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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 129Hodgkin’s Disease

, MD and , MD.

History

The life and accomplishments of Thomas Hodgkin have been detailed in an excellent biography of this distinguished physician and scientist.1,2 Briefly, in his historic paper entitled “On Some Morbid Appearances of the Exorbant Glands and Spleen,” presented to the Medical Chirurgical Society in London on January 10, 1832, Thomas Hodgkin described the clinical history and postmortem findings of the massive enlargement of lymph nodes and spleens of six patients studied at Guy’s Hospital in London and of a seventh patient who had been seen by Carswell in 1828.3 Hodgkin recognized that these patients had suffered from a disease that started in the lymph nodes located along the major vessels in the neck, chest, or abdomen.

Hodgkin began his work at Guy’s Hospital in London in 1825 after graduating from Edinburgh Medical School in Scotland. At Guy’s, he assembled and catalogued anatomic specimens relevant to specific diseases that led to his discovery in 1832. Although Hodgkin is best known for his study of malignancy and the abnormalities of the spleen and lymph nodes, he also contributed to the study of heart disease, promoted the use of the microscope, and advocated reforms in medical education and public health. Despite these achievements, Hodgkin was passed over for a teaching position and left Guy’s Hospital in 1837, ending his academic career.1,4 For the remainder of his life, he increasingly devoted himself to the plight of the native populations of colonial countries and their treatment by Western civilization.

It was not until 1865, a year before his death, that Hodgkin was credited with his discovery. This occurred due to the work of two physicians at Guy’s Hospital. Dr. Richard Bright, an expert on kidney disease, had written a paper on abdominal tumors in 1838.5 This included the history and postmortem findings of Hodgkin’s cases 1 and 2, specifically citing his original discovery. Independently in 1856, Sir Samuel Wilks, a Guy’s Hospital pathologist, described 10 postmortem cases that had “a peculiar enlargement of the lymphatic glands frequently associated with disease of the spleen.” Unknown to him, his report included Hodgkin’s original cases 1, 2, 3, and 4, which had been preserved in the Gordon Museum at Guy’s Hospital. By the time Wilks completed his work, he had come across Bright’s reference to Hodgkin’s original cases, and he credited Hodgkin with the initial discovery. By 1865, Dr. Wilks had collected 15 cases that were published in a second paper entitled “Cases of the Enlargement of the Lymphatic Glands and Spleen (or Hodgkin’s Disease) with Remarks.”6 This linked Hodgkin’s name permanently to this newly identified disease.

Wilks was one of the first physicians to use the microscope to study Hodgkin’s disease. Although he and other physicians noted the characteristic giant cells present in the lymph nodes and spleens of patients with Hodgkin’s disease, Dr. WS. Greenfield in 1878 was the first to contribute drawings of them from a low microscopic magnification of a lymph node specimen.7 Despite Greenfield’s findings, Dr. Carl Sternberg in 1898 and Dr. Dorothy Reed in 1902 are credited with the first definitive microscopic descriptions of Hodgkin’s disease.8,9

Both Sternberg and Reed, along with many other physicians, believed that Hodgkin’s disease was caused by an associated infection rather than by a separate malignant process of the lymph nodes. Eight of Sternberg’s 13 cases of Hodgkin’s disease had coexistent tuberculosis, and he believed Hodgkin’s disease to be a variant of tuberculosis. Reed and others refuted this. They felt that Hodgkin’s disease was an independent illness with which tuberculosis might sometimes be associated. Still, Reed considered Hodgkin’s disease to be an inflammatory illness rather than a malignancy. Other physicians believed that Hodgkin’s disease was a cancer of the lymph nodes. Clinical and pathologic studies, available in the early twentieth century, helped to confirm their view.10–12

Radiation Therapy

The early treatment of Hodgkin’s disease with crude x-rays in 1901 soon followed the discovery of x-rays by Roentgen, radioactivity by Becquerel, and radium by the Curies at the end of the nineteenth century. Prior to this time, serum and other biologic preparations, arsenic, iodine, and surgery, all used in the treatment of Hodgkin’s disease, resulted in poor outcomes. The first reports of x-ray treatments that would dramatically shrink enlarged lymph nodes produced great excitement and premature predictions for the curability of Hodgkin’s disease.13,14

During the first 2 decades of the twentieth century, physicians used two methods to treat Hodgkin’s disease with radiation. Small doses of radiation were administered to the entire trunk at weekly intervals for many weeks, or a single massive dose was given just to the tumor. Neither strategy controlled Hodgkin’s disease and both caused severe side effects.10 Both techniques shrank enlarged nodes, but recurrence and spread to previously uninvolved nodes invariably followed. After several “successful” courses of radiotherapy (RT), Hodgkin’s disease became more resistant to treatment, and all patients died from it. These multiple recurrences were not attributed to poor RT techniques, but were viewed as inherent to the disease itself.15 By 1920, most physicians stopped using radiation as a means of curing Hodgkin’s disease; for the next 40 years, treatment was mainly palliative: to shrink large nodes that were painful or interfered with movement, eating, or breathing.

The development of modern RT techniques for the treatment of Hodgkin’s disease began in the 1920s with the work of Gilbert, a Swiss radiotherapist.16 One of the first physicians to point out certain clinical patterns in the behavior of Hodgkin’s disease, Gilbert attempted to adapt his RT techniques to these patterns. He began to advocate treatment of apparently uninvolved adjacent lymph node chains that might contain suspected microscopic disease, as well as of the evident sites of lymph node involvement.17

Peters also adapted this technique at the Princess Margaret Hospital in the late 1930s and early 1940s. In her historic paper published in the American Journal of Roentgenology in 1950, Peters provided evidence that patients with limited Hodgkin’s disease could be cured with aggressive RT that treated involved nodal disease and adjacent nodal sites.18 She reported 5- and 10-year survival rates of 88 and 79%, respectively, for patients with stage I Hodgkin’s disease, rates that were notably high for a disease in which virtually no one survived 10 years. Despite these results, the concept that early-stage Hodgkin’s disease might be curable with RT was slow to be accepted. Prior to the 1960s most patients with limited Hodgkin’s disease were not treated at all, or only with small doses of radiation.

No one deserves greater credit than Henry Kaplan for the development of successful modern treatment for Hodgkin’s disease. His accomplishments are many. He pioneered work on the development of the linear accelerator,19,20 defined radiation field sizes and doses for a curative approach for early Hodgkin’s disease,20,21 refined and improved diagnostic staging techniques, developed models for translating laboratory findings into clinical practice, and promoted early randomized clinical trials in the United States. In 1972 and 1980, he published two definitive works on Hodgkin’s disease.10,22

The development of the linear accelerator that allowed for the use of higher doses and larger radiation fields,19,20,23 the proposal of new classification systems for histologic subtyping24 and staging, the pioneering of methods for more precise radiographic and surgical staging (bipedal lymphangiography [LAG] and staging laparotomy),25 and the development of an effective multiagent chemotherapy regimen26 all contributed to the development of curative treatment for early-stage Hodgkin’s disease. From these advances, the philosophy and practice of managing early-stage Hodgkin’s disease changed dramatically by the late 1960s. Early-stage patients who 10 years earlier would not have been treated now received extensive staging and RT with wide-fields and high doses, resulting in a cure of a high proportion of patients.

Chemotherapy

The history of the development of cytotoxic agents dates to the early part of the twentieth century.27 By the early 1960s, a number of individual chemotherapeutic agents were known to produce regression of lymph nodes and symptomatic improvement of patients with Hodgkin’s disease. These agents included the alkylating agent anthracycline, vinblastine, vincristine, and nitrogen mustard.28,29 The treatment of Hodgkin’s disease with multiple chemotherapeutic agents was developed from sequential studies defining curative treatment for acute lymphoblastic leukemia in children.30,31 These studies were designed to find combinations of agents, each of which had similar antitumor activity but different normal tissue effects, so that full doses could be given with more than one agent without significantly increasing toxicity.32 In 1963, a pilot study was initiated to test the feasibility of using a combination of chemotherapeutic agents, cyclophosphamide, vincristine, methotrexate, and prednisone, followed by RT for the treatment of Hodgkin’s disease.33

The first reports of the use of multiple drug combinations for acute leukemia and Hodgkin’s disease demonstrated high complete remission rates, rapid tumor regression, and durability with short-term follow-up. By the early 1970s, data were available on nearly 200 patients with stage III and IV Hodgkin’s disease treated with MOPP chemotherapy, a regimen that substituted nitrogen mustard for cyclophosphamide and procarbazine for methotrexate in the original regimen reported by Moxley et al.33 Nearly 50% of patients who achieved a complete remission remained in remission more than 2 years after treatment. Recurrences were seen primarily in sites of initial nodal involvement.34

Meanwhile, many investigators began to design and test new chemotherapeutic regimens to be delivered first in MOPP-resistant patients and then to substitute or complement the four drugs used in the MOPP regimen. The ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) program developed by Gianni Bonadonna in Milan, Italy, was the first and most effective.35 Over the past 20 years, this regimen has gradually replaced the MOPP regimen as the most commonly used chemotherapeutic regimen for advanced-stage Hodgkin’s disease. It is being used increasingly in early-stage disease as well. In head-to-head trials, it has been found to be superior to MOPP in advanced-stage disease.36 Although the regimen carries some risk of cardiac and pulmonary toxicity, it is not associated with leukemogenesis or sterility, the two major complications associated with MOPP.

Epidemiology and Etiology

There are approximately 7,400 new cases of Hodgkin’s disease diagnosed each year in the United States. The incidence has been stable over the last 2 decades. Slightly more men than women develop this malignancy (1.4:1). In economically developed countries, there is an age-related bimodal incidence for Hodgkin’s disease. The first peak occurs in the third decade of life with a second rise in incidence occurring after the age of 50.37–39

The incidence of Hodgkin’s disease by age differs by histologic subtype. Lymphocyte-predominant and mixed cellularity disease are more common in patients 40 years of age or older; the nodular sclerosis subtype occurs more frequently in patients between 16 and 39 years of age.40 Lymphocyte-predominant histology is more frequently seen under the age of 16 and has a high male to female predominance (4:1) compared to the other subtypes. The epidemiologic significance of the age- and gender-related differences remain unknown.

Several different theories have been proposed for the epidemiology and etiology of Hodgkin’s disease. Historically, Mycobacterium tuberculosis was first suspected to be the etiologic organism for Hodgkin’s disease because of the high coexistence of tuberculosis.8,41–43 Later, it was appreciated that Hodgkin’s disease was associated with deficits in the immune system, making the presence of associated infections more likely.10 Several studies in the 1970s suggested that Hodgkin’s disease might be contagious because of reports of clustering of the disease. The first reports, by Vianna et al., noted clustering among high school students exposed to Hodgkin’s disease.44,45 However, population-based studies, using cancer registries in Connecticut and California, convincingly made the argument that the reported clusters occurred by chance alone. A study that repeated the methodology of Vianna and coworkers in a different location failed to confirm their findings.46,47

A number of studies have suggested that, under certain circumstances, there is a genetic predisposition for Hodgkin’s disease. There is an increased incidence in Jews and among first-degree relatives. Siblings appear to have a 2 to 5-fold increased risk; in siblings of the same sex, there is as much as a nine-fold increased risk.48–51 An even higher risk has been reported in monozygotic twins of Hodgkin’s disease cases.52 There is an increased risk among parent-child pairs but not among spouses, again suggesting a genetic rather than an infectious etiology. In addition, Hodgkin’s disease has been linked with certain human leukocyte antigens (HLA).53–56

There is less support for other proposed causes of Hodgkin’s disease. Although there have been scattered reports of the association of Hodgkin’s disease with environmental exposure to toxic agents, the data have not been confirmed in case-control studies. It has been suggested that Hodgkin’s disease might be due to an altered immune response (especially as patients with Hodgkin’s disease have altered immunity). Although there are theories that this might occur on the biologic level, there is no clinical evidence that Hodgkin’s disease is an illness of chronic immune suppression. In contrast to other malignancies, Hodgkin’s disease is rarely seen as a second malignancy and does not appear to be increased in patients with illness- or treatment-related chronic immunosuppression.

There is increasing evidence to suggest a viral etiology for Hodgkin’s disease. In economically developed countries, there is an association between Hodgkin’s disease in younger patients (especially those of age 15–39 years) and increased maternal education, decreased numbers of siblings and playmates, early birth order, and single-family dwellings in childhood.57–59 This association between Hodgkin’s disease and childhood factors that decrease exposure to infectious agents at an early age has led to the proposal that Hodgkin’s disease appears to mimic a viral illness that has an age-related host response to infection (such as seen with polio and infectious mononucleosis). Under this circumstance, a viral infection that would be mild in young children but more persistent and severe in young adults, perhaps with prolonged immunogenic stimulation, would trigger development of Hodgkin’s disease.57–59 Supporting this theory is the infrequent occurrence of Hodgkin’s disease in children under 10 years old in economically developed countries.

Epstein-Barr virus (EBV) is a leading candidate as the causative agent for Hodgkin’s disease.60–62 EBV is the causative agent in African Burkitt’s lymphoma, and EBV-associated lymphomas are documented in patients with immunodeficiency disorders and following organ transplantation. There is a 2- to 3-fold excess in the incidence of Hodgkin’s disease among patients with a prior history of mononucleosis, a disease caused by EBV. In addition, there appears to be an altered antibody pattern to EBV in patients prior to clinically presenting with Hodgkin’s disease with elevated titers against the viral capsid antigen and against the EBV nuclear antigen (EBNA).63 This suggests that these patients may have had more severe initial EBV infections or more frequent viral replication associated with the development of Hodgkin’s disease.

Recent cellular and molecular biology data have provided additional support for the association of EBV and Hodgkin’s disease (reviews64,65). Through the use of sensitive molecular probes, 30 to 50% of Hodgkin’s disease specimens have been found to contain EBV genome fragments in the diagnostic Reed-Sternberg cells.66–70 EBV genome status appears to be stable over time when studied in initial biopsies and at relapse.71 EBV genome-positive Reed-Sternberg cells express the phenotype latent membrane protein (LMP)+/EBNA2-, which is found in EBV genome-positive nasopharyngeal carcinoma and in a small portion of T-cell non-Hodgkin’s lymphomas. The latent gene products, LMP and EBNA 2, have important roles in EBV-induced cell transformation in vitro.

Despite these compelling data, direct evidence for EBV as a causative agent for development of Hodgkin’s disease remains to be determined. The lack of an animal model and the difficulties in studying the malignant cells in Hodgkin’s disease continues to frustrate investigators. Additional epidemiologic, serologic, and molecular data are needed to determine the role of EBV in Hodgkin’s disease.

