Hodgkin Lymphoma

Overview Hodgkin lymphoma is a malignancy of the lymphatic system with an incidence of about 3 cases per 100,000 persons per year in developed countries. In 2016 approximately 8,500 new cases of Hodgkin lymphoma will be diagnosed in the United States, with an estimated 1,120 deaths. Over the past 4 decades, advances in radiation therapy and the advent of combination chemotherapy have tripled the cure rate of patients with Hodgkin lymphoma. At present, more than 80% of all newly diagnosed patients can expect a normal, disease-free life span following completion of treatment. Epidemiology Gender The male-to-female ratio of Hodgkin lymphoma is 1.3:1. Age 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. Race Hodgkin lymphoma occurs less commonly in African Americans (2.3 cases per 100,000 persons) than in Caucasians (3 per 100,000 persons). Geography The age-specific incidence of Hodgkin lymphoma differs markedly in various countries. In Japan, the overall incidence is low, and the early peak is absent. In some developing countries, there is a downward shift of the first peak into childhood. Signs and Symptoms Hodgkin lymphoma is a lymph node–based malignancy and commonly presents as an asymptomatic lymphadenopathy that may progress to predictable clinical sites. Location of Lymphadenopathy More than 80% of patients with Hodgkin lymphoma present with lymphadenopathy above the diaphragm, often involving the anterior mediastinum; the spleen may be involved in about 30% of patients. Less than 10% to 20% of patients present with lymphadenopathy limited to regions below the diaphragm. The commonly involved peripheral lymph nodes are located in the cervical, supraclavicular, and axillary areas; para-aortic pelvic and inguinal areas are involved less frequently. Disseminated lymphadenopathy is rare in patients with Hodgkin lymphoma, as is involvement of Waldeyer’s ring and occipital, epitrochlear, posterior mediastinal, and mesenteric sites. Systemic Symptoms About 30% of patients experience systemic symptoms, so-called B symptoms. They include fever, drenching night sweats, and weight loss. These symptoms occur more frequently in older patients and have a negative impact on prognosis (see section on “Staging and prognosis”). Extranodal Involvement Hodgkin lymphoma may affect extranodal tissues by direct invasion (contiguity; the so-called E lesion) or by hematogenous dissemination (stage IV disease). The most commonly involved extranodal site is the lungs. Liver, bone marrow, and bone may also be involved. Diagnosis The initial diagnosis of Hodgkin lymphoma can only be made by biopsy. Because reactive hyperplastic nodes may be present, multiple biopsies of a suspicious site may be necessary. Needle aspiration is inadequate because the architecture of the lymph node is important for diagnosis and histologic subclassification. Pathology Reed-Sternberg Cell In a biopsied lymph node, the Reed-Sternberg (R-S) cell is the diagnostic tumor cell that must be identified within the appropriate cellular milieu of lymphocytes, eosinophils, and histiocytes. Hodgkin lymphoma is a unique malignancy pathologically in that the tumor cells constitute a minority of the cell population, whereas normal inflammatory cells are the major cell component. As a result, it may be difficult to identify R-S cells in some specimens. Also, other lymphoproliferations may have cells resembling R-S cells. The R-S cell is characterized by its large size and classic binucleated structure with large eosinophilic nucleoli. Two antigenic markers are thought to provide diagnostic information: CD30 and CD15. These markers are present on R-S cells and their variants but not on background inflammatory cells. It is also important to obtain a stain for CD20, since it may be positive in the minority of patients with classic Hodgkin lymphoma. The prognostic significance of CD20-positive R-S cells in classic Hodgkin lymphoma is controversial. Studies have confirmed the B-cell origin of the R-S cell. Single-cell polymerase chain reaction (PCR) analysis of classic R-S cells shows a follicular center B-cell origin for these cells with clonally rearranged but crippled V heavy-chain genes, presumably leading to inhibition of apoptosis. Also, high levels of the nuclear transcription factor-kappa-B (NF-kB) have been found in R-S cells; these high NF-kB levels may play a role in pathogenesis by interfering with apoptosis. Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) accounts for about 5% of Hodgkin lymphoma cases. It differs from the histologic subtypes of classic Hodgkin lymphoma in terms of immunophenotype, clinical presentation, and course. The malignant lymphocyte-predominant cells consistently express CD20, which is only infrequently found in classic Hodgkin lymphoma. In contrast to classic Hodgkin lymphoma, NLPHL is mostly diagnosed in early favorable stages, often in peripheral nodes, and rarely involves the mediastinum. These patients are often sufficiently treated with limited-field radiotherapy alone, as Chen et al have discussed. Patients presenting with more advanced disease are usually treated in a manner very similar to that for classic Hodgkin lymphoma, with an excellent long-term outcome (as described by NogovÃ¡ et al). However, regular follow-up is mandatory even in the case of long-term remission, since patients with NLPHL tend to have late relapses more often than those with classic Hodgkin lymphoma and, with a relapse rate of up to 30% at 20 years, transformation into aggressive B-cell non-Hodgkin lymphoma appears to be more common than was previously reported (as discussed by Al-Mansour et al). Histologic Subtypes According to the present World Health Organization classification, there are four histologic subtypes of classic Hodgkin lymphoma. Nodular sclerosis As the most common subtype, nodular sclerosis is typically seen in young adults who have early-stage supradiaphragmatic presentations. Its distinct features are the presence of (1) broad birefringent bands of collagen that divide the lymphoid tissue into macroscopic nodules and (2) an