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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 138CHodgkin’s Disease in Children and Adolescents

, MD, PhD, , MD, and , MD.

Hodgkin’s disease (HD) accounts for about 5% of pediatric malignancies in the developed world. With current treatments, 80 to 90% of all pediatric patients will be surviving without evidence of disease 10 or more years after diagnosis. The current research in the treatment of childhood Hodgkin’s disease is aimed at (1) identification of minimal treatment necessary for cure, (2) development of effective salvage therapy for the minority of patients with disease resistant to current treatments, and (3) amelioration, reduction or elimination of late effects of treatment. Efforts to determine the etiology of HD through a better understanding of its biology are also receiving much attention.

Clinical Presentation and Staging

The clinical presentation of childhood HD resembles that seen in young adults. The majority of patients are asymptomatic at diagnosis, and the disease is first suspected after the development of painless adenopathy in the cervical area. The involved nodes are often described as firm and “rubbery;” they may have some tenderness, if there has been rapid growth. The disease may be indolent with adenopathy present for several years prior to diagnosis, even including prior nondiagnostic biopsy. Up to 80% of patients have disease noted in the neck, with about 60% having at least some disease in the mediastinum. 1 Between 25 and 30% of children have systemic symptoms, which may include the “B” symptoms of fever (otherwise unexplained, > 38° C), weight loss (unintended and > 10% of body weight in the previous 6 months) and drenching night sweats. Fatigue and anorexia are often noted but are vague and nonspecific. Unexplained pruritus and pain that worsens with ingestion of alcohol should particularly lead to a consideration of Hodgkin’s disease. Most commonly, the disease spreads to adjacent lymph nodal regions; exclusive subdiaphragmatic disease is rare in both children and adults. 2 Rare but well-described presentations include autoimmune hemolytic anemia and immune thrombocytopenia. 3 Due to the frequency of mediastinal disease, chest radiography is an important initial step in the evaluation of cervical adenopathy. Once the diagnosis of HD is established via node biopsy, additional evaluation and staging are indicated.

CT scan of the chest has been shown to frequently discover disease not seen on the initial radiograph; this is critical in the planning of radiation therapy fields. 4 Most pediatric patients are now clinically staged on the basis of careful physical examination, CT scan of the neck, chest, abdomen and pelvis, and a Gallium-67 scan (positive in about 70% of patients), which may be particularly useful in the evaluation of the response of mediastinal disease. 5

Various modifications of the Ann Arbor staging classification 6 have been used in pediatrics. The usual stage I patient has involvement of a single lymph node region, while stage II patients have disease only on one side of the diaphragm (almost always above the diaphragm). Stage III patients have disease on both sides of the diaphragm, while stage IV indicates those patients with involvement of one or more extralymphatic organs or tissues, such as the liver, lung parenchyma, bone or bone marrow. With the widespread use of combined modality therapy, only a minority of pediatric patients now undergo a formal surgical staging procedure to establish pathologic stage; it is felt that this is indicated only if the findings will significantly alter therapy. Since clinical staging will miss subdiaphragmatic disease in up to 25 to 30% of patients, 7 it is strongly recommended that surgical staging be employed if treatment with radiation therapy alone is planned. Clinically staged patients treated with radiation alone have inferior event-free survival (EFS) when compared with surgically staged patients. 8

Biology

The challenge for improving the outcome of patients with HD requires a paradigm shift in our assessment of children and adolescents with HD from clinical to biologic parameters. Areas of investigation include (1) identification of the histogenesis of HD; (2) clarification of the morphology and immunohistochemical phenotypes; (3) determination of the prognostic significance of expression of markers of apoptosis; (4) identification of the surrogate biomarkers that increase the risk of treatment related second malignant neoplasms (SMNs).