Pathology

Histopathology

Hodgkin’s disease is unique among lymphomas for its histologic diversity. Involved lymph nodes contain varying degrees of normal reactive and inflammatory cells, fibrosis, and a scattering of the characteristic malignant cells of Hodgkin’s disease, the Reed-Sternberg cells, and their mononuclear variants. The typical Reed-Sternberg cell has abundant cytoplasm, and two or three nuclei, each with a single prominent nucleolus. The large size and unusual appearance of the Reed-Sternberg cell sets it apart from the adjacent smaller background cells. The mononuclear variants have nuclear and cytoplasmic features of Reed-Sternberg cells but only have a single nucleus, and by themselves are not pathognomonic of Hodgkin’s disease. Although the diagnosis of Hodgkin’s disease should rarely be made in the absence of Reed-Sternberg cells, the presence of these cells is not sufficient alone to make the diagnosis. Reed-Sternberg-like cells have been found in infectious mononucleosis, non-Hodgkin’s lymphomas, and in nonlymphoid malignancies including carcinomas and sarcomas.73 Thus, criteria for the diagnosis of Hodgkin’s disease includes both the presence of the Reed-Sternberg cell and the characteristic background of normal lymphocytes, plasma cells, and eosinophils.

In the early twentieth century, physicians began to describe different cellular patterns of Hodgkin’s disease and suggest microscopic classifications. But it was not until 1944 that the division of Hodgkin’s disease, as proposed by Jackson and Parker, into the three subcategories of paragranuloma, granuloma, and sarcoma gained wide acceptance.74 This classification was not challenged for 20 years, despite its limited clinical utility, perhaps because of the lack of effective treatment. The Jackson-Parker classification identified 10% of patients with the most favorable and 10% with the least favorable prognoses as paragranuloma and sarcoma, respectively; the remaining 80% of patients had the granuloma subtype. An alternative classification, devised by Lukes and Butler, was proposed for international adoption at a conference entitled “Obstacles to the Control of Hodgkin’s Disease” held in Rye, New York, in September 1965. Their proposal contained six histologic subtypes. Later, this was simplified to four subtypes. The classification appeared to correlate well with clinical stage and aggressiveness of disease24 and, as a result, rapidly replaced the Jackson and Parker classification. Most of the Rye classification has been included as part of the newer Revised European American Lymphoma (R.E.A.L.) and World Health Organization classifications. The R.E.A.L. classification proposed modest changes in the histopathologic classification of Hodgkin’s disease.75 These changes mainly reflect the distinct entity of nodular lymphocyte predominance Hodgkin’s disease (NLPHD) and the new classification of lymphocyte-rich classic Hodgkin’s disease. The new system includes (1) classic Hodgkin’s disease: nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich classic Hodgkin’s disease (predominance of lymphocytes but Reed-Sternberg cell morphology and immunophenotype of classic Hodgkin’s disease); (2) NLPHD; and (3) Hodgkin’s disease unclassifiable.

Although the subtypes proposed in the Rye classification initially correlated with aggressiveness of disease, with modern treatment, subtyping of Hodgkin’s disease has become less important in guiding clinical management, prognosis, and therapy. Nevertheless, the histologic subtypes of Hodgkin’s disease are associated with different sites of presentation, distinct natural histories, and variable prognoses. These differences are most evident in the nodular lymphocyte predominance subtype.

Classic Hodgkin’s Disease

(For a more detailed review, see Weiss et al.73) Mixed cellularity Hodgkin’s disease (MCHD) has an inflammatory background abundant in normal cells as well as frequent malignant Reed-Sternberg cells and their mononuclear variants with 5 to 15 malignant cells per high-power field (Fig. 129.3). Lymphocytes, plasma cells, eosinophils, and histiocytes are frequent. Patients with mixed cellularity histology are older, are more likely to have symptoms of fever, sweats, or weight loss, and often have abdominal involvement or advanced disease. Approximately 25% of patients with Hodgkin’s disease in the United States present with MCHD. The subtype is more commonly seen in underdeveloped countries. Because of the background cellular pattern, MCHD can be confused with peripheral T-cell lymphoma. Immune markers may help distinguish the two entities.

Figure 129.3. Reed-Sternberg (R-S) cells and variants in Hodgkin’s disease of nodular sclerosis type.

Figure 129.3

Reed-Sternberg (R-S) cells and variants in Hodgkin’s disease of nodular sclerosis type. Large multinucleated or multilobated cells and a few mononuclear cells with macronucleoli stand apart from cellular background elements.

The diagnosis of lymphocyte-depleted Hodgkin’s disease (LDHD) is rarely made today and accounts for less than 1% of Hodgkin’s disease in economically advanced countries. Generally, patients with LDHD present with advanced disease. With advances in immunohistochemistry, some patients with a prior diagnosis of LDHD would now be classified as having non-Hodgkin’s lymphoma.76 In LDHD, Reed-Sternberg cells and “pleomorphic” variant cells are more frequently seen in comparison to normal lymphocytes. Most cases have only sparse numbers of normal lymphocytes. The original Lukes and Butler classification described two subtypes of LDHD: the reticular and diffuse fibrosis forms. The reticular subtype contains sheets of pleomorphic neoplastic cells and without immunohistochemistry may be difficult to distinguish from a high-grade non-Hodgkin’s lymphoma. The diffuse fibrosis subtype is more common and contains a pattern of diffuse fibroblastic proliferation.

Nodular sclerosis Hodgkin’s disease (NSHD) is morphologically and clinically distinct from the other subtypes. Two histologic features differentiate this form of Hodgkin’s disease from all others: (1) a proliferation of collagenous bands divide the lymph node into circumscribed nodules and (2) these nodules contain a variant of the Reed-Sternberg cell called the lacunar cell.77,78 In formalin-fixed tissue, this cell’s abundant pale cytoplasm often retracts and gives the appearance of a cell in space (Figs. 129.4,129.5,129.6). Nodular sclerosis is the only subtype of Hodgkin’s disease as common in women as in men. It occurs in adolescents and young adults and is unusual in patients over 50. It has a striking propensity to involve lower cervical, supraclavicular, and mediastinal lymph nodes and has an orderly pattern of spread.40 It makes up 60 to 70% of Hodgkin’s disease in economically developed countries, but is less commonly seen in underdeveloped countries. Patients with this histology, particularly those with localized disease, have a good prognosis.

Figure 129.4. Hodgkin’s disease, mixed cellularity type.

Figure 129.4

Hodgkin’s disease, mixed cellularity type. R-S cells in histiocyte-rich cellular background. Insert: multinucleated R-S cell at higher magnification.

Figure 129.5. Immunostain for EBV-LMP in Hodgkin’s disease, mixed cellularity type (same biopsy as figure 129.

Figure 129.5

Immunostain for EBV-LMP in Hodgkin’s disease, mixed cellularity type (same biopsy as figure 129.4).

Figure 129.6. Hodgkin’s disease, nodular sclerosis.

Figure 129.6

Hodgkin’s disease, nodular sclerosis. A fibrous band is present in the left lower part of the field. Neoplastic lacunar cells having abundant, clear cytoplasm stand out against the lymphocytic background.

The British National Lymphoma Investigation subclassified NSHD into two subtypes, NS I and NS II, based on the number of Reed-Sternberg cells and variants, the degree of atypia, and the quality and quantity of fibrosis (Figs. 129.7,129.8).79–82 In the British National Lymphoma Investigation study, patients with NS I histology had a better prognosis than NS II.82 Using identical histologic criteria, the adverse prognosis of NS II histology has been supported by some studies83–85 but not by others.86,87 The potential importance of this designation remains controversial.

Figure 129.7. Immunostain for CD15 in Hodgkin’s disease, nodular sclerosis type.

Figure 129.7

Immunostain for CD15 in Hodgkin’s disease, nodular sclerosis type. Neoplastic R-S cells and mononuclear Hodgkin’s cells show positive immunoreactivity.

Figure 129.8. Hodgkin’s disease, nodular sclerosis, BNLI grade 2.

Figure 129.8

Hodgkin’s disease, nodular sclerosis, BNLI grade 2. Sheets of neoplastic large cells (middle of field), some with R-S cell morphology, border on a focal area of necrosis (lower right of field).

Lymphocyte-rich classic Hodgkin’s disease, nodular or diffuse, is a new classification proposed by the R.E.A.L. classification in 1994. Several recent reports have described the histopathologic and clinical characteristics of NLPHD and lymphocyte-rich classic Hodgkin’s disease.88–90 Lymphocyte-rich classic Hodgkin’s disease may resemble either mixed cellularity, nodular sclerosis, or NLPHD and may be nodular or diffuse. Many cases resemble MCHD with a diffuse or vaguely nodular appearance on low magnification. Reed-Sternberg cells are relatively rare and the background is dominated by small mature lymphocytes (Figs. 129.9,129.10). Eosinophils and neutrophils are usually restricted to blood vessels. Some cases of lymphocyte-rich classic Hodgkin’s disease may show a distinctly nodular appearance that may closely mimic NLPHD. The nodules of lymphocyte-rich classic Hodgkin’s disease often contain small reactive germinal centers, with Hodgkin and Reed-Sternberg cells present in and near the mantle zones, a pattern that has been called follicular Hodgkin’s disease.91

Figure 129.9. Hodgkin’s disease, nodular sclerosis, BNLI grade 2 (same biopsy as figure 129.

Figure 129.9

Hodgkin’s disease, nodular sclerosis, BNLI grade 2 (same biopsy as figure 129.8). Neoplastic large cells show diffusely positive immunoreactivity for CD30, positive immunoreactivity for CD15 (insert) and variable immunoreactivity for CD20 (not shown). (more...)

Figure 129.10. Lymphocyte-rich classic Hodgkin’s disease.

Figure 129.10

Lymphocyte-rich classic Hodgkin’s disease. R-S cells and mononuclear Hodgkin’s cells are relatively rare within the background proliferation of small lymphocytes and histiocytes.

The immunophenotype of the neoplastic cells in lymphocyte-rich classic Hodgkin’s disease is identical to that of classic Hodgkin’s disease, that is, CD15+ and CD30+, whereas those of NLPHD are CD20 positive and lack CD15 and CD30. There are, however, differences in the background cells, as many cases of lymphocyte-rich classic Hodgkin’s disease present with a B-cell-rich infiltrate, in contrast to the marked T-cell predominance usually found in other types of classic Hodgkin’s disease. This immunohistochemical staining pattern of lymphocytes and follicular dendritic cells of lymphocyte-rich classic Hodgkin’s disease is similar to that of NLPHD: the nodules are composed predominantly of B cells with nodular meshworks of follicular dendritic cells.

In NLPHD, the lymph node architecture is usually effaced, although a remnant of normal nodal architecture may remain. NLPHD contains an abundance of benign-appearing cells. Malignant Reed-Sternberg cells are scarce, but variant lymphocytic and histiocytic (L and H) cells are more frequent (Figs. 129.11,129.12). These cells often have multilobated nuclei and have been called popcorn cells because of their resemblance to a popped kernel of corn. Fibrosis is not usually seen. In the nodular subtype of NLPHD, the L and H or “popcorn” variants of Reed-Sternberg cells occur in background of polyclonal B lymphocytes.88,92 (Fig. 129.13) L and H cells are usually positive for a B-cell marker (CD20) but negative for Leu-M1 (CD15) and negative or weakly positive for CD30.93–96 (Figs. 129.14and129.15) Classic Reed-Sternberg cells contain polytypic immunoglobulin, and EBV is rarely detected in the nodular LP subtype.97,98

Figure 129.11. Lymphocyte-rich classic Hodgkin’s disease (same biopsy as figure 129.

Figure 129.11

Lymphocyte-rich classic Hodgkin’s disease (same biopsy as figure 129.10). Binucleated R-S cell in center of field. In same biopsy, R-S cells immunostained positively for CD15 (insert).

Figure 129.12. Lymphocyte predominant Hodgkin’s disease.

Figure 129.12

Lymphocyte predominant Hodgkin’s disease. The vaguely nodular histologic pattern is apparent.

Figure 129.13. Lymphocyte predominant Hodgkin’s disease at higher magnification (same biopsy as figure 129.

Figure 129.13

Lymphocyte predominant Hodgkin’s disease at higher magnification (same biopsy as figure 129.12). Within the background of lymphocytes and histiocytes are scattered large lobated cells having a fine chromatin pattern, relatively small nucleoli, (more...)

Figure 129.14. Lymphocyte predominant Hodgkin’s disease (same biopsy as figures 129.

Figure 129.14

Lymphocyte predominant Hodgkin’s disease (same biopsy as figures 129.12 and 13). Immunostain for CD20 demonstrates positive staining of L and H cells as well as a high percentage of lymphocytes within a nodule.

Figure 129.15. Lymphocyte predominant Hodgkin’s disease (same biopsy as figures 129.

Figure 129.15

Lymphocyte predominant Hodgkin’s disease (same biopsy as figures 129.12, 13, and 14). Immunostain for CD57 reveals a marked increase in immunoreactive cells showing localization around non-immunoreactive L and H cells within a nodule. The CD3 (more...)

Progressive transformation of germinal centers often is associated with NLPHD. The architecture of nodes undergoing progressive transformation of germinal centers is altered by large nodules that contain dispersed follicular center cells in clusters. Reed-Sternberg cells and L and H variants are absent. Patients with NLPHD often have a history of previously enlarged nodes, which, when biopsied, demonstrate progressive transformation of germinal centers. Progressive transformation of germinal centers also can be seen in association with NLPHD in the same lymph node specimen or follow it in other sites.93 It is important to distinguish NLPHD from progressive transformation of germinal centers, which is a benign disorder.93 However, the diagnosis of progressive transformation of germinal centers should alert the clinician to the possible presence or development of NLPHD.

NLPHD makes up 5 to 10% of Hodgkin’s disease in the United States. It often presents with a long natural history and has the longest time to recurrence of any of the subtypes of Hodgkin’s disease. Death from this subtype of Hodgkin’s disease is rare. NLPHD has distinct patterns of presentation compared to the other subtypes. It occurs more often in males (3:1 to 4:1) and in patients under 15 or over 40 years of age.40 It is often localized to a single peripheral nodal region (high cervical, submandibular, epitrochlear, or inguinal or femoral nodes) and infrequently involves (8%) mediastinal or abdominal nodes. In contrast, NSHD occurs almost equally in males and females, has its peak incidence between the ages of 15 and 40 years of age, and almost always involves central nodal regions.40 NLPHD is distinctive, clinically and histologically, from other subtypes of Hodgkin’s disease; it should be reported separately in clinical studies.

Sometimes, Hodgkin’s disease morphologically resembles certain large-cell non-Hodgkin’s lymphomas including anaplastic large-cell lymphoma, T-cell lymphoma, and large-cell lymphoma with sclerosis. Immunohistochemical markers can aid in distinguishing between these entities; however, in some cases, such differentiation remains difficult. The study of patients with composite lymphomas may eventually help in understanding potential histologic and molecular biologic differences between these difficult to classify lymphomas and more classic Hodgkin’s disease and non-Hodgkin’s lymphoma (see Jaffe and Mueller-Hermelink99).

