Odile Oberlin
Aetiology, biology, epidemiology, and incidence
Hodgkin, in his first description of the disease subsequently named after him, called it lymphogranuloma malignum, a name which remains appropriate.1 While the aetiology of Hodgkin disease remains unknown, the biology of the disease confirms neoplastic behaviour. Cytogenetic studies suggest that the Reed–Sternberg cells are the malignant cells in Hodgkin disease. Most authorities believe that these cells originate from activated lymphocytes. With present technical progress in the development of single-cell analysis of Hodgkin/Reed–Sternberg cells, it appears that the majority of these cells may represent a B-cell-derived monoclonal population.2 There are many possible sources of transformation in Hodgkin cells, including cytogenetic abnormalities, evidence for proto-oncogene involvement, and Epstein–Barr virus (EBV) infection and/or activation. There is now strong evidence linking Hodgkin disease with EBV genomes, and gene products can be detected in Reed–Sternberg cells in a proportion of cases. This proportion is 40 per cent in developed countries, but is much higher in countries such as China, Brazil, Costa Rica, and Kenya.3,4 The heterogeneity of the clinical and histologic appearances of Hodgkin disease and the multitude of different and controversial cellular markers might be explained by the theory that Hodgkin disease is a group of pathophysiologically associated, but not identical, disease entities. The origin could be the same target cell transformed at different stages of maturation, or there could be several biologically related diseases, each with a different pathogenesis.
The disease has been reported to occur more frequently among young children from developing countries than among those from countries of advanced socio-economic status. Genetic factors are implicated to explain ethnic variations and familial history of Hodgkin disease, with an increased risk of disease among parents, siblings, and identical twins.5,6 It has been suggested in a number of studies that susceptibility to Hodgkin disease is influenced by the HLA class II region. One of the underlying mechanisms could be the influence of this factor on the immune response to an infectious agent,7 and detailed HLA studies may help to elucidate the complex variations between populations in the risk of Hodgkin disease and its principal subtypes. An increased incidence is observed in patients with congenital immunodeficiency such as ataxia–telangectasia.8
Age-specific incidence rates reveal a characteristically bimodal curve, with the first peak at age 15–30 years and a second peak at age 45–55 years. Thus, children <15 years of age represent the minority. There is a male predominance in patients aged <10 years. However, during the adolescent peak both sexes are affected equally.9
Diagnosis and pathology
Accurate diagnosis of Hodgkin disease can be made only by microscopic examination of one or more tissue specimens. It is best to perform an excisional biopsy of an enlarged lymph node. Definitive diagnosis from extranodal tissue, such as lung or bone marrow, is much more difficult. Needle-aspiration biopsy and frozen section material are not optimal for examining the architecture and stromal cellular pattern of a lymph node. Identification of the characteristic Reed–Sternberg cell, a large multinucleated giant cell with inclusion-like nucleoli, facilitates the diagnosis of Hodgkin disease. However, the presence of these cells alone does not confirm the histological diagnosis, since cells of similar appearance have been found in reactive processes including infectious mononucleosis, phenytoin-induced pseudolymphoma, rubeola, graft versus host disease, and non-Hodgkin lymphoma.
The Rye classification has been replaced by the Revised European–American Lymphoma (REAL) classification in which the nodular lymphocyte predominance subtype is now recognized as a separate entity and distinguished from the classical type Hodgkin lymphoma, which includes lymphocyte-rich, mixed cellularity, and nodular sclerosis subtypes. Lymphocyte depletion has been maintained as an extremely rare subtype, and cases otherwise not subtyped are diagnosed as classical Hodgkin lymphoma, unclassifiable (Table 15.1).10
In Europe and the USA, the majority of children present with nodular sclerosis.11,12,13 In developing countries, mixed cellularity is more common.14 Even in Europe and the USA, the distribution of histological subtypes varies with age, with the nodular sclerosis subtype being more common in adolescents and adults than in young children. Conversely, mixed cellularity is more common in young children than in adolescents.
Histological subtypes also correlate with certain patterns of disease. The lymphocyte-predominant type is often associated with localized cervical or inguinal–femoral disease, while the nodular sclerosing subtype commonly presents in the mediastinum. The mixed cellularity and lymphocyte-depletion subtypes often present with advanced stage disease.