The tumor cells in most cases of HD have been recently recognized to originate from the B-cell lineage. 9– 13 Preliminary data have shown that the histogenesis may be assessed by monitoring the expression pattern of Bcl-6, a transcription factor expressed in germinal center (GC) B cells, and CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation. 14– 16 Tumor cells in lymphocyte predominant HD consistently express a Bcl-6 (-)/syn-1 (-) phenotype indicating their origin from GC B cells. 15 Conversely, in classic HD, nodular sclerosis and mixed cellularity types, the expression is heterogeneous, with cases expressing a Bcl-6 (-)/syn-1 (+) reflecting a post-GC origin and cases with a mixture of these two immunophenotypic profiles. 16 The HD cells expressing Bcl-6 (-)/syn-1 (+) phenotype are surrounded by T cells expressing the CD40L, consistent with the observation that CD40 signaling downregulates Bcl-6 expression. 14, 15

The Rye histologic classification schema for HD has been the gold standard system for almost three decades. 17 Recently, other systems that define nodular lymphocyte predominance and classic HD, nodular sclerosis (NS) and mixed cellularity, and others which identify a grade I and II syncytial variant of NS have been used. Although with dose-intensive curative contemporary treatment regimens the Rye histologic schema has less prognostic significance, it remains to be determined whether the newer classifications and immunophenotypic analysis will be determinants of outcome. 18– 21

The response of HD to therapy may be dependent on host factors, including induction of the apoptotic pathway, proliferation rate, and drug resistance and sensitivity. Many of the currently used chemotherapeutic agents require cellular proliferation and act by inducing apoptosis in tumor cells. Initial studies into the role of apoptosis as a prognostic factor in HD have been conflicting. The apoptotic index for the Reed-Sternberg (R-S) cells at the time of diagnosis was not found to be an independent prognostic indicator, although an elevated index was associated with poor outcome. 22 Analysis of the proapoptotic markers FAS and FAS ligand has been associated with increased p53 mutations, which may cause loss of apoptosis and tumor cell progression. 23– 25 No association of apoptosis levels with BAX staining in R-S cells could be demonstrated, and study of antiapoptotic protein expression found high levels of Bcl-X and to a lesser extent Bcl-2 in R-S cells. 26 When high R-S cell expression of Bcl-2 has been found in conjunction with low p53, it has been associated with a poorer outcome when compared with cases with low expression of Bcl-2 and p53 suggesting that interactions between these factors may be of importance. 27

Proliferation may also play a role in sensitivity to therapy. Studies of proliferative activity have shown that R-S cells have a relatively high level of activity as measured by MIB-1, but no study has linked proliferative activity and response to therapy or relapse in HD.

The induction of apoptosis by chemotherapy and radiotherapy may be enhanced by topoisomerase inhibitors; however, for tumors to respond, they must express detectable levels of topoisomerases within the tumor. 28 Topoisomerase IIα has been found to be present in R-S cells of patients with lymphocyte-predominant histology. 29

The clinical association between endogenous and exogenous somatic events and the pathogenesis of pediatric cancer may be analyzed by the presence or absence of polymorphisms in common drug/carcinogen metabolizing enzymes.

Some of the best studied biomarkers of susceptibility for cancers include the polymorphic phase I cytochrome P450 enzymes (CYP1A1) and the polymorphic phase II glutathione-S-transferase genes (GSTM1 and GSTT1) that function in the activation and detoxification of chemotherapy drugs and environmental and endogenous carcinogens. 30, 31 Additional studies have identified other metabolizing enzymes, such as myeloperoxidase (MPO), NAD(P)H:quinone oxidoreductase (NQO1), cytochrome P450 3A4 and glutathione-S-transferase pi (GST-P1). These genetic polymorphisms may result in altered expression and/or function of these enzymes and may be important in cancer etiology research. Since many of these enzymes are also involved in the metabolism of alkylating agents, anthracyclines, epipodophyllotoxins, and Vinca alkaloids, their role in increasing the risk of chemotherapy-related second malignancies may be important. 32– 35 In addition, surrogate markers of genotoxic damage, such as N- and K-ras oncogene mutations, microsatellite instability, and DNA adducts may heighten the potential risk of second malignancies. In view of the significant risk of SMNs in survivors of childhood HD, the presence of these biomarkers may identify a cohort of patients who may benefit from chemoprevention.

Treatment

Developmental issues of the child and young adolescent differentiate the therapy of pediatric HD from that of the adult. While the therapeutic responsiveness of HD in children and adults is similar, effects of therapy on the host differ. A quick review of pediatric regimens reveals similarity to adult regimens with reliance on classic MOPP (Nitrogen, Mustard, Onocvin, Procarbazine, Prednisone) 36 and ABVD (Adriamycin, Bicomycin, Vinblastine, Dacarbazine); 37 yet, the approach, particularly in regard to radiation, diverges considerably (see Table 138C–1). Since multiple regimens exist that lead to cure rates of 85 to 90%, the focus in pediatric HD has become the reduction of long term effects.

