Because non-hodgkin's lymphoma is a more frequent and distinct disease I will discuss it in more details in this site study.

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1 Southern New Hampshire Medical Center Site report 2009 Lymphomas. Roger Hakimian, MD Foundation Hematology/Oncology 10 Prospect Street, Suite 202 Introduction Lymphomas are group of heterogeneous malignancy involving lymph nodes and lymphatic systems. Hodgkin's disease, non-hodgkin's lymphoma, and leukemias were uniformly fatal disease before Hodgkin's disease and childhood leukemia where the first cancer discovered to be highly curable with the development of multiple agent chemotherapy and modern radiation therapy. Many of the strategies used to cure the 2 diseases have been successfully applied in improving the survival and cure rates of patients with non-hodgkin's lymphoma and adult leukemias. The outgrowth of the successful treatment of these diseases also has provided prototype for strategies for the curative treatment of other cancers over the past 30 years. Because non-hodgkin's lymphoma is a more frequent and distinct disease I will discuss it in more details in this site study. Incidence and age of distribution Between years 2003 and 2008, 120 patients at Southern New Hampshire Medical Center were diagnosed with lymphoma (101 NHL, 19HL). The mean age at diagnosis is 59 (12-88). Gender distribution: 62 men, 58 women. In 2009, an estimated 65,980 people (35,990 men and 29,990 women) in the United States will be diagnosed with NHL. It is estimated that 19,500 deaths (9,830 men and 9,670 women) from this disease will occur this year. Although NHL is a common childhood cancer, most cases occur in adults. NHL is the sixth most common cancer in men and the fifth most common cancer in women. It is also the ninth most common cause of cancer death in men and sixth most common cause of cancer death among women.

2 The incidence rate per 100,000 population had increased from 8.8 t o 19.1 over the last three decades. Except for high-grade lymphoblastic and Burkitt lymphomas, the median age at presentation for all subtypes of non-hodgkin lymphoma exceeds 50+ years. Lowgrade lymphomas account for 37% of NHL in patients between the age of 55 and 64 years at diagnosis but for only 16% of cases in those a younger than age 35. Overall, the incidence varies by race, with whites at high risk than blacks and Asian American's. Certain geographic factors appear to influence the development of non-hodgkin lymphoma in specific areas. For example: Burkitt lymphoma is more frequent in Africa then it is in the USA, follicular lymphomas are more common in North America and Europe than the rest of the world. Peripheral T-cell lymphomas are more common in Europe and China than in the north America. For Hodgkin disease the male to female ratio is The age specific incidence of the disease is bimodal with the greatest peak in the third decade of life and a second, smaller peak after the age of 50 years. Hodgkin's disease occurs less commonly in African Americans than in caucasians. The incidence of Hodgkin's disease differs markedly in different countries. For example in Japan, the overall incidence is low and the early peak is absent. Between years 2003 and 2008, 120 patients at Southern New Hampshire Medical Center were diagnosed with lymphoma (101 NHL, 19HL). The mean age at diagnosis is 59 (12-88). Gender distribution: 62 men, 58 women. Risk factors Environmental factors have been linked to the development of NHL. Workers who are exposed to certain chemicals are at a slightly increased risk of developing the disease. Those chemicals include a variety of pesticides and herbicides, solvents and organic chemicals, wood preservatives, dusts (wood and cotton) and some components in hair dye. Prior exposure to chemotherapy and radiation therapy can also increase the risk of developing NHL. An increased incidence of GI lymphomas can be seen in patient's with celiac disease and inflammatory bowel disease particularly Crohn's disease. Several viruses have been implicated in the pathology of non-hodgkin lymphoma including EBV, HTLV-I, HHV8 hepatitis C and HIV virus. Certain bacterial infection also increase the risk of NHL for example Helicobacter pylori infection is associated with gastric MALToma, also there is a possible association between Lyme Disease and patients with primary cutaneous B cell NHL as well as B-cell marginal zone lymphoma.

