In the year 2000, approximately 7,200 new cases of Hodgkin’s disease will be diagnosed in the United States. In contrast to the increasing incidence of non-Hodgkin’s lymphoma (NHL) over the past several decades, the annual incidence of Hodgkin’s disease has remained stable. Over the last four decades, advances in radiation therapy and the advent of combination chemotherapy have tripled the cure rate of patients with Hodgkin’s disease. In 2000, more than 75% of all newly diagnosed patients can expect a disease-free normal life span.
Gender The male to female ratio of Hodgkin’s disease is 1.3:1.0.
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. The second peak is probably an artifact of histologic misclassification, since recent studies have shown that many cases diagnosed as Hodgkin’s disease in this older age group were, in fact, NHL.
Race Hodgkin’s disease occurs less commonly in African-Americans (1.6 cases per 100,000 person-years) than in Caucasians (2.9 per 100,000 person-years).
Geography The age-specific incidence of Hodgkin’s disease differs markedly in different 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.
The cause of Hodgkin’s disease remains unknown, and there are no well-defined risk factors for its development. However, certain associations have been noted that provide clues to possible etiologic factors.
Familial factors For example, same-sex siblings of patients with Hodgkin’s disease have a 10 times higher risk for the disease. Patient-child combinations are more common than spouse pairings. Higher risk for Hodgkin’s disease is associated with few siblings, single-family houses, early birth order, and fewer playmates¾all of which decrease exposure to infectious agents at an early age. The monozygotic twin sibling of a patient with Hodgkin’s disease has a 99 times higher risk of developing Hodgkin’s disease than a dizygotic twin sibling of Hodgkin’s disease patient. These associations suggest a genetic predisposition and/or a role for an infectious or environmental agent during childhood or early adolescence in the etiology of the disease.
Viruses Familial aggregation may imply genetic factors, but other epidemiologic findings mentioned above suggest an abnormal response to an infective agent. Both factors may play a role in the pathogenesis of the disease. The Epstein-Barr virus (EBV) has been implicated in the etiology of Hodgkin’s disease by both epidemiologic and serologic studies, as well as by the detection of the EBV genome in 20%-80% of tumor specimens.
There have been no conclusive studies regarding the possible increased frequency of Hodgkin’s disease in patients with human immunodeficiency (HIV) infection. However, Hodgkin’s disease in HIV-positive patients is associated with advanced stage and poor therapeutic outcome. (For further discussion of Hodgkin’s disease in patients with HIV infection, see chapter 27.)
Other possible risk factors The proposed association of Hodgkin’s disease with tonsillectomy or appendectomy has been refuted. Rare reports have suggested an increased hazard for people engaged in woodworking.
Hodgkin’s disease is a lymph node–based malignancy and commonly presents as an asymptomatic lymphadenopathy that may progress to predictable clinical sites.
The course of Hodgkin’s disease seems to be altered by infection with the HIV. Frequent extranodal presentations, a preponderance of mixed cellularity, and even lymphocyte depletion histology (see below) have been reported in Hodgkin’s disease patients with HIV infection.
Location of lymphadenopathy More than 80% of patients with Hodgkin’s disease present with lymphadenopathy above the diaphragm, often involving the anterior mediastinum; < 10%-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; inguinal areas are involved less frequently. Disseminated lymphadenopathy is rare in patients with Hodgkin’s disease, as is involvement of Waldeyer’s ring and occipital, epitrochlear, posterior mediastinal, and mesenteric sites.
Systemic symptoms About 40% of patients experience systemic symptoms. These include fever, night sweats, or weight loss (so-called B symptoms) and chronic pruritus. These symptoms occur more frequently in older patients and have a negative impact on prognosis (see “Staging and prognosis” below).
Extranodal involvement Hodgkin’s disease 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 sites are the spleen, lungs, liver, and bone marrow.
The initial diagnosis of Hodgkin’s disease 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.
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’s disease 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 (Ber-H2) and CD15 (Leu-M1). These markers are present on R-S cells and its variants but not on background inflammatory cells.