Table 138C.1. Recent Trials in Pediatric Hodgkin’s Disease.

Table 138C.1

Recent Trials in Pediatric Hodgkin’s Disease.

Combined Modality Therapy as Standard of Care

Adult HD is traditionally treated with full-dose radiation alone for low-stage disease, with chemotherapy considered only for advanced-stage disease. Although low-stage pediatric HD can also be cured with radiotherapy alone, full-dose radiation delivered to the growing child results in cosmetically significant hypoplasia manifested by clavicular shortening, mandibular growth restriction, and reduced sitting height and neck circumference. 38, 39 Recognition of this has led pediatric oncologists and radiotherapists to avoid full-dose radiotherapy. Since the early 1980s, pediatric investigators have used lower doses (15–30 Gy) of limited-field radiotherapy in combination with chemotherapy in most children. 40 With this approach, efficacy is excellent and long-term effects are reduced.

Until recently, this approach was reserved for the pre- and peripubertal child. With recognition of the risks of breast cancer 41, 42 and myocardial ischemia 43, 44 occurring 10 to 20 years after full-dose radiotherapy, postpubertal children are also more likely to receive combined modality therapy.

Contribution of Chemotherapy to Cure

The excellent efficacy of MOPP and ABVD with radiotherapy has resulted in the cure of 85 to 90% of patients with HD. 36, 37 With the passage of time, it is clear, however, that many patients suffer from long-term effects of the chemotherapy itself. As children with all stages of disease now receive chemotherapy, our ability to mitigate these effects is paramount.

The German studies initiated in 1978 led the way for stepwise improvement in the therapy of pediatric HD. In addition to carefully evaluated procedures to determine the need for staging laparotomy and splenectomy, 45, 46 this group has attempted to minimize the use of alkylating agents to reduce the incidence of sterility and second malignancy. Pioneering a regimen known as OPPA/COPP (Oncovin, Procarbazine, Prednisone, Adriamycin/Cyclophosphamide, Oncovin), this group replaced nitrogen mustard with doxorubicin in one cycle (OPPA) and with cyclophosphamide in the other (COPP). 47 When the subsequent elimination of procarbazine resulted in a significant increase in therapeutic failure in higher-risk patients, etoposide was used in boys to replace procarbazine. With this change, the gender-based approach has reduced gonadal toxicity, while maintaining efficacy. 48, 49

Numerous studies in adults have compared MOPP and ABVD used alone, in alternating fashion and as a hybrid cycle. Doxorubicin-containing regimens appear to enhance outcome. Although ABVD does not have the significant risk of sterility or secondary malignancy that is associated with MOPP or COPP, it does carry the risk of anthracycline-induced cardiotoxicity and bleomycin-induced pulmonary toxicity. Hybrid regimens have the advantage of administering restricted cumulative doses of each effective agent. In an alternative approach, the Pediatric Oncology Group is studying dexrazoxane to see if it can prevent cardiopulmonary toxicity. 50

Chemotherapeutic intensity also appears important. 51– 53 The German studies of adult HD comparing a standard COPP/ABV regimen administered every 4 weeks with a similar dose-intensified regimen of BEA-COPP administered every 3 weeks with cytokine support found significant improvement in efficacy with the dose-intensive regimen, particularly as the cyclophosphamide dose was intensified. 54 Dose-intensive regimens of short duration can potentially minimize cumulative doses and, thus, long-term toxicity. Bartlett and colleagues reported a 3-year EFS of 87% in adults with advanced-stage disease treated with a 12-week, dose-intensive regimen. 55 The Pediatric Oncology Group (POG) is currently using dose-intensive regimens, with duration determined by early response. 50

Other chemotherapeutic agents may have fewer or nonoverlapping toxicities. Cytosine arabinoside and etoposide have shown promise in a number of regimens. 56, 57 Investigators at St. Jude Hospital have added methotrexate to vinblastine, doxorubicin, and prednisone to establish an effective regimen in low-stage disease that does not require alkylating agents. 58 The ability to replace such agents with antimetabolites in higher-stage disease remains unclear.