Clinical presentation and staging
Painless cervical lymphadenopathy is the most common presenting sign in children with Hodgkin disease, often with a fluctuating course leading to a delay in diagnosis. While 80 per cent of children present with neck disease, only 60 per cent have mediastinal involvement. Fewer than 5 per cent present with disease limited to the upper cervical lymph nodes, above the level of the hyoid bone. The majority of patients present with supradiaphragmatic disease, although subdiaphragmatic presentation does not indicate an unfavourable prognosis. Some 20–30 per cent of children present with systemic B symptoms, as defined by the Ann Arbor staging criteria of fever over 38°C, drenching night sweats, and an unexplained weight loss of >10 per cent of body weight at the time of presentation. The frequency of these symptoms increases with advanced stage of disease. The staging classification now in use has been defined in the Cotswold report (Table 15.2). It incorporated minor revisions but maintained the anatomically orientated nature of the Ann Arbor classification.
Clinical staging involves careful history-taking and physical examination with special attention to the lymphatic system. If an enlarged lymph node is palpable at a site where involvement would influence staging or treatment, it is a wise policy to biopsy the node to assess involvement. Any suspicious lymph nodes should also be biopsied or treated as if involved. Characteristically, involved lymph nodes are not painful or tender but have a ‘rubbery’ firmness to palpation, often with a variable growth rate. Although involvement of Waldeyer's ring is infrequent, it may present as symmetric tonsillar enlargement; thus examination of the nasopharynx and oropharynx is important.
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Table 15.1. REAL classifications of Hodgkin disease |
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Table 15.2. Staging classification according to the Cotswold revision of the Ann Arbor definitions |
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Routine laboratory studies involved in the staging of children should include a complete blood count, erythrocyte sedimentation rate, and liver function studies including alkaline phosphatase. Eosinophilia occurs in approximately 15 per cent of patients, while lymphopenia, often a sign of advanced disease, is less common. An elevated erythrocyte sedimentation rate is related to both stage and systemic symptoms, and is an important prognostic indicator as well as a useful marker of disease activity. The alkaline phosphatase level is a non-specific indicator of disease activity and is less useful in children than in adults, since it is characteristically elevated as a function of active growth. However, unusually elevated alkaline phosphatase, with or without symptoms of bone pain, is a signal to evaluate the skeletal system by bone scan. Serum copper, also a non-specific marker of disease activity, is useful as an indicator of relapse, but false-positive evaluations of serum copper have been observed in children with Hodgkin disease secondary to inflammatory disease. Elevated serum levels of interleukin 2 receptor and CD8 antigen correlate with advanced disease, B symptoms, and a poor prognosis.15,16
A chest radiograph with posteroanterior and lateral views is the first imaging. A mediastinal mass ratio of greater than one-third of the intrathoracic diameter is generally considered to represent advanced disease, which is optimally treated more aggressively than is limited disease.
Thoracic CT defines the status of intrathoracic lymph node groups (including hila and cardiophrenic angle), lung parenchyma, pericardium, pleura, and chest wall. The major value of CT is in the detection of subtle mediastinal adenopathy in the child with an apparently normal chest radiograph; it is also of value in the child with obvious intrathoracic disease. In
50 per cent of previously untreated patients, disease including pericardial or chest wall invasion, retrocardiac masses, and pulmonary parenchymal involvement is discovered on thoracic CTafter having been previously missed on plain film. The value of MRI in the staging of the chest is being evaluated. It appears to be complementary to CT but of less value in assessing the pulmonary parenchyma than is the thoracic CT. Although mediastinal adenopathy is common, hilar adenopathy is less so and rarely appears in the absence of mediastinal adenopathy. Pulmonary and pleural involvement is also uncommon and seldom occurs without mediastinal/hilar disease. Pleural effusions may be commonly seen, but are usually secondary to lymphatic obstruction from large central disease and are rarely cytologically positive for Hodgkin disease. Children present the unique problem of how to differentiate the normal thymus gland from thymic infiltration with Hodgkin disease. Thymic involution secondary to immunosuppressive chemotherapy with subsequent thymic enlargement following cessation of chemotherapy has been observed, and may be mistaken for disease progression.
Optimal imaging studies for subdiaphragmatic and retroperitoneal areas have been a matter of controversy for a long time. Lymphography is useful for detecting involved retroperitoneal lymph nodes, visualizing both size and architecture of these nodes. However, this procedure is technically difficult, requires general anaesthesia in young children, and cannot be performed in patients with massive mediastinal and lung involvement. Abdominopelvic CT scan and ultrasound are easier and less invasive procedures than a lymphogram. The accuracy of current CT scans and ultrasound has progressively improved; they are now more accurate than the lymphogram, providing information not only on all the abdominal nodes, but also on the echogenicity of the spleen and liver.