Nature of the Reed-Sternberg Cell

Surface Antigens

Despite vastly improved laboratory techniques, the origin of the neoplastic cell in classic Hodgkin’s disease remains controversial.100 Theories have included derivation from B lymphocytic, macrophage-reticulum cell, follicular center dendritic cell, or histiocytic lineages. However, more recent evidence suggests a lymphocyte origin for the Hodgkin and Reed-Sternberg cells. Reed-Sternberg cells of classic Hodgkin’s disease usually express antigens found on resting or activated lymphocytes including B-cell (CD19, CD20, CD22, CD79a) and T-cell surface (CD3, CD4, CD8, T-cell receptor B chain) antigens, although some Reed-Sternberg cells express neither phenotype. However, overall, the antigen profile of the Hodgkin and Reed-Sternberg cells suggests a derivation from activated lymphoid cells of B-cell type and T-cell type. The L and H cells of NLPHD consistently carry B-cell antigens, suggesting their derivation from B cells.

Both CD15 and CD30 antigens are on the surface of most Reed-Sternberg cells. The CD15 antigen is found on Reed-Sternberg cells and their mononuclear counterparts and can be detected in paraffin-embedded sections. Nearly all patients with MCHD and 80 to 90% patients with NSHD are CD15 positive. In contrast, the Reed-Sternberg cells in NLPHD rarely stain for CD15.100–103 The Reed-Sternberg cells of LP Hodgkin’s disease are CD15- and CD45+ (leukocyte common antigen). The Reed-Sternberg cells in MC and NS Hodgkin’s disease are CD15+ and CD45-. Anti-CD15 antibodies, such as Leu-M1, also react with normal granulocytes, various epithelial cells, and a subset of B and T cells following activation or transformation by EBV. The CD15 antigen also has been found on Reed-Sternberg-like dysplastic follicular dendritic reticulum cells of patients with Castleman’s disease, a disorder of follicular centers characterized by hyperplasia of the follicular dendritic reticulum cell. A monoclonal antibody, Ki-1 (CD30), prepared against Hodgkin’s-derived cell lines also reacts with Hodgkin’s cells in frozen sections of involved nodes. However, similar to CD15, this antigen is not specific for Hodgkin’s disease or the Reed-Sternberg cell. It is expressed on some activated T cells, B cells, EBV-transformed cell lines, and the cells of Ki-1-positive anaplastic large-cell lymphomas.104,105 Reed-Sternberg cells also express antigens characteristic of activated T or B cells including interleukin-2 (IL-2) receptors, transferrin receptors, HLA-DR antigens, and Ki-1.

A number of reports have studied Reed-Sternberg cells for evidence of clonal rearrangement of immunoglobulin and T-cell receptor genes (see Stein et al.100 In B cells, in contrast to other somatic cells, the immunoglobulin genes are rearranged; this takes place during B-cell development. The recombination of the immunoglobulin gene segment is random and associated with random incorporation of nucleotides (N segments) between the rearranged immunoglobulin gene segments in the IgG gene and the IgL gene. The result is that each single mature nonmalignant B cell contains distinct IgG and IgL gene rearrangements that are individually B cell specific. In contrast to reactive B cells, neoplastic B cells have identically rearranged immunoglobulin genes confirming that each B-cell lymphoma is derived from a single transformed B cell.

To determine whether the Hodgkin and Reed-Sternberg cells and L and H cells in Hodgkin’s disease are clonal, many research groups have analyzed DNA extracted from Hodgkin’s disease biopsy specimens for the presence of monoclonal immunoglobulin rearrangements. The results of these studies are heterogeneous, with the majority being negative. This is not surprising, given the low sensitivity of the Southern blot technique (requires more than 5% identical cells) and the low percentage of malignant Hodgkin’s disease cells in each specimen. However, the development of the more sensitive polymerase chain reaction assay and improvements in single-cell isolation techniques from tissue samples led to a greater percentage of specimens demonstrating monoclonality. With increased technical sophistication, analysis of 40 cases of classic Hodgkin’s disease revealed clonal B cell rearrangements greater than 90% of the time. All 21 cases of NLPHD demonstrated B-cell clonality.100 These results provide additional evidence for the B-cell nature of Hodgkin’s disease. The presence of identical immunoglobulin gene rearrangements in Hodgkin and Reed-Sternberg and L and H cells suggests their origin from a single transformed B-cell.

Cytogenetics

Cytogenetic abnormalities are common in Reed-Sternberg cells; however, no consistent pattern has been described.106,107 The t(14:18) translocation, common in follicular, small-cleaved-cell B-cell lymphomas, is unusual in Hodgkin’s disease (less than 2% of cases studies).106 However, Reed-Sternberg cells have been reported to express bcl-2 oncogene products more frequently. One explanation for this inconsistency is that bcl-2 expression is likely related to bystander normal lymphocytes that carry the 14:18 translocation.

One hypothesis to explain evidence for a multilineage origin of the Reed-Sternberg cell suggests that the malignant cell represents an in vivo hybridoma that results from an unidentified viral infection that promotes fusion of the interdigitating reticular cell and B cell, T cell, or both lymphocytes.108,109 This hypothesis proposes that the multiple and varied expression of the genome of the Reed-Sternberg cell and its mononuclear variants could represent components of lymphoid cells incorporated into the malignant cell, including the EBV genome and the described translocations.

Cytokine Secretion

It has been hypothesized that cytokines are responsible for the marked inflammatory component, fibrosis, and the diverse histologic patterns of Hodgkin’s disease.104,110 For example, transforming growth factor (TGF)-B1, a known stimulus for fibroblast proliferation and collagen formation, has been associated with the formation of NSHD.111 Others have demonstrated messenger RNA transcripts for tumor necrosis factor, lymphotoxin, IL-5, and IL-6 in the malignant cells of most cases of Hodgkin’s disease and in Hodgkin’s disease cell lines.112

Hsu et al. have proposed an elaborate network of cytokine production and responses in Hodgkin’s disease.113 They suggest that cytokines affect the proliferation and differentiation of the Reed-Sternberg cells because these cells express receptors for IL-2, IL-6, M-CSF, and CD30. IL-2 and IL-6 can promote growth of Reed-Sternberg cells in culture. Similarly, TGF-B is expressed by Reed-Sternberg cells in culture and is found on the surface of Reed-Sternberg cells in NSHD.111,114,115 As TGF-B may be synthesized by both Reed-Sternberg cells and reactive inflammatory cells, some investigators have hypothesized that TGF-B can inhibit the growth of Reed-Sternberg cells that express TGF-B receptors.116 Accordingly, loss of TGF-B receptors could be a mechanism of tumor progression in NSHD. The exaggerated production of TGF-B, a potent immunosuppressant, could also be responsible for some of the poorly understood immunosuppressive effects commonly observed in Hodgkin’s disease patients.111,117

Immunologic Abnormalities in Patients

Hodgkin’s disease is characterized by functional deficits in cellular immunity and in T-cell-mediated immune responses that exist prior to treatment. These deficits persist in cured patients and include impairment of delayed cutaneous hypersensitivity, depressed proliferative responses to T-cell mitogen stimulation, enhanced immunoglobulin production, and decrease in natural killer cell cytotoxicity.118–123 These abnormalities suggest an immunosuppression secondary to chronic overstimulation by cytokines.120,124,125 In patients with active Hodgkin’s disease, these findings are consistent with increased cytokine secretion by Reed-Sternberg cells. However, it has been difficult to explain the persistence of these abnormalities in patients after Hodgkin’s disease.

Hodgkin’s disease is characterized by the presence of Hodgkin’s-Reed-Sternberg (H-RS) cells surrounded by predominantly CD4+ T-lymphocytes. These cells express a variety of activation markers but are incapable of mounting an effective immune response against tumor cells.123 There appear to be three potential causes of immune suppression after treatment for Hodgkin’s disease: residual effects from RT and chemotherapy, immunocompromise from splenectomy after staging laparotomy, and persistence of abnormalities present at diagnosis biologically related to Hodgkin’s disease.

Treatment-induced immunosuppression returns to normal at varying times after Hodgkin’s disease but appears to have its greatest effect over the first few years.126 One of the clinical consequences of this immunosuppression is the development of herpes zoster. There is an excess of herpes zoster infections during the first year after initiation of treatment for Hodgkin’s disease. Over 75% of Hodgkin’s disease-associated herpes zoster cases occur within the first year. Few cases occur after the third year (only 6% of all cases).127–129 In addition, the risk of zoster appears highest in patients receiving intensive RT and chemotherapy (50–57%).127 In contrast, the risk of zoster is only 14 to 23% for patients receiving RT or chemotherapy alone. The incidence of zoster appears less with the ABVD regimen than with the more immunosuppressive MOPP chemotherapy.

Unlike the deficits in delayed hypersensitivity, most patients with Hodgkin’s disease at diagnosis appear to have relatively normal B-cell numbers and function.123 However, B-cell function is adversely affected by treatment with chemotherapy or combined chemotherapy and RT, and the ensuing consequences may be greater after prior splenectomy.

To counteract the risks of bacterial sepsis, patients in the past were vaccinated prior to staging laparotomy and splenectomy. Antibody response to the 14-valent pneumococcus vaccine, combined with Haemophilus influenzae type B and meningococcus type C, is normal in patients with untreated Hodgkin’s disease and similar to that of healthy controls, asplenic controls, and patients treated with RT alone. However, patients who receive chemotherapy or combined chemotherapy and radiation therapy appear to have an impaired antibody response to vaccination, especially if the vaccines are administered within 10 to 14 days of initiation of chemotherapy. Fortunately, the development of polysaccharide-conjugate vaccines over the past 15 years has benefited immunocompromised patients with significant antibody titers post-immunization compared to responses to prior vaccines.130–132 All patients who have undergone staging laparotomy and patients who are to receive splenic radiation as part of treatment for Hodgkin’s disease should undergo vaccination with H. influenzae type B polysaccharide-conjugate, pure polysaccharide meningococcal, and 23-valent pure polysaccharide pneumococcal vaccines prior to treatment.133 In addition, it now appears that patients should be revaccinated every 5 to 6 years.133 Even with improvements in vaccines, neither immunization nor antibiotic prophylaxis can be guaranteed to prevent the development of sepsis due to encapsulated microorganisms in patients with Hodgkin’s disease whose staging included splenectomy or who have been heavily treated with CMT. Both physicians and patients should remain alert to this risk.

Staging

Natural History and Patterns of Spread

The Swiss radiotherapist Gilbert is credited with first reporting that Hodgkin’s disease spread by contiguity from one lymph node chain to adjacent regions.10,16,17 Peters, and later Kaplan and others, extended his work by evaluating the use of prophylactic RT to lymph nodes adjacent to those involved with disease.18,20,134,135 The development of new radiographic studies and the routine use of staging laparotomy improved understanding of the presentation, distribution, and evolution of Hodgkin’s disease.20,25,135–141 Although there is strong evidence that Hodgkin’s disease begins in a single group of lymph nodes and then spreads to contiguous lymph nodes, eventually the malignant cells become more aggressive, may invade blood vessels, and spread to organs by hematogenous dissemination.20

One study of over 700 patients recently evaluated continuous nodal involvement from a combination of clinical and laparotomy staging.40 Evidence for contiguous spread was most convincing for patients with NSHD or MCHD. The mediastinum, left side of the neck, and right side of the neck were each involved in more than 60% of patients. These sites were four or more times as common as other nodal sites above or below the diaphragm, suggesting that most cases of NSHD or MCHD begin in the chest or neck. Significant associations were found between the mediastinum and the right or left neck, the neck and the ipsilateral axilla, the mediastinum and the hilum, and the spleen and abdominal nodal involvement. There was a negative association between the right and left neck if the mediastinum was not involved, suggesting that spread from one neck to the other occurred through the mediastinal nodes.

A study evaluating sites of relapse in patients with minimal stage IIIA Hodgkin’s disease treated with RT alone provides additional information.142 It appears that when the spleen is involved with Hodgkin’s disease, even minimally, there is a high risk of extranodal involvement. This suggests that Hodgkin’s disease spreads from above the diaphragm to the spleen, perhaps through the vascular system, and that splenic involvement may herald spread to extranodal sites through a similar process.

Most patients with NSHD or MCHD have a central pattern of lymph node involvement (cervical, mediastinal, para-aortic). In contrast, certain nodal chains (mesenteric, hypogastric, pre-sacral, epitrochlear, popliteal) are seldom involved. Occult adenopathy in the upper abdomen ranges from 6 to 35%. The spleen is involved more frequently with adenopathy below the diaphragm, systemic symptoms, and in patients with mixed cellularity histology variants. Involvement of the liver in an untreated patient is rare and almost always occurs with concomitant splenic involvement. Infiltration of the bone marrow is usually focal and almost invariably associated with extensive disease, systemic symptoms, and unfavorable histology. The same observation applies to renal and osseous involvement, which are rare events early in the course of the disease. In the great majority of patients, the initial pattern of spread occurs nonrandomly and predictably via lymphatic channels to contiguous lymph node chains. This important observation, first made over 50 years ago, continues to form the basis for prophylactic irradiation of adjacent lymph node bearing regions in patients with apparently localized Hodgkin’s disease.

Patterns of Relapse

A relapse is a new manifestation of disease documented after complete tumor remission. In more than 80% of patients, initial relapses occur within the first 5 years of treatment for Hodgkin’s disease. The median time to relapse is stage and treatment dependent; recurrences occur earlier in patients with large mediastinal adenopathy than in patients without bulky disease,143,144 or in patients with NLPHD. Late relapses, for example, those occurring beyond the first 5 years, are uncommon and range from 5 to 15% in published series.145,146 Relapses among patients treated with RT generally occur outside the radiation field, whereas relapses among patients treated with chemotherapy occur at previous sites of involvement.143,147 True recurrence, that is, relapse within a treated field, is a rare finding when a tumoricidal dose of RT of above 30 Gy is applied. Marginal recurrence or relapse appearing at or immediately adjacent to the margin of the irradiated field is more frequent and related to treatment and extent of disease. The sites of initial recurrence after chemotherapy alone correlate with the sites of largest disease prior to therapy; however, recurrences occur even with chemotherapy alone in patients with less bulky disease.147 To date, there are no reliable estimates for the risk of nodal recurrence after chemotherapy alone by number of sites or size of disease in patients with less bulky disease. As a result, adjuvant RT is usually recommended in patients with localized disease after treatment with chemotherapy.

Staging Classification

The advent of new imaging modalities and the frequent use of combined modality treatment have made staging procedures simpler and less invasive in recent years. In deciding what examination to perform, the information gathered should be worth the cost, both in physical and economic terms. If the cost of discovering the presence of lymphoma in a certain location would have a great impact on the therapy, the test is warranted. On the contrary, a test of limited accuracy should probably not be done; the same applies when the prevalence of disease in a given anatomic area is known to be low.

