respond to it (H. pylori–negative patients).²³^,²⁴ The techniques for treatment of gastric lymphoma have been described in detail.²⁵

MALT lymphomas have also been described in various nongastric sites such as salivary glands, skin, orbit, conjunctiva, lung, thyroid, larynx, breast, kidney, liver, bladder, prostate, urethra, small intestine, rectum, pancreas, and even in the intracranial dura.²⁴ The optimal management of nongastric MALT lymphomas has not yet been clearly established. Retrospective series included patients treated with surgery, radiotherapy, and chemotherapy, alone or in combination. Marginal zone lymphomas are exquisitely sensitive to relatively low doses of radiation. Specifically, MZLs in sites such as salivary glands, ocular structures, conjunctivae, thyroid, breast, and bladder have been successfully eradicated with IFRT encompassing the involved organ alone with a dose of 24 to 36 Gy.²⁰^,²² Even unusual sites (e.g., larynx, base of skull, urethra, prostate) not easily amenable to surgery have been well controlled by IFRT.

Radiation Therapy for Relapsed and Refractory Low-Grade Lymphomas

Chemotherapy and antibody therapy are the primary treatments of advanced-stage low-grade lymphomas, but the very high sensitivity of these lymphomas to radiation should not be ignored. Even extremely low doses of radiation can provide long-standing local control and effective palliation.

Several European groups showed that patients with low-grade lymphoma and persistent or relapsed disease following several regimens of chemotherapy responded to only two treatments of 2 Gy each (a total of 4 Gy). Using this schedule, a Dutch group reported on 109 patients (304 symptomatic sites), mostly with FL, with an overall response rate of 92% and a complete response rate of 61%.²⁶^,²⁷ The 2-year actuarial freedom from local progression (FFLP) rate was 56%. Similarly, a French team reported an objective response of 81% of the sites, with 57% attaining a complete remission. The 2-year actuarial FFLP rate was 56%.²⁸

Intermediate-Grade (Aggressive) Lymphomas

Mantle Cell Lymphoma

Mantle cell lymphoma presents as stage IV in most patients and is treated primarily with chemotherapy, but its exquisite sensitivity to radiation should be appreciated. A British Columbia Cancer Center study indicated that patients with MCL stages I and II benefited significantly from localized RT alone or RT combined with chemotherapy. The 5-year progression-free survival (PFS) was 68% for those receiving RT, compared to only 11% in patients not receiving RT (P < .002), 6-year overall survival was 71% and 25%, for RT versus no RT (P < .13).²⁹

At MSKCC, we used low-dose RT for local control and palliation of 38 sites in 21 advanced-stage patients previously treated with chemotherapy. Local control with radiation was obtained in all sites, and a complete response was achieved in 64% of sites.³⁰ In symptomatic patients, 94% obtained pain control with RT. Local progression occurred in 34% of patients at a median time to progression of 10 months. Since only a low dose of radiation is required (15 to 30 Gy) in MCL, large nodal sites may be treated with only minor side effects and without jeopardizing other future therapeutic options.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes approximately 30% of all NHLs. Its incidence has been increasing over the past few decades, particularly in older age groups. The median age of patients is in the seventh decade, but the range is broad and includes children. Male-to-female ratio is equal. The immunophenotype is characterized by pan–B-cell markers (CD19, CD20, CD22) and clonal surface immunoglobulin (usually IgM) in about 75% of patients and CD10 in about 25% of patients. The bcl-2 rearrangement and t(14;18) are found in about 30% of patients and probably represent transformation of CD10-positive follicle center lymphomas. Recently, bcl-6 rearrangements were identified in a significant subset of patients characterized by primary involvement of extranodal tissues, lack of bone marrow involvement, and favorable prognosis.

Patients with DLBCL typically present with a rapidly enlarging, often symptomatic mass at a single nodal or extranodal site; 40% are at least initially confined to extranodal sites. Although DLBCL is an aggressive disease that without treatment has a rapidly lethal course and a median survival of 8 months, it is potentially curable with appropriate treatment in all stages. About 40% of patients in advanced-stage, and approximately 80% to 90% of patients with stages I to II disease, are curable with chemotherapy or combined-modality therapy, respectively. Almost half of these patients present with localized disease. Radiation therapy, as part of a combined-modality approach, has an important role in their treatment.