3 Chronic and acquired states of immunosuppression may increase the risk of developing NHL. The cause of Hodgkin's disease remains unknown. There are no well-defined risk factors for its development. There is evidence that Hodgkin's disease cases can aggregate in some families. An identical twin of a patient with Hodgkin's disease has a 99 times higher risk of developing Hodgkin's disease then a non-identical twin sibling. The Epstein-Barr virus has been implicated in the etiology of Hodgkin disease by both epidemiologic and serologic studies. Also there is some evidence of increased Hodgkin disease frequency in HIV infected patients. Signs and symptoms Fever, weight loss, and night sweats, referred to as systemic B symptoms, as well as fatigue and weakness, are more common in advanced or aggressive NHL but may be present in all stages and histological subtypes. Low grade NHL: painless, slowly progressive adenopathy is the most common clinical presentation in patients with low grade NHL. Patients sometimes report a history of waxing and waning adenopathy before seeking medical attention. Spontaneous regression of enlarged lymph nodes can occur and can cause low-grade lymphoma to be confused with an infection condition. Primary extranodal involvements and B symptoms are uncommon at presentation; however both are common in advanced and end stage disease. Bone marrow is frequently involved, sometimes in association with cytopenias. Splenomegaly is seen in 40% of patients, but the spleen is rarely the only involved site at presentation. Intermediate and high grade NHL: The clinical presentation is more varied. Although the majority of patients will present with adenopathy, more than one-third present with extra nodal involvement, the most common site being the GI tract, thyroid and CNS. B symptoms are more common, occurring in about 30% to 40% of patients. Lymphoblastic lymphoma often presents with an anterior mediastinal mass, superior vena cava syndrome, and leptomeningeal; disease with cranial nerve palsies.

4 American patient with Burkitt s lymphoma often present with large abdominal mass and symptoms of bowel obstruction. Hodgkin s disease commonly presents as an asymptomatic lympadenopathy that may progress to predictable clinical sites. More than 80% of patients present with a lymphadnopathy above the diaphragm, often involving the anterior mediastinum. The commonly involved lymph nodes include the cervical, supraclavicular and axillary areas. Inguinal areas are involved less frequently. About 30% of patients experience systemic symptoms. These symptoms occur more frequently in older patients and have a negative impact on prognosis. Hodgkin s disease may affect extranodal tissues by direct invasion or by hematogenous dissemination (stage IV disease) The commonly involved extarnodal site are the spleen, lungs, liver and bone marrow. Screening and diagnosis No effective methods are available for screening or identifying populations at high risk of developing NHL. A definitive diagnosis can be made only by biopsy of pathologic lymph nodes or tumor tissue. It is critical to perform an excisional node biopsy (fine-needle aspiration [FNA] is insufficient for diagnostic purposes) to avoid false-negative results and inaccurate histologic classification. When clinical circumstances make surgical biopsy of involved lymph nodes or extranodal sites prohibitive, a core biopsy obtained under CT or ultrasonographic guidance may suffice but often requires the integration of histologic examination and immunophenotypic and molecular studies for diagnosis. A formal review by an expert hematopathologist is mandatory. Additional studies, such as immunophenotyping and genotyping, are often necessary. Initial diagnostic evaluation of patients with lymphoproliferative malignancy should include the following: Careful history (night sweats, weight loss, fever; neurologic, musculoskeletal, or GI symptoms) Comprehensive physical examination Biopsy of peripheral lymphadenopathy (excisional biopsy)

5 X-ray, CT scan and MRI. Test s to be directed by the history and physical exam for staging, treatment response and follow up. PET scans (selected cases: B-cell follicular and aggressive histologies) for staging at diagnosis, response, assessment, and relapse Bilateral bone marrow biopsy and aspirate CBC with differential and platelet count. General chemistry panel (including lactic dehydrogenase [LDH] level determination) is mandatory. HIV serology in at-risk patients with diffuse large cell and other aggressive and Burkitt histologies; HTLV-1 serology in select patients with cutaneous T-cell lymphoma, especially if they have hypercalcemia Cytogenetic, immunophenotyping and molecular analyses of lymph node, bone marrow, and peripheral blood. Pathology The Working Formulation was proposed in 1982 as a modification of the Rappaport classification of NHL based on morphology and biologic aggressiveness. Although many subtypes were not recognized, including T-cell lineage lymphomas, a revised European- American classification of lymphoid neoplasms (REAL classification) was introduced in 1994 incorporating T-cell malignancies, subtypes of Hodgkin lymphoma and newer defined lymphoma-proliferative disorders. The WHO (World Health Organization) classification for lymphomas (introduced in 1999) uses the principles of the REAL classification and defines each entity according to morphologic features, immunophenotype, genetic features, postulated normal counterpart, and clinical features. The WHO classification is similar to the REAL classification, with some modifications based on current data (Table 1) WHO Classification The most frequently occurring clinical entities recognized by the REAL/WHO classification are DLBCL (31%), follicular lymphoma (22%), lymphoma of MALT type (8%), small lymphocytic lymphoma (7%), mantle cell lymphoma (6%), peripheral T-cell lymphoma (7%), primary mediastinal large B-cell lymphoma (2%), anaplastic large T- /null-cell lymphoma (2%), lymphoblastic lymphoma of T- or B-cell lineage, marginal