The latest international staging classification was proposed in 1989 during a meeting held in Cotswolds, England.148 The Cotswolds classification (Table 129.1) is a modification of the Ann Arbor classification using information from staging and treatment obtained in the 1970s and 1980s. Some of the recommended modifications include adding criteria for clinical involvement of the spleen and liver to include evidence of focal defects with two imaging techniques and eliminating the findings of abnormal liver function. The suffix “X” was added to designate bulky disease (greater than 10-cm maximum dimension). A new category of response to therapy, that is, unconfirmed/uncertain complete remission, was introduced to accommodate the difficulty of persistent radiologic abnormalities of uncertain significance following primary therapy. A category of localized extranodal disease (e.g., lung, pleura, chest wall, bone) contiguous to involved nodes was added and classified in the appropriate lymph node system stage followed by the subscript E. Patients with localized extranodal disease have a more favorable prognosis than patients with disseminated involvement (stage IV).

Table 129.1. The Cotswolds Staging Classification for Hodgkin’s Disease.

Table 129.1

The Cotswolds Staging Classification for Hodgkin’s Disease.

Recommended staging procedures are listed in Table 129.2. An adequate surgical biopsy, possibly of more than one intact lymph node, is required for histopathologic examination. When the diagnosis of Hodgkin’s disease is made from biopsy of an extranodal site, a concomitant node biopsy confirmation of diagnosis is desirable unless the diagnosis is considered unequivocal.

Table 129.2. Recommended Staging.

Table 129.2

Recommended Staging.

Radiographic Staging above the Diaphragm

The radiologic assessment of patients with newly diagnosed Hodgkin’s disease is summarized below. Over 60% of patients have radiographic evidence of intrathoracic involvement. Frontal and lateral chest radiographs should be routinely ordered and also represent the ideal for subsequent surveillance. Computerized (axial) tomography (CT) scanning can provide additional information in patients who have an abnormal chest radiograph. This examination also may reveal adenopathy when the chest radiograph is normal.

Massive mediastinal adenopathy (large mediastinal adenopathy [LMA]) has been arbitrarily defined as the ratio greater than one-third between the largest transverse diameter of the mediastinal mass over the transverse diameter of the thorax at the diaphragm on a standing posterio-anterior chest x-ray (Fig. 129.1).144,149 Alternatively, others have defined extensive mediastinal disease as greater than 35% of the thoracic diameter at T5-T6 or as measuring greater than 5 to 10 cm in width. Patients with LMA have an increased risk of relapsing in nodal and extranodal sites above the diaphragm following RT alone.144,149–154 These patients make up 20 to 25% of CS I-II patients, generally present with involvement of multiple supradiaphragmatic nodal chains, and may have extension of tumor into the lung, pericardium, or chest wall.144,155 Systemic symptoms are frequently present.

Figure 129.1. Standing posteroanterior chest radiograph of a patient with Hodgkin’s disease.

Figure 129.1

Standing posteroanterior chest radiograph of a patient with Hodgkin’s disease. Measurements of mediastinal mass ratio are made by dividing the width of the mediastinal mass at its widest diameter by the diameter of the thorax (inside rib to inside (more...)

Staging with thoracic CAT scanning can more precisely identify sites of initial involvement.156 CT scanning is especially apt at detecting pulmonary disease, pleural or pericardial involvement, apical cardiac nodal enlargement, and extension into the chest wall, and in defining the extent of involved axillary lymph nodes (Fig. 129.2). Such information has considerable potential to alter clinical management.157 Identification of the extent of thoracic disease will help define the use of combination chemotherapy and the dose, extent, and need for RT.

Figure 129.2. Thoracic CT image from a patient with NS Hodgkin’s disease.

Figure 129.2

Thoracic CT image from a patient with NS Hodgkin’s disease. Note the very large involvement of the left axillary nodes, involvement of the right pleura, and the anterior mediastinal disease.

With improved gamma camera resolution, several investigators have described the ability of gallium 67 (67Ga) scanning to detect intrathoracic lymphadenopathy, although the reported sensitivities and specificities are somewhat less than those of CAT scanning. Today, the primary role for 67Ga scanning in the thorax is to answer specific questions that arise following treatment (e.g., whether a residual mass represents viable tumor rather than necrosis or fibrosis). It is important to know that, in children, and at times in young adults, gallium accumulation represents rebound thymic hyperplasia. As an alternative to gallium scanning, PET is being explored in Europe and in the United States.158

Recent investigations suggest that the ability of magnetic resonance imaging (MRI) to detect tumor in mediastinum or hilar lymph nodes is not superior to that of CAT scanning.159 Although MRI can probably function as an alternative to CAT scanning in the thorax, particularly at the level of chest wall involvement, its high cost still prevents this modality from being used routinely. Ultrasonography may be successfully used in judging response to treatment and in evaluating the presence of pericardial fluid, but, under most circumstances, its use remains limited.

Radiographic Staging below the Diaphragm

CT scanning, lymphangiography, MRI, PET, and gallium scanning all have limitations in the radiologic evaluation of the abdominal nodes. No single study is reliable for detecting Hodgkin’s disease in normal size nodes and all studies have a 20 to 25% false-negative rate due to the inability to detect occult Hodgkin’s disease in the spleen.140,141,160 Ninety percent of patients who are upstaged have splenic involvement either alone or in addition to infradiaphragmatic nodal disease.141 Comparisons of bipedal LAG and CT scanning suggest that LAG has a small statistical advantage over CT scanning because it provides useful information on lymph node architecture. This makes the LAG especially valuable in the evaluation and treatment of patients who present with Hodgkin’s disease below the diaphragm. In contrast, CT scanning can better evaluate adenopathy in the celiac axis, splenic hilus, porta hepatis, and mesentery, relying almost exclusively on increases in the size of the nodes. CT scanning can also demonstrate foci of Hodgkin’s disease in the liver and spleen; however, the false-negative results are too numerous to allow one to rely heavily on CT assessment of these organs.

During the past few years, bipedal LAG has given way to CT scanning as the examination of choice. In part this is because contemporary radiologists have been reluctant to champion an examination they perceive to be tedious and difficult to perform and interpret. MRI may be more sensitive than CT scanning in the evaluation of abdominal nodes, but information on its usefulness is still limited. MRI appears to be a potentially valuable tool in investigating bone marrow involvement and can help in directing image-guided biopsies. Gallium scanning can also be complementary to CT scanning; however, its use in the abdomen may be hampered by normal uptake in the liver, spleen, and bowel. With the infrequent use of staging laparotomy and splenectomy in the staging of Hodgkin’s disease, the risk of overstaging based on a single radiographic test of abdominal involvement (false positive) has greater potential consequences. Therefore, we recommend that two separate studies (i.e., CT scanning and gallium scanning) be used to assess abdominal involvement and positive findings on both tests be used to confirm abdominal involvement for the routine radiographic staging of Hodgkin’s disease.

Staging Laparotomy

Staging laparotomy was extensively used when RT was the only curative treatment for early-stage Hodgkin’s disease and when it was mandatory to define the extent of abdominal disease to help determine the extent of radiation needed below the diaphragm. With the increasing use of combination CT, staging laparotomy gradually evolved into a tool to help determine whether RT or CT should be selected as definitive treatment. With many groups using prognostic factors to determine treatment for Hodgkin’s disease, laparotomy has disappeared as a routine staging procedure, and its use should be reserved only for patients with limited disease who are to receive minimal treatment.

Treatment of Stage I-II Hodgkin’s Disease

Randomized Clinical Trials: Meta-Analysis of Trials from the 1970s

Significant advances in the treatment of early-stage Hodgkin’s disease have been derived from information obtained from clinical trials. In the 1970s and 1980s, many of the randomized trials evaluated field size in patients treated with RT alone. A separate set of trials evaluated the role of chemotherapy in stage I-II Hodgkin’s disease. Specht et al. published a meta-analysis of 23 randomized trials involving 3,888 patients with early-stage Hodgkin’s disease treated in the 1970s and 1980s.161 Early Hodgkin’s disease was defined as patients with clinically or laparotomy staged I-II disease; in some cases, patients with stage III disease were included. Patients with B symptoms and patients with extensive thoracic Hodgkin’s disease were also included. Specht et al. divided the randomized trials into two groups: eight trials compared more extensive RT to less extensive RT and 13 trials compared multiagent chemotherapy and RT to RT alone. Individual patient data including age, stage, date of entry, treatment allocation, date of recurrence, and date and cause of death or date last seen were collected for each patient randomized.

Eight trials evaluated treatment with larger versus smaller radiation field sizes.161 Larger fields generally included subtotal nodal irradiation (mantle and upper abdomen) or total nodal irradiation; smaller fields included involved fields and regional fields. Although approximately half of the trials showed a significant advantage in disease-free survival with larger field compared to smaller field irradiation, survival differences were not seen in any of the individual eight studies. The combined risk of failure and survival by treatment, in the eight trials of more extensive versus less extensive RT at 10 years, was 43.4% for patients treated with less extensive RT compared to 31.3% for those treated with more extensive RT (p < .00001). Ten-year actuarial survival rates were 77% for both groups (p > .1). The lack of a survival difference suggests that salvage chemotherapy for relapse after initial RT is effective enough to minimize the impact of the increase in relapse. In addition, the small increased mortality from recurrent Hodgkin’s disease in patients receiving smaller field irradiation appeared to be balanced by an increased mortality from treatment-related causes in patients receiving more extensive RT.

Thirteen trials evaluated treatment with multiagent chemotherapy and RT compared to RT alone.161 Most trials used MOPP or MOPP-like chemotherapy for six monthly cycles. Approximately half of the individual trials showed a significant advantage in disease-free survival with combined chemotherapy and RT compared to RT alone; survival differences were not seen in any of the individual 13 studies. The risk of relapse and survival by treatment for the combined 13 trials for multiagent chemotherapy and RT versus RT alone at 10 years was 32.7% for patients treated with RT alone and 15.8% for those treated with chemotherapy and RT (p < .00001). The 10-year actuarial survival rates were 76.5% for patients treated with RT alone and 79.4% for those treated with chemotherapy and RT (p > .1).

Most patients received alkylating agent chemotherapy (usually MOPP—mechlorethamine, vincristine, procarbazine, prednisone—or an equivalent) in the trials analyzed in the meta-analysis by Specht et al. Thus, these results may not strictly apply to current practice in which MOPP has been replaced by more effective treatment regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

Prognostic Factors for Stage I-II Hodgkin’s Disease

Prognostic factors such as age, size of nodal involvement, and presence of systemic symptoms help determine initial treatment strategies. Patients with stage I-II Hodgkin’s disease with favorable prognostic factors are candidates for RT alone or for modified RT and chemotherapy. Patients with unfavorable prognostic factors should receive chemotherapy and RT as initial treatment. Although many of the adverse prognostic factors have lost significance as more intensive combined RT and chemotherapy regimens have been used, these factors continue to be very important in the design of clinical trials that evaluate reduction of RT and chemotherapy for early-stage Hodgkin’s disease.

Prognostic Factors for Freedom From Treatment Failure (FFTF) and Survival in Laparotomy-Staged (PS)/Clinically Staged (CS) I-II Patients

Prognostic factors have been identified for stage I-II Hodgkin’s disease that predict for a higher risk of relapse or a lower rate of survival. Many factors predict for recurrence after treatment with RT alone; fewer predict for relapse after chemotherapy and RT. Only older age at diagnosis has been consistently reported as a significant adverse factor for survival, both after RT alone and after combined RT and chemotherapy.162

A number of studies have identified prognostic factors for PS/CS I-II patients presenting an analysis of significance adjusted for other factors.143,151,163–165 All studies report large mediastinal adenopathy or large tumor burden as a major factor predicting an increased risk of relapse. In neither the Stanford University nor the Harvard University study did large mediastinal adenopathy predict for a lower survival rate;143,151 patients with a large tumor burden had a lower survival rate in the Danish study.163

Retrospective studies have consistently identified large mediastinal adenopathy as an adverse prognostic factor for relapse in PS IA-IIB patients treated with RT alone.144,149,151,152166–170 The majority of recurrences in patients with extensive thoracic Hodgkin’s disease are in lymph nodes or extranodal sites above the diaphragm.144,149,150,152167–169171,172 Patients with pericardial nodes, extensive pericardial involvement, bulky axillary disease, or significant involvement of the pleura or lung on radiographic evaluation have a high risk of relapse after RT alone. The potential toxicity associated with the large radiation volumes needed to treat extensive thoracic Hodgkin’s disease has been a strong argument for treatment with combination chemotherapy followed by involved field or mantle irradiation. This approach eliminates the need for abdominal irradiation, allows for reduction of the field size and dose of RT, and results in a much improved freedom from recurrence compared to RT alone.144

Most reports also have identified B symptoms as an important factor for recurrence and survival. A large retrospective study combining data from PS IB-IIB patients treated at Stanford University Medical School and Harvard Medical School suggested that patients with night sweats without other B symptoms treated with RT alone had a prognosis similar to that of patients with PS IA-IIA disease. However, the presence of fevers, weight loss, large mediastinal adenopathy, and age 40 or older all independently predicted for an increased risk of relapse, and survival was impaired in patients who had both fevers and weight loss.173 Other studies evaluating clinically staged patients have also identified B symptoms as risk factors for relapse.

Two other factors, large number of regions involved and elevated erythrocyte sedimentation rate (ESR), have been identified as adverse factors for freedom from treatment failure in clinically staged patients.164,165 Many factors, including B symptoms (similar to ESR), male sex, number of sites of involvement, and, to a lesser extent, age, also predict for an increased risk of occult abdominal involvement in CS I-II patients.140,141 This may in part explain why some of these factors are identified for clinically staged, but not for laparotomy-staged, patients. In current clinical trials, B symptoms are often combined with an elevated ESR in defining an unfavorable prognosis.

Older patients appear to have a lower survival rate, but if treated as younger patients do not have a higher recurrence rate.143,163 Older patients appear to be less successfully treated at relapse,174–177 and they have a greater absolute excess risk of mortality from causes other than Hodgkin’s disease, such as second tumors and cardiac disease.153,177–179 Thus, their reduced survival is both disease and treatment related. This argues for treatment strategies that minimize both the risk of recurrence and the risk of long-term complications in this group of patients. This may not be feasible until new, less toxic, and more effective treatment approaches are developed. Age over 50 is used as the criteria for unfavorable prognosis in current trials.