R-S cell variant, the lacunar cell. Mixed cellularity This is the second most common histology. It is more often diagnosed in older males, who usually present with generalized lymphadenopathy or extranodal disease and with associated systemic symptoms. R-S cells are frequently identified; bands of collagen are absent, although fine reticular fibrosis may be present; and the cellular background includes lymphocytes, eosinophils, neutrophils, and histiocytes. Lymphocyte-rich Hodgkin lymphoma Lymphocyte-rich classic Hodgkin lymphoma has morphologic similarity to NLPHL (see below). However, the R-S cells have a classic morphology and phenotype (CD30-positive, CD15-positive, and the surrounding lymphocytes are reactive T cells) and should be managed like other classic Hodgkin lymphoma histologies. Lymphocyte-depleted Hodgkin lymphoma This is a rare diagnosis, particularly since the advent of antigen marker studies, which led to the recognition that many such cases represented T-cell non-Hodgkin lymphomas. R-S cells are numerous, the cellular background is sparse, and there may be diffuse fibrosis and necrosis. Patients usually have advanced-stage disease, extranodal involvement, an aggressive clinical course, and a poor prognosis. Nodular Lymphocyte-predominant Hodgkin lymphoma This is an infrequent form of Hodgkin lymphoma in which few R-S cells or their variants may be identified. The cellular background consists primarily of lymphocytes in a nodular or sometimes diffuse pattern. The R-S variants termed lymphocyte-predominant cells express a B-cell phenotype (CD20-positive, CD30-negative, CD15-negative). B-cell clonality has also been demonstrated by PCR of the immunoglobulin heavy-chain genes in single R-S variant cells in biopsy material from patients with NLPHL. This finding has led investigators to propose that NLPHL is a B-cell malignancy with a mature B-cell phenotype, distinct from the other four histologic types of Hodgkin lymphoma. NLPHL is often clinically localized, is usually treated effectively with limited-field irradiation alone at early stages, and may relapse late (a clinical feature reminiscent of low-grade non-Hodgkin lymphoma). The 15-year disease-specific survival is excellent (> 90%). Staging and Prognosis Precise definition of the extent of nodal and extranodal involvement with Hodgkin lymphoma according to a standard staging classification system is critical for selection of the proper treatment strategy. Staging System The staging system is detailed in Table 1, and the anatomic regions that provide the basis for the staging classification are illustrated in Figure 1. The assignment of stage is based on: - the number of involved sites - whether lymph nodes are involved on both sides of the diaphragm and whether this involvement is bulky (particularly in the mediastinum) - whether there is contiguous extranodal involvement (E sites) or disseminated extranodal disease - whether typical systemic symptoms (B symptoms) are present. TABLE 1: The Cotswold staging classification for Hodgkin lymphoma FIGURE 1: Anatomic regions for staging of Hodgkin lymphoma. In defining the disease stage, it is important to note how the information was obtained, since this fact reflects on remaining uncertainties in the evaluation for extent of disease. Clinical staging refers to information that has been obtained by initial biopsy, history, physical examination, and laboratory and radiographic studies only. A pathologic stage is determined by more extensive surgical assessment of potentially involved sites. Also, various designations relating to the presence or absence of B symptoms or bulky disease (see Table 1) can be applied to any disease stage. For example, a patient with no B symptoms but with a bulky mediastinal mass and involvement of the cervical lymph nodes would be defined as having CS IIAX disease. A patient with axillary disease and fever who underwent a staging laparotomy that revealed involvement of the para-aortic lymph nodes and spleen would be staged as PS III2B. Most recent studies in stage I/II disease distinguish between favorable and unfavorable early-stage disease, according to the European Organisation for Research and Treatment of Cancer (EORTC) definitions outlined in Table 2. Clinical Staging Evaluation TABLE 2: EORTC prognostic definition of early-stage disease Disease-associated symptoms As mentioned previously, disease-associated symptoms may occur in up to one-third of patients. They may include B symptoms, pruritus, and, less commonly, pain in involved regions after ingestion of alcohol. In each anatomic stage, the presence of B symptoms is an adverse prognostic indicator and may strongly affect treatment choices. B symptoms are carefully defined in the staging system. Unexplained fever should be > 38°C and recurrent during the previous month, night sweats should be drenching and recurrent, and unexplained weight loss should be considered significant only if > 10% of body weight has been lost within the preceding 6 months. Physical examination The physician should carefully determine the location and size of all palpable lymph nodes. Inspection of Waldeyer’s ring, detection of splenomegaly or hepatomegaly, and evaluation of cardiac and respiratory status are important. Laboratory studies These should include a complete blood cell count with white blood cell (WBC) differential and platelet count, the erythrocyte sedimentation rate (ESR), tests for liver and renal function, and assays for serum alkaline phosphatase and lactate dehydrogenase (LDH). A moderate to marked leukemoid reaction and thrombocytosis are common, particularly in symptomatic patients, and usually disappear with treatment. ESR studies may provide helpful prognostic information. At some centers, treatment programs for patients with early-stage disease are influenced by the degree of ESR elevation. In addition, changes in the ESR following therapy may correlate with response and relapse. Abnormalities of liver function studies should prompt further evaluation of that organ, with imaging and possibly a biopsy. An elevated alkaline