Recent 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 an 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.
| Bräuninger et al recently reported two unusual cases of composite lymphomas in which the clonal gene rearrangement was identical in the Hodgkin’s disease and NHL tumors. The first patient, a 75-year-old women, developed a follicular small cleaved cell lymphoma and mixed cellularity Hodgkin’s disease in the same node. The other case developed in a 75-year-old man with Gardner’s syndrome and cutaneous T-cell–rich B-cell lymphoma, who developed “classic” Hodgkin’s disease 3 years later. The authors postulate that a common transforming event occurred within the germinal center, resulting in heavy-chain V gene rearrangement. Subsequently, distinct transforming events resulted in the separate development of Hodgkin’s disease and NHL (Bräuninger A. Hansmann M-L, Strickler J, et al: N Engl J Med 340:129-1247, 1999). |
Histologic subtypes
According to the Rye classification (based on the number and appearance of R-S cells, as well as the background cellular milieu), there are four histologic subtypes of Hodgkin’ s disease.
Nodular sclerosis, the most common subtype, is typically seen in young adults (more commonly in females) 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 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 a fine reticular fibrosis may be present; and the cellular background includes lymphocytes, eosinophils, neutrophils, and histiocytes.
Lymphocyte-predominant Hodgkin’s disease is an infrequent form of Hodgkin’s disease in which few R-S cells or their variants may be identified. The cellular background is primarily lymphocytes in a nodular or sometimes diffuse pattern. The R-S variants express a B-cell phenotype (CD20-positive, CD15-negative). B-cell clonality has also been demonstrated by PCR of the immune globulin heavy-chain genes in single R-S variant cells in biopsy material from patients with lymphocyte-predominant Hodgkin’s disease.
This has led investigators to propose that lymphocyte-predominant Hodgkin’s disease is a B-cell malignancy with a mature B-cell phenotype, distinct from the other three histologic types of Hodgkin’s disease. Lymphocyte-predominant Hodgkin’s disease is often clinically localized, is usually effectively treated with irradiation alone, and may relapse late (a clinical feature reminiscent of low-grade lymphoma).
| An expert panel of pathologists recently reviewed clinical data and biopsy material from patients with lymphocyte-predominant Hodgkin’s disease seen at 17 European and American centers. Of 426 assessable cases, 51% were lymphocyte-predominant Hodgkin’s disease, 27% were lymphocyte-rich classic Hodgkin’s disease; 5%, classic Hodgkin’s disease; 3%, NHL; and 3%, reactive lesions. Failure-free and overall survival rates did not differ significantly between the 219 patients with lymphocyte-predominant Hodgkin’s disease and the 115 patients with lymphocyte-rich classic Hodgkin’s disease. However, among relapsing patients, multiple relapses occurred in 27% of patients with lymphocyte-predominant Hodgkin’s disease vs 5% of those with lymphocyte-rich classic Hodgkin’s disease. The pattern of multiple relapses is similar to that seen in some patients with low-grade B-cell NHLs. Among patients with lymphocyte-predominant histology, the 15-year Hodgkin’s disease–specific survival rate was > 90% . Old age and stage IV disease were adverse prognostic factors (Diehl V., Sextro M, Franklin J, et al: J Clin Oncol 17:776-783, 1999). |
Lymphocyte depletion is a rare diagnosis, particularly since the advent of antigen marker studies, which led to the recognition that many such cases represented T-cell NHLs. R-S cells are numerous, the cellular background is sparse, and there may be diffuse fibrosis and necrosis. This subtype may be associated with HIV infection and is most commonly diagnosed in the elderly and people from underdeveloped countries. Patients usually have advanced-stage disease, extranodal involvement, an aggressive clinical course, and a poor prognosis.
Precise definition of the extent of nodal and extranodal involvement with Hodgkin’s disease according to a standard staging classification system is critical for selection of the proper treatment strategy.