A significant subset of patients with DLBCL present with predominantly mediastinal disease. Patients with mediastinal B-cell lymphoma are usually young (fourth decade) and female. This lymphoma is locally invasive and may cause airway compromise and superior vena cava syndrome. The treatment approach is similar to that of other localized aggressive lymphomas: combination chemotherapy followed by IFRT.

Early-Stage Diffuse Large B-Cell Lymphoma

In the past, radiation alone was considered an appropriate treatment for patients with localized (stage I to II) DLBCL. Young patients with low-bulk stage I DLBCL obtained 10 years survival of 87%, but other patients have relapsed at a rate higher than 50%. Most of the relapses in patients treated with radiotherapy alone were extranodal or occurred outside the irradiated field.

The advent of effective chemotherapy made radiotherapy alone obsolete for most patients with early-stage aggressive lymphoma. Several randomized studies indicated that adjuvant chemotherapy following IFRT or extended-field radiotherapy results in significantly better relapse-free survival and overall survival rates than treatment with radiation alone in early-stage aggressive lymphoma. Over the last 2 decades, the treatment of early-stage DLBCL with 3 to 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by IFRT has become the standard of care. More recently, several randomized studies showed that adding rituximab (anti-CD20) to chemotherapy improves outcome. R-CHOP followed by IFRT is currently the preferred treatment for early-stage DLBCL.

The question of whether the addition of radiotherapy improves the relapse-free and overall survival rate in patients with early-stage aggressive lymphoma who attained a complete response with chemotherapy is an issue marked by controversy.³¹^,³²

Adjuvant radiation therapy has become the standard of care in early-stage aggressive NHL following the analysis of two large randomized studies by the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG).³³ These studies are summarized in Table 61-8. The ECOG study involved patients with bulky or extranodal stage I and stage II intermediate-grade NHL.³⁴ All patients received 8 cycles of CHOP chemotherapy. Patients who attained only a partial response following chemotherapy received IFRT to 40 Gy, and 28% converted to complete-response status. Patients in complete response (61%) following chemotherapy alone were randomly assigned either to receive radiotherapy of 30 Gy to site pretreatment involvement or to observation alone. The recent 15-year update showed a statistically significant advantage to the adjuvant radiotherapy arm. The patients who received adjuvant radiotherapy attained a better failure-free survival rate than those receiving CHOP alone (54% versus 39%; P < .06).³⁴ Overall survival that included all causes of death in this aging population was better in the irradiated group (60% versus 44%), but the difference was not statistically significant. Cause-specific survival was not reported.

Table 61-8 Role of Radiotherapy in Stage I to II Aggressive Lymphomas: Randomized Studies

The SWOG study enrolled patients with stage I and non-bulky stage II aggressive NHL.³⁵ The patients were randomly assigned to receive either 8 cycles of CHOP chemotherapy alone or 3 cycles of CHOP followed by an involved field of 40 Gy (with an optional boost of up to 55 Gy). At a median follow-up of 4 years, the progression-free survival rate was significantly greater for the short-course CHOP plus radiotherapy group: 77% compared with 66% in the group receiving 8 cycles of CHOP with no radiotherapy. The combined-modality treatment also resulted in a superior overall survival rate (87% versus 75%; P < .01). Additionally, reversible toxicity occurring during therapy also favored the combined-modality arm.³⁵ Recent analysis of the SWOG data suggested that patients with early-stage modified high IPI had inferior survival and may require more than 3 cycles of chemotherapy.³⁶