phosphatase level may be a nonspecific marker, but it may also indicate bone involvement that should be appropriately evaluated by a radionuclide bone scan and directed skeletal radiographs. Imaging studies Radiologic studies should include a chest x-ray and CT scan of the neck, chest, abdomen, and pelvis with intravenous contrast. Positron emission tomography (PET) can provide additional information on the extent of disease and a baseline for evaluation of response to treatment. Radionuclide bone scan and magnetic resonance imaging (MRI) of the chest or abdomen are contributory only under special circumstances. Evaluation for supradiaphragmatic disease. The CT scans of neck and thorax detail the status of cervical and intrathoracic lymph node groups, the lung parenchyma, pericardium, pleura, and chest wall. Since the chest CT scan may remain abnormal for a long time after the completion of therapy, the PET scan is used to evaluate pretreatment involvement and response to therapy. Evaluation of the abdomen and pelvis. The CT scan and PET scan are basic imaging studies for evaluating the abdomen. They are recommended as part of initial staging and are critical in the new International Working Group Criteria for assessing response after treatment. In the United States, PET is of the whole body and is not optional. A change from a positive pretreatment PET/CT scan to negative following completion of therapy is considered to be the criterion for complete response even if a residual mass is found on CT scan. Bone marrow biopsy Bone marrow involvement is relatively uncommon in Hodgkin lymphoma, but because of the impact of a positive biopsy on further staging and treatment, unilateral bone marrow biopsy should be part of the staging process. However, there is growing evidence that bone marrow puncture is no longer necessary when PET-CT is performed in the course of staging (eg, as reported by El-Galaly et al). Treatment Hodgkin lymphoma 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 A common treatment choice for favorable and unfavorable early-stage Hodgkin lymphoma 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 2 cycles in patients with favorable early-stage Hodgkin lymphoma and 4 cycles in patients with unfavorable early-stage Hodgkin lymphoma followed by IFRT of 30 to 36 Gy for both patient groups. More recently, even IFRT fields have been further reduced in volume to include only the involved nodal site or involved node (if precise pre-chemotherapy or pre-resection information is available). The current recommended RT fields are called involved-site radiotherapy (ISRT) or involved node radiotherapy (INRT), respectively. The evolution of RT fields and current design requirements are detailed below. Currently, ongoing trials evaluate whether it is possible to omit RT in patients with a negative PET scan after the end of chemotherapy. However, the definitive role of PET scans in assessing response during or after chemotherapy and the possibility of sparing RT in patients with negative PET scans is not ultimately defined. The recent data from two randomized studies (EORTC/LYSA [Lymphoma Study Association] /FIL [Fondazione Italiana Linfomi] H10 and the British RAPID trial) have conflicting results and controversial interpretations. The mature data from two large randomized trials in early-stage patients with Hodgkin lymphoma have been presented by the German Hodgkin Study Group (GHSG). The HD 10 trial, reported in 2010 by Engert et al, studied the efficacy of reducing both the number of chemotherapy cycles and the involved-field radiation dose in a combined-modality program. A total of 1,370 patients with early-stage, favorable-prognosis Hodgkin lymphoma were randomized into four arms: ABVDX4 + radiotherapy at 30 Gy; ABVDX4 + 20 Gy; ABVDX2 + 30 Gy; and ABVDX2 + 20 Gy. With a median follow-up of > 7 years, there were no differences in progression-free survival, freedom from treatment failure (FFTF), and overall survival between the arms. These rates were excellent at 92.4%, 92%, and 96.8%, respectively (at 5-year follow-up). The results in the arm in which patients received the least treatment were almost identical to those of the arm with the most treatment. However, toxicity from chemotherapy was significantly higher for patients randomized to ABVDX4 compared with ABVDX2, and it was slightly higher for IFRT at 30 Gy than for 20 Gy. This study demonstrated the efficacy and safety of reducing treatment in favorable patients. The twin GHSG trial HD 11, reported by Eich et al, randomized 1,395 patients with unfavorable early-stage Hodgkin lymphoma into four arms: ABVDX4 + 30 Gy; ABVDX4 + 20 Gy; baseline BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, and prednisone) (X4 + 30 Gy; and baseline BEACOPPX4 + 20 Gy. The complete response rate was the same for all arms: 94%. The 5-year FFTF was 85%, progression-free survival was 86%, and overall survival was 95%. More acute side effects were recorded with baseline BEACOPP than with ABVD and with 30 Gy in comparison with 20 Gy. When IFRT of 30 Gy was used, there was no difference in FFTF between ABVD and BEACOPP. Yet with only 20 Gy IFRT, FFTF with BEACOPP was better than with ABVD by 5.7%. The study thus suggests that in unfavorable patients, ABVDX4 should be supplemented by IFRT at 30 Gy, while if baseline BEACOPP is used, the radiotherapy dose can safely be reduced to 20 Gy. Chemotherapy alone Five prospective randomized studies compared chemotherapy alone with chemotherapy followed by IFRT or regional radiotherapy in patients with early-stage Hodgkin lymphoma. The Children’s Cancer Group tested the role of radiation therapy in young patients (< 21 years old) who attained a complete response with risk-adapted chemotherapy (mostly COPP [cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone])/ABV [Adriamycin (doxorubicin), bleomycin, and vinblastine], for 4 to 6 cycles). They enrolled 829 patients into the study (68% had early-stage disease); 501 patients who achieved a complete response were then randomized to receive either low-dose (21 Gy) IFRT or no further treatment. The