Radionuclide studies have limited usefulness in Hodgkin disease. Routine liver and spleen scans are not useful. Although gallium scanning is often employed, it has limited accuracy in subdiaphragmatic sites, with true-positive findings (sensitivity) in only 40 per cent of patients. Technetium-99 m bone scanning is helpful in symptomatic children with bone complaints and in those with an unexplained elevation of serum alkaline phosphatase.
Bone marrow biopsies should be performed in all children with systemic symptoms and in those with clinical stage III or IV disease. The bone marrow needle biopsy has a low yield of involvement in children with supradiaphragmatic clinical stage IA and IIA disease. Bone marrow aspiration is not adequate for the staging of Hodgkin disease and is not an alternative to percutaneous needle or open bone marrow biopsy.
Staging laparotomy was the gold standard when radiotherapy was used as a single modality therapy; it was indicated to determine the radiotherapy volumes. However, this procedure became questionable when other treatment options were chosen, such as chemotherapy combined with radiation therapy, and such strategies demonstrated that chemotherapy can control radiologically inapparent disease in the vast majority of patients.
Therapy
Treatment for children with Hodgkin disease may involve radiotherapy, chemotherapy, or combined modality therapy. Many of the guidelines determined from studies in adults may be applied to children, since young age is a favourable prognostic indicator and children fare as well as or better than adults. However, when planning treatment programmes for the paediatric population who are undergoing active growth and development at the time of diagnosis and treatment, practical consideration must be given to tissue development and organ function.
Late consequences of treatment
High-dose large-volume radiotherapy administered to young and prepubescent children is known to result in impairment of soft tissue and bone growth. The growth disturbance is related largely to the age of the child at the time of treatment and the radiation dose administered.17 The most marked impairment is observed when radiation doses >35 Gy are given to children <13 years old.18 It appears that doses <25 Gy do not cause the disproportionate standing- and sitting-height abnormalities seen with higher doses. Thus a dose of 25 Gy, in fractions of 1.8–2 Gy, may be a threshold beyond which growth retardation is more likely to occur.
Gonadal toxicity in both boys and girls remains a major problem. Pelvic lymph node irradiation is known to carry a high likelihood of ablating ovarian function. The likelihood of maintaining ovarian function following radiotherapy is directly related to pelvic dose and age at the time of treatment. The younger the girl at the time of treatment, the higher the probability of maintenance of regular menses following therapy. Oophoropexy with appropriate shielding at the time of radiotherapy has allowed the preservation of ovarian function, and normal pregnancies after such a procedure have been reported. The pregnancies have been uncomplicated, the offspring normal, and there has been no increased fetal wastage or spontaneous abortion.
In contrast with girls, the issue of sterility in boys is of much greater severity and requires longer periods of follow-up for accurate assessment. High doses of irradiation to the pelvis, in a standard inverted-Y field, may be associated with transient oligospermia or azoospermia. Testicular shields should be routinely used during pelvic radiotherapy, although they are anatomically difficult to use effectively in prepubertal boys. Testicular injury following combination chemotherapy, specifically mustard, oncovin, procarbazine, and prednisone (MOPP), is more complete than that observed following radiotherapy. There are no data to suggest that the prepubertal testis is in any way protected from the testicular injury that is observed among pubertal boys receiving six cycles of MOPP chemotherapy.19 However, some data now suggest potential recovery of spermatogenesis 12–15 years after six cycles of MOPP.20 The adriamycin–bleomycin–vinblastine–DTIC (ABVD) combination appears to carry a lower risk of sterility.21
Hypothyroidism, as judged by an elevated level of thyroid-stimulating hormone, is common following mantle irradiation. The incidence of elevated thyroid-stimulating hormone in children with Hodgkin disease is higher than in adults, suggesting a greater sensitivity of the thyroid in the rapidly growing pre-adolescent or adolescent age group. The risk of hypothyroidism appears to be related to radiation dose.22 Among children who receive neck irradiation of 26 Gy, the incidence of hypothyroidism is only 17 per cent compared with 78 per cent incidence among children who receive doses >26 Gy.23 Children who are chemically or clinically hypothyroid are candidates for thyroid replacement therapy, as the long-term effect of unopposed stimulation of the thyroid gland is unknown, and both thyroid adenomas and thyroid carcinomas are frequently reported among long-term survivors.24