Staging system
The recently modified 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
In defining the disease stage, it is important to note how the information was obtained, since this 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, eg, by surgical staging laparotomy and splenectomy.
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.
Clinical staging evaluation
Disease-associated symptoms As mentioned above, disease-associated symptoms may occur in up to 40% of patients. These 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 choice. 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 is significant only if > 10% of body weight has been lost within the preceding 6 months. Although pruritus is no longer considered to be a B symptom, the presence of generalized itching is considered by many to be an adverse prognostic symptom.
Certain combinations of B symptoms are more prognostically significant than others. For example, the combination of fever and weight loss has a worse prognosis than night sweats alone.
Physical examination 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 should include a CBC with WBC differential and platelet count, an 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 The ESR 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 possible biopsy.
Alkaline phosphatase and LDH 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. A significantly elevated LDH has been associated with a poor prognosis in some studies.
Imaging studies Radiologic studies should include a chest x-ray and CT scan of the chest, abdomen, and pelvis with IV contrast. In most patients, a bipedal lymphogram and gallium radionuclide scan will provide important information and are highly recommended. Radionuclide bone scan, MRI of the chest or abdomen, and CT scan of the neck are contributory only under special circumstances.
Evaluation for supradiaphragmatic disease The thoracic CT scan details the status of 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 evaluation of pretreatment involvement and response to therapy is assisted by the use of a gallium scan.
The gallium scan may be a sensitive indicator of disease above the diaphragm, particularly when a dose of 10 mCi and a single-photon emission CT (SPECT) technique are employed. A negative follow-up gallium scan supports the supposition that there is no active disease after the completion of treatment even in the presence of a residual abnormality on the CT scan.
Evaluation of the abdomen and pelvis A CT scan and bipedal lymphogram are the basic imaging studies for evaluation of the abdomen and pelvis. The lymphogram detects abnormalities in the lymph nodes, based not only on lymph node size but also on internal architecture. The lymphogram is particularly accurate in evaluating the retroperitoneal and pelvic lymph nodes. The internal iliac, splenic hilar, porta hepatis, and mesenteric nodes are not opacified during lymphography and are best evaluated with a CT scan.
Bone marrow biopsy Bone marrow involvement is relatively uncommon, 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.
Staging laparotomy
Staging laparotomy is the most definitive method for detecting occult infradiaphragmatic Hodgkin’s disease. A major problem with all imaging techniques for Hodgkin’s disease is their inability to identify splenic involvement. In about 30% of patients with normal-sized spleens, Hodgkin’s disease is found in the resected spleen. Conversely, approximately 50% of patients with clinical or radiologic enlargement of the spleen do not have pathologic involvement at splenectomy.
Staging laparotomy includes splenectomy; sampling of the celiac, splenic hilar, porta hepatis, para-aortic, paracaval, and iliac nodes (with special attention given to areas that look suspicious on imaging studies); sampling of the liver with a wedge and/or needle biopsy under direct vision; and open iliac crest bone marrow biopsy, if such a biopsy was not performed previously. Areas of biopsy are marked with a clip, and an abdominal radiograph during laparotomy assists in verifying the removal of suspicious nodes shown by lymphography. Oophoropexy (ie, movement of the ovaries into a shielded area, typically behind the uterus) is also performed in females of reproductive age. Metallic clips marking the ovaries are used for identification and subsequent shielding during radiotherapy. An appendectomy may be included.
Complications The complications of staging laparotomy include the nonspecific risks of general anesthesia and abdominal surgery. Reviews of laparotomy series report the risk of major postoperative complications to be between 3% and 7%. Surgical mortality is rare (< 1%), and many large series report no operative deaths. Because of occasional severe bacterial infections occurring after splenectomy, pneumococcal vaccine (Pneumovax, Pnu-Imune) should be administered prior to staging laparotomy.