accrual was stopped earlier than planned because of a significantly higher number of relapses on the no-radiotherapy arm. The 3-year event-free survival rate with an intent-to-treat analysis was 92% for patients randomized to receive radiotherapy and 87% for those randomized to receive no further treatment (P = .057). The EORTC/Groupe d’Etude des Lymphomes de l’Adulte (GELA) conducted a large randomized trial in patients with favorable early-stage classic Hodgkin lymphoma. All patients received 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, and prednisone). Only patients who achieved a complete response were randomized to receive either IFRT of 36 Gy, IFRT of 20 Gy, or no irradiation. After an interim analysis, the EORTC/GELA groups closed the entry to the no-radiotherapy arm because of the excessive number of relapses. It should be noted that in previous EORTC studies, EBVP with IFRT was found to be inferior to MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, prednisone)/ABV with IFRT in patients with unfavorable disease, but this regimen provided excellent results when compared with radiotherapy alone in patients with favorable disease. The National Cancer Institute of Canada (NCIC) and Eastern Cooperative Oncology Group (ECOG) conducted a trial including 405 patients with nonbulky stage I/II disease. They were randomized to receive either “standard therapy,” namely, subtotal nodal irradiation (STNI) for favorable patients, and ABVD (2 cycles) followed by STNI for unfavorable patients (those with B symptoms, elevated ESR, ≥ 3 sites, age ≥ 40 years, mixed-cellularity histology) or experimental therapy consisting of 6 cycles or 4 cycles (if complete response was attained after 2 cycles) of ABVD and no radiotherapy. At a median follow-up of 11.3 years, progression-free survival with ABVD alone was significantly inferior (P = .006; hazard ratio [HR], 3.3; 1%); 12-year estimates of disease progression–free survival were 86% with ABVD alone compared with 94% for ABVDX2 + STNI. However, the overall survival of patients who received ABVD followed by STNI (a very large RT field that has been abandoned for over two decades) was lower (92% without vs 81% with STNI). While the study showed that a significant fraction of patients can have good survival rate with 6 cycles of ABVD (and, in some patients, 4 cycles) and no RT, the study was criticized for using excessive RT volume and scoring death events in the RT arm that were irrelevant to the treatment. The Memorial Sloan Kettering Cancer Center (MSKCC) trial included 152 patients with nonbulky, early-stage Hodgkin lymphoma. Patients were randomized up front to receive either ABVD for 6 cycles alone or ABVD for 6 cycles followed by radiotherapy. At 60 months, the duration of complete response and freedom from disease progression for patients treated with ABVD and radiotherapy vs ABVD alone were 91% vs 87% (P = .61) and 86% vs 81% (P = .61), respectively. Overall survival was 97% with ABVD and radiotherapy vs 90% with ABVD alone (P = .08). Although the differences between the outcome of the two treatment groups were not statistically significant, the study was not powered to detect differences between the treatment strategies that were smaller than 20%, due to the small number of patients and events. In a prospective, randomized study reported from India, patients with Hodgkin lymphoma who achieved a complete response after ABVD were randomized to receive either IFRT or no further therapy. The 8-year event-free and overall survival rates were significantly better for patients who received consolidation with IFRT than for those who received ABVD alone. Subset analysis indicated that the benefit from added IFRT was more prominent in advanced-stage than in early-stage disease. The National Comprehensive Cancer Network (NCCN) guidelines recommend combined-modality therapy or ABVD or Stanford V alone as treatment options for favorable or unfavorable classic Hodgkin lymphoma. For patients with bulky mediastinal involvement, combined-modality therapy remains the standard of care. However, because of concern about the late morbidity and mortality related to radiotherapy, including second malignancies and cardiovascular complications, some medical oncologists favor the use of chemotherapy only for patients with nonbulky stages I and II Hodgkin lymphoma. The treatment regimen employed is usually 6 cycles of ABVD or 4–6 cycles of ABVD (complete response + 2 additional cycles). A systematic review and meta-analysis of randomized controlled trials comparing chemotherapy alone vs the same chemotherapy plus radiotherapy (combined-modality therapy, or CMT) in early-stage Hodgkin lymphoma was performed by the Cochrane Hematological Malignancies Group. Five randomized studies involving 1,245 patients were identified. The meta-analysis, reported by Herbst et al, showed that the patients receiving CMT had significantly better tumor control and overall survival compared with those receiving the same chemotherapy alone. The HR for tumor control in CMT patients was 0.41 (95% CI, 0.25–0.66) compared with chemotherapy alone, and for overall survival HR was 0.40 (CI, 0.27–0.59) in favor of CMT. Similar results were recently reported by Olszewski in an analysis using the National Cancer Data Base. The new radiation fields design Several decades ago, when radiation therapy alone was frequently used as a curative treatment in early stages of disease, very large fields of RT were used to encompass all lymph nodes and the spleen, the fields were called mantle (for the upper body) and inverted Y (for the lower body); their sequential combination was called total lymphoid irradiation (TLI). RT of these large extended fields is rarely practiced today. Over the last two decades, combined modality became the preferred therapy, and the radiation fields were reduced to to include only the involved region(s). Borders of regions were defined by bony landmarks and still included uninvolved nodes and normal tissues that could be spared from radiation. This approach is known as involved-field radiotherapy (IFRT). In recent years, further reductions in the radiation fields were recommended. The design of the new fields is based on imaging information, preferably PET-CT obtained prior to chemotherapy as well as post-chemotherapy at the time of designing the radiation field. As previously discussed, INRT limits the radiation field to only the pre-chemotherapy or pre-resection volume of the involved lymph node(s). It also avoids non-lymphatic tissues that were not invaded by Hodgkin lymphoma, like lung and bone, and which after chemotherapy have re-occupied their original volume. When using this technique, it is mandatory that very precise pre-chemotherapy information is available and can be adjusted to the radiation treatment position at RT planning. Since, in most cases, accurate information about the original disease extent and precise location is not fully available, the International Lymphoma Radiation Oncology Group (ILROG) recommended the use of ISRT (involved-site radiotherapy) as a practical concept that still markedly reduces the irradiated volume in Hodgkin lymphoma and non-Hodgkin lymphoma compared with IFRT, but allows more flexibility if pre-chemotherapy anatomic pathology information is not perfectly available. ISRT and INRT (in appropriately imaged cases) also allow the application of newer techniques such as intensity-modulated radiation therapy (IMRT), 4-dimensional imaging, image-guided radiotherapy (IGRT) and deep inspiration breath hold (DIBH) techniques when necessary. Overall, ISRT and INRT provide less exposure of normal tissue to radiation, while the involved site of concern is fully irradiated. Initial comparisons of RT volume reduction using this new concept, by the Vancouver group and by the EORTC/GELA/IIL H10 study, demonstrated excellent disease control using the ISRT/INRT concept. Radiation therapy dose considerations When irradiation alone is used to treat Hodgkin lymphoma, the standard total dose to each field is 3,600 cGy, delivered in daily fractions of 180 cGy over 4 weeks. In addition, clinically involved areas are given a boost of 360 to 540 cGy in 2 to 3 fractions to bring the total dose to these areas up to 3,960 to 4,140 cGy. Patients who receive irradiation as consolidation after chemotherapy receive a total dose of 2,000 to 3,600 cGy in 150- to 180-cGy fractions. Simple 3-D beam arrangements are appropriate for most patients. However, IMRT and other techniques mentioned in the previous sections are appropriate for selected cases. Recent studies suggest that a reduction in the size of radiation fields and doses delivered may decrease the risk of breast cancer. Side Effects and Complications of Radiotherapy 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. Acute effects The potential acute side effects of involved fields in the upper body include mouth dryness, change in taste, pharyngitis, nausea, dry cough, dermatitis, and fatigue. These side effects are usually mild and transient. The main potential side effects of subdiaphragmatic irradiation are loss of appetite, nausea, and increased bowel movements. These reactions are usually mild and can be minimized with standard antiemetic medications. Irradiation of more than one field, particularly after long or intensive chemotherapy, may cause myelosuppression; the most common effect is neutropenia, which necessitates a short course of granulocyte-colony stimulating factor support. The effect of radiation dose and field reduction on the risk of long-term complications was analyzed in two studies. A French collaborative group randomized 188 patients with favorable early-stage Hodgkin lymphoma to receive either ABVDX3 followed by radiotherapy at 40 Gy to the involved sites and 30 Gy to uninvolved sites, including the paraaortic and splenic areas (control arm) or the same chemotherapy followed by 30 Gy to involved areas and 24 Gy to uninvolved sites. While FFTF and overall survival were the same in both arms, long-term severe adverse events, either cardiac or second tumors, at a median follow-up of 10 years were observed only in the control arm with the higher radiation doses. Rates of complications in the control group were similar to those of patients in an older study (reported by Arakelyan et al) who were treated with higher doses of radiation therapy (and ABVDX3). In another study, researchers from the Netherlands Cancer Institute analyzed 1,122 female 5-year survivors treated for Hodgkin lymphoma between 1965 and 1995; 806 were irradiated (36–44 Gy) to a mantle field that included the bilateral axillae or axillae alone, while in 126 patients who received radiation only to the mediastinum, the axillae (and thus most of the breast tissue) were spared from radiation. Sparing the axillae markedly reduced the risk of breast cancer (by 2.7-fold) compared with patients who received a full mantle field. Nowadays, in most patients treated with IFRT, the axillae are not included (eg, as discussed by De Bruin et al, 2009). Delayed effects Delayed side effects may develop anywhere from several weeks to several years after the completion of radiotherapy. Pneumonitis and pericarditis. During the same period, radiation pneumonitis and/or acute pericarditis may occur in < 5% of patients who receive large fields of radiation to the mediastinum; these side effects occur more often in those who have extensive mediastinal disease and normally resolve after a short course of steroid therapy. Both inflammatory processes have become rare with modern radiation techniques. Herpes zoster infection. Patients with Hodgkin lymphoma, regardless of treatment type, have a propensity to develop herpes zoster infection within 2 years after therapy. Usually, the infection is confined to a single dermatome and is self-limited. If the cutaneous eruption is identified promptly, treatment with systemic acyclovir will limit its duration and intensity. Lhermitte’s sign. An electric shock sensation radiating down the backs of both legs when the head is flexed (Lhermitte’s sign) 6 weeks to 3 months after full dose radiotherapy to neck. It is rarely seen with modern dose-reduced