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Hodgkin Disease

I. Background:

Hodgkin disease (HD) is a potentially curable malignant lymphoma with distinct histology, biologic behavior, and clinical characteristics. Thomas Hodgkin first described HD in 1832. Histologically, the picture is unique, with 1-2% of neoplastic cells (Reed-Sternberg [RS] cells) in a background of a variety of reactive mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes.

II. Epidemiology :

HD had a worldwide incidence of 59,000 cases annually (0.7% of all cancers) and accounts for 26,000 deaths (0.5% of all cancers). The 5-year disease-specific survival for patients with stages I and II, III, and IV is 90%, 84%, and 65%, respectively.

HD is more common among whites and less common among Asians. In the United States, the incidence is 3 cases per 100,000 population in whites and 1.8 cases per 100,000 population in African Americans. In developing countries, the incidence of the mixed-cellularity subtype in children is higher. On the other hand, in developed countries, young adults have the highest incidence of the NS subtype. Also, socioeconomic class is associated with a higher risk of HD.

HD is more common in males than in females, with an age-standardized incidence of 1.8 cases per 100,000 population in males and 0.8 cases per 100,000 population in females. This male predominance is particularly evident in children, where 85% of the cases are in males.

Age-specific incidence rates have a bimodal distribution in both sexes, peaking in young adults (aged 15-34 y) and older individuals (>55 y). In the United States, young adults (15-34 y) typically have NS HD, whereas children (0-14 y) and older individuals more commonly have the mixed-cellularity subtype.

III. Etiology:

The etiology of HD is unknown.

• Infectious agents, especially the Epstein-Barr virus (EBV), may be involved in the pathogenesis of HD.

• In as many as 50% of HD cases, the tumor cells are EBV-positive; EBV positivity is higher with MCHD (60-70%) versus NS HD (15-30%). Almost 100% of HIV-associated HD cases are EBV-positive.

• Patients with HIV infection have a higher incidence of HD compared to the population without HIV infection. However, HD is not considered an AIDS-defining neoplasm.

• Genetic predisposition may play a role in the pathogenesis of HD. Approximately 1% of patients with HD have a family history of the disease. Siblings of an affected individual have a 3- to 7-fold increased risk for developing HD. This risk is higher in monozygotic twins. HLA-DP alleles are more common in HD.

IV. Pathophysiology:

The RS cells represent a clonal proliferation of B lymphocytes that derive from the germinal centers of lymph nodes and that have lost their ability to express their antibodies because of the introduction of multiple somatic mutations. They consistently express CD15 (Leu-M1) and CD30 (Ki-1) antigens.

⇨ CD30 is a marker of lymphocyte activation and is expressed by reactive and malignant lymphoid cells. It is present in non-Hodgkin lymphoma. CD30 is expressed in the majority of nodular sclerosis (NS) and mixed-cellularity subtypes of HD.

⇨ CD15 is a marker of late granulocytes, monocytes, and activated T cells. It can be induced by viral infections along with the interleukin 2 (IL-2) receptor (CD25).

⇨ CD19 and CD20, which are B-lymphocyte antigens, are uncommon in NS HD and mixed-cellularity Hodgkin disease (MCHD).

Some of the clinical manifestations of HD (eg, eosinophilia) are attributed to the production of cytokines. The role of oncogenes in the pathophysiology of HD has been the subject of intense research. Upregulation of bcl2 has been shown to be of prognostic significance, which correlates with EBV expression.

V. Clinical

V.1. History:

• Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients).

• Constitutional symptoms (eg, unexplained weight loss, fever, night sweats) are present in 40% of patients.

• Chest pain, cough, and/or shortness of breath may be present due to a large mediastinal mass or lung involvement. Rarely, hemoptysis is observed.

• Patients may present with pruritus.

• Alcohol-induced pain at sites of nodal disease is specific for HD and occurs in less than 10% of patients.

• Intermittent fever is observed in approximately 25% of cases. Infrequently, the classic Pel-Ebstein fever (high fever for 1-2 wk followed by an afebrile period of 1-2 wk) is observed.

• Back or bone pain occurs rarely.

V.2. Physical:

• Palpable painless lymphadenopathy occurs in the cervical area (60-80%), axilla (6-20%), and, less commonly, in the inguinal area (6-20%). It is described as rubbery adenopathy.