Patient selection Although staging laparotomy remains the most precise way to determine the presence and extent of infradiaphragmatic Hodgkin’s disease, it is not a routine staging procedure and should be considered only if the additional information may significantly alter the treatment choice. Thus, it is relevant only for patients who are potential candidates for radiotherapy alone and who, based on clinical parameters, have more than a 10% risk of infradiaphragmatic disease. Data from retrospective studies have indicated that the following subgroups have less than a 10% risk of abdominal involvement: females with clinical stage I disease, patients with involvement of the mediastinum alone, males with stage I lymphocyte-predominant histology, and young (< 27 years old) females with limited stage II disease. These patients may be treated with radiotherapy alone without a staging laparotomy.
Hodgkin’s disease is very 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 STAGES I-II Disease
Treatment options
Subtotal lymphoid irradiation (ie, treatment of the mantle and para-aortic fields only) remains the gold standard for the management of most patients with surgically confirmed early-stage Hodgkin’s disease (stages I-II). In patients who undergo pathologic staging (laparotomy) and are treated with primary irradiation alone, several large series report a 15- to 20-year survival rate of nearly 90% and relapse-free survival rate of 75%-80%. Most relapses (75%) occur within the first 3 years after the completion of therapy; very late relapses are uncommon. Importantly, more than half of patients who relapse after radiotherapy alone are still curable with standard chemotherapy.
The standard approach in many US centers has been to insist on pathologic staging of Hodgkin’s disease prior to recommending radiotherapy alone. However, Canadian and European studies have reported excellent overall survival results in patients selected for radiotherapy on the basis of clinical prognostic factors alone. Thus, radiation alone can be safely offered to clinically staged patients with favorable prognostic factors (see “Staging laparotomy” above).
When radiation is used as the sole therapeutic modality, the standard radiation field used in patients with early-stage disease who did not undergo a staging laparotomy is subtotal lymphoid irradiation. This is because clinically staged patients who were irradiated to a small field had a high relapse rate. Patients in whom laparotomy was negative may be treated safely with mantle-field irradiation alone. A different approach can be used for patients with lymphocytic-predominant histology, namely, less extensive irradiation without surgical staging.
Chemoradiation An alternative treatment approach used in patients with early-stage disease is combined treatment with irradiation and chemotherapy. Combined-modality therapy reduces the relapse rate but, in most studies, does not change the overall survival rate.
New strategies that combine shorter, less toxic chemotherapy regimens with radiation to clinically involved sites are currently under evaluation. A recent randomized study from Milan documented excellent results (rate of freedom from relapse, 94%) in patients with unfavorable stage I-II disease who were treated with only 4 cycles of ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) and involved-field radiotherapy.
Early-stage patients with bulky mediastinal disease, significant B symptoms, or clinically staged patients at high risk for subdiaphragmatic involvement (eg, mixed cellularity or lymphocyte-depletion histology, age > 40 years) attain better relapse-free survival rates with combined-modality therapy than with radiotherapy alone.
Combination chemotherapy In two recent prospective, randomized studies, radiotherapy alone was as effective as or superior to MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone) chemotherapy in improving the survival of early-stage patients. While the relapse rate after chemotherapy is similar to that after radiotherapy, conventional dose-salvage chemotherapy used after failure of chemotherapy have poor results; this translates into an inferior overall survival. Although other drug combinations, such as ABVD, may be more effective and less toxic than MOPP, they have not been tested alone in early-stage Hodgkin’s disease and should not be used outside of a controlled clinical trial.
Technical aspects of radiation therapy
Radiation fields
Successful therapy with radiation alone requires treatment of all clinically involved lymph nodes and all nodal and extranodal regions at risk for subclinical involvement. The Hodgkin’s disease radiation fields were designed to conform to the philosophy of treating regions beyond the immediately involved area, while accounting for normal tissue tolerance and the technical constraints of field size.