Cardiopulmonary complications may be related to both radiotherapy and chemotherapy. Pneumonitis and fibrosis may result from radiation and/or bleomycin, and are dose and volume dependent. While most children are asymptomatic following radiotherapy, echocardiography and pulmonary function or exercise tests reveal that approximately three-quarters have some abnormalities in pulmonary function.25 In combined modality programmes, pulmonary dysfunction appears to be related more to the chemotherapy dose than the radiotherapy dose.26 In the Stanford series of children, who received 15–25 Gy and six cycles of ABVD + MOPP, alterations in pulmonary function were observed in as many as 40 per cent of cases, with abnormalities in diffusing capacity in 55 per cent.27 The Children's Cancer Study Group reported that 9 per cent of children who received 12 courses of ABVD followed by 21 Gy regional radiation developed grade 3 or 4 pulmonary toxicity, largely abnormalities in carbon monoxide diffusing capacity, and that one child died of pulmonary toxicity.26 The incidence of pericarditis and pancarditis was reported to be as high as 13 per cent in children during the era when high-dose large-volume mantle radiotherapy was used.28 However, with the more recent use of low doses of mantle radiation to smaller volumes, radiation-related cardiac injury is much reduced. On the other hand, the addition of adriamycin in the ABVD combination may well enhance cardiac injury. In the Stanford series of children receiving only three cycles of ABVD and low-dose radiation, 14 per cent of asymptomatic children had cardiac abnormalities at short-term follow-up, demonstrated by cardiac nuclear-gated angiogram testing.27 Longer follow-up is certainly necessary, as premature coronary artery disease with coronary fibrosis and accelerated atherogenesis has been observed in long-term survivors of Hodgkin disease. The true risk of cardiac and pulmonary injury following current therapy remains unknown, but may be responsible for late mortality of cured patients.29
Second malignant tumours represent a major concern for those who treat children with Hodgkin disease, most of whom will be successfully treated and will have a very long lifespan. Large studies on survivors of childhood Hodgkin disease show that the incidence of any second neoplasm 15 years after diagnosis is 6–8 per cent.30,31,32,33 The Late Effects Study Group (LESG) followed a cohort of 1380 patients treated for Hodgkin disease between 1955 and 1986. They reported that the risk of leukaemia reaches a plateau of 2.8 per cent at 15 years, while the incidence of solid second tumours continues to rise even 25 years after diagnosis. The study demonstrated that the incidence of leukaemias is related to the doses of alkylating agent chemotherapy given. All these studies emphasize the high risk of developing breast cancer. In the LESG study, the estimated cumulative probability approached 35 per cent at 40 years of age. Older age at diagnosis (10–16 years versus. <10 years) and a higher dose of radiation (20–40 Gy versus <20 Gy) were associated with increased risk of breast cancer.30 This mandates adequate surveillance and screening of this very-high-risk population.
Psychosocial problems among young people with Hodgkin disease include a decline in energy and sexual activity, perception of impaired body image, work-related problems, and difficulties in obtaining health insurance. These problems have received little attention but are extremely important issues for the child who is cured of his or her disease.
Because of the known late effects of both chemotherapy and radiotherapy in children, arguments for the last 15 years have been in favour of single modality treatments to minimize the toxicity of therapy. The different approaches available will be summarized and the advantages of combined modality treatment discussed.
Radiation therapy alone
Even adults, for whom late effects linked to growth do not occur, the choice between radiation therapy alone or combined with chemotherapy in favourable cases continues to be a point of controversy. Several criteria have been defined as indications for combined modality treatment in adults: massive mediastinal mass, B symptoms, the dissemination of Hodgkin lymphoma to three or more lymph node areas, infra-diaphragmatic disease, an elevated erythrocyte sedimentation rate, and mixed cellularity or lymphocyte-depleted subtype. The French EORTC–GELA group demonstrated that three cycles of MOPP and involved field are more effective than subtotal nodal irradiation in adults with favourable supradiaphragmatic clinical stage I–II.34 Moreover, in this subgroup of patients selected for radiation therapy alone, laparotomy and splenectomy should be included in the staging procedure to delineate the radiation fields, although these procedures have inherent risks. High doses (40–44 Gy) and extended fields, such as subtotal nodal irradiation, are required.