The results of both randomized studies confirm the importance of adjuvant radiation therapy to the involved field in patients who attained a complete response following short (3 cycles) or long (8 cycles) chemotherapy. A relatively low dose of 30 Gy was adequate for patients who attained a complete response in the ECOG study (using 8 cycles of CHOP), while a higher dose (40 to 55 Gy) was used in the short chemotherapy arm of the SWOG study. At MSKCC, the standard consolidation dose is 30 to 36 Gy for patients who attained an unquestionable complete response following 3 to 6 cycles of chemotherapy. This is based on our and others’ excellent local control data with this dose range. A recent randomized study from England confirmed the adequacy of 30 Gy as well.¹⁷ At MSKCC, a higher dose (40 to 50 Gy) is still advised for uncertain complete responses or for patients that failed chemotherapy but are still potentially curable. For evaluating response, it is now recommended to obtain a PET-CT scan prior to and following chemotherapy, since a positive PET scan following chemotherapy may indicate an incomplete response that mandates a more aggressive approach.

Advanced-Stage Diffuse Large B-Cell Lymphoma

The standard treatment for patients with advanced-stage (III or IV) aggressive lymphoma is combination chemotherapy, and R-CHOP is the most commonly used combination.³⁶ In North America, radiation therapy as consolidation to even bulky sites or incomplete responders is only occasionally considered, although supported by retrospective studies.³⁷ Surprisingly, the data regarding the irrelevance of radiotherapy in these situations are scanty and/or indirect at best.³⁸

Unfortunately, even though the superiority of combined modality over chemotherapy alone has been established for early stages, the concept and feasibility have not been tested in trials for advanced-stage NHL in the United States. It is of interest that recent randomized studies from other countries suggest that radiotherapy, particularly if administered to areas of originally bulky disease, may significantly improve the relapse-free and overall survival of patients who attained a CR with chemotherapy.³⁹^–⁴² Investigators from National Cancer Institute in Mexico conducted two consecutive randomized studies with a similar design. In the first study, 218 patients with stage IV diffuse large-cell lymphoma were included. Following chemotherapy, 155 patients (71%) achieved a complete response. Of the complete responders, 88 patients (56%) originally presented with bulky disease (>10 cm) and therefore were prospectively randomized to observation or to receive IFRT to a dose of 40 to 50 Gy. At 5 years, 72% of 43 patients randomized to receive radiotherapy were alive and disease-free, compared to only 35% of the 45 patients who were not irradiated (P < .01). Most relapses occurred in the original site. Overall survival was also improved for the irradiated patients (81% versus 55%; P < .01).³⁹ In the more recent study, 341 patients with aggressive DLCL and presence of nodal bulky disease (tumor mass >10 cm) in pathologically proven complete response after intensive chemotherapy were randomized to either radiotherapy (involved fields, 40 Gy) or observation. The 5-year EFS and OS in irradiated patients were 82% and 87%, respectively, which were superior to the control group: EFS, 55% (P < .001) and OS, 66% (P < .01). Radiotherapy was considered “well tolerated,” and acute toxicity was “mild.”⁴²

In Milan, 97 patients with stages III to IV diffuse large-cell lymphoma that were in CR after chemotherapy were either observed or received consolidation radiotherapy. At 5 years, patients with bulky disease (<10 cm) who received radiotherapy had a significantly longer time to relapse and a better overall survival (P < .05) compared with patients who were not irradiated. A multivariate analysis showed that the use of radiotherapy was an independent favorable prognostic factor for relapse (P < .001) and survival (P < .05).⁴⁰

In Paris, patients with NHL who underwent high-dose chemotherapy with stem cell transplantation as upfront treatment or treatment for relapse and received posttransplantation radiotherapy had a better event-free survival compared with patients who had not received radiotherapy (P < .02 in multivariate analysis). Other studies have also supported the use of consolidation radiotherapy after high-dose chemotherapy and bone marrow transplantation.⁴¹

These data support the notion that intermediate-grade NHL is a systemic disease, and all stages should be treated primarily with chemotherapy. Yet, radiotherapy to bulky or residual disease may improve the outcome of the treatment program. More studies should address the potential benefit of radiation therapy in advanced-stage disease, but the above data provide an adequate basis to justify the combined-modality approach in selected cases.