The mantle irradiation field extends from the base of the mandible to the diaphragm, covering the lymph node areas above the diaphragm, including the submandibular, cervical, supraclavicular, infraclavicular, axillary, mediastinal, and hilar nodal areas. Individually contoured Cerrobend blocks shield the lungs and cardiac apex. In addition, depending on anatomy and disease location, supplementary blocks are placed over the humeral heads, occiput, and mouth posteriorly and anteriorly. We also insert half-value layer blocks to shield the larynx anteriorly and the cervical cord posteriorly throughout the treatment course. If high cervical lymph nodes are involved (above the thyroid notch), the preauricular nodes are treated prophylactically to a dose of 3,000-3,600 cGy.
The para-aortic field includes all of the para-aortic lymph nodes between the aortic bifurcation and the bottom of the mantle field. This field is normally positioned to encompass the lateral transverse processes of the lumbar vertebrae, unless imaging or surgical data indicate more extensive disease. It is also designed to encompass the spleen and splenic hilar nodes. When the spleen has been removed, only the splenic pedicle is included. Attention should be paid to the location of the kidneys, as they may be partially included in the field, and proper shielding can decrease the renal volume that is irradiated. The inferior border of the para-aortic field is placed at the bottom of the L-4 vertebral body.
The pelvic field encompasses the iliac, inguinal, and femoral nodes. The superior border is at the level of L-5, matched, with an appropriate gap, to the bottom of the para-aortic field. A large, customized Cerrobend block shields the midline structures that are not at risk, including the bladder, rectum, and centrally transposed ovaries in women or testes in men. Iliac wing blocks are placed to spare the bone marrow.
The inverted-Y field combines the para-aortic and pelvic fields.
Total vs subtotal lymphoid irradiation The term “total lymphoid irradiation” refers to treatment of the mantle, para-aortic, and pelvic fields (Figure 2). “Subtotal lymphoid irradiation” denotes treatment of the mantle and para-aortic fields only (Figure 2). To avoid excessive toxicity, the radiation fields are treated sequentially, the total dose is fractionated, and the irradiated volumes are carefully tailored with individualized divergent blocks. When patients require separate treatment to adjacent regions, the calculation of field separation is particularly important to avoid overlap at the spinal cord.
Involved-field irradiation In a combined-modality setting, irradiation of the involved lymph node chain, with or without adjacent sites, and tailoring of the field borders to the post-chemotherapy tumor volume (in critical areas such as the mediastinum) are recommended.
Dose considerations
When radiation alone is used to treat Hodgkin’s disease, 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 540-900 cGy in 3-5 fractions to bring the total dose to these areas up to 4,140-4,500 cGy. Patients who receive radiation as consolidation after chemotherapy receive a total dose of 2,000-3,600 cGy in 150- to 180-cGy fractions. We use opposed anterior and posterior fields that are evenly weighted, and treat both fields daily.
Special clinical situations may require treatment of the entire cardiac silhouette to a dose of 1,500 cGy. When irradiation of the whole lung is considered, treatment with partial (37%) transmission blocks allows for concomitant low-dose irradiation of the lungs during full-dose mantle field irradiation.
When whole-liver irradiation is considered, use of a partial (50%) transmission liver block during para-aortic field irradiation keeps the dose below the radiation tolerance of the liver.
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 acute side effects of mantle field irradiation 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 chemotherapy, can cause myelosuppression, which may necessitate treatment delays.
Delayed effects Delayed side effects may develop anywhere from several weeks to several years after the completion of radiotherapy.
Lhermitte’s sign Approximately 15% of patients may note 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 mantle-field radiotherapy. Possibly secondary to transient demyelinization of the spinal cord, Lhermitte’s sign resolves spontaneously after a few months and is not associated with late or permanent spinal cord damage.
Pneumonitis and pericarditis During the same time period, radiation pneumonitis and/or acute pericarditis may occur in < 5% of patients; these side effects occur more often in those who have extensive mediastinal disease. Both inflammatory processes have become rare with modern radiation techniques.
Herpes zoster infection Patients with Hodgkin’s disease, 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 (Zovirax) will limit its duration and intensity.
Subclinical hypothyroidism Mantle field radiotherapy can induce subclinical hypothyroidism in about one-third of patients. This is detected by elevation of thyroid-stimulating hormone (TSH). Thyroid replacement with levothyroxine (T4) is recommended, even in asymptomatic patients, to prevent overt hypothyroidism and decrease the risk of benign thyroid nodules.
