Marcel P. Devetten‡
*Section of Hematology/Oncology, West Virginia University, Morgantown, West Virginia
†Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
‡Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Hodgkin lymphoma (HL) is among the most common malignancies of young adults. It constitutes approximately 1% of all malignancies and 18% of all lymphomas, and, in the United States, 3 of every 100,000 people develop this condition. In Europe and North America, there is a bimodal age distribution, with an increasing frequency between the second and third decades, and a second peak in the seventh decade.
ETIOLOGY AND RISK FACTORS
HL is a neoplastic disorder of the lymphoid system, usually arising from B lymphocytes. Typically, a small number of scattered giant neoplastic cells (RS cells) are surrounded by an inflammatory background.
Reed–Sternberg Cells or Variants
FIG. 29.1. A: Diagnostic Reed–Sternberg cell, seen in classic types of Hodgkin lymphomas (mixed cellularity, nodular sclerosis, lymphocyte depletion). B: Variants of Reed–Sternberg cells seen in nodular lymphocyte-predominant Hodgkin lymphomas: popcorn cells or L and H cells (lymphocytic or histiocytic predominance). Reed–Sternberg cells of the classic type generally are not seen in a nodular lymphocyte-predominant Hodgkin lymphoma.
In 1994, the International Lymphoma Study Group introduced a classification incorporating immunologic and molecular data as part of a Revised European–American Lymphoma classification (REAL) for HL, which replaced the older Rye classification. The REAL classification was incorporated in the classification of the World Health Organization (WHO) in 2001 (see Table 29.1).
TABLE 29.1. Classification systems
The REAL/WHO classification recognizes two distinct diseases with distinguishing histopathologic features and immunophenotypes:
Features and immunophenotypes of classic HL and LPHL are described in Table 29.2.
TABLE 29.2. Features and immunophenotypes of Hodgkin lymphomas
Staging [Ann Arbor/American Joint Committee for Cancer (AJCC) and Cotswold] is outlined in Table 29.3.
TABLE 29.3. Staging
Staging laparotomy and splenectomy were done routinely in the past for patients with early stage disease above the diaphragm and for whom definitive radiation treatment was considered. Now, with newer radiologic testing such as PET scans, it is rarely used.
Unfavorable Prognostic Features
The most important unfavorable prognostic features are advanced stage, B symptoms, and presence of bulky disease.
o Unfavorable: mixed cellularity and lymphocyte depletion
o Favorable: lymphocyte-predominant and nodular sclerosis
MANAGEMENT OF NEWLY DIAGNOSED HODGKIN LYMPHOMA
HL is treated with a curative intent. In view of the high cure rates, studies have increasingly addressed long-term toxicities to define best treatment strategies. Treatment selection is therefore not only influenced by stage and unfavorable prognostic factors but also by toxicity.
Risk Stratification and PROGNOSIS
Two major risk groups are distinguished, early and advanced disease:
Other criteria might be included to subdivide the two major risk groups further to avoid under- or overtreatment of patients with early stage disease.
For example, the Canada Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) separate early stage Hodgkin Disease HD into:
Low risk: includes nodular lymphocyte-predominant Hodgkin disease (NLPHD) and nodular sclerosing histology, affects individuals younger than 40 years, ESR is less than 50, and three or less disease-site regions are involved.
High risk: includes all other diseases in stages I to II, excluding bulky disease >10 cm.
Radiation is the most effective single therapeutic modality for HL. In general, the management of HL with radiation therapy consists of treating regions of known disease (“involved field”). An “extended field” treats unaffected adjacent nodal groups in addition to the involved regions (see Table 29.4).
TABLE 29.4. Radiation guidelines
Radiation covering extended fields is used to three major fields, known as the mantle, paraaortic, and pelvic or inverted-Y fields (see Fig. 29.2).
FIG. 29.2. Radiation therapy fields used in treating Hodgkin disease (A, B, C, and D). When the fields shown in C and D are combined, this is commonly called total nodal irradiation (TNI). (From Haskell CM. Cancer Treatment. 4th ed. Philadelphia: WB Saunders, 1995:965, with permission.)