The Contribution of Radiation to Cure

Standard regimens for children and adolescents now include both low-dose radiation and chemotherapy. In the 1980s, the POG investigated the relative role of radiation and chemotherapy. No difference in outcome was noted between low-stage patients treated with two cycles each of MOPP and ABVD plus 25.5 Gy to involved fields versus three cycles of these agents without radiation therapy, suggesting either an equivalence between a cycle of chemotherapy and low-dose radiation or a sufficiency of treatment after two cycles each of MOPP/ABVD. 59 For advanced-stage patients, 5-year EFS was identical (78%) after four cycles each of MOPP and ABVD, regardless of subsequent randomization to no further therapy versus 21 Gy of total nodal irradiation. 60

Advanced-stage patients treated in the Children’s Cancer Group (CCG) also had similar EFS, regardless of whether six cycles of ABVD were supplemented with 25 Gy of radiation or with six cycles of MOPP. 61 A more recent CCG study showed that although the majority of patients could be treated without radiation, the relapse rate was significantly higher in all stages of disease without radiation. 62 Patients with bulk disease and “B” symptoms were at higher risk of relapse without radiation therapy. Radiation therapy thus plays an important role in the initial therapy of HD, but there are subsets of patients who may be safely treated without it.

The efficacy of radiation therapy is always dependent on the accuracy with which it is administered. Chemotherapists must remember that while stage alone may define the chemotherapy of choice, sites of disease define the radiation fields. The decision to use chemotherapy does not obviate the need to know the exact extent of disease.

Optimizing Combined Modality Regimens

The potential equivalence of radiation versus additional cycles of chemotherapy must be considered in light of the relative toxicities of each modality. While the relative risk of radiation-induced breast cancer may favor a chemotherapy-based regimen in many girls, the risk-benefit ratio in boys may favor radiation to avoid the risk of sterility with alkylating agents. Assessing the balance of risks is complex and made more difficult by the limited knowledge of risk with lower doses of radiation therapy. Multi-modality involvement at diagnosis is needed to ensure optimal treatment outcome for each patient.

Relapse

Most pediatric patients now receive multi-modality therapy upfront. Except for late, out-of-field relapse in minimally treated patients, the likelihood of cure with conventional approaches is limited after relapse. Autologous bone marrow transplantation offers a 30 to 50% chance of long-term survival and thus is the preferred approach. 63

Late Effects of Childhood Hodgkin’s Disease

The great majority of children now experience long-term survival after treatment for pediatric HD. A major focus of current research is on the detection, amelioration, and prevention of late effects of treatment. While virtually all organ systems are at risk for late effects, we will highlight five long-term complications with significant impact on survival and/or quality of life. The importance of this issue is highlighted by recent reports indicating that beyond the 10-year survival point, more patients die of treatment-related toxicity than of HD itself. 64, 65 These data emphasize the need for treatment strategies aimed at the reduction of late effects. The challenge for current treatments is to accomplish a reduction of late effects without a substantial decline in the primary cure rate.

Secondary Malignancy

The most feared late effect of HD is the development of a second malignancy. The earliest reports focused on secondary acute nonlymphocytic leukemia (ANLL) after treatment of HD with MOPP chemotherapy. Secondary ANLL is fatal in the great majority of cases. 66 Data from adults and children indicate the rate of secondary leukemia reaches a plateau 10 years after treatment of HD with very few cases noted more than 10 years after treatment. 67 The risk of secondary leukemias is related to drug dose: reduction or total elimination of suspect drugs has been successful in reducing the number of secondary leukemias. 68 Alternatives include use of ABVD, with some potential increase in the risk of both cardiac and pulmonary toxicity, while another has included the use of VP-16, which is known to cause secondary ANLL itself. The risk of secondary ANLL appears to be low with limited total doses of VP-16, 69 although it does not appear possible to reduce this risk to zero. 70 ANLL may occur after treatment with radiation only or ABVD alone or combined with radiation. 8, 71