Infertility Irradiation of the pelvic field may have deleterious effects on fertility. In most patients, this 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 of the mantle and para-aortic fields alone does not increase the risk of sterility.
Secondary malignancies Hodgkin’s disease patients who were cured with radiotherapy and/or chemotherapy have an increased risk of secondary solid tumors (most commonly, lung, breast, and stomach cancers, as well as melanoma) and NHL, 10 or more years after treatment. Unlike MOPP and similar chemotherapy combinations, radiotherapy for Hodgkin’s disease is not leukemogenic.
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 has been detected mostly in smokers.
Breast cancer The increase in breast cancer risk is inversely related to the patient’s age at Hodgkin’s disease treatment; no increased risk has been found in women irradiated after 30 years of age. Breast cancer is curable in its early stages, and early detection has a significant impact on survival. Thus, breast examination should be part of the routine follow-up program for women cured of Hodgkin’s disease, and routine mammography should begin about 8 years after treatment.
Coronary artery disease An increased risk of coronary artery disease has recently been reported among patients who have received mediastinal irradiation. To reduce this hazard, patients should be monitored and advised about other established coronary disease risk factors, such as smoking, hyperlipidemia, hypertension, and poor dietary and exercise habits.
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’s disease are chemotherapy-based, and radiotherapy is limited to low doses.
Treatment of stages III-IV disease
Chemotherapy has become curative for many patients with advanced stages of Hodgkin’s disease. MOPP has been the primary effective combination chemotherapy regimen for advanced-stage disease since the 1960s. Over the last several years, ABVD has been shown to be more effective and less toxic than MOPP, particularly with respect to sterility and secondary leukemia.
Combination chemotherapy regimens
Doxorubicin-containing regimens A doxorubicin-containing regimen, such as ABVD or ABVD alternating with MOPP (Table 2), 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 ³ 85% of the expected chemotherapy dose, particularly in the ABVD group. In addition, rates of significant and life-threatening neutropenia were higher in patients treated with the MOPP-containing regimens.
| The German Hodgkin’s Lymphoma Study Group compared COPP/ABVD with standard- and escalated-dose regimens of BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin, and prednisone). All three regimens were combined with local irradiation. In a recently published interim analysis of this randomized trial, performed after the entry of 505 patients and a median follow-up of 23 months, the 24-month rate of freedom from treatment failure was significantly inferior for the COPP/ABVD arm, as compared with the pooled standard- and escalated-dose BEACOPP arms (75% vs 84%; P = .034). The progression rate also was significantly higher with COPP/ABVD (Diehl V, Franklin J, Hasenclever D, et al: J Clin Oncol 16:3810-3821, 1998). |
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’s disease. However, a recent intergroup study that compared ABVD to MOPP/ABV hybrid (without radiation) was closed early because of concerns of excess treatment-related deaths and second malignancies (mostly acute myelogenous leukemia and lung cancer) in the MOPP/ABV hybrid arm.
Shortened dose-intense regimens Recently, shortened dose-intense regimens have shown promise. For example, the 12-week Stanford V regimen (see Table 2) combined with involved-field irradiation produced a 3-year overall survival rate of 96% and a failure-free survival rate of 87%; these results were maintained at 5 years. Toxicity was increased in patients receiving this regimen; grade 4 neutropenia developed in 67% of patients.
Combined-modality therapy
Although the role of consolidation radiotherapy after induction chemotherapy remains controversial, radiation is routinely added in 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.
Interpretation of the impact of radiation in prospective studies has been controversial. However, a Southwest Oncology Group (SWOG) randomized study of 278 patients with stage III or IV Hodgkin’s disease suggested that the addition of low-dose radiation to all sites of initial disease after a complete response to MOP-BAP (mechlorethamine, Oncovin, prednisone, bleomycin, Adriamycin, and procarbazine) chemotherapy improves remission duration in patients with advanced-stage disease. An intention-to-treat analysis showed that the advantage of combined-modality therapy was limited to patients with nodular sclerosis. No survival differences were observed.