The British experience of radiation alone as a single treatment for stage I showed a 92 per cent overall survival, but 30 per cent of the children relapsed and required salvage chemotherapy.35 This rate that seems too high considering the results of similar patients treated by a short chemotherapy course and low-dose radiation.11,36
Chemotherapy alone or combined modality therapy?
As soon as chemotherapy was proved to be effective, the next question was whether children could be cured without the use of radiation. The rationale for most protocols based on chemotherapy alone was always based on the experience of Olweny et al. 37 in Uganda where radiotherapy machines were not available. On the base of these encouraging results, several teams opted for chemotherapy alone. The earliest chemotherapy-alone studies used 6–12 courses of MOPP or MOPP-like regimens.38,39,40 Some trials have excluded patients with large nodal masses38 or large mediastinum.35 In all these studies, children received at least four cycles, and generally six or more cycles, of chemotherapy including alkylating agents and procarbazine. In our paediatric and adult experience, six cycles of MOPP induce male sterility in >90 per cent of patients20,41 as well as an increased risk of secondary leukemia42 that we consider unjustifiable.
The German–Austrian HD-95 study evaluated the possibility of avoiding radiation therapy in children in complete remission after induction chemotherapy tailored to the stage at diagnosis. In the low-risk group (stage I–IIA), relapse-free survival was similar for irradiated and non-irradiated patients, whereas relapse-free survival was significantly lower in nonirradiated than in irradiated patients at more advanced stages (stages IIB–IV).43
There have been three large randomized paediatric trials addressing the question of the efficacy of chemotherapy alone versus chemotherapy combined with radiation therapy.
The US Paediatric Oncology Group (POG) compared four cycles of MOPP plus four cycles of ABVD with or without 21 Gy total or subtotal nodal irradiation in children with stages IIB, IIIA2, IIIB, and IV disease. The event-free survival (EFS) rates of the two arms were not statistically different using an ‘intent to treat’ analysis.44 However, when considering the treatment actually delivered, superior results were observed in children treated with chemotherapy plus radiation therapy. Survival was comparable in the two groups (94 per cent and 88 per cent, respectively).45
A randomized study was conducted in stage III and IV disease by the US Children's Cancer Group (CCG) comparing MOPP alternating with ABVD for 12 months with ABVD for 6 months followed by 21 Gy irradiation. The EFS rates of the two schedules were similar (87 and 77 per cent).46 The addition of radiotherapy did not seem to offer a significant advantage over chemotherapy alone. However, it is noteworthy that the children treated by chemotherapy alone in this study received 12 cycles of chemotherapy (six MOPP and six ABVD). The risks of six cycles of MOPP have already been mentioned. Six cycles of ABVD lead to high cumulative doses of adriamycin (300 mg/m2) and bleomycin (120 mg/m2). These doses account for the very high pulmonary toxicity, with one death reported in this study. These results should dissuade physicians from administering so many courses of ABVD in combination with radiation therapy to the mediastinum.26 The same comments apply to the potential late toxicity of the six cycles of ABVD given in the Dutch study attempting to treat patients with stage I–IV disease by chemotherapy alone.47
The CCG investigated whether radiation could be omitted in patients achieving a complete response to chemotherapy. The chemotherapy was stratified according to stage. Children with stages I–III disease were given chlorambucil–vincristine–procarbazine–prednisone (COPP) plus adriamycin–bleomycin–vinblastine (ABV); stage IV patients received additional cytarabine–etoposide combinations. Patients who achieved a complete response after chemotherapy were randomized to receive 21 Gy involved field or no further treatment. There was no difference in the overall survival rates of the two groups, but there was an advantage for the combined modality arm in terms of EFS (92 versus 87 per cent) which was even more impressive with an ‘as-treated’ analysis (93 versus 85 per cent).48
The known late effects of splenectomy, high-dose radiation therapy, and high cumulative doses of chemotherapy and the improved outcome for children treated with combined modality therapy argue in favour of the wide use of combined modality therapy to treat childhood Hodgkin disease. Such an approach would enable a gradual decrease of both radiation therapy and chemotherapy.