• Involvement of the Waldeyer ring or occipital or epitrochlear areas is observed infrequently.

• Splenomegaly may be present.

• Patients may have hepatomegaly.

• Superior vena cava syndrome resulting from massive mediastinal lymphadenopathy is observed rarely.

• Central nervous system (CNS) symptoms or signs may be due to paraneoplastic syndromes, including cerebellar degeneration, neuropathy, Guillain-Barré syndrome, or multifocal leukoencephalopathy.

VI. Investigations

VI.1. Lab Studies:

• Erythrocyte sedimentation rate (ESR) may be elevated. An elevated ESR has been associated with worse prognosis. However, the ESR is a nonspecific test that should not be used for HD screening.

• Lactate dehydrogenase (LDH) may be increased. LDH may correlate with the bulk of disease.

• Complete blood count (for anemia, lymphopenia, neutrophilia, or eosinophilia) should be performed. The anemia usually is due to anemia of chronic disease. However, it may be due to bone marrow involvement or the presence of an autoantibody (positive findings on a warm Coombs test). Cytopenias are common in advanced disease. Platelet counts can be increased or decreased.

• Rarely, HD is associated with nephrotic syndrome.

• Alkaline phosphatase may be increased due to the presence of liver or bone involvement. Other uncommon laboratory findings include hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies).

• Serum cytokines (interleukin 6, interleukin 10) and IL-2 receptors correlate with tumor burden, systemic symptoms, and prognosis.

VI.1. Imaging Studies:

• CT scans of the chest, abdomen, and pelvis

o Possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly with or without focal parenchymal abnormalities, lung nodules or infiltrates, and pleural effusions.

o A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding.

• Positron emission tomography (PET) scanning is now considered essential to the initial staging of Hodgkin lymphoma, and this is often performed in conjunction with CT scanning.

• A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding in classic Hodgkin lymphoma, although it is uncommon in nodular lymphocyte-predominant Hodgkin disease (NLPHD).Previous

VI.3. Other Tests:

• Flow cytometry may be helpful in establishing the diagnosis.

• Lymphangiography

o It is used infrequently because it is technically challenging.

o Lymphangiography may demonstrate abnormalities, even in normal-sized lymph nodes.

o One additional advantage of this technique is that residual dye may be present in the lymph nodes for months to years, and the size of affected lymph nodes can be followed easily with plain radiographs.

• Thoracentesis with cytology of pleural fluid may be performed. The fluid may be an exudate or transudate, or, it may be chylous.

• CNS evaluation should be performed if symptoms or signs of CNS involvement are present. CNS involvement with HD is exceedingly rare, but it has been reported.

VI.4. Procedures:

A histological diagnosis always is required.

Because the lymph node architecture is important for histological classification, an excisional lymph node biopsy is recommended. When a patient presents with neck lymphadenopathy that may be due to a head and neck cancer, a fine-needle aspiration usually is advised as the initial diagnostic step, followed by excisional biopsy if squamous cell histology is excluded. A concern exists that an incisional or a needle-core biopsy will result in regional spread of a head and neck squamous cell carcinoma.

Staging laparotomy includes splenectomy, needle and wedge biopsy of the liver, and biopsies of the paraaortic, mesenteric, portal, and splenic hilar lymph nodes. Currently, this procedure is very rarely indicated. It was used when radiation was contemplated as the sole treatment modality in early-stage HD.

Bilateral bone marrow biopsies - because HD is seen as patchy infiltrates in the bone marrow, bilateral bone marrow biopsies are advised. Bone marrow involvement is more common in elderly individuals, in patients with advanced-stage disease, in the presence of systemic symptoms, and in patients with a histology indicating a poor prognosis. A bone marrow biopsy can be omitted in patients with stage I HD and selected patients with stage II HD without hematologic abnormalities.

VI.5. Histologic Findings:

According to the recent World Health Organization (WHO) classification, the first 4 subtypes are referred to as classic HD.

1. Nodular sclerosis Hodgkin disease - 60-80% of all cases. The morphology shows a nodular pattern. The broad bands of fibrosis divide the node into "nodules." The capsule is thickened. The characteristic cell is the lacunar-type RS cell, which has a monolobated or multilobated nucleus and a small nucleolus with abundant and pale cytoplasm. NS frequently is observed in adolescents and young adults and usually involves the mediastinum and other supradiaphragmatic sites.