A recent meta-analysis demonstrated that the addition of radiotherapy to chemotherapy reduces the rate of relapse but did not show a survival benefit for the combined-modality approach (see box).
| A meta-analysis of 918 patients from seven randomized trials comparing combination chemotherapy alone vs the same combination chemotherapy plus radiation therapy showed that irradiation reduces the relapse hazard rate by nearly 40%. However, there was no survival difference between the two groups, due to an excess of deaths from causes other than Hodgkin’s disease in the patients who received combined-modality therapy. A second meta-analysis comparing adjuvant radiation therapy to programs with either more cycles of chemotherapy or additional chemotherapy combinations in 837 patients found no significant differences in disease-free survival between the randomized approaches. Overall survival was better (P = .045) in patients given chemotherapy alone. More deaths from causes other than Hodgkin’s disease, including leukemia, occurred in the combined-modality group. However, causes of death were available in only half of the patients (Loeffler M, Brosteanu O, Hasenclever D, et al: J Clin Oncol 16:818-829, 1998). |
LONG-term toxicities of combination chemotherapy
The CALGB trial and the intergroup trials mentioned above (see “Combination chemotherapy regimens”) noted differences in the long-term toxicities of different combination chemotherapeutic regimens (Table 3).
Myelodysplasia and acute leukemia MOPP therapy is known to be related to the development of the myelodysplastic syndrome (MDS) and acute leukemia. Gruenwald and Rosner found a predominance of acute myelogenous leukemia following therapy for Hodgkin’s disease, and only a small percentage of acute lymphocytic leukemias or unclassified leukemias. These secondary hematologic malignancies began 2 years following therapy and declined by 10 years, with the maximum risk between 5 and 9 years. Patients with these malignancies have a poor prognosis, with a median survival of 6 months when treated with standard antileukemic regimens.
The incidence of secondary leukemia appears to increase with cumulative doses of chemotherapy, age > 40 years when receiving chemotherapy for Hodgkin’s disease, 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 observed with increasing frequency after chemotherapy are mostly lung cancer or NHL. These malignancies have a longer latency period and usually are not observed until 15 years post-therapy.
Infertility is another long-term complication seen with combination chemotherapy. At least 80% of males are found to have permanent azoospermia or oligospermia following more than 3 cycles of MOPP chemotherapy; < 10% of men will have recovery of spermatogenesis within 1-7 years following the end of chemotherapy. The risk of infertility with ABVD is significantly lower, approximately 15%-25%. All men who desire childbearing potential following therapy should be counseled regarding sperm banking.
In females, there is a 50% rate of primary ovarian failure overall. The risk is 25%-30% in patients treated at age 25 or under, but increases to 80%-100% in women over age 25. Many women who do maintain ovarian function during chemotherapy will have premature menopause following therapy.
Pulmonary complications have been reported with ABVD and are related to bleomycin-induced lung toxicity. In a Memorial Sloan-Kettering Cancer Center study of 60 early-stage Hodgkin’s disease patients receiving ABVD with or without mediastinal irradiation, 53% reported dyspnea on exertion or cough during ABVD and 37% had a significant decline in pulmonary function. 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 carbon monoxide (DLCO). Radiotherapy following ABVD resulted in a further decrease in FVC but did not significantly affect functional status. At longer follow-up, only 1 of 60 patients reported persistent dyspnea with minimal exertion.
In the CALGB trial, there were 3 fatal pulmonary complications in 238 patients; all 3 patients were over 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 is a recognized complication of doxorubicin therapy but is not commonly seen in patients receiving ABVD. Patients who are treated with 6 cycles of ABVD 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’s disease who relapse after initial therapy with irradiation alone have excellent complete remission rates and 50%-80% long-term survival rates when treated with MOPP or ABVD. The dose regimens used for salvage therapy are the same as those outlined in Table 2.