Prognostic Factors Determine Treatment in Clinical Trials

Cooperative groups identify favorable and unfavorable prognostic groups for different clinical trials. These prognostic factors predict for likelihood of occult disease in the abdomen and for the effectiveness of treatment in maintaining a high level of freedom from recurrence. Prognostic factors for the current European Organization for the Research and Treatment of Cancer (EORTC) and the German Hodgkin’s Study Group (GHSG) are listed below. Favorable prognostic factors are listed in Table 129.3 and unfavorable prognostic factors are listed in Table 129.4. For the EORTC and GHSG, favorable prognosis means the absence of each of the factors listed in Table 129.3. Approximately 55% of patients with CS I-II Hodgkin’s disease will fall into the favorable prognosis group. For the EORTC and GHSG, unfavorable prognosis means the presence of any of the factors listed in Table 129.4. Approximately 35% of patients with CS I-II Hodgkin’s disease will have either B symptoms or large mediastinal adenopathy and about 10% will have four or more sites involved without B symptoms or large mediastinal disease. The International Prognostic Factor Project analyzed additional prognostic factors in patients with advanced-stage Hodgkin’s disease to determine poor prognostic groups of patients who might need more aggressive initial treatment (Table 129.5).180 The role of these factors in stage I-II Hodgkin’s disease remains uncertain.

Table 129.3. Favorable Prognosis Stage I-II Hodgkin’s Disease.

Table 129.3

Favorable Prognosis Stage I-II Hodgkin’s Disease.

Table 129.4. Unfavorable Prognosis Stage I-II Hodgkin’s Disease.

Table 129.4

Unfavorable Prognosis Stage I-II Hodgkin’s Disease.

Table 129.5. Final Cox Regression Model, International Prognostic Factor Project.

Table 129.5

Final Cox Regression Model, International Prognostic Factor Project.

Risk of Occult Abdominal Involvement in Patients with Clinical Stage I-II Hodgkin’s Disease

The probability of occult abdominal involvement must be factored into treatment approaches for patients with CS I-II Hodgkin’s disease. Approaches include surgical staging to rule out abdominal involvement (rarely used), prophylactic upper abdominal and splenic irradiation (option for favorable prognosis patients), or sufficient combination chemotherapy to control occult abdominal involvement. Twenty to 30% of CS IA-IIA and 35% of CS IB-IIB patients with Hodgkin’s disease have occult splenic or upper abdominal nodal involvement not detected by bipedal lymphangiography, computed axial tomography, MRI, PET, or gallium imaging.140,141 Ninety percent of patients with CS I-II/PS III Hodgkin’s disease have disease limited to the spleen with or without upper abdominal nodal involvement. Often the disease is microscopic and not detected radiologically.160

Studies of the results of staging laparotomy have demonstrated that selected prognostic factors can predict for the risk of occult abdominal involvement in CS I-II patients.140,141,181,182 Selected subgroups, making up approximately 10 to 15% of all CS I-II patients, including CS IA females, CS IA males with disease limited to the high neck, CS IA patients with interfollicular histology, and CS IA patients with lymphocyte-predominant histology, appear to be at lowest risk for occult abdominal involvement (4 to 6%). CS IIA females 26 years or younger with three regions or less involved and CS IA males with mediastinal involvement also have been identified in one study as having a low-risk incidence.140 The remainder of CS IIA and all CS IB-IIB patients remain at substantial risk for Hodgkin’s disease in the spleen or abdominal nodes (24–36%).140,141 Identifying patients at low risk for abdominal involvement may allow use of RT alone without treatment below the diaphragm or limited chemotherapy combined with RT. Patients at moderate risk must be treated with strategies that will control potential Hodgkin’s disease below the diaphragm. One option involved the use of mantle para-aortic and splenic irradiation; alternatively, combined chemotherapy and RT can be used with radiation limited to involved fields. Current clinical trials are studying how much chemotherapy is needed to achieve such control.

Long-Term Outcome of Treatment for Early-Stage Hodgkin’s Disease

Much of the long-term follow-up data for early-stage Hodgkin’s disease is derived from laparotomy-staged patients treated with RT alone. Large, single institutional studies demonstrate approximately an 80% actuarial 10 to 20-year freedom from relapse and less than a 10% mortality from Hodgkin’s disease following mantle and para-aortic irradiation for PS IA-IIA patients.143,151,183 These results have been achieved through careful delineation of the extent of Hodgkin’s disease, precise delivery of RT and the successful treatment of patients who relapse with multiagent chemotherapy.

The treatment of early-stage Hodgkin’s disease has become so successful that at 15 to 20 years post-treatment, the overall mortality rate from causes other than Hodgkin’s disease exceeds that seen from Hodgkin’s disease.177,184–186 Thus, it is in the second and third decades after Hodgkin’s disease that improved survival of early-stage patients might be seen with reduced treatment regimens.

There are a number of published reports that detail causes of mortality after Hodgkin’s disease.177,185,187,188 Deaths from Hodgkin’s disease occurred most frequently in the first 5 to 10 years; causes of death other than Hodgkin’s disease were most common after 5 to 10 years. The absolute excess risk of mortality by 5-year interval ranged from 104 to 125 per 10,000 person-years. Thus, patients had a 1.04 to 1.25% excess risk of mortality per year over the first 20 years after Hodgkin’s disease177 (Table 129.6). These data are from laparotomy-staged patients treated with wide-field RT with or without MOPP or MOPP-like regimens. Current clinical trials are based on the theory that reduction of field size and dose of radiation and the use of modified nonalkylating agent regimens should reduce this late mortality incidence.

Table 129.6. Excess Mortality after Hodgkin’s Disease.

Table 129.6

Excess Mortality after Hodgkin’s Disease.

The three most common causes of death after treatment for Hodgkin’s disease (Hodgkin’s disease, secondary malignancy, cardiac disease) are discussed below. Patients who develop recurrent Hodgkin’s disease after RT alone are as likely to be cured with combination chemotherapy as if the chemotherapy were used as part of initial treatment. The 10-year actuarial survival rate of patients initially treated with RT alone after relapse and treatment with multiagent chemotherapy is 57 to 62%.175,176 Most of the patients in these studies received MOPP chemotherapy for relapse; treatment with ABVD is likely to yield greater 10-year survivals given the advantage of ABVD over MOPP in advanced-stage Hodgkin’s disease.36

Survival rates are significantly worse for patients who relapse after chemotherapy alone or combined RT and chemotherapy; most of the data is from patients who initially had advanced Hodgkin’s disease. Treatment with similar or alternative chemotherapy regimens after relapse from chemotherapy alone yields 5- to 10-year survival rates of only 20 to 32%189–191 suggesting cross-resistance among different chemotherapy regimens. Because of the poor overall prognosis of patients who relapse after standard chemotherapy, many centers recommend high-dose chemotherapy and autologous bone marrow rescue at first relapse for patients initially treated with chemotherapy or CMT. Although the results of high-dose therapy are promising, many patients with recurrent disease are not eligible for this approach due to poor tumor response or occasionally comorbid disease or advanced age. Patients who undergo transplant and are subsequently cured of Hodgkin’s disease face significant long-term treatment-related morbidity and mortality risks. One study reports a low rate of survival in patients with early-stage disease who relapsed after treatment with chemotherapy alone (9-year actuarial 56% survival rate)192; these results await further study. Until more data are available, current information suggests that when chemotherapy is used as definitive treatment for early-stage Hodgkin’s disease, treatment should be designed to minimize relapse. This is probably best achieved with the combined use of both chemotherapy and RT.

Many years after chemotherapy and/or RT, patients with Hodgkin’s disease have an increased risk of developing acute nonlymphoblastic leukemia, non-Hodgkin’s lymphoma, and second solid tumors.193–206 This increased risk may be multifactorial, resulting both from the immune dysregulation associated with Hodgkin’s disease and/or its treatment and the carcinogenic effects of RT and chemotherapy. Certain cytotoxic agents, especially those contained in the MOPP and ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone) regimens, are associated with a marked increase in acute nonlymphoblastic leukemia after Hodgkin’s disease.203,204 The total incidence of acute leukemia, usually occurring within 10 years of treatment, ranges from 2 to 6%.196,204 The routine use of ABVD has dramatically reduced the risk of leukemogenesis, but there remains concern for secondary leukemia with alternating or hybrid regimens.203,204 Regimens that contain significant amounts of alkylating agents known to cause leukemia should not be used in treating favorable prognosis CS I-II patients.

Nearly all cases of non-Hodgkin’s lymphoma occurring after Hodgkin’s disease are of intermediate or high-grade histology.195,204,206–208 The histologies represented are similar to lymphomas seen in patients with immunodeficiency diseases or under chronic immunosuppression for organ transplantation or autoimmune disorders. These lymphomas have a cumulative risk of 1.2 to 2.1% at 15 years.196,198,207,209 The risk is probably not treatment related.

The absolute excess risk of developing a solid tumor is greater than that of developing leukemia or non-Hodgkin’s lymphoma after Hodgkin’s disease. Solid tumors constitute 55 to 75% of the second malignancies in long-term studies.196,206,207 The relative risk of solid tumors continues to be elevated more than 20 years after Hodgkin’s disease.206 Risk factors for developing a solid tumor after treatment for Hodgkin’s disease include initial treatment with RT (various solid tumors), treatment with chemotherapy (lung cancer), sex (higher for women), age at treatment, and environmental factors post-treatment (smoking and lung cancer). Volume and dose of RT and type of chemotherapy may all be independent risk factors for the development of second tumors. Additional data are needed to determine the extent to which current treatment reduction strategies will result in a lower second tumor mortality. However, reduction in the radiation field size will almost certainly result in a lower second tumor risk, as many of the radiation-induced tumors occur within or on the edge of the treatment field. Reduction of radiation field size is being studied in stage I-II trials that use combined RT and chemotherapy. Female patients less than 25 to 30 years of age at treatment have an increased risk of breast cancer years after mantle irradiation200,201,206,210; techniques to combine chemotherapy and radiation limited to involved fields should reduce this risk.

Complications related to cardiac irradiation (arrhythmias, myocardial infarction and coronary artery disease, pericarditis, myocarditis, pericardial effusion, and tamponade) have been carefully documented after RT to the mediastinum.153,172,185,211–218 In many of the earlier studies, these complications are related to treatment techniques that resulted in a high radiation dose to the anterior mediastinum and heart (lower energy machinery, anterior weighted fields, doses per fraction of greater than 200 cGy, treatment with one field per day). Current practice, which restricts the dose to the whole heart, blocks the subcarinal region part way into treatment, delivers treatments equally from front and back, and permits lower radiation dose and volume by the use of pre-radiation chemotherapy, has yielded more satisfactory results. This is illustrated in a study by Boivin et al. that demonstrated a significant age-adjusted increased risk of death from myocardial infarction (RR, 2.56; CI, 1.11–5.93) after mediastinal irradiation.213 This risk did not differ by age at treatment or time from treatment. However, when analyzed by year of diagnosis of Hodgkin’s disease, the risk was greater for patients treated in 1966 or earlier (RR, 6.33; CI, 1.73–23.16) than for patients treated in 1967 or later (RR, 1.97; CI, 0.75–5.17), suggesting that modern treatment techniques reduce the risk of cardiac complications. Similar data have been reported from the Stanford University Medical School.217,218

Other complications that have factored into the development of clinical trials include pulmonary toxicity and loss of fertility. Radiation pneumonitis typically occurs 1 to 6 months after completion of mantle irradiation. Symptomatic radiation pneumonitis is characterized by a mild, nonproductive cough, low-grade fever, and dyspnea on exertion. Infection and recurrent Hodgkin’s disease must also be considered in the diagnosis. The overall incidence of symptomatic pneumonitis is less than 5% after mantle irradiation; patients with large mediastinal adenopathy who receive CMT have a two- to three-fold greater risk (10–15%).153 Radiographically, pneumonitis is characterized by the formation of infiltrates confined to the original radiation fields. Infection, rather than pneumonitis, is more likely if the infiltrates extend into areas of the lung initially protected from radiation by lung shielding. Severe pneumonitis may require treatment with steroids. If the symptoms do not respond to steroid treatment, the presence of a superimposed infection, such as pneumocystis carinii, should be considered. Patients who develop pneumonitis usually do not have long-term pulmonary dysfunction after the acute effects subside.

The risk of symptomatic radiation pneumonitis is increased after combined mantle radiotherapy and MOPP chemotherapy, a regimen that is rarely used in the initial treatment of Hodgkin’s disease today, compared to RT alone. In part, this may result from the prednisone in the MOPP regimen.153 Although additional data are needed, this increased risk may also exist after ABVD and mantle irradiation.219 After bleomycin-containing regimens, a reticulomicronodular pattern located generally at the lower lung zones occurs in 10 to 15% of patients when the cumulative dose of bleomycin exceeds 200 mg/m2. For much lower cumulative doses, such as used in the delivery of four to six cycles of ABVD, early pulmonary toxicity occurs 5% or less of the time and radiologic findings are reversible with the help of corticosteroids. If left undetected, particularly when bleomycin-containing chemotherapy is administered after prior pulmonary irradiation, the initial findings often evolve into a coarse striking reticulation. In turn, this can evolve into restrictive lung fibrosis.

Gonadal dysfunction is an important iatrogenic toxicity that considerably affects the quality of life in patients after Hodgkin’s disease. MOPP or MOPP-like combinations induce azospermia in 90 to 100% of patients. Only 10 to 20% of patients eventually show recovery of spermatogenesis even after long periods. Following MOPP alternated with ABVD, where the cumulative doses of MOPP are 50% of those in full-course MOPP, the incidence of permanent azospermia is still nearly 50%. About half of women become amenorrheic after 6 courses of MOPP, and premature ovarian failure appears to depend on age (over 30 years, 75–85%; under 30 years, about 20%). This is most probably related to the total dose of drugs and is a progressive phenomenon. The Milan Cancer Institute has reported that the administration of ABVD chemotherapy produces only transient germ cell toxicity in men and no drug-induced amenorrhea.220 Thus, to circumvent chemotherapy-induced sterility, the use of nonalkylating agent regimens is recommended. An alternative for men undergoing MOPP or MOPP-ABVD involves sperm storage prior to chemotherapy. However, about one-third of male patients with Hodgkin’s disease have low sperm count or sperm motility before starting cytotoxic treatment; this may affect the success of the procedure.

Reduction of Staging or Treatment: Ongoing and Recently Completed Trials for Favorable Prognosis CS I-II Hodgkin’s Disease

Increasing concern for the long-term consequences of treatment has prompted many investigators to re-examine the aggressive approaches developed for the staging and treatment of early-stage Hodgkin’s disease in the 1970s and 1980s. Many of the ongoing and recently completed studies were developed in an attempt to reduce the long-term complications of treatment without increasing mortality from Hodgkin’s disease. These include studies that:

1.Evaluate RT alone and study reduction of radiation dose or reduction of radiation field size;

2.Evaluate combined RT and chemotherapy and attempt to identify the optimal chemotherapy regimen, identify the optimum number of cycles of chemotherapy, or determine the optimal radiation volume and dose when combined with chemotherapy; and

3.Evaluate combination chemotherapy alone.

Most studies listed below have relatively short follow-up or are ongoing and would not be expected to demonstrate survival differences. High relapse rates and significant acute toxicity are the main criteria for adverse outcome.