2. Mixed-cellularity Hodgkin disease - 15-30% . Histologically, the infiltrate usually is diffuse. RS cells are of the classic type (large, with bilobate, double or multiple nuclei, and a large eosinophilic inclusionlike nucleolus). It commonly affects the abdominal lymph nodes and spleen. Patients with this histology typically have advanced-stage disease with systemic symptoms and immunodeficiency.

3. Lymphocyte-depleted Hodgkin disease - Less than 1% The infiltrate in lymphocyte-depleted Hodgkin disease (LDHD) is diffuse and often appears hypocellular. Large numbers of RS cells and bizarre sarcomatous variants are present. It is associated with older age and HIV positivity. Patients usually present with advanced-stage disease. EBV proteins are expressed in many of these tumors. Many cases of LDHD diagnosed in the past actually were non-Hodgkin lymphomas, often of the anaplastic large-cell type.

4. Lymphocyte-rich classic Hodgkin disease - 5% In this type of HD, RS cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes. It requires immunohistochemical diagnosis. Some cases may have a nodular pattern. Clinically, the presentation and survival patterns are similar to those for MCHD.

5. Nodular lymphocyte-predominant Hodgkin disease - 5% In contrast to the other histological subtypes, the typical RS cells in nodular lymphocyte-predominant Hodgkin disease (NLPHD) are not observed or appear infrequently. Instead, a variant of RS cells, the lymphocytic and histiocytic cells (L&H), or popcorn cells (their nuclei resemble an exploded kernel of corn), are seen within a background of inflammatory cells, predominantly benign lymphocytes. The L&H cells are positive for B-cell antigens, such as CD19 and CD20, but generally are negative for CD15 and CD30.

NLPHD has a distinct natural history characterized by a generally indolent clinical course, late relapses, and the subsequent development of aggressive non-Hodgkin lymphomas. Patients with NLPHD usually are young males who present with localized disease to the peripheral lymph nodes. Although late relapses are observed, this subtype of HD is curable. Because of the very small likelihood of disseminated disease, patients with stage IA NLPHD may be treated with involved-field radiotherapy alone. The above features, reminiscent of low-grade non-Hodgkin lymphoma, have led to the separate classification of this entity.

VII. Staging:

The Ann Arbor classification (1971) is used most commonly. Clinical staging involves assessment of disease extent by clinical examination and imaging techniques. When staging laparotomies are used as part of staging, disease extent is designated pathologic staging.

|Stage I - denotes a single lymph node area or single extranodal site. |

|Stage II - denotes 2 or more lymph node areas on the same side of the diaphragm. |

|Stage III - denotes lymph node areas on both sides of the diaphragm. |

|Stage IV - denotes disseminated or multiple involvement of extranodal organs. Involvement of the liver or the bone marrow is considered stage |

|IV disease. For staging classifications, the spleen is considered a lymph node area. |

|A or B designations denote the presence or absence of B symptoms. |

|B designation includes the presence of 1 or more of the following: (1) fever (temperature >38°C), (2) drenching night sweats, and (3) |

|unexplained loss of more than 10% of body weight within the preceding 6 months. |

|A designation is the absence of the above (pruritus is not a B symptom). |

The stage of HD correlates with prognosis. Also, the bulk of nodal disease and the extent of subdiaphragmatic involvement have been found to correlate with prognosis.

Approximately one third of new patients have splenic involvement based on laparotomy data. However, this depends on the histologic subtype. Two thirds of patients with mixed-cellularity but only one third of patients with lymphocyte-depleted and NS have splenic involvement. When liver or bone marrow involvement is present, the spleen is likely to be involved.

Spread in HD takes place via the lymphatics, hematogenous routes, and direct extension. Contiguous involvement of extranodal sites, eg, involvement of the lung parenchyma due to direct extension of large mediastinal lymphadenopathy, is not considered stage IV disease.

VIII. Prognosis

The 5-year disease-specific survival rates for patients with Hodgkin lymphoma are as follows :

• Stages I and II - 90%

• Stage III - 84%

• Stage IV - 65%

In addition to the stage of the disease, many factors contribute to the likelihood of survival from Hodgkin lymphoma (see Staging).

Survivors of Hodgkin lymphoma may have long-term sequelae from their therapy, including cardiac disease, pulmonary disease, secondary cancers, infertility, and infectious complications.