radiation therapy Lhermitte’s sign resolves spontaneously after a few months and is not associated with late or permanent spinal cord damage. Subclinical hypothyroidism. Radiotherapy of the neck can induce subclinical hypothyroidism in about one-third of patients. This condition is detected by elevation of thyroid-stimulating hormone. Thyroid replacement with levothyroxine is recommended, even in asymptomatic patients, to prevent overt hypothyroidism and decrease the risk of benign thyroid nodules. Infertility Irradiation of the pelvis may have deleterious effects on fertility. In most patients, this problem can be avoided by appropriate gonadal shielding. In females, the ovaries can be moved into a shielded area laterally or inferomedially near the uterine cervix. Irradiation fields that spare the pelvis do not increase the risk of sterility. Secondary malignancies The rate of second malignancies following radiation therapy with or without chemotherapy for Hodgkin lymphoma is approximately 1% per year. The most common second malignancies were breast cancer, gastrointestinal cancers, lung cancer, thyroid cancer, soft tissue and bone sarcomas, and acute leukemias, which are associated with chemotherapy as mentioned below in this chapter. The risk of developing breast cancer following radiation therapy increases with length of follow-up. Addition of alkylating agent–containing chemotherapy of the MOPP type seems to reduce this risk, probably because of effects on the ovaries that reduce estrogen production. The risk is increased with larger fields and higher doses of radiation therapy. 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. Alkylating agents (such as in the MOPP regimen) and radiation therapy were associated with an increased risk of lung cancer in an additive and dose-dependent fashion. These effects were multiplied by tobacco use. Among solid tumors, only alkylating agent–based regimens of the MOPP type are associated with an increased risk of lung cancer. Second malignancies are the leading cause of late morbidity and mortality in early-stage patients cured of Hodgkin lymphoma. Breast cancer. The increase in breast cancer risk is inversely related to the patient’s age at Hodgkin lymphoma 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 Hodgkin lymphoma, 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 Hodgkin lymphoma 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. The most common valve lesion was aortic stenosis, which occurred in 14 cases. At least 1 cardiac risk factor was present in all patients who developed CAD. The only treatment-related factor associated with the development of CAD was use of a radiation technique that resulted in a higher total dose to a portion of the heart (relative risk [RR], 7.8; 95% CI, 1.1–53.2; P = .04). No specific treatment-related factor was associated with carotid or subclavian artery disease or valvular dysfunction. Freedom from cardiovascular morbidity was 88% at 15 years and 84% at 20 years. In a cohort of 2,201 people who were 5-year survivors of Hodgkin lymphoma treated between 1965 and 1995 with full dose large-field irradiation, irradiation of the neck and mediastinum was associated with a 2.55 increased risk of ischemic cerebrovascular disease. However, currently used doses of radiation are markedly smaller than those practiced during the study era. To reduce the hazard of late cardiovascular effects, 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 risk factors for CAD, such as smoking, hyperlipidemia, hypertension, and poor dietary and exercise habits. Cholesterol levels should be monitored and treated if elevated. The risk of late mortality from myocardial infarction is increased with use of supradiaphramatic radiotherapy, especially total nodal radiation therapy. The risk also was higher in patients given various chemotherapy regimens (particularly ABVD) with, and even without, supradiaphragmatic radiotherapy. Effects on bone and muscle growth In children, high-dose irradiation will affect bone and muscle growth and may result in deformities. Current treatment programs for pediatric Hodgkin lymphoma are chemotherapy-based; radiotherapy is limited to low doses. Treatment of Stage III/IV Disease Chemotherapy has become curative for many patients with advanced stages of Hodgkin lymphoma. MOPP has been the primary effective combination chemotherapy regimen for advanced-stage 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. In the past 20 years, ABVD has been challenged by the BEACOPP protocol, which provides significantly better tumor control than ABVD but is also associated with increased acute and long-term toxicity. Combination chemotherapy regimens Doxorubicin-containing regimens. A doxorubicin-containing regimen, such as ABVD (Table 3), 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%). One reason for the improved response rate in the groups treated with doxorubicin-containing regimens was the higher percentage of patients who were able to receive ≥ 85% of the expected chemotherapy dose, particularly in the ABVD group. Subsequent trials compared ABVD, alternating MOPP/ABVD, and a MOPP/ABV hybrid. Alternating MOPP/ABVD and the MOPP/ABV hybrid were found to be equally effective in treating advanced-stage Hodgkin lymphoma. However, an Intergroup study that compared ABVD with MOPP/ABV hybrid (without irradiation) was closed early because of concerns regarding treatment-related deaths and second malignancies (mostly acute myeloid leukemia and lung cancer) in the MOPP/ABV hybrid arm. ABVD and the MOPP/ABV hybrid yielded similar 5-year failure-free and overall survival rates. TABLE 3: Chemotherapeutic regimens used for the treatment of Hodgkin lymphoma Shortened dose-intense regimens Shortened dose-intense regimens have initially shown promise. For example, the 12-week Stanford V regimen (see Table 3) combined with IFRT produced a 5-year overall survival rate of 96% and a freedom-from-disease-progression rate of 89% in a single center setting. 