Radiation Therapy Alone

Trials of Radiation Therapy Alone Evaluating Radiation Dose

Although a few studies have comprehensively reviewed dose-response data for Hodgkin’s disease,221–224 only one prospective randomized study has been completed. This multicenter trial by the GHSG evaluated the tumoricidal doses for subclinical involvement by Hodgkin’s disease.225 A total of 376 laparotomy-staged favorable prognosis IA-IIB Hodgkin’s disease patients were enrolled. Only patients without adverse risk factors were included in the trial. Patients were randomized to receive either 40 Gy extended field radiation therapy or 30 Gy extended field radiation therapy followed by an additional 10 Gy to involved lymph node regions. Recurrences were analyzed by a panel of four radiation oncologists for technique, treatment volume, and time and dose of RT and classified as in-field, marginal, or out-field recurrences.225 The 5-year freedom from treatment failure results favored the 30 Gy extended field plus 10 Gy arm over the 40 Gy extended field arm (81 vs. 70%, respectively, p = .026). The 5-year survival results also favored the 30 Gy extended field arm (98 vs. 93%, respectively, p = .067), suggesting that 30 Gy is sufficient for treating subclinical involvement of Hodgkin’s disease with RT alone.

Trials with Radiation Therapy Alone Evaluating Radiation Field Size

The Princess Margaret Hospital has reported results of treating CS I-II Hodgkin’s disease with RT alone. In a report of 250 patients, the 8-year actuarial freedom from relapse rate was 71.6% with a median follow-up time of 6.3 years.165 Patients with CS I-II Hodgkin’s disease with favorable prognostic features (age < 50, ESR < 40, and lymphocyte predominance/nodular sclerosis histology) treated with mantle and para-aortic-splenic irradiation had only a 12.7% actuarial risk of relapse at 8 years. This treatment approach was used as the control arm in the favorable prognosis EORTC and GHSG trials.

Mantle Irradiation Alone in CS IA-IIA Patients

The advantages of mantle irradiation alone for early-stage Hodgkin’s disease include the short treatment time (5 weeks) and elimination of the long-term risks of radiation to the upper abdomen (second tumors, small-bowel obstruction). Results from prospective and retrospective studies of mantle irradiation alone for unselected CS I-II patients have been disappointing. The EORTC H1 trial, one of the first studies to evaluate the role of chemotherapy in early-stage Hodgkin’s disease, randomized clinically staged I-II patients to receive mantle irradiation alone or combined with vinblastine chemotherapy. All CS I-II patients were enrolled. Fewer recurrences were seen in patients who received both mantle irradiation and vinblastine chemotherapy. However, relapse rates were high in both groups (freedom from recurrence was only 38% in the mantle alone group, the 15-year survival rate was only 58%), suggesting that mantle irradiation alone was not adequate treatment for unselected patients with CS I-II Hodgkin’s disease.164,226 Similarly, the Toronto series reported that a 10-year rate of freedom from recurrence was only 54%.227 These high recurrence rates in unselected patients are not surprising, as over 20% of CS I-II patients have occult abdominal involvement, and absence of treatment (with RT or chemotherapy) to cover potential abdominal disease therefore results in higher recurrence rates than achieved with more extensive treatment. When mantle irradiation was restricted to clinically staged, asymptomatic patients with a single lymph node region involved (CS IA), better results have been seen with 10- to 15-year freedom-from-recurrence rates of 58 to 81%.227–229

What is the appropriate treatment for patients who by prognostic criteria have a very low risk (5%) of abdominal involvement? These include female patients with CS IA disease, CS IA patients with NLPHD or interfollicular Hodgkin’s disease, and CS IA males with high neck involvement.140,141 A similar subgroup of patients was defined by the EORTC (women less than 40 years of age with CS IA NSHD or NLPHD and an ESR < 50 mm) and treated with mantle irradiation alone without staging laparotomy in the EORTC H7VF (VF, very favorable) and H8VF trials. In the H7VF trial, 40 patients were treated according to this concept and complete remission was reached in 95%. However, 23% of patients relapsed, yielding a 6-year event-free survival rate of 66%, a relapse-free survival rate of 73%, and overall and cause-specific survival rates of 96%.230 The relapse rates were thought to be unacceptably high in this selected subgroup of stage IA patients, and these patients are now managed according to the EORTC strategy for the favorable subgroup.

Mantle Irradiation Alone in PS IA-IIA Patients

To determine the role of prophylactic abdominal irradiation in early-stage Hodgkin’s disease, the EORTC H-5 trial (1977–1982) compared the use of mantle and para-aortic-splenic pedicle irradiation to mantle irradiation alone in patients with favorable early-stage Hodgkin’s disease.164,231 This study included only patients with nodular sclerosis or lymphocyte predominance histology, age 40 or younger, PS I or PS II with mediastinal adenopathy, and an ESR of less than 70. No differences were seen in disease-free survival or overall survival between the two treatment groups. The 9-year cumulative treatment failure probability was 31% for mantle and 30% for mantle and para-aortic irradiation. The 9-year overall survival rates were 94% and 91%, respectively. A 1997 update of this trial, with 15-year follow-up, still shows no statistical difference between the two treatment arms, either for cumulative treatment failure probability (p = .62) or overall survival (p = .69). These excellent results with mantle irradiation alone in laparotomy-staged patients have been corroborated in other retrospective studies.228,232

In 1988, a single-arm trial was initiated at Harvard University Medical School for laparotomy-staged IA-IIA Hodgkin’s disease patients to identify patients most suitable for mantle irradiation alone. The eligibility criteria for the study included a negative laparotomy, the absence of large mediastinal adenopathy and B symptoms, and nodular sclerosis or lymphocyte predominance histology. In contrast to the EORTC H5F study, patients over 40 years old and patients with a high ESR (> 70) were included in the study. The Harvard Joint Center for Radiation Therapy trial also defined parameters for eligibility and treatment of patients with mediastinal involvement. Thoracic computed axial tomographic scanning and gallium scanning were required to establish the extent of thoracic involvement, and patients with Hodgkin’s disease in hilar, subcarinal, or cardiophrenic lymph node regions were not eligible for the trial. In patients without mediastinal involvement, the bottom of the mantle field extended to the bottom of T7 or T8 to include the hilar and subcarinal nodes but excluded most of the heart from the radiation field. In patients with upper mediastinal involvement, the bottom of the mantle was extended to the bottom of T10 or T11 to include the medial cardiophrenic nodes; a subcarinal block was added at 30 Gy. The mantle was treated to 30 to 36 Gy with a cone down to a total dose of 38 to 44 Gy to regions of initial involvement. Eighty-four patients have been enrolled. Preliminary results of the trial have been published.233,234 The 5-year actuarial rate of freedom from recurrence continues to be greater than 80%.

Combined Radiation Therapy and Chemotherapy

Randomized Clinical Trials Identifying the Optimum Chemotherapy Combination

Randomized trials of combined modality therapy are based on the premise that this approach results in a very high freedom from recurrence in early-stage Hodgkin’s disease, and that the efficacy of combined chemotherapy and radiation can be maintained by using chemotherapy regimens that contain less toxic drug combinations. Listed in Table 129.7 are recent trials using modified chemotherapy regimens and RT. The regimens are combined with involved field or regional (or mantle) RT with the premise that the drugs being tested will be able to control occult abdominal disease in clinically staged patients without upper abdominal and splenic irradiation. In the southwest oncology/cancer and leukemia Group B trial, subtotal nodal and splenic irradiation (STLI-S) was used in the CMT arm presumably due to concerns for limited doses of Adriamycin and velban to control abdominal disease. The newer short-course VAPEC-B and Stanford V trials only use RT above the diaphragm. Analysis of patterns and frequency of failure will eventually provide better guidelines for such modified regimens to control occult Hodgkin’s disease not appreciated on physical examination or radiographic evaluation either in adjacent nodes or below the diaphragm.

Table 129.7. Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimum Chemotherapy Combination.

Table 129.7

Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimum Chemotherapy Combination.

Stanford trial of vinblastine, methotrexate, bleomycin, and regional irradiation versus mantle and para-aortic-splenic pedicle irradiation in CS IA-IIA patients

With the objective of reducing acute toxicity and chronic morbidity (sterility, increased risk of leukemia), Horning et al. developed the VBM (vinblastine, methotrexate, bleomycin) regimen, which was tested in a randomized trial of PS IA-IIB and PS IIIA patients. The trial compared subtotal nodal/total nodal irradiation to involved field irradiation (44 Gy) followed by VBM.235 The freedom-from-disease progression at 9 years favored involved field irradiation and VBM (98%) over subtotal nodal/total nodal irradiation (78%) (p = .01). No differences were seen in overall survival. The British National Lymphoma Investigation (BNLI) has confirmed the efficacy of VBM with involved-field irradiation, but in their experience this approach produced unacceptable pulmonary and hematologic toxicity.236 Favorable results with VBM and extended-field RT in CS IA-IIA Hodgkin’s disease also have been reported by the Gruppo Italiano per lo Studio Dei Linformi.237 In that study of 50 patients, the 5-year progression-free survival rate was 82%. Eight patients in the trial experienced pulmonary toxicity. In the completed follow-up Stanford University trial,238 patients with CS IA-IIA Hodgkin’s disease were treated either with subtotal nodal and splenic irradiation or two cycles of VBM, followed by regional (mantle) irradiation, followed by four additional cycles of VBM (with a reduced bleomycin dose). No differences in the 4-year freedom from disease progression or survival were noted (see Table 129.7).

EORTC H7F trial (1988–1993)

EBVP II and involved field irradiation (n = 168) versus mantle and para-aortic-splenic irradiation (n = 165) for favorable prognosis CS IA-IIA patients. The EORTC EBVP II regimen (epirubicin, bleomycin, vinblastine, and prednisone, one dose per cycle) was proposed as a potentially less toxic but similarly effective regimen compared to ABVD. In the H7F trial, six cycles of EBVP were combined with involved-field radiation and randomly compared with subtotal nodal and splenic irradiation. At 6 years, the relapse-free survival rate was significantly higher for patients on the combined chemotherapy and RT arm than for those on the RT alone arm (92 vs. 81%, respectively, p = .004). The 6-year survival rate was excellent in both treatment arms (98 vs. 96%, respectively, p = .156).230,239 In contrast, in the H7U trial for patients with unfavorable disease, EBVP and involved-field RT was inferior to MOPP/ABV and involved-field RT, suggesting that defining prognostic factors is crucial in selecting patients for modified chemotherapy and RT regimens.

Manchester pilot study and BNLI trial

VAPEC-B chemotherapy for 4 weeks and involved field irradiation versus mantle irradiation alone. Preliminary reports from the Manchester pilot study using the relatively brief 4-week VAPEC-B regimen (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, prednisolone) in early-stage Hodgkin’s disease provide background data for the ongoing BNLI trial. In the Manchester study, 111 CS IA-IIA patients without mediastinal bulk have been randomized since 1989 to receive either limited RT alone or VAPEC-B followed by local irradiation only to the involved regions. With a median follow-up time of 3.3 years, there have been only two recurrences in the VAPEC-B plus local irradiation arm. The progression-free survival rate at 3 years is 91% for those who received combined VAPEC-B and radiation.240 The current BNLI study has a similar design; however, the RT alone arm includes full mantle irradiation rather than a more limited field.

SWOG/CALGB study of three cycles of adjuvant doxorubicin and vinblastine plus subtotal nodal and splenic irradiation versus subtotal nodal and splenic irradiation alone in CS IA-IIA Hodgkin’s disease patients

This study is ongoing (see Table 129.7). As of June 1998, 284 patients had been enrolled in the study (information provided by courtesy of Dr. Todd Wasserman, June 1998 CALGB update). Fifty-four patients are ineligible due to protocol violations. Eighty patients on the subtotal nodal and splenic irradiation arm and 82 patients in the doxorubicin/vinblastine and radiation arm have been evaluated for short-term toxicity. This trial should provide answers to the following question: Is the extra toxicity of the doxorubicin and vinblastine in a group of patients with an expected favorable prognosis with treatment with RT alone justified? Subsequent trials have been designed not to use extended field irradiation when combined with CT.

Modified Stanford V for early-stage favorable prognosis HD

The relatively short but intensive Stanford V chemotherapy regimen, given for 12 weeks to patients with poor prognosis stage I-II disease,241 has been modified for favorable prognosis CS IA-IIA patients to 8 weeks of the Stanford V regimen and involved field irradiation to sites of initial involvement (identified radiographically as nodal enlargement of 1.5 centimeters or greater). The chemotherapy regimen includes mechlorethamine (6 mg/m2 on weeks 1 and 5), doxorubicin (25 mg/m2 on weeks 1, 3, 5, and 7), vinblastine (6 mg/m2 on weeks 1, 3, 5, and 7), prednisone (40 mg/m2 on days 1–36 then taper off), vincristine (1.4 mg/m2 on weeks 2, 4, 6, and 8), bleomycin (5 u/m2 on weeks 2, 4, 6, and 8), and VP-16 (60 mg/m2 on days 15 and 16 and days 43 and 44). This regimen will evaluate the ability of brief but intense chemotherapy to control Hodgkin’s disease outside of initially involved sites in favorable prognosis CS I-II patients.

Randomized Clinical Trials Identifying the Optimum Number of Cycles of Standard Chemotherapy

The trials noted here use standard combination chemotherapy regimens combined with RT and study the number of cycles of chemotherapy needed (Table 129.8).

Table 129.8. Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimal Number of Chemotherapy Cycles.

Table 129.8

Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimal Number of Chemotherapy Cycles.

The German Hodgkin’s Study Group HD7 Trial (1994–1998)

The GHSG accrued 643 favorable CS IA-IIB Hodgkin’s disease patients. The study randomized patients to subtotal nodal and splenic irradiation alone or to two courses of ABVD and the RT regimen. The first 365 patients are available for analysis. The data are preliminary (generously provided by Dr. Volker Diehl), but a borderline advantage in freedom from treatment failure is seen in the patients receiving ABVD X 2 and subtotal nodal and splenic irradiation (96%) compared to those treated with subtotal nodal and splenic irradiation alone (87%, p = .05). There are several questions that may be eventually answered by this study. First, with an expected long-term freedom from treatment failure in favorable CS IA-IIA Hodgkin’s disease of approximately 80 to 90%,165 is the added small benefit in freedom from treatment failure with ABVD X 2 worth the extra risk from the doxorubicin and bleomycin? Second, is it more difficult to salvage patients who recur after subtotal nodal and splenic irradiation and ABVD X 2 than after subtotal nodal and splenic irradiation alone? Do patients who relapse after combined chemotherapy and RT more frequently require high-dose chemotherapy and stem cell rescue as opposed to standard chemotherapy? New strategies for reducing late treatment-related mortality include reduction of field size. This strategy is being adopted by the GHSG HD 10 trial listed below.