More recently, a major focus has been on secondary solid tumors. This problem has taken longer to be recognized because the greatest risk appears to occur more than 10 years after treatment for HD. 42, 65, 67 Numerous studies in the past decade have indicated an increase in breast cancer in female survivors of HD; most data show that increased risk is related to younger age at diagnosis (obviously impacting on pediatric patients), as well as total dose of radiation therapy. Since the lag time for the development of breast cancer has been 10 to 20 years, it is difficult even now to know the full extent of this problem: between 10 and 35% of female survivors may eventually face this second malignancy. 42, 67 Alterations in treatment, initiated in the 1980s, include lower doses of radiation, techniques to move breast tissue out of the radiation fields, and differing treatments for males and females. Only in the next decade will the data mature sufficiently to determine whether these alterations have been successful in dealing with this problem. Close monitoring of all female survivors of HD is indicated at this time. 72

Cardiac Disease

An increased risk of ischemic heart disease, pericarditis, and valvular heart damage as well as premature death from cardiac disease have been reported primarily in adult patients after radiation therapy. In different studies, excess risk of cardiac disease and mortality has been related to underlying cardiac risk factors, 73 female gender, 74 or higher dose of radiation therapy. 75 A recent study of 50 patients from one institution suggested that attention to dosing and technique may reduce this risk. 76 Clearly, pediatric treatment techniques require meticulous attention to minimizing dose delivered to the heart for preventing this potentially fatal toxicity.

Pulmonary Disease

Pulmonary toxicity may relate to original disease in the mediastinum but is certainly a function of treatment with bleomycin as well as radiation to the lungs. Radiation pneumonitis and both restrictive and obstructive changes in pulmonary function testing are well described. Pulmonary function test abnormalities are found in 15 to 50% of survivors, with some studies indicating that the frequency of abnormalities is dose related. 77, 78 While most patients are asymptomatic, a number of deaths have been reported; the implications for patients 30 to 40 years after treatment remain unknown. Strategies to minimize this problem include changes in therapy, such as elimination of or minimizing the dose of bleomycin and other pulmonary-toxic drugs, blocking this effect with protective drugs, and reduction of radiation therapy doses to the minimum possible, while maintaining current cure rates. Data from one POG study indicate similar pulmonary toxicity in patients treated with combined modality therapy versus radiation therapy as a single modality; of course, the patients treated without chemotherapy received higher doses of radiation. 79 Clearly survivors of pediatric HD should be counseled to avoid exposure to environmental agents known to have pulmonary toxicity.

Infertility

Studies of long-term survivors of MOPP and related chemotherapy regimens have demonstrated significant rates of infertility, especially among males. 80, 81 Nitrogen mustard, procarbazine, and cyclophosphamide are the drugs most likely responsible for infertility. The probability of infertility is related to the total dose of these drugs. This has provided motivation for treatments that either reduce the total dose of these drugs, by alternating chemotherapy courses (MOPP/ABVD alternating and hybrid-type regimens), or eliminate the drugs altogether. ABVD alone, OEPA (Oncovin, Etoposide, Prednisone, Adriamycin), DBVE (Doxorubicin, Bleomycin, Vincristine, Etoposide), and other regimens that eliminate these drugs appear to be associated with far lower rates of infertility. 82, 83

Hypothyroidism

Since the majority of children present with disease in the neck, radiation therapy fields often include the thyroid gland. This may damage the thyroid gland, with subsequent hypothyroidism. Patients need to be monitored with annual thyroid function tests for at least a decade after treatment. Several studies indicate that 40 to 60% of patients eventually have abnormal thyroid function tests. 84– 85 Probably the most common initial laboratory finding is a normal thyroid hormone level with an elevation of thyroid stimulating hormone (TSH). When this is persistent, thyroid hormone replacement is initiated since this will prevent the subsequent development of clinical hypothyroidism and probably reduce the risk of late thyroid cancer, which is also known to occur in these patients. 85, 86 Thyroid-related late effects would probably be prevented by the elimination of radiation therapy from the initial treatment. However, most pediatric treatment protocols continue to employ radiation therapy in order to reduce total chemotherapy, which relates to other late effects as discussed above.

Conclusion

The great majority of pediatric patients with HD are presently cured of their disease. Efforts to reduce late effects through alterations of the initial therapy as well as monitoring for and amelioration of late effects of treatment are critical to maximize the life expectancy and quality of life of the survivors of past and present treatments.

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Bookshelf ID: NBK20936

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