The usual dose of radiation is 25 to 30 Gy to uninvolved areas and 35 to 44 Gy to the involved field. Radiation doses can be lower when used in conjunction with chemotherapy
The first “curative regimen” was mechlorethamine, Oncovin, procarbazine, prednisone (MOPP), which resulted in a 70% complete remission in patients with stage III and stage IV
cancer. Subsequently, many regimens have been developed, including MOPP variants, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) and its variants, and hybrids of MOPP/ABVD.
Choosing between MOPP, ABVD, and MOPP/ABVD
In a randomized study, the Cancer and Leukemia Group B (CALGB) showed ABVD and MOPP/ABVD to be superior to MOPP alone in terms of remission, freedom from progression, and survival. At 10 years, the risk of developing treatment-related leukemia with the MOPP regimen is 2% to 3%, whereas it is 0.7% with ABVD. Infertility rates are much lower with ABVD than with MOPP (see Table 29.5).
TABLE 29.5. Cancer and Leukemia Group B study comparing combination treatments
A recent randomized intergroup trial demonstrated that MOPP/ABV is associated with a greater incidence of acute toxicity, myelodysplasia (MDS), and leukemia than ABVD is, with no difference in failure-free survival or overall survival at 5 years. ABVD should be considered the standard regimen for treatment of advanced HD (see Table 29.6).
TABLE 29.6. Commonly used treatment regimens
Combined Modality Treatment
A meta-analysis of 23 trials of patients with early stage HD showed that the 10-year rate of freedom from relapse was higher with combined modality therapy than with radiation, but survival rates were not significantly different.
Primary Treatment Options
High-dose Therapy and Autologous Stem Cell Transplantation
High-dose therapy with autologous transplant has no defined role for consolidation in the treatment programs for newly diagnosed unfavorable-risk HL that respond to standard chemotherapy. One randomized trial from the United Kingdom demonstrated no advantage in patients with highly unfavorable prognosis in achieving complete response with the European regimen PVACE-BOP.
Evaluation of Treatment Response with Positron Emission Tomography
PET is a new tool in managing patients with lymphomas. A negative PET scan at completion of therapy indicates a favorable prognosis. Persistently positive PET scans at the end of chemotherapy seem to have a high sensitivity for predicting subsequent relapse and need close follow-up; however, some of those patients may remain in prolonged remission. More prospective studies are needed to define the usefulness and limitations of PET scans more precisely.
TREATMENT OF RELAPSED HODGKIN LYMPHOMA
In general, relapsed HL is still curable.
Relapses usually occur within 2 to 3 years after primary therapy. There are currently no clear parameters to predict the 15% to 20% of patients who will progress during treatment or relapse early. Patients with relapse within 1 year of primary treatment or with a second relapse have a survival of less than 20% at 5 years. For successful choice of management, one should consider the following:
If the relapse is due to inadequate initial treatment, retreatment with chemotherapy or radiation is considered.
Relapse after primary radiation is best managed with chemotherapy.
Early relapse (<1 year) or persistent disease after primary therapy with adequate numbers of cycles of combination chemotherapy should be treated with salvage chemotherapy followed by autologous stem cell transplantation with curative intent.
Late relapse (particularly with favorable features: no B symptoms, long disease-free interval, no bulk, disease confined to lymph nodes, best only one site) has a chance for cure with salvage chemotherapy (and radiation if applicable). But consolidation with autologous stem cell transplantation should always be considered. Chemosensitive relapse treated with transplantation has the best prognosis.
SALVAGE CHEMOTHERAPY REGIMENS
EVA (etoposide, vincristine, and doxorubicin)
ASHAP (doxorubicin, cisplatin, high-dose cytarabine, and methylprednisolone)
Prognostic Factors in Relapse (Stanford Study)
Gemcitabine emerges as new active agent in refractory HL
COMPLICATIONS OF THERAPY
Late Complications of Radiation for Hodgkin Lymphoma
Secondary neoplasms arise 20 years after radiation treatment in 75% of cases in the radiation field at a rate of 20% to 25%. Studies raise the possibility that splenic field radiation and splenectomy increase the risk of treatment-related cancer.
Long-term follow-up for chemotherapy has not been documented beyond 15 years and is therefore not yet comparable with long-term data for radiation toxicity.
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