Relapse after combination chemotherapy
Among patients with advanced-stage Hodgkin’s disease, 70%-90% will have complete responses 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 as poor prognostic factors for response to first-line chemotherapy: B symptoms, age > 45 years, bulky mediastinal disease, extranodal involvement, low hematocrit, high ESR, and high levels of CD30 and soluble interleukin-2 receptor. A new prognostic factors index for advanced-stage Hodgkin’s disease was recently published (see box). Once patients have relapsed, they are classified into three groups: those who achieve a complete response lasting > 12 months, those who relapse within 12 months, and those who never obtain a complete response to first-line chemotherapy.
A review of patients with relapsed Hodgkin’s disease treated with salvage combination chemotherapy at the National Cancer Institute (NCI) found that patients with a longer disease-free survival have a greater likelihood of obtaining a durable remission than those with a short or no response to initial therapy.
Patients with durable responses to initial therapy Patients who relapse after a long disease-free interval have a 79% complete response rate to standard salvage chemotherapeutic regimens, half of which are durable remissions. These patients may benefit from high-dose chemotherapy salvage programs, although standard-dose salvage therapy is also a reasonable approach.
Patients with no or short response to initial therapy The choice of chemotherapeutic regimens for patients who never achieve a response or who relapse within 1 year is more difficult. It is unlikely that these patients will attain a lasting response to standard-dose chemotherapy. They should be offered high-dose chemotherapy, with or without radiotherapy, followed by hematopoietic cell support.
Two randomized studies (from Great Britain and Germany) demonstrated an event-free survival advantage with the high-dose therapy approach. While a significant survival advantage was not observed due to the crossover design of the studies, most patients with refractory disease or post-chemotherapy relapse are currently managed with high-dose chemoradiation and peripheral blood progenitor-cell transplantation (PBPCT).
Recently, Hasenclever and Diehl published a prognostic model of advanced Hodgkin’s disease 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 gender, stage IV, age ³ 45 years, WBCs ³ 15,000/mm³, and lymphocytes < 600/mm³, or < 8% of the WBC count. The worst prognostic group (7%) with five or more factors had a 5-year overall survival rate of 56% and a failure-free survival rate of 42% (Hasenclever D, Diehl V: N Engl J Med 339:1506-1514, 1998). Biological factors have also been correlated with prognosis. Serum levels of interleukin-10 (IL-10), an immunosuppressive and antiapoptotic cytokine, have been associated with a shortened failure-free survival in both univariate and multivariate analyses of a series of untreated patient with Hodgkin’s disease (Sarris AH, Kliche K-O, Pethambaram P, et al: Ann Oncol 10:433-440, 1999). |
Salvage radiotherapy Relapse usually occurs in previous sites of disease, and selected patients initially treated with chemotherapy can also be treated with salvage radiotherapy.
High-dose chemotherapy with hematopoietic support The most effective treatment for patients who do not respond to standard-dose chemotherapy is high-dose chemotherapy, with or without radiation therapy, followed by hematopoietic reconstitution with bone marrow transplantation (BMT) or PBPCT. No standard conditioning regimen has been used in this setting, as patients have had prior treatment with a variety of combinations of chemotherapy and radiation therapy. Although most patients who have received bone marrow have been treated with several regimens or have had poorly responsive disease from initial diagnosis, the complete response rate has ranged from 50% to 80%, with approximately 40%-80% of responding patients achieving durable remissions.
Recent analysis of prognostic factors in patients receiving high-dose salvage therapy indicated that B symptoms at relapse, extranodal disease, and more than minimal disease at transplantation are factors associated with a poor outcome. Patients with these poor-prognosis factors may require more than one intensive course of therapy, but only scanty information is available on this strategy.
Allogeneic BMT does not offer a survival advantage over autologous stem-cell transplantation in Hodgkin’s disease. The safety of high-dose therapy programs for Hodgkin’s disease has improved over the last decade; most major transplant centers report < 5% mortality in recent series.