The German Hodgkin’s Study Group HD10 trial (open 1998)

This study randomized patients to four treatment arms: two cycles of ABVD followed by 30 Gy involved field radiation therapy; two cycles of ABVD followed by 20 Gy involved field radiation therapy; four cycles of ABVD followed by 30 Gy involved field radiation therapy; and four cycles of ABVD followed by 20 Gy involved field radiation therapy. The questions being asked in this ongoing trial are how many cycles of ABVD are needed to control occult Hodgkin’s disease in the abdomen and in apparently uninvolved sites adjacent to known Hodgkin’s disease and what dose of radiation is needed to control Hodgkin’s disease when combined with limited chemotherapy? This trial should give physicians further guidelines for reduction of treatment in early-stage favorable prognosis Hodgkin’s disease.

EORTC H8F trial (1993–1998)

Three cycles of MOPP/ABV hybrid and involved field irradiation versus mantle and para-aortic-splenic irradiation for favorable prognosis CS IA-IIA patients. This trial, completed in 1993, should give answers to the following important questions: Are three cycles of standard chemotherapy sufficient to control subclinical Hodgkin’s disease in favorable prognosis CS IA-IIA patients? Can patients who relapse after three cycles of MOPP/ABV and involved field RT be cured with alternative treatment short of high-dose chemotherapy and stem cell rescue? The trial uses a hybrid regimen, which confers some risk of sterility and leukemogenesis in these favorable prognosis Hodgkin’s disease patients. Because of this concern, ABVD and EBVP without MOPP are being proposed for subsequent trials.

Randomized Clinical Trials Identifying the Appropriate Radiation Volume and Dose when Combined with Chemotherapy

Two ongoing trials in favorable prognosis early stage Hodgkin’s disease are evaluating radiation dose to involved sites after chemotherapy. The GHSG HD10 trial (see Table 129.8) evaluates the number of cycles of chemotherapy and radiation dose. Patients are randomized to two or four cycles of ABVD. Patients in complete remission will be randomized to either 20 Gy or 30 Gy involved field radiation. Four groups of patients will be studied: ABVD X 2 and 20 Gy, ABVD X 2 and 30 Gy, ABVD X 4 and 20 Gy, and ABVD X 4 and 30 Gy. The EORTC H9F trial is evaluating 36 Gy, 20 Gy, or no radiation to involved sites in patients who have achieved a complete remission after six cycles of EBVP II.

Chemotherapy Alone

Randomized Clinical of Chemotherapy Alone versus Radiation Therapy Alone

Two randomized trials in PS I-II patients have been published evaluating MOPP CT alone versus STLI alone. The National Cancer Institute (NCI) study was initially designed to include patients with both favorable and unfavorable prognosis early-stage Hodgkin’s disease. However, the most favorable patients with PS IA Hodgkin’s disease in peripheral sites were not included in the trial and were treated with RT alone, and patients with an unfavorable prognosis (B symptoms, large mediastinal adenopathy, and limited stage III disease) were included in the trial.242 Patients were randomized to 6 months of MOPP chemotherapy alone or subtotal nodal irradiation alone. After researchers recognized that patients with massive mediastinal involvement and PS IIIA disease were not optimal candidates for the RT alone arm, the eligibility criteria were changed while the study was ongoing. Table 129.9 shows the data for the IA (central sites), IB, IIA, and IIB patients without large mediastinal involvement. No difference in disease-free or overall survival is seen at 10 years.

Table 129.9. Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials of Chemotherapy Alone versus Radiation Therapy Alone.

Table 129.9

Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials of Chemotherapy Alone versus Radiation Therapy Alone.

The Italian prospective randomized study randomized patients with PS IA-IIA Hodgkin’s disease randomized to receive either 6 months of MOPP alone or subtotal nodal irradiation alone.192 There were no differences in freedom from progression (see Table 129.9). However, the survival rate was significantly higher in patients treated with RT alone (93%) than in those treated with chemotherapy alone (56%). The difference in survival was attributed to the inability to salvage patients relapsing after MOPP chemotherapy. These results are similar to the poor results of salvage ABVD in patients who relapsed after MOPP for advanced Hodgkin’s disease (see earlier discussion). Both the NCI and the Italian studies demonstrated greater acute toxicities in patients who received MOPP chemotherapy. In the Longo study, more than 50% of patients treated with MOPP had at least one hospital admission for fever and neutropenia.

Both trials demonstrate FFTF rates of only 64 to 82% with MOPP alone. These rates are too low when compared with results with CMT where the FFTF rates are 85 to 90%. The increased risk of relapse after CT alone is of concern until more is known abut the success and toxicity of salvage treatment for relapse after CT for early-stage Hodgkin’s disease.

The National Cancer Institute of Canada (NCIC) CTG HD6 Study is a modification of the NCI and Italian studies with the randomization of clinically staged patients and the use of ABVD as the chemotherapy regimen. Favorable prognosis patients (nodular sclerosis or lymphocyte predominance histology, age less than 40, ESR less than 50, one to three sites of involvement) are randomized to subtotal nodal irradiation and splenic irradiation versus four cycles of ABVD alone. The study is open for accrual.

Randomized Clinical Trials of Trials of Chemotherapy Alone versus Combined Modality Therapy

The ongoing EORTC 3-armed trial (H9F) for favorable prognosis CS I-II patients compares six cycles of the EBVP II regimen alone to the same regimen with different doses of involved field irradiation. Patients who achieve a complete remission after the chemotherapy are randomized to 36 Gy involved field irradiation versus 20 Gy involved field irradiation versus no RT (Table 129.10). This trial is designed to evaluate the role of involved field irradiation in favorable prognosis early-stage Hodgkin’s disease and to evaluate potential differences in the dose of radiation delivered.

Table 129.10. Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials of Chemotherapy alone versus Combined Modality Therapy.

Table 129.10

Randomized Clinical Trials in Favorable Prognosis Stage I-II Hodgkin’s Disease: Trials of Chemotherapy alone versus Combined Modality Therapy.

The Memorial Sloan Kettering Cancer Center trial randomizes CS I-IIIA patients who have achieved a complete remission after six cycles of ABVD to either mantle irradiation (35 Gy) or no further treatment. Patients with large mediastinal adenopathy and nodes greater than 10 centimeters are not eligible; however, CS IIB and CS IIA patients are included: thus, this trial is not restricted to early-stage favorable prognosis Hodgkin’s disease. This trial has enrolled approximately 120 patients out of a planned total of 200 patients.

Recommendations and Future Directions

Standard care currently provides a number of treatment options for patients with early-stage favorable prognosis Hodgkin’s disease. These include the use of mantle irradiation alone for selected patients after a negative laparotomy, mantle-para-aortic and splenic irradiation without laparotomy, and combination chemotherapy and RT, often with a modified number of cycles of chemotherapy and some modification of radiation field sizes and doses. Reasonable modification of chemotherapy off-study includes giving ABVD for four cycles. Reasonable modifications of RT off-study include involved fields to 36 to 40 Gy when combined with four to six cycles of chemotherapy, and mantle irradiation (for supradiaphragmatic presentations) to 25 to 30 Gy followed by a boost to 30 to 40 Gy when combined with four cycles of chemotherapy.

Current clinical trials are evaluating the use of alternative chemotherapy combinations, shortened courses of chemotherapy, chemotherapy with smaller radiation fields or lower radiation doses, and chemotherapy without RT. Fortunately, death from Hodgkin’s disease in favorable prognosis early-stage patients is unusual and mortality from causes other than Hodgkin’s disease occurs many years later; however, this means that survival is not a useful parameter to evaluate results in early-stage Hodgkin’s disease. Current trials must be judged by freedom from first recurrence rates, acute morbidity, and by new criteria such as quality of life and cost-effectiveness.187 Trial objectives to obtain the highest freedom from first recurrence possible may not provide the optimum treatment once long-term (10–20 year) data are available; treatment-related mortality may exceed Hodgkin’s disease mortality in favorable prognosis early-stage patients as a result of this strategy. New methods in decision analysis should also help in the design of trials and in the analysis of retrospective data.187

Despite the increasing availability of guidelines for the treatment of Hodgkin’s disease, there must remain room for individualization of treatment. With different treatment options, some of which may result in a higher recurrence risk at the gain of less toxic initial treatment (without any difference in long-term survival), patient preferences must be assessed. In addition, treatment should be individualized when a particular treatment approach might result in a higher risk of serious late complications, even when these complications may not influence overall survival (i.e., treatment of young female patients with large radiation fields and the risk of late breast cancer).

Unfavorable Prognosis CS I-II Hodgkin’s Disease

A number of clinical trials comparing RT alone versus combined modality therapy for unfavorable prognosis stage I-II Hodgkin’s disease were conducted in the 1970s and 1980s. The high recurrence rates with RT alone led to the development of strategies in current trials that use various combinations of both combination chemotherapy and RT. To illustrate, the large EORTC (H5U) trial randomized patients with unfavorable prognostic factors to total nodal irradiation versus MOPP chemotherapy (six cycles) and mantle irradiation. There were differences in treatment failure (35 vs. 16%, p < .001) favoring the CMT arm, but no overall survival differences (69% in both groups at 15 years).231

Trials To Identify the Best Chemotherapy Combination

The evolution of studies to identify the best chemotherapy combination for unfavorable early-stage Hodgkin’s disease paralleled trials to identify the optimal chemotherapy for advanced Hodgkin’s disease. Early trials evaluated MOPP versus MOPP-like combinations, later trials compared these combinations with ABVD, and, finally, the most recent trials compare new intense chemotherapy combinations with ABVD. Representative trials are shown in Table 129.11.

Table 129.11. Randomized Clinical Trials in Unfavorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimal Chemotherapy Combination.

Table 129.11

Randomized Clinical Trials in Unfavorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Optimal Chemotherapy Combination.

The first combined modality trial to test MOPP versus ABVD in unfavorable prognosis patients was the Milan study conducted between 1974 and 1982. Split-course treatment was employed, with three cycles of chemotherapy preceding and following subtotal nodal irradiation. There was no significant difference in 5-year freedom from progression.243 However, the number of patients enrolled is small. The EORTC H6U trial (1982–1988) also used split-course chemotherapy and RT and compared MOPP and ABVD.244,245 Three hundred sixteen patients were randomized. The 10-year survival was equivalent in both arms, but the freedom from treatment failure rate was significantly higher with ABVD than with MOPP

The Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA) trial and the EORTC H7U trial (see Table 129.11) studied modified nonalkylating regimens versus standard alkylating agent regimens in unfavorable prognosis early-stage patients. All patients received combined RT and chemotherapy. In both trials, the arms using modified chemotherapy were associated with significantly higher recurrence rates. In the EORTC, the recurrence rate was high enough to result in early closure of the trial. In the GATLA trial, the event-free survival was 66% for doxorubicin vincristine prednisone etoposide and involved field RT versus 85% (p = .009) for CVPP (cyclophosphamide, etoposide, procarbazine, and prednisone) and IFRT.246 In the EORTC trial, the event-free survival was 68% for EBVP II and IFRT versus 90% (p = .0001) for MOPP/ABV.246a These trials illustrate the importance of careful assessment of prognostic factors prior to treatment for early-stage Hodgkin’s disease. Minimal CMT treatment approaches may not be ideal for patients with unfavorable prognosis CS I-II disease.

Based mainly on trials in advanced Hodgkin’s disease, ABVD has become the standard regimen used in patients with CS I-II disease. A number of current trials compare combined modality therapy using ABVD with more intense, novel regimens. Both the EORTC H9U and GHSG HD11 studies of combined modality therapy are comparing four cycles of ABVD with four cycles of BEACOPP-baseline (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone).90 In the ECOG 2496 trial of combined modality therapy, six cycles of ABVD are being compared to 3 months of Stanford V.235

Trials To Identify the Optimal Number of Cycles of Chemotherapy

Two large randomized trials are currently evaluating whether four cycles of combination chemotherapy and RT is sufficient treatment compared to six cycles of chemotherapy and RT. The recently closed EORTC H8U study randomized patients to combined modality therapy with four or six cycles of MOPP/ABV, but the results have not yet been reported (Table 129.12). The new EORTC H9U trial randomizes patients between four or six cycles of ABVD.90 A number of retrospective or prospective single-arm trials have evaluated the role of number of cycles of chemotherapy in patients with large mediastinal disease.247–250 The results vary and the number of patients studied is small; a more definitive answer will need to come from large randomized trials.

Table 129.12. Randomized Clinical Trials in Unfavorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Appropriate Radiation Volume.

Table 129.12

Randomized Clinical Trials in Unfavorable Prognosis Stage I-II Hodgkin’s Disease: Trials To Identify the Appropriate Radiation Volume.

Trials To Identify the Appropriate Radiation Therapy Volume

Several randomized trials have studied radiation field size when combined with chemotherapy for unfavorable prognosis early-stage Hodgkin’s disease. The French trial reported by Zittoun et al. randomized 218 stage I-II unfavorable prognosis patients to six cycles of MOPP sandwiched around involved field (40 Gy) or extended field (40 Gy) irradiation.251 The 6-year disease-free survival rates were 87 and 93%, respectively (p = .15), for the involved field and extended field arms. The Milan study reported by Santoro and colleagues incorporated only 4 months of chemotherapy (ABVD), followed by involved field (36 Gy) or subtotal nodal irradiation (30–36 Gy). One hundred thirty-three patients were treated; 20% had bulky disease.252 The 5-year freedom-from-progression rates were 96% and 93%, respectively (see Table 129.12). The EORTC/GELA H8U trial, closed in 1998, randomized patients to four cycles of MOPP/ABV plus involved field radiation (36 Gy) versus 4 cycles of MOPP/ABV plus subtotal nodal irradiation in two of the three arms. The GHSG HD8 trial, conducted between 1993 and 1998, used two cycles (4 months) of COPP/ABVD followed by either involved field or extended field irradiation to 30 Gy (see Table 129.12). Preliminary evidence from these randomized trials, as well as several nonrandomized studies, suggests that radiation fields may be safely limited to involved regions in most combined modality programs.253–255

Trials of Chemotherapy Alone versus Combined Modality Therapy

Only one prospective trial of chemotherapy alone versus combined modality therapy in unfavorable prognosis stage I-II has been reported. The GATLA randomized 104 patients with unfavorable disease characteristics to six cycles of CVPP alone or six cycles of CVPP sandwiched around involved field irradiation (30 Gy). The 7-year survival rates were 66 and 84%; the freedom-from-relapse rates were 34% and 75% (p < .001), both favoring combined modality treatment.256

The ongoing NCIC HD6 trial evaluates patients with unfavorable disease characteristics but excludes patients with large mediastinal adenopathy or nodes greater than 10 centimeters. Patients are randomized to receive combined modality therapy with two cycles of ABVD followed by irradiation (an extended mantle plus splenic irradiation or mantle plus para-aortic and splenic irradiation) or four to six cycles of ABVD alone (depending upon the rapidity of response).