VIII.1. Unfavorable factors in limited-stage Hodgkin lymphoma

In patients with stage I or II disease, the following factors are considered unfavorable and, if present, will increase the intensity of the recommended initial therapy:

• Bulky disease

• An ESR of 50 mm/h or higher, if the patient is otherwise asymptomatic

• More than 3 sites of disease involvement

• The presence of B symptoms

• The presence of extranodal disease

For this purpose, bulky disease is defined as a mediastinal mass greater than one third of the intrathoracic diameter on a chest radiograph or greater than 35% of the thoracic diameter at vertebral level T5-6. Hodgkin lymphoma also qualifies as bulky disease if it is greater than 10 cm in diameter on a CT scan.

VIII.2. Unfavorable factors in advanced Hodgkin lymphoma (stage III and IV)

The following characteristics were determined to each contribute independently to an increased relative risk for Hodgkin lymphoma progression despite therapy:

• Serum albumin less than 4 g/dL

• Hemoglobin less than 10.5 g/dL

• Male sex

• Stage IV disease

• Age 45 years or older

• White blood cell (WBC) count greater than 15,000/μL

• Lymphocyte count less than 600/μL or less than 8% of the total WBC count

The International Prognostic Score (IPS) is considered to be the number of features that are present at diagnosis for Hodgkin lymphoma. The IPS correlates with the rate of freedom from disease progression and overall survival. Patients with 0-1 of these factors would be predicted to have a 90% overall survival. In contrast, patients with 4 or more of these factors may have an overall survival rate of only 59%.

IX. Medical Care:

Treatment of Hodgkin lymphoma is tailored to disease type, disease stage, and an assessment of the risk of resistant disease. Hodgkin lymphoma is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. Therefore, advances in treatment protocols have sought to (1) minimize the treatment given to patients with early-stage, low-risk disease and (2) safely maximize the treatment given to patients with disease that is likely to be refractory to standard therapies.

Published guidelines from the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO), and the International Harmonization Project provide consensus opinions from leading experts on evidence-based approaches to the diagnosis and treatment of Hodgkin lymphoma.

Combined-modality therapy (radiation therapy [XRT] and chemotherapy) is frequently the preferred approach in for most patients.

- In early-stage disease, combined-modality therapy provides a synergistic effect while limiting the total exposure to any particular agent. However, some randomized trials have suggested that radiation may not be necessary in early stage disease and adds considerable toxicity.

- In patients with advanced Hodgkin lymphoma, involved-field XRT can be used for sites of persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a standard feature of the Stanford V regimen.

Despite the high rate of cure for this disease, many cases Hodgkin lymphoma do relapse. In most of these cases, salvage chemotherapy followed by high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support is indicated. The role of allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma is being explored

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Goals of Therapy

The primary goal of therapy is to induce a complete remission (CR), which is defined as the disappearance of all evidence of disease, as evaluated by PET/CT scanning, physical examination, and bone marrow examination (if appropriate). PET/CT scanning should be obtained at least 3 weeks and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses.

A partial remission (PR) is defined as "regression of measurable disease and no new sites" of disease. A failure to achieve a CR with initial therapy or a relapse after having attained a CR is an indication for additional HDC and/or XRT, often with autologous hematopoietic stem cell support.

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Assessment of Treatment Response

The high sensitivity of positron emission tomography (PET) scanning for classic Hodgkin lymphoma has won this imaging modality a prominent role in the assessment of treatment response in affected patients. A positive PET scan following therapy correlates strongly with a high risk of relapse. An early attainment of a negative PET scan during therapy is a positive prognostic indicator, but studies have not yet provided information on whether a course of therapy can be safely shortened in this situation.

PET/CT scans should be obtained at least 3 weeks, and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses. Biopsies of PET-positive lesions are typically done in order to test for persistent Hodgkin lymphoma.

IX.1. Radiation therapy

⇨ The involved field encompasses the involved lymph node area plus one contiguous region.

⇨ Extended fields are the mantle (encompassing the cervical, axillary, and mediastinal nodes) or the inverted Y (encompassing the paraaortic, pelvic, and inguinal nodes).

⇨ Subtotal nodal irradiation involves the mantle plus the paraaortic field. The dose is 40-45 Gy when given alone or lower (usually 30 Gy) when used in combination with chemotherapy.

o The mantle field is shaped accordingly in order to reduce radiation to the heart and lungs.