6 zone (monocytoid) B-cell lymphoma (2%), lymphoplasmacytic lymphoma (2%), Burkitt lymphoma (2%), and other (9%). The WHO classification includes three types of follicular lymphoma (grades 1 3). Grades 1 and 2 correspond to follicular small-cleaved cell and follicular mixed smallcleaved and large cell lymphoma, which are considered to be low-grade lymphomas by the Working Formulation. Grade 3 corresponds to follicular large cell lymphoma, which is considered an intermediate-grade NHL in the Working Formulation, and is generally treated as a large cell lymphoma. The WHO classification considers B-cell small lymphocytic lymphoma to be synonymous with chronic lymphocytic leukemia (CLL). Other indolent lymphomas recognized by the WHO classification, but not by the Working Formulation, include lymphoplasmacytic lymphoma, splenic marginal zone B- cell lymphoma, extranodal marginal zone lymphoma of MALT type, and nodal marginal zone B-cell lymphoma. The WHO classification has recognized marginal zone lymphomas (MZLs) as unique clinical and pathologic entities, ie, extranodal (MALT), nodal, and splenic NHL subtypes. MALT NHL is extremely indolent and presents as localized stages I to II disease, infrequently disseminating. The stomach is the most frequent site, but low-grade NHLs (and former pseudolymphomas) of the lungs, thyroid, salivary gland, and orbit are of this type Staging and prognostic factors Determining the extent of disease in patients with NHL provides prognostic information and is useful in treatment planning. However, histologic subclassification (WHO classification) is the primary determinant of survival and potential for cure. Compared with patients with limited disease, those with extensive disease usually require different therapy, and certain extranodal sites of involvement, such as the CNS and testes, require specific treatment modalities. Ann Arbor system Although initially devised for Hodgkin lymphoma, the Ann Arbor system has been routinely applied to NHL (table2) Prognostic factors Histology and morphology remain the major determinants of treatment outcome and prognosis, but gene expression signatures are likely to be the principal determinants in the future. Some patients with slow-growing low-grade lymphoma may remain well for many years with minimal or no initial therapy, whereas survival of patients with some types of high-grade lymphoma is measured only in weeks

7 unless aggressive treatment is initiated promptly. The biologic and clinical behaviors of these disorders vary among the different histologic subtypes. The International Prognostic Index (IPI) was developed as a prognostic factor model for aggressive NHL treated with doxorubicin-containing regimens. Clinical features that have been independently predictive of survival are included in Table 3. This index appears to be a useful guide for selecting treatment for patients with aggressive, diffuse large cell NHL, by identifying subsets of patients in whom intensified primary therapy may be warranted. Because younger and older patients have markedly different prognoses and younger patients are more likely to be considered for more intensive investigational regimens, an age-adjusted model for patients 60 years old has been proposed. In younger patients, stage (III or IV), high LDH level, and nonambulatory performance status are independently associated with decreased survival. In the postrituximab (Rituxan) era, persons with no risk factors have a predicted 5-year overall survival of 94%, compared with 55% for high-risk patients with three to five risk factors. The IPI also appears to be useful in predicting outcome in patients with low-grade lymphoma, mantle cell lymphoma, and relapsed or refractory large B-cell lymphoma in patients undergoing autologous stem-cell transplantation (SCT). A prognostic factor model has been devised based on a study of 919 cases of follicular lymphoma, known as the Follicular Lymphoma IPI FLIPI (table 4) Treatment-related factors Time to complete remission has been identified as an important treatment-related prognostic factor in aggressive NHL. Patients who require more than 5 cycles of standard chemotherapy to achieve remission have a high risk of relapse. Similarly, patients with PET-avid tumors who have persistent PET uptake at the midpoint of treatment are less likely to have durable remissions. Treatment Non-Hodgkin s lymphoma groups include many heterogeneous diseases that require different therapeutic strategies and carry different prognosis. Reviewing the treatment of each subgroup is probably beyond the scope of this site study. I will review treatment options and prognosis of the 2 most frequent NHL: B-cell follicular lymphoma and diffuse large B-cell non-hodgkin lymphoma (DLBCL)