Recommendations and Future Directions

The outcome of treatment for patients with unfavorable prognosis stage I-II Hodgkin’s disease has improved dramatically in the past 3 decades. Mainly, this is due to the use of combined modality therapy, since historically fewer than 50% of patients in some subgroups remain free in first remission when RT alone is used as initial treatment. Combined RT and chemotherapy not only enhances the likelihood of local tumor control, but it also should control occult nodal and extranodal disease in the majority of patients. Current clinical trials are exploring new combinations of RT and chemotherapy to try to reduce late morbidity and mortality while maintaining a high probability of freedom from first recurrence.

Continued refinement of the definition of “unfavorable prognosis” is needed in current trials. Current combined modality management protocols for favorable prognosis disease may be sufficient for patients who have three sites of disease or an ESR > 50, factors considered unfavorable in some clinical trials groups, but may not be sufficient for B symptoms or large mediastinal adenopathy. Detailed analysis of completed clinical trials may permit this redefinition, which would permit some patients to be treated with less aggressive management approaches.

Treatment of Advanced Hodgkin’s Disease

The management of Hodgkin’s disease utilizing chemotherapy represents one of the first major accomplishments of medical oncology. Although patients with localized Hodgkin’s disease could occasionally be cured with the radiotherapeutic techniques available in the mid-twentieth century, advanced Hodgkin’s disease was uniformly fatal. Even though mechlorethamine was shown to be an active drug in the 1940s, and numerous other active agents were discovered over the next 20 years,29 it was not until the 1960s that combination chemotherapy was used for patients with Hodgkin’s disease.33 Using single agents, less than 5% of the patients survived 5 years.257 In the mid-1960s, investigators at the NCI first treated patients with a four-drug combination chemotherapy regimen using mechlorethamine, vincristine, methotrexate, and prednisone (MOMP).33 When procarbazine became available, this drug was substituted for methotrexate (MOPP).26 The initial results with this regimen demonstrated improved complete remissions and prolonged survival, overcoming the concerns that “using up” all active drugs at one time would shorten survival.258 Since the curability of advanced Hodgkin’s disease with MOPP became accepted, numerous other chemotherapy regimens have been developed. These have been aimed at improving the effectiveness of therapy and at reducing toxicity. In recent years, combinations of increasing numbers of drugs, combined modality therapy, and high-dose therapy with autologous bone marrow transplantation have all been studied in an attempt to improve cure rates.

Early in the use of chemotherapy to treat malignancies, the model of leukemia where maintenance therapy was used was often applied. However, randomized trials documented the lack of benefit of maintenance chemotherapy in Hodgkin’s disease.259 It also became clear that comparatively brief courses of chemotherapy could affect cure in Hodgkin’s disease. Between 6 and 12 cycles of treatments have frequently been used. One randomized trial demonstrated that eight cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) was comparable to 12 cycles of alternating ABVD and MOPP.36 At present, the most frequently used duration of chemotherapy is six to eight cycles of ABVD—with the goal of treating two cycles after achieving remission. In some cases of Hodgkin’s disease, residual masses are apparent on CT scans at the completion of therapy. The distinction between persisting lymphoma and residual fibrous tissue can be difficult. Frequently, gallium scans are used to try to resolve this dilemma, with patients showing a positive gallium scan receiving further therapy.

The most popular chemotherapy regimen used in the treatment of advanced Hodgkin’s disease, for many years, was MOPP (Table 129.13). DeVita et al. reported 198 patients treated with this regimen.26 The complete remission rate was 81%. Eventually, 36% of the complete responders relapsed, giving a 52% 10-year disease-free survival rate. The overall survival at 10 years was 50%, reflecting some deaths from treatment-related toxicity. Several subsequent trials using MOPP36,260,261 have shown disease-free survivals of 36 to 47%.

Table 129.13. Chemotherapy Regimen Used for Hodgkin’s Disease.

Table 129.13

Chemotherapy Regimen Used for Hodgkin’s Disease.

A number of variations on the MOPP regimen have been reported (see Table 129.1).262–272 The most popular have been MVPP (mechlorethamine, vinblastine, procarbazine, and prednisone),263,264,268 ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone),262,269–272 and BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone).261 These regimens have led to disease-free survival rates approximately comparable to MOPP. The ChlVPP regimen has been reported to have less immediate toxicity and frequently has been used for the treatment of older patients.

The first major alternative to the MOPP regimen was reported by Bonadonna et al. in 1975.35 This regimen used ABVD. Whereas MOPP was administered for 14 days and then no treatment for 14 days, ABVD was administered every other week with all of the drugs given intravenously (see Table 129.1). There have now been a number of randomized trials comparing MOPP and ABVD.35,36 In no case has MOPP been found to be superior; it was generally found to have an inferior outcome. In addition, ABVD appeared to have less toxicity.273,274 A study by Cancer and Leukemia Group B showed a failure-free survival of 61% for ABVD and 50% for MOPP.36 The results of this study have caused ABVD to be, by far, the most frequently used regimen for treating advanced Hodgkin’s disease in the United States.

Bonadonna et al. first reported using a combination of MOPP and ABVD to treat patients with Hodgkin’s disease.260 The two regimens have been combined in a variety of ways in subsequent trials. Some patients received alternating cycles of MOPP and ABVD.260 Other studies combined MOPP and ABVD in a single cycle with the first 7 days of the cycle using the drugs from MOPP with the drugs in ABVD being given on day 8. In these studies, the dacarbazine was frequently deleted.275–278 Some studies found no difference between the two approaches,275–277 whereas others identified superiority to using MOPP/ABV in a “hybrid” regimen.278 A randomized trial comparing the alternating or hybrid regimens to ABVD alone did not show an advantage to the more complex regimen.36 This has further solidified the place of ABVD as the “standard” regimen for the treatment of advanced Hodgkin’s disease.

Unfortunately, 30 to 40% of patients with advanced Hodgkin’s disease treated with ABVD fail to achieve an initial remission or relapsed from remission. The proportion of patients with a large number of adverse risk factors that fail ABVD is even higher. These results have led to attempts at identifying improved treatment regimens. The most popular of these have been Stanford V and BEACOPP (Table 129.14).241,279–281 The Stanford V regimen uses doxorubicin, vinblastine, mechlorethamine, bleomycin, vincristine, etoposide, and prednisone. The drugs are administered weekly for 12 weeks.241 The regimen is followed by adjuvant RT to sites of bulky disease (i.e., ≥ 5-cm masses). The initial results of Stanford V showed an 8-year disease-free survival of 89% and overall survival of 96%.279 This regimen is now being tested in an intergroup trial with patients being randomized to receive Stanford V or ABVD.

Table 129.14. New Chemotherapy Regimen for Hodgkin’s Disease.

Table 129.14

New Chemotherapy Regimen for Hodgkin’s Disease.

Investigators in Germany have piloted a dose-intense regimen named BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (Table 129.14).280 The regimen has been used at two dose levels, with the higher dose level requiring hematopoietic growth factors and more intensive supportive care. When compared to COPP/ABVD in a randomized trial, the BEACOPP regimen (i.e., both dose levels were combined for the analysis) had a superior progression-free survival (i.e., 82 vs. 68% and overall survival 92 vs. 88%).281 Results were most striking in patients with a large number of adverse risk factors. Investigators were particularly impressed by the absence of early progression in patients treated with BEACOPP.

The place of combined modality therapy in advanced Hodgkin’s disease is clear in only a few instances. Patients with bulky mediastinal masses certainly benefit from adjuvant radiotherapy. The Stanford V regimen is a combined modality regimen and has initially been shown to have excellent results. The BEACOPP regimen also uses radiotherapy for bulky sites of disease at the completion of chemotherapy. In patients without bulky disease, most clinicians would avoid RT in an attempt to minimize long-term toxicity.

The optimal chemotherapy regimen for the treatment of patients with advanced Hodgkin’s disease remains unknown. All regimens fail to cure some patients and long-term toxicity is a significant concern. The risk of secondary leukemia seems to be a reflection of the dose of alkylating agents in the treatment regimen. Secondary acute leukemia or myelodysplasia is an unusual complication of treatment with ABVD but occurs more frequently in patients treated with MOPP-like regimens.282 The risk of secondary solid tumors seems to be primarily related to the use of RT in the treatment regimen, although alkylating agents are associated with an increased risk of lung cancer, especially in patients who smoke.198,283 Other toxicities including heart disease, lung disease, endocrine dysfunction, and infertility are seen in a subset of patients.284,285 However, in patients with poor-risk Hodgkin’s disease, the cure rate does not seem to be high enough with available treatments to reduce dose intensity, although in good-risk patients with advanced disease this might be a reasonable consideration.

Very high-dose therapy and autologous bone marrow transplantation have also been tested as part of the primary therapy in patients with very poor-risk Hodgkin’s disease. Carella et al. reported 15 patients who underwent autologous transplantation after an initial remission with MOPP/ABVD and compared these patients to 24 nonrandomized controls.286 At 3 years, 87% of the patients who underwent transplant remained in remission, in contrast to 33% of the control patients.287 The European Group for Bone and Marrow Transplantation compared 56 patients transplanted in complete remission with 168 patients who were matched by risk factors from the GHSG. Freedom from relapse was superior in patients undergoing transplantation, but overall survival did not differ. At present, the place of bone marrow transplantation in the primary therapy of patients with Hodgkin’s disease remains uncertain.

Salvage Therapy

For the purposes of this section, salvage therapy refers to treatment administered to patients with Hodgkin’s disease who fail to achieve an initial complete remission or relapse after achieving an initial complete remission. Although seemingly straightforward, the diagnosis of treatment failure is not always easy. Patients with bulky mediastinal or retroperitoneal masses regularly have residual, albeit smaller, masses on imaging studies at the completion of successful therapy. In these patients, previously abnormal gallium scans and elevated ESR usually revert to normal, but this may take some time. In many cases, a biopsy will be required to prove persistent lymphoma. Biopsy should always be done in the patient who achieves a complete remission and then develops new adenopathy or imaging abnormalities. A patient with Hodgkin’s disease can develop non-Hodgkin’s lymphoma, other malignancy, and tuberculosis or other infections. Failure to establish a firm diagnosis of relapse can be tragic.

Patients who are treated initially with RT alone and progress have an excellent outcome with salvage chemotherapy.175,176,288 When compared to patients who are treated with chemotherapy from the outset, those receiving similar chemotherapy regimens for relapse after RT have an equivalent or superior outlook.175 The use of RT to rescue patients who fail chemotherapy is occasionally an effective treatment maneuver. In patients with localized relapse, extended field RT can achieve durable remissions in 25 to 50% of cases.289–293 It must be emphasized that only occasional patients with nonbulky disease confined to a few node-bearing areas and who do not have systemic systems are candidates for this treatment approach.

Unfortunately, 30 to 60% of patients with advanced Hodgkin’s disease will either fail to achieve a remission with chemotherapy or relapse after complete remission. Those patients, who are primarily refractory and never achieve an initial remission to an effective chemotherapy regimen, have a particularly poor outlook. Early experience with ABVD showed that some patients who failed MOPP could be successfully treated, whereas the converse was less often true.189 Even so, the durable remission rate in this setting is less than 20%.191

Early autologous bone marrow transplantation in patients who are primarily refractory to an excellent chemotherapy regimen for Hodgkin’s disease can produce durable remissions in a significant proportion of patients. The North American Autologous Blood and Marrow Transplant Registry reported 103 such patients. The overall in progression-free survival at 5 years was 40%.294 The European Group for Blood and Marrow Transplantation described 290 patients with primary refractory Hodgkin’s disease and reported a 5-year failure-free survival of 30%.295 Investigators at Stanford University performed a case-control study for primary chemotherapy failures. They found an event-free survival at 4 years of 52% for transplantation in contrast to 10% for alternate standard chemotherapy regimens.296 Patients who fail to achieve remission with primary chemotherapy are best treated with autologous bone marrow transplantation, and this probably represents the clearest indication for autologous transplantation in patients with Hodgkin’s disease.

Patients who achieve an initial complete remission and relapse represent a heterogeneous group of patients. In general, the longer the initial complete remission, the better the outlook with any form of salvage therapy.191,297 A follow-up analysis of the original MOPP-treated patients from the NCI found that those patients who had an initial remission longer than 12 months achieved second complete remissions 74% of the time, in contrast to only 28% in patients with initial remissions lasting less than 1 year.191 However, even in patients with long initial remissions, the eventual survival from first relapse was only 24%. Similar results have been reported from Milan,297 Vancouver,298 and Paris.299 In addition to a brief initial remission, other adverse prognostic factors include advanced age, more extensive initial disease, systemic symptoms, and elevated serum lactate dehydrogenase level.299

A variety of treatment regimens have been used for patients with relapsed Hodgkin’s disease. In addition to MOPP or ABVD in patients who received the opposite regimen initially, a number of other treatments have been used.300–306 Unfortunately, the number of patients achieving extended survival free of Hodgkin’s disease is quite poor, although patients with no adverse risk characteristics (see above) have been reported to have 5-year failure-free survivals as high as 50%.191,297 In patients with multiple treatment failures, the results are much less good. In these patients, there is often a point where further intensive chemotherapy regimens are more likely to do harm than good, and a palliative treatment approach should be adopted. Treatment approaches such as low-to-moderate doses of vinblastine administered weekly307 and the judicious use of involved-field radiotherapy can alleviate symptoms and produce a reasonable quality of life. Asymptomatic patients might be best followed without therapy. Patients with fevers refractory to other treatment approaches can sometimes be effectively palliated with nonsteroidal anti-inflammatory drugs such as naproxen or indomethacin.

Autologous bone marrow transplantation has been shown to be able to rescue occasional patients with multiply relapsed Hodgkin’s disease.308–319 Unfortunately, the results in this setting are usually disappointing. Because of the superior results in patients treated early in the course of the disease, most advocates of bone marrow transplantation would prefer to use it as part of the treatment of the initial relapse following any effective initial chemotherapy regimen. In this setting, patients who receive an alternate standard chemotherapy regimen and achieve at least a partial remission then undergo autologous transplantation. The results in this setting have yielded durable remissions in 47 to 85% of patients.320–322

Allogeneic bone marrow transplantation has been performed in patients with relapsed Hodgkin’s disease, but the results have been disappointing. Treatment-related mortality rates have varied from 31 to 61%.323–327 The explanation for the high treatment-related mortality with allogeneic transplantation might relate to patient selection or other, as yet unidentified, factors making these patients more susceptible to treatment toxicity. At the present time, allogeneic bone marrow transplantation should rarely be selected as a salvage treatment for patients with Hodgkin’s disease.

Summary

Tremendous progress has been made in the last 3 decades toward the cure of Hodgkin’s disease. Additional work, however, is needed to further minimize the morbidity and mortality associated with the disease and its treatment. This includes the need to better understand the etiology and pathology of Hodgkin’s disease, to optimize control rates, especially in patients with unfavorable prognosis or advanced-stage disease, to modify therapeutic approaches to reduce the long-term complications, and to increase the awareness of physicians and patients to the potential late effects of treatment so that patients will receive appropriate follow-up care.

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