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 75%; P = .0001). Of interest, among 142 patients from Stanford, no secondary leukemia was observed, and 42 pregnancies were reported. However, the Stanford V regimen could not be shown to be more effective than ABVD in the randomized E2496 trial by Gordon et al; the Stanford V regimen was even associated with an impaired outcome when a modified version of it (with less RT) was compared with ABVD within the HD9601 trial from Italy, as reported by Chisesi et al. An escalated-dose version of BEACOPP was found to have a statistically significant superior freedom from treatment failure at 10 years compared with standard-dose BEACOPP and alternating monthly COPP and ABVD in patients with advanced-stage Hodgkin lymphoma. Short-term hematologic toxicity was greatest for escalated BEACOPP, and an increased risk for secondary acute leukemias was also seen as compared with standard-dose BEACOPP and COPP/ABVD. However, the improved efficacy appears to outweigh the moderate increase of treatment-related deaths with escalated BEACOPP. This impression is supported by a large network meta-analysis revealing a 5-year overall survival advantage of 7% with escalated BEACOPP as compared with ABVD. In advanced-stage disease, PET scanning during or after chemotherapy is emerging as a powerful predictor of outcome. Patients with advanced-stage disease who have positive PET scans after 2 cycles of ABVD are at a higher risk of relapse following treatment than are patients who have negative PET scans. Risk-adapted clinical trials based on this finding are ongoing and opening in the United States and Europe. At present, a change in therapy due to PET scan results during treatment cannot be recommended outside of the setting of a clinical trial. The PET scan currently is standard for assessing response after the completion of therapy. Combined-modality therapy Although the role of consolidation radiotherapy after induction chemotherapy remains controversial, irradiation is routinely added for patients with advanced-stage disease who present with bulky disease or who remain in uncertain complete remission after chemotherapy. Retrospective studies have demonstrated that adding low-dose radiotherapy to all initial disease sites after chemotherapy-induced complete response decreases the relapse rate by ~25% and significantly improves overall survival. However, a meta-analysis demonstrated that the addition of radiotherapy to chemotherapy reduced the rate of relapse but did not show a survival benefit for the combined-modality approach. The EORTC conducted a randomized trial in patients with stages III and IV Hodgkin lymphoma in which those achieving a complete remission with MOPP/ABV hybrid were randomized to receive either low-dose IFRT or no radiotherapy. Of the 739 patients enrolled, 421 achieved a complete remission. The median follow-up was 79 months. There was no statistically significant difference in 5-year event-free or overall survival. Partial responders received low-dose IFRT, and their event-free and overall survival rates were similar to those of patients who achieved a complete remission. More recently, an analysis of data collected prospectively within a randomized controlled trial of induction chemotherapy that included ABVD showed that patients who received consolidation radiotherapy had significantly better 5-year progression-free and overall survival compared with those who had not received radiation. The GHSG HD15 trial revealed that additional radiotherapy after 6 to 8 cycles of chemotherapy with escalated BEACOPP is only necessary in patients with PET-positive residual lymphoma tumor larger than 2.5 cm. The negative prognosis value of PET defined as the proportion of PET-negative patients without progression, relapse, or radiotherapy within 12 months was 94.6%. Long-Term Toxicities of Combination Chemotherapy Myelodysplasia and acute leukemia Multi-agent chemotherapy, particularly regimens including topoisomerase-II-inhibitors and/or alkylating agents, is known to be associated with the development of myelodysplastic syndromes 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 Hodgkin lymphoma, 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 Other types of cancer also are being observed with increasing frequency after chemotherapy (most regimens included alkylating agents), particularly lung cancer and other solid tumors. These malignancies have a longer latency period and usually are not observed until 15 years after therapy. Infertility The inability to conceive a child after trying for 1 year is another long-term complication seen with combination chemotherapy. At least 80% of males have permanent azoospermia or oligospermia following more than 3 cycles of MOPP chemotherapy; < 10% of men will have recovery of spermatogenesis within 1–7 years following the end of chemotherapy. The risk of infertility with ABVD chemotherapy is significantly lower (~ 15%–25%) than that with MOPP or BEACOPP. 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 maintain ovarian function during chemotherapy will have premature menopause following therapy. Female fertility appears to be well preserved following administration of ABVD, which does not contain alkylating agents of the nitrogen mustard type or procarbazine. Pulmonary complications Lung problems have been reported with ABVD chemotherapy and are related to bleomycin-induced lung toxicity. In an MSKCC study of 60 patients with early-stage Hodgkin lymphoma receiving ABVD chemotherapy with or without mediastinal irradiation, bleomycin was discontinued in 23% of patients. Following ABVD therapy, there was a significant decline in median forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide. Radiotherapy following ABVD chemotherapy resulted in a further decrease in FVC but did not significantly affect functional status. 