8 DIFFUSE LARGE B-CELL LYMPHOMA Clinical presentation DLBCL makes up about one-third of the cases of NHL and is classified as a mature peripheral B-cell neoplasm by WHO. The clinical presentation is variable, but generally patients present with either peripheral lymphadenopathy (neck, axillae) or enlarged nodes in the mediastinum, the mesenteric region, or the retroperitoneum. These sites predict symptoms, which may include chest pain; facial swelling and suffusion of the eyelids (superior vena cava [SVC] syndrome from mediastinal disease); abdominal discomfort, ascites (mesenteric), or back pain; or renal obstruction (retroperitoneal presentations). More than 30% of patients present with disease in extranodal sites. B symptoms, consisting of fever, sweats, and weight loss, are more common in DLBCL than in the indolent lymphomas and occur in about 30% of patients. The median age at presentation is 60 years. Treatment Prior to the 1970s, most patients with stage I/II large cell lymphoma (intermediate grade in the Working Formulation) were treated with irradiation alone, with overall cure rates of 40% to 50%. Patients with pathologically favorable stage I/II disease had even better outcomes, but relapse rates, even in these patients, were still 20% to 30%. Pathologic staging, therefore, selected a group suitable for irradiation alone. This approach is no longer appropriate, in view of the success of combined chemotherapy and irradiation in clinically staged patients. Until further studies define the optimal therapy for stages IA to IIA DLBCL (nonbulky), many investigators consider 3 to 4 cycles of R-CHOP (riuximab, cyclophosphamide, adriamycin, vincristine and prednisone) and involved field radiation therapy (IFRT) the initial treatment of choice. For patients with bulky disease, a minimum of 6 cycles of R- CHOP is typically administered. Irradiation doses of 30 to 36 Gy, delivered in 1.75 to 1.8 Gy over 3 to 4 weeks after completion of systemic therapy, appear to be adequate. Radiation fields usually include involved lymph node sites or an involved extranodal site and its immediate lymph node drainage areas. Furthermore, the disease should be easily encompassed in a radiation field with acceptable toxicity. Disease site or potential toxicities may influence the treatment plan: Lymphomas of the head and neck may be managed with chemotherapy alone to avoid the acute mucositis and long-term xerostomia associated with radiation therapy. Fully resected gastric or small intestinal lymphoma may be treated with chemotherapy alone. Alternatively, chemotherapy followed by local irradiation allows gastric preservation and is preferred in most patients. For patients with more advanced stage (III or IV) disease, CHOP has been the standard (now with rituximab) for 6 to 8 cycles or 2 cycles beyond remission. Recent data suggest an advantage to dose-dense therapy, shortening the interval between cycles from 3 to 2

9 weeks with growth factor support. More data are needed to validate these results. Many studies now suggest an advantage to the addition of immunotherapy in the form of rituximab, and in almost every study, the combination of rituximab and chemotherapy has improved the response rate and disease-free survival. There appears to be no advantage to maintenance therapy with rituximab in this setting, however, as long as rituximab is included in the induction. Responses are seen in upward of 80% of patients, and approximately 50% to 60% achieve a complete remission. It appears that 50% of these patients (30% to 50% overall) are likely cured. For patients who either do not have a complete remission or who relapse, alternative therapies are possible, but long-term responses have been seen mostly with autologous or allogeneic stem cell transplantation (SCT). Patients who do not have responsive disease prior to SCT generally do poorly. The IPI has been used to predict outcome for transplantation in DLBCL. The role of autologous SCT for high-risk patients remains open to debate. A randomized clinical trial of early versus delayed high-dose therapy for patients with high- and high-intermediate risk diffuse aggressive lymphoma conducted by the US Intergroup is just completing accrual. If this trial confirms the benefit of early SCT in poor-risk patients with chemosensitive diffuse aggressive NHL, subsequent studies will focus on increasing the number of patients who become eligible for transplant consolidation. Investigational treatments include novel antibodies, radioimmunotherapy, and single-agent chemotherapy drugs. Nonmyeloablative SCT is being evaluated in patients with recurrent or refractory disease. Some investigators believe that irradiation for stages III and IV (advanced or extensive) DLBCL may be added after the completion of definitive chemotherapy if there is localized residual disease to improve local tumor control. Irradiation may also be delivered after chemotherapy to areas of initially bulky disease, again to enhance local tumor control. These recommendations are based on the observation that when DLBCL relapses after definitive chemotherapy, it usually does so in initially involved or bulky areas of disease. The benefits and potential side effects of irradiation should be weighed against the use of alternative chemotherapy salvage regimens. FOLLICULAR LYMPHOMA Follicular lymphoma comprises 22% of all NHLs; only DLBCL is more common. The clinical presentation may be nodal or extranodal, and bone marrow involvement occurs in the majority of cases. Extensive intra-abdominal adenopathy without peripheral node enlargement is not uncommon. Clinical behavior is variable, reflecting the heterogeneity of the underlying biology; some patients survive decades, whereas others progress rapidly to resistant disease or transform to a more aggressive histology. There are rare spontaneous remissions. Transformation is common, occurring in 3% to 6% of patients each year and ultimately 30% to 50% of all patients. Although generally responsive to treatment, the clinical course is characterized by repeated relapses. Median survival for advanced-stage disease is 6 years. Although there was no improvement in survival for