Careful avoidance of the spinal cord prevents myelitis. Shielding the testes and oophoropexy are important during the reproductive years. If these cannot be ensured, sperm and ova banking may be advisable.

IX.2. Chemotherapy

a. Conventional chemotherapy :

➢ MOPP - (Mustargen [ie, mechlorethamine], Oncovin (ie, vincristine), procarbazine, and prednisone) is a 4-drug regimen developed by DeVita et al at the National Cancer Institute (NCI) in the mid 1960s. It was the first curative combination chemotherapy for HD.

➢ ABVD - (Adriamycin, bleomycin, vinblastine, dacarbazine) was developed in Italy by Bonadonna et al in the early 1970s. This combination has now become the standard chemotherapy regimen for HD because it is associated with a very low incidence of sterility and leukemia, and it has been shown to be superior in terms of disease-free survival (DFS) in a head-to-head comparison with MOPP.

➢ Alternating regimens (MOPP/ABVD) and hybrid regimens (MOPP/ABV) have been tested but were not found to be superior to ABVD.

➢ Stanford V is a multidrug regimen developed at Stanford University consisting of doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, and prednisone. The drugs are administered weekly, alternating myelosuppressive and nonmyelosuppressive agents, for 12 weeks. Involved-field radiotherapy at the conclusion of the 12-week regimen is considered part of this regimen.

➢ BEACOPP includes the following chemotherapeutic drugs: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. A dose-intensified version of BEACOPP, with higher doses of etoposide, Adriamycin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (G-CSF) for neutrophil support, also has been developed (escalated BEACOPP). Although preliminary studies have shown encouraging results, both of these regimens, BEACOPP and escalated BEACOPP, are associated with a higher incidence of sterility and leukemogenesis.

Third-generation regimens (eg, Stanford V, BEACOPP) may improve the outcome of patients with advanced HD. Many investigators have advocated these more aggressive chemotherapy regimens.

IX.3. High-dose chemotherapy with transplantation

High-dose chemotherapy (HDC) at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous transplantation) or infusion of stem cells from a donor source (allogeneic transplantation).

The most commonly used chemotherapeutic regimens are BEAM (BCNU [bischloroethylnitrosourea], etoposide, AraC [arabinosylcytosine], melphalan) and CBV (cyclophosphamide, carmustine, etoposide) followed by stem cells derived from peripheral blood or stem cells derived from bone marrow.

Currently, with the use of peripheral stem cells and advances in supportive care, the mortality rate with HDC and autologous hematopoietic stem cell transplantation is approximately 1%. This has made the use of HDC more appealing for the treatment of relapsed HD.

IX.4. Treatment guidelines according to stage are as follows:

• Early stages (I-IIA)

o The treatment of early-stage favorable (absence of unfavorable characteristics) disease is controversial. Acceptable treatment options include the following:

▪ Extended-field radiotherapy, if pathologically staged (20% will be upstaged upon laparotomy)

▪ Subtotal nodal irradiation, if clinically staged (approximately 20% will relapse, usually at nonirradiated sites)

▪ Combined modality therapy (third option above) usually represents chemotherapy (ABVD) for 2-4 cycles, followed by radiotherapy of the involved field.

▪ ABVD alone without radiation, which may be adequate therapy for early-stage disease (under investigation).

o Treatment for special presentations (ie, extremely low-risk groups) includes the following:

▪ For patients with clinical stage IA disease with neck involvement and NLPHD histology, radiotherapy alone is adequate therapy.

▪ For patients with clinical stage IA disease that is nonbulky and involves the mediastinum with NS histology, mantle irradiation alone may be adequate therapy.

o Treatment for early-stage unfavorable (ie, presence of at least 1 unfavorable characteristic) disease is as follows:

▪ Combined modality therapy, which is chemotherapy (ABVD) for 4-6 cycles followed by involved-field radiotherapy, is used.

▪ Approximately 80% of patients are cured, and treatment fails in 20%. Of these, 5% progress during treatment and 15% relapse.

▪ The use of more aggressive chemotherapy for the treatment of unfavorable early-stage HD is being explored.