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% as compared with 90% (P = .001) in patients without BPT. In the CALGB trial, there were three fatal pulmonary complications in 238 patients; all three patients were older than age 40. Pulmonary fibrosis has also been described after combined-modality therapy. Pulmonary function testing usually reveals a decreased diffusion capacity and restrictive changes prior to the onset of symptoms. Cardiomyopathy Deteriorated myocardial function 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/m2; cardiac toxicity is rarely seen in patients who receive a total dose ≤ 400 mg/m2. Management of Relapsed Disease Relapse after radiation therapy Patients with early-stage Hodgkin lymphoma who relapse after initial therapy with irradiation alone have excellent complete remission rates and 50% to 80% long-term survival rates when treated with ABVD. The dose used for salvage therapy is the same as outlined in Table 3. Relapse after combination chemotherapy Among patients with advanced-stage Hodgkin lymphoma, 70% to 90% will have a complete response to treatment; however, up to one-third of patients with stage III or IV disease will relapse, usually within the first 3 years after therapy. Various studies have identified the following poor prognostic factors for response to first-line chemotherapy: B symptoms, age > 45 years, bulky mediastinal disease, extranodal involvement, low hematocrit, high ESR, high levels of serum soluble CD30, and high levels of serum interleukin-10 (IL-10) and soluble IL-2 receptor. An International Prognostic Index (IPI) has been devised for advanced Hodgkin lymphoma based on a retrospective analysis of 1,618 patients from 25 centers. In the final model, seven factors were used: albumin < 4 g/dL, hemoglobin < 10.5 g/dL, male sex, stage IV disease, age ≥ 45 years, WBC ≥ 15,000/Î¼L, and lymphocytes < 600/Î¼L (or 8% of the WBC count). The worst prognostic group (7%) had a 5-year overall survival rate of 56% and a failure-free survival rate of 42%. In a comparison of seven well-known prognostic models for Hodgkin lymphoma applied retrospectively to a population of patients with advanced-stage disease, three were found to be the most predictive of outcome. One was the IPI mentioned above, and the other two were the MSKCC model employing age, LDH, hematocrit, inguinal nodal involvement, and mediastinal mass bulk; and the database on Hodgkin Lymphoma model employing stage, age, B symptoms, albumin level, and sex. Integration of the three models into a linear model improved their predictive power. High-Dose Therapy With Autologous Stem-Cell Transplantation The preferred salvage method for patients who relapsed after combined-modality therapy or chemotherapy alone or remained refractory to those programs is high-dose therapy with autologous stem-cell transplantation (ASCT). Two randomized studies demonstrated an event-free survival advantage with the high-dose therapy approach. Although a significant survival advantage was not observed due to the crossover design of the studies, most patients with refractory disease or postchemotherapy relapse are currently managed with high-dose chemotherapy and ASCT. A study from MSKCC reported the results of high-dose chemotherapy with ASCT in 65 patients with relapsed or refractory Hodgkin lymphoma. At a median follow-up of 43 months, overall survival was estimated to be 73%, and event-free survival was estimated to be 58% by intent-to-treat analysis. In a multivariate logistic regression model, there were three adverse prognostic factors: extranodal sites of relapse or refractory disease, complete remission duration of < 1 year or refractory disease, and B symptoms. Patients with no or one adverse factor had an overall survival of 90% and an event-free survival of 83%, those with two adverse factors had an overall survival of 57% and an event-free survival of 27%, and those with three adverse factors had an overall survival of 25% and an event-free survival of 10%. A follow-up study of a risk-adapted approach based on the study previously described suggested that patients with adverse prognostic factors may benefit from further augmentation of high-dose programs, including a “double-transplant” for selected patients. More recently, the value of PET was retrospectively assessed in patients with relapsed Hodgkin lymphoma undergoing high-dose chemotherapy and ASCT. It was demonstrated that patients who achieved a metabolic remission after induction chemotherapy and prior to high-dose chemotherapy and ASCT had a significantly improved outcome when compared to patients who were still PET-positive. Ongoing trials aim to confim these findings prospectively. The most promising novel drug in Hodgkin lymphoma evaluated in recent years is the antibody–drug conjugate brentuximab vedotin. A response rate of 75% was reported by Younes et al after single-agent treatment with brentuximab vedotin within a phase II trial including 102 patients with Hodgkin lymphoma who relapsed after high-dose chemotherapy followed by ASCT. Based on these results, the drug was approved by the US Food and Drug Administration for the treatment of Hodgkin lymphoma patients in whom high-dose chemotherapy and ASCT fails. Ongoing trials aim to evaluate brentuximab vedotin in further indications. Recently, a randomized phase III study reported by Moskowitz et al has shown that brentuximab vedotin consolidation for up to 48 weeks after high-dose chemotherapy and autologous stem cell transplantation results in an improved progression-free survival in high-risk patients. Other randomized studies aiming at the implementation of brentuximab vedotin into first-line protocols are still ongoing Further promising new agents for Hodgkin lymphoma include the anti–programmed cell death (PD)-1 antibody nivolumab that was shown to produce high response rates in heavily pretreated patients. Suggested Reading Al-Mansour M, Connors JM, Gascoyne RD, et al: Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin’s lymphoma. J Clin Oncol 28 793–799, 2010. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319, 2015. Arakelyan N, Jais JP, Desablens B, et al: Reduced versus full doses of radiation after 3 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine in early stage Hodgkin ly,phomas: Results of a randomized trial. Cancer 116:4054–4062, 2010. 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