10 patients with follicular lymphoma for many years, there is new evidence that outcomes have improved, independent of the introduction of rituximab. It is likely that there will be further improvement associated with the use of rituximab in combination with chemotherapy. As previously mentioned, the FLIPI is a prognostic index designed specifically for follicular lymphomas based on five adverse prognostic factors (Table 3). Age is the most important factor. Three risk categories have been defined, each consisting of approximately one-third of patients. More than two-thirds of low-risk patients but only one-third of high-risk patients survive 10 years. Whereas clinical parameters are surrogates for biologic characteristics, DNA expression profiling using microarray technology may soon supersede clinical prognostic indicators such as the FLIPI. Early stage disease For the relatively small number of patients with stage I or II follicular lymphoma, radiotherapy continues to be the standard of care. A recent update from the Princess Margaret Hospital s series of involved-field radiotherapy (IFRT) for early-stage disease showed cumulative relapse rates of 54% and 56% at 15 and 25 years, with only a 2% risk of relapse beyond 15 years. Combined-modality therapy has also resulted in excellent disease control, and a randomized trial comparing IFRT with combined-modality therapy is ongoing The recommended dose is approximately 30 Gy for nonbulky disease showing prompt regression and 36 Gy for bulky or slowly regressive disease, in 1.75 to 2.0 Gy daily fractions. As the majority of subsequent relapses occur outside previous radiation fields, often in adjacent or distal lymph nodes, extended-field or total lymphoid irradiation has been used to try to improve cure rates. Clinical series have shown improvement in freedom from relapse only, with no significant difference in long-term survival. Advanced stage disease Watch and wait The standard management of asymptomatic patients with follicular lymphoma has been a watch-and-wait approach. Treatment is delayed until symptoms or cytopenias intervene or there is impending compromise of vital organs. In the prerituximab era, multiple phase III randomized trials comparing immediate chemotherapy with observation for asymptomatic patients with advanced-stage follicular lymphoma have shown no difference in outcome. In fact, for patients older than age 70, the chances of not requiring chemotherapy were 40% at 10 years in a recently published trial. The median time to first systemic therapy for patients randomized to the observation arm was 2.6 years. Complete remission rates, however, were higher in the patients treated immediately after diagnosis than in those who were observed and later treated (63% vs 27%). The achievement of a complete remission may prove to be important if the ultimate goal is to administer postremission therapy (eg, vaccine) that is likely to be most effective in the presence of minimal residual disease. A phase III trial comparing the watch-and-wait approach with rituximab therapy for asymptomatic advanced-stage