• Advanced stages (IIB-IV)

o Chemotherapy is the mainstay of therapy, with radiation reserved for initial bulky sites or residual PET activity. Patients with this category of disease receive either 8 cycles of the ABVD regimen or the standard-dose BEACOPP regimen, with involved-field XRT applied only to tumors initially more than 7.5 cm or to sites of residual disease following chemotherapy. For patients with advanced-stage disease, the use of the escalated BEACOPP regimen has support in the literature..

• Relapsed or resistant HD

o Patients with Hodgkin lymphoma who have never entered a CR, or whose disease has relapsed after the attainment of a CR, have a very poor prognosis when treated with standard chemotherapy and radiation. Therefore, high-dose chemotherapy with autologous stem cell transplantation is recommended for these patients.

o In this procedure, salvage chemotherapy is first administered to help reduce the size of the persistent disease and obtain a CR, if possible. The number of cycles to be administered depends on how well the disease is responding to therapy. Following one of the cycles of salvage chemotherapy, hematopoietic stem cells are collected from the peripheral blood by leukapheresis and are stored frozen. Following the administration of myeloablative chemotherapy (eg, BEAM), the stored hematopoietic stem cells are thawed and reinfused into the patient to facilitate hematopoietic recovery. HDC with autologous stem cell transplantation can provide better than 50% long-term, progression-free survival for patients with relapses, although specific predicted outcomes vary widely depending on patient-specific risk factors.

o Patients with localized asymptomatic relapse may be treated with conventional chemotherapy or even radiation therapy. However, HDC may produce longer DFS for these patients. All other patterns of relapse require HDC. Approximately 50% (30-70%) of patients with relapsed HD are cured with HDC.

o Cases of relapse after autologous transplant represent a therapeutic challenge. Various conventional chemotherapy combinations, single agents (eg, vinorelbine or gemcitabine), allogeneic transplantation, or investigational therapies (eg, radiolabeled antibodies) may be considered.

Immunotherapy - Targeted immunotherapeutic agents are currently being evaluated for potential use in Hodgkin lymphoma. The CD30 cell surface antigen, which is expressed at high levels on Reed-Sternberg cells, is a target of 2 monoclonal antibodies, SGN-30 and MDX-60. In August 2011, the US Food and Drug Adminisration (FDA) granted fast-track approval to brentuximab, a CD30 antibody–drug condjugate, for the treatment of relapsed/refractory Hodgkin lymphoma that has progressed on 2 other lines of multiagent chemotherapy. This agent was approved based on early clinical trials suggesting a complete response rate of 34% and an objective response rate of 74%.

X. Complications:

• Survivors of HD may have long-term sequelae of their therapy. In the Stanford series, which provides long-term follow-up of more than 2000 patients with HD, treatment-related causes (mainly second primary tumors and cardiac disease) exceeded HD as the predominant cause of death at 15 years. With the current widespread use of nonleukemogenic chemotherapy (ABVD) and the use of smaller radiation fields and doses, the rate of treatment-related deaths is expected to decrease.

• Cardiac disease

o Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease, and defects in the conduction system.

o Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac death.

o ABVD contains Adriamycin, which is cardiotoxic. However, the risk of symptomatic congestive heart failure with 6 cycles of ABVD (cumulative dose of Adriamycin of 300 mg/m2) is low.

• Pulmonary disease

o ABVD contains bleomycin, a drug associated with dose-related pulmonary toxicity, mainly interstitial pneumonitis, that may lead to fibrosis.

o The addition of mantle irradiation enhances lung injury. Pulmonary symptomatology, such as cough or dyspnea upon exertion, is observed in half the patients, and declining pulmonary function parameters are observed in approximately one third of patients during ABVD chemotherapy with or without radiation therapy. This may lead to dose reductions or even discontinuation of bleomycin.

o Baseline tests and follow-up evaluation with pulmonary function tests are recommended. The best parameter to follow is the carbon monoxide diffusion capacity.

o Although acute toxicity is common, the incidence of severe long-term pulmonary toxicity is low. Fatal pulmonary toxicity has been reported in up to 2-3% of patients treated with ABVD.

• Myelodysplasia/leukemia

o In the Stanford series, the projected risk for developing acute leukemia (predominantly acute myelogenous leukemia [AML]) over a follow-up period of 35 years was 2%, and the relative risk compared to matched controls was 38%. Myelodysplasia (MDS)/AML usually is seen in the first 3-8 years following treatment for HD; subsequently, the risk appears to decline. These findings are consistent with the biology of secondary leukemias following alkylator therapy.

o MDS/AML usually develops in the context of an MDS with cytogenetic abnormalities in chromosomes 5 and/or 7. Exposure to alkylating agents (mainly nitrogen mustard) has been implicated.

o Exposure to epipodophyllotoxins (etoposide and teniposide) also may result in AML, which develops earlier, within 3 years, and is associated with chromosomal abnormalities at band 11q23.

o MOPP is associated with an approximately 5% incidence of MDS/leukemia. With ABVD, the risk is low, less than 1%.

• Infertility

o MOPP causes permanent infertility in nearly 100% of males and approximately 50% of females. Young females may maintain their ovarian function.

o ABVD is not associated with permanent sterility. However, recommend that male patients undergo pretreatment sperm banking because many patients have low sperm counts at the time of diagnosis as a result of their disease.

• Breast cancer

o Patients treated with mantle radiation when they are younger than 30 years are 19 times more likely to develop breast cancer. If women are exposed to chest radiation when they are younger than 15 years, this relative risk increases to 136.

o MOPP chemotherapy also produces an increased risk for breast cancer when combined with radiation.

• Non-Hodgkin lymphoma

o The relative risk rate for non-Hodgkin lymphoma is 35% compared to matched controls, which results in an excess of 16 cases per 10,000 person-years compared to the expected number of cases.

o The risk is constant throughout the period of follow-up.

• Other solid tumors

o The most common secondary malignancy is lung cancer.

o The following risks were reported in the Stanford series on 2162 patients (relative risk/absolute risk, excess of cases per 10,000 person-years). For lung cancer, relative risk is 10 and absolute risk is 16. For melanoma, relative risk is 12 and absolute risk is 4. For soft-tissue sarcoma, relative risk is 24 and absolute risk is 4. For salivary gland tumors, relative risk is 38 and absolute risk is 2. For thyroid cancer, relative risk is 11 and absolute risk is 2.

o With the widespread use of ABVD as the preferred chemotherapeutic combination, MDS/leukemia and other secondary malignancies are expected to be infrequent treatment-related complications.

• Infectious complications

o Bacterial sepsis postsplenectomy: Patients who have undergone splenectomy are predisposed to bacterial sepsis secondary to encapsulated microorganisms (especially pneumococcal organisms). Empiric antibiotic therapy should be instituted promptly in patients who have undergone splenectomy and present with fever. Pneumococcal vaccination prior to splenectomy also is recommended.

o Herpes zoster usually appears in previously irradiated dermatomes, but it also may occur in patients who have not been irradiated.

• Hypothyroidism after neck/mediastinal radiotherapy

o Elevation of TSH occurs in one third of adult patients.

o Lhermitte syndrome develops in approximately 15% of patients after mantle irradiation. Patients describe an electric shock sensation radiating along the back and legs upon flexion of the neck. Lhermitte syndrome is not associated with the development of radiation myelitis, and it does not require treatment. This syndrome may last for many months, but eventually it resolves without long-term sequelae.

• Immunodeficiency after chemotherapy and/or radiation therapy

o Patients undergoing chemotherapy are at higher risk of becoming neutropenic. Blood counts should be followed closely.

o Furthermore, patients receiving pelvic radiation may have long-term pancytopenias due to direct radiation to the bone marrow.

XI. Long-Term Monitoring

Both the NCCN and the ESMO guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission. Most relapses occur in the first 3 years after therapy. Follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.

Follow-up examinations include the following:

• History and physical examination

• Complete blood cell count and chemistry panel, including lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), glucose, and lipid levels

• Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck XRT)

• Chest x-ray or CT scans of the chest every 6-12 months in the first 2-5 years

• Abdominal and pelvic CT scans may be added every 6-12 months in the first 2-3 years, especially if the disease originally occurred below the diaphragm

• Spiral chest CT scans may be appropriate annually, starting 5 years after therapy, to screen patients at increased risk for lung cancer

• Female patients who have received chest irradiation should be screened annually with mammography, starting at age 40 years or 5-8 years following the XRT

Use of PET scans for surveillance in patients with complete remission is specifically not encouraged by the NCCN, due to the possibility of false-positive results.

Vaccinations against pneumococcus (especially in patients who have had splenectomy), Haemophilus influenzae, meningococcus, and influenza (annually, especially in patients who have received bleomycin or chest XRT), should be maintained.

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