11 disease is ongoing in Europe. At the same time, an American Intergroup trial comparing two different rituximab dosing regimens is enrolling patients with low tumor burden indolent lymphoma who are asymptomatic. Irradiation Irradiation for clinical stages III and IV, low-grade, extensive-stage NHL is used locally for palliation of symptomatic sites of disease and is extremely effective. Abbreviated fractionated schedules (25 to 30 Gy in 2.5 to 3 Gy daily fractions, respectively) are often used Rituximab For patients with symptoms or other reasons for treatment, there are many treatment options, including single or multiagent chemotherapy, monoclonal antibodies or radioimmunoconjugates, combinations of chemotherapy and immunotherapy with anti-idiotype vaccines, and new agents such as bortezomib (Velcade). Treatment with rituximab results in overall response rates of nearly 50%, with a median response duration of approximately 1 year, in relapsed or refractory indolent lymphomas. In previously untreated patients, however, the overall response rate was 80%, and the median progression-free survival is 18 months in one trial from France. Of note, 28% of all treated patients and 34% of all complete and partial responders maintained their responses for 5 or more years. Similar results have been reported by the US North Central Cancer Treatment Group (NCCTG To improve on response rates and duration of response, additional doses of rituximab have been administered as maintenance therapy. The median event-free survival is prolonged with this approach, especially for previously untreated patients. In previously treated patients, the total duration of benefit from rituximab appears to be the same whether patients receive maintenance rituximab on a scheduled basis or reinduction with rituximab only at the time of disease progression. Chemotherapy with and without rituximab Studies comparing single-agent chemotherapy with multiagent therapy in patients with advanced-stage follicular lymphoma have not shown meaningful differences in outcomes. Fludarabine (Fludara), identified in the 1980s as an active agent in follicular lymphoma, has been incorporated into combination regimens with high response rates (including molecular remissions) but has not been shown to prolong the duration of remission when compared with other multiagent regimens. Four phase III trials comparing combinations of chemotherapy and rituximab with chemotherapy alone in previously untreated patients have now been reported. Overall response rates and either median time to treatment failure or event-free survival were superior in the chemoimmunotherapy arm in every series. An overall survival benefit has been demonstrated in three of the four trials and in the high-risk subset of the fourth study.

12 Radioimmunotherapy The anti-cd20 radioimmunoconjugates Y-90 ibritumomab (Zevalin) and I-131 tositumomab (Bexxar) both deliver ionizing radiation to target cells and their neighbors and have proven to be relatively easy to administer, safe, and effective. Response rates are higher and remissions more durable when radioimmunoconjugates are used early in the clinical course. Both agents are likely to have their greatest impact when used in previously untreated patients. In previously treated patients, Y-90 ibritumomab, a high-energy beta-emitter, yielded an overall response rate of 80% for relapsed or refractory follicular or transformed CD20+ B-cell NHL, with a median duration of response of 14 months. For patients refractory to rituximab, response rates with Y-90 ibritumomab are high (74% overall response rate), but the median duration of response is relatively short (6.4 months; range months). The dose-limiting feature of this approach is hematologic toxicity. Short-lived myelosuppression occurs 7 to 9 weeks post treatment. Novel agents New agents targeting specific molecular targets such as the ubiquitinproteasome pathway have shown promise in the treatment of follicular lymphoma. In recently reported phase II trials, bortezomib has shown activity in follicular lymphoma as well as in mantle cell lymphoma. New combinations including bortezomib are now being investigated. Bendamustine (Treanda) is a novel alkylator with activity in both rituximabrefractory and rituximab-sensitive indolent NHL that has recently been approved by the US Food and Drug Administration (FDA) for relapsed disease that is refractory to rituximab. Other new agents are also showing activity, including the histone deacetylase inhibitors, lenalidomide (Revlimid), and mammalian target of rapamycin (mtor) inhibitors. Novel antibodies such as anti-cd80 and combinations of antibodies have also shown promise in the treatment of follicular lymphoma. Stem cell transplantation The only phase III trial to address the role of autologous SCT in patients with relapsed follicular lymphoma closed prematurely because of poor accrual. Nonetheless, progression-free and overall survival rates were significantly longer with high-dose chemotherapy (HDCT) and autologous SCT (with purged or unpurged autografts) than with conventional alkylator therapy. Several groups have investigated the role of autologous SCT as consolidation therapy for patients in first complete or partial remission. Although progression-free survival may be prolonged, an impact on survival has not been demonstrated consistently. Contemporary trials evaluating the role of autologous SCT for follicular lymphoma in first remission induced with rituximab-containing regimens are needed. Allogeneic SCT has been investigated primarily in young patients with HLA-identical sibling donors and extensive disease and/or marrow involvement. Low relapse rates suggest that this approach is potentially curative but is associated with high treatmentrelated morbidity and mortality. Reduced-intensity transplantation is based on the

13 assumption that a graft-versus-lymphoma effect is operative and has the potential to cure follicular lymphoma. Hodgkin s lymphoma HL is sensitive to radiation and many chemotherapeutic drugs, and, in most stages, there is more than one effective treatment option. Disease stage is the most important determinant of treatment options and outcome. All patients, regardless of stage, can and should be treated with curative intent. TREATMENT OF STAGE I/II DISEASE The treatment of choice for favorable and unfavorable early-stage classic HL is brief chemotherapy followed by involved-field radiotherapy (IFRT). Most of the experience that yielded excellent treatment results with low toxicity was with ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) for 4 cycles and IFRT of 30 to 36 Gy. Disease free survival rate with this approach is close to 90%. The National Comprehensive Cancer Network (NCCN) guidelines recommend combined-modality therapy as the treatment of choice for favorable or unfavorable classic HL. Opinions differ as to the use of chemotherapy alone, and it remains highly controversial. Side effects of radiotherapy depend on the irradiated volume, dose administered, and technique employed. They are also influenced by the extent and type of prior chemotherapy, if any, and by the patient s age. Secondary malignancies Patients with HL who were cured with radiotherapy and/or chemotherapy have an increased risk of secondary solid tumors (most commonly, lung, breast, and stomach cancers, as well as melanoma) and NHL 10 or more years after treatment. Chemotherapy combinations that do not include alkylating agents or a new brief program (such as Stanford V) as well as the smaller involved fields and lower doses are less likely to have the increased risk observed with extended fields and/or MOPP or MOPP-like chemotherapy. Lung cancer Patients who are smokers should be strongly encouraged to quit the habit because the increase in lung cancer that occurs after irradiation or chemotherapy with alkylating agents has been detected mostly in smokers.

14 Breast cancer The increase in breast cancer risk is inversely related to the patient s age at HL treatment; no increased risk has been found in women irradiated after 30 years of age. The risk of breast cancer is increased with higher radiation breast dose and is reduced in patients who received chemotherapy or ovarian irradiation that induced early menopause. In most situations, modern IFRT should spare the breast. Breast cancer is curable in its early stages, and early detection has a significant impact on survival. Breast examination should be part of the routine follow-up for women cured of HL, and routine mammography should begin about 8 years after treatment. Cardiovascular disease An increased risk of cardiovascular morbidity has been reported among patients who have received mediastinal irradiation. In a retrospective study evaluating the cardiac risks of 450 patients cured of HL with radiotherapy alone or in combination, 42 patients (10%) developed coronary artery disease (CAD) at a median of 9 years after treatment, 30 patients (7%) developed carotid and/or subclavian artery disease at a median of 17 years after treatment, and 25 patients (6%) developed clinically significant valvular dysfunction at a median of 22 years after treatment. To reduce this hazard, radiation fields should conform to the involved postchemotherapy volume, and the dose should be reduced to 20 to 30 Gy if possible. Patients who have received radiation to the mediastinum should be monitored and advised about other established CAD risk factors, such as smoking, hyperlipidemia, hypertension, and poor dietary and exercise habits. Cholesterol levels should be monitored and treated if elevated. TREATMENT OF STAGE III/IV DISEASE Chemotherapy has become curative for many patients with advanced stages of HL. MOPP has been the primary effective combination chemotherapy regimen for advancedstage disease since the 1960s. Over the past several years, ABVD has been shown to be more effective and less toxic than MOPP, particularly with respect to sterility and secondary leukemia. Doxorubicin-containing regimens A doxorubicin-containing regimen, such as ABVD is the treatment of choice for patients presenting with stage III or IV disease, as demonstrated by a randomized phase III trial undertaken by the Cancer and Leukemia Group B (CALGB). This trial showed higher complete response rates with ABVD and ABVD/MOPP (82% and 83%, respectively) than with MOPP alone (65%). Subsequent trials compared ABVD, alternating MOPP/ABVD, and a MOPP/ABV hybrid. Alternating MOPP/ABVD and the MOPP/ABV hybrid was found to be equally effective in treating advanced-stage HL. Shortened dose-intense regimens Shortened dose-intense regimens have shown promise. For example, the 12-week Stanford V regimen combined with IFRT produced a 5-year overall survival rate of 96% and a freedom-from-disease-progression rate of 89%. The freedom-from-disease-progression rate was significantly superior among patients with a prognostic score of 0 2, compared with those with a score of 3 and higher (94% vs

15 75%; P =.0001). Of interest, in 142 patients from Stanford, no secondary leukemia was observed, and 42 pregnancies were reported. An escalated dose version of BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, and prednisone) was found to have a statistically significant superior freedom from treatment failure at 5 years compared with standard-dose BEACOPP and alternating monthly COPP and ABVD for patients with advanced stages of HL. Short-term hematologic toxicity was greatest for escalated BEACOPP, and a significant increased risk for secondary acute leukemias was also seen as compared with standard-dose BEACOPP and COPP/AB Although the role of consolidation radiotherapy after induction chemotherapy remains controversial, irradiation is routinely added in patients with advanced-stage disease who present with bulky disease or who remain in uncertain complete remission after chemotherapy. A meta-analysis demonstrated that the addition of radiotherapy to chemotherapy reduces the rate of relapse but did not show a survival benefit for the combined-modality approach. LONG-TERM TOXICITIES OF COMBINATION CHEMOTHERAPY Myelodysplasia and acute leukemia MOPP therapy is known to be related to the development of myelodysplastic syndromes (MDS) and acute leukemia. These secondary hematologic malignancies begin 2 years following therapy and decline by 10 years, with the maximum risk between 5 and 9 years. Patients with these malignancies have a poor prognosis. The incidence of secondary leukemia appears to increase with cumulative doses of chemotherapy, age > 40 years when receiving chemotherapy for HL, and splenectomy. It is controversial whether combined-modality therapy increases the risk of leukemia compared with chemotherapy alone. Cytogenetic studies of secondary leukemias reveal a loss of the long arm of chromosome 5 and/or 7. Less frequently, there is a loss of chromosome 18 or rearrangement of the short arm of chromosome 17. A balanced rearrangement of 11q23 and 2lq22 also has been described with etoposide therapy. Other malignancies also are being observed with increasing frequency after chemotherapy (most regimens included alkylating agents), particularly for lung cancer and NHL. These malignancies have a longer latency period and usually are not observed until 15 years after therapy. Infertility is another long-term complication seen with combination chemotherapy. At least 80% of males are found to have permanent azoospermia or oligospermia following more than 3 cycles of MOPP chemotherapy; The risk of infertility with ABVD chemotherapy is significantly lower than that with MOPP chemotherapy, approximately

16 15% to 25%. All men who desire childbearing potential following therapy should be counseled regarding sperm banking. In females, there is a 50% rate of primary ovarian failure overall. The risk is 25% to 30% in patients treated at age 25 or younger but increases to 80% to 100% in women older than age 25. Many women who do maintain ovarian function during chemotherapy will have premature menopause following therapy. Pulmonary complications have been reported with ABVD chemotherapy and are related to bleomycin-induced lung toxicity. In a study from the Mayo Clinic, bleomycin pulmonary toxicity (BPT) was observed in 18% of patients. Increasing age, and use of ABVD and granulocyte colony-stimulating factor were associated with development of BPT. Patients with BPT had a 5-year overall survival of only 63% compared with 90% (P =.001) in patients without BPT. The omission of bleomycin had no effect on obtaining complete remission or on progression-free or overall survival. Cardiomyopathy is a recognized complication of doxorubicin therapy but is not commonly seen in patients receiving ABVD chemotherapy. Patients who are treated with 6 cycles of ABVD chemotherapy receive a total doxorubicin dose of 300 mg/m 2 ; cardiac toxicity is rarely seen in patients who receive a total dose 400 mg/m 2. Summary Lymphomas are a group of heterogeneous diseases. Hodgkin s disease treatments and successes were used as model for improving the prognosis of other tumors. Non-Hodgkin s lymphomas should not be considered as a single entity and their classification is a work in progress. Treatment is evolving and more people are being cured and/or living longer. Long term and careful follow-up of survivors is paramount as patients can still be at risk for relapse and delayed treatment complications. References: 1. Non-Hodgkin s lymphoma. Peter. M Mauch. Lippincott Williams and Wilkins Cancer Facts and Figures: American Cancer Society 3. State of New Hampshire Cancer Registry 4. Cancer management: a multidisciplinary approach. 11 th edition

17 5. National Comprehensive Cancer Network: NCCN clinical practice guidelines in Oncology.V