Risk-adapted combined modality treatment and prognostic factors for reducing therapy
Reducing the duration of chemotherapy and avoiding MOPP
MOPP chemotherapy was the standard regimen for many years until the effectiveness of ABVD was established, first in patients who had failed MOPP and then as front-line chemotherapy, using six cycles or more in advanced stages. Compared with MOPP, second malignancies and sterility were less common. The predominant adverse effects of ABVD are pulmonary toxicity related to bleomycin and cardiovascular toxicity secondary to adriamycin. The intention was to use a short chemotherapy course, decreasing the number of cycles of MOPP while also diminishing the side effects associated with six cycles of ABVD. In the first French cooperative study, patients with stage I and II disease were randomized and treated with either four cycles of ABVD or two cycles each of MOPP and ABVD. Patients with more advanced stages (IB, IIB, III, and IV) were treated with three cycles each of MOPP and ABVD. Radiation was delivered at a dose of 20 Gy in patients who had a good response to chemotherapy; otherwise the classical 40 Gy dose was used. The conclusion of that study was that, in favourable stages, ABVD alone was equivalent to MOPP combined with ABVD and that chemotherapy followed by 20 Gy radiation was a valid approach in the vast majority of children.49 The Milan paediatric team corroborated the efficacy of three cycles of ABVD alone combined with low-dose radiation therapy in a non-randomized study.50
Even in patients with more advanced disease (stage III), the results of the French studies showed that the number of MOPP + ABVD courses could be reduced from the six used in the MDH82 study to four courses in the MDH90 study without compromising the excellent 96 per cent survival.49,51
Using other combinations than MOPP or ABVD
Up to 1985, the German paediatric group used vincristine, prednisone, and procarbazine at MOPP doses, combined with adriamycin (OPPA) and COPP (cycles comparable to MOPP but with cyclophosphamide replacing mustine). In 1985, this group initiated a study to try to eliminate procarbazine. OPPA became OPA, and methotrexate replaced procarbazine in the COPP combination, giving rise to the COMP regimen. Progressions and relapses were significantly higher in advanced stages than in the preceding protocol, and so the study was stopped prematurely on the grounds that a more effective drug was needed to replace procarbazine.52
Active drugs which are non-toxic or have acceptable toxicity are few in Hodgkin disease. Data indicated etoposide as a potential alternative, and this drug has been included in the German–Austrian studies in place of procarbazine in OPPA, which became OEPA in the German HD90 study.12
Adapting the treatment strategy to the initial response to chemotherapy
The SFOP MDH90 study adopted such a strategy for patients with stage I and II disease. As induction chemotherapy, all were given vinblastine, bleomycin, VP16-etoposide, and prednisone (VBVP) without alkylating agents and doxorubicin. Based on radiological evaluation, patients achieving a good response were given 20 Gy involved field radiation. Poorly responding patients were given one or two additional cycles of OPPA (vincristine, procarbazine, prednisone, and adriamycin–doxorubicin). Radiation therapy dose was decided according to evaluation after OPPA: 20 Gy for good responders and 40 Gy for poor responders. For the 202 patients included in the study, the 5-year survival and EFS were 97 per cent and 91 per cent, respectively. Altogether, 86 per cent of the children were cured with only four courses of VBVP and 20 Gy radiation; 14 per cent received additional OPPA cycles or a higher radiation dose. Significant predictors of worse EFS were nodular sclerosis histology, haemoglobin <10.5 g/dl and the presence of B biological factors.11
Identification of factors to select children at low or high risk of relapse
Identification of factors to select children at low or high risk of relapse is of paramount importance to tailor the intensity and duration of treatment.
In the German–Austrian DAL-HD 90 study, significant univariate predictive factors for EFS were nodular sclerosis type 2 histology, presence of B symptoms, number of involved regions, and treatment groups. There was a higher risk for patients with bulky compared with nonbulky disease. In the multiple regression model, only nodular sclerosis type 2 and B symptoms remained strong predictive factors.53
Smith et al. 13 developed a prognostic index based on five pretreatment factors associated with poorer disease-free survival on multivariate analysis : male gender, stage IIB–IIB or IV, bulky mediastinal disease; white blood cell count > 13.500/mm3, and haemoglobin <11.0 /dl.
The Stanford, Dana–Farber and St Jude Children's Research Hospital obtained excellent results (5-year survival and EFS were 99 per cent and 93 per cent, respectively) in a very selective group of patients (clinical stage I and II without bulky disease or B symptoms). Nodular sclerosing histology and number of involved nodes had an impact on the failure rate, and all he failures occurred in patients with this histological subtype.36 The subgroup of patients treated in this study represents only 34 per cent of the whole cohort of children with Hodgkin disease, in contrast with the French study in which 60 per cent of the children were treated.11
The combined modality regimens used in both these studies are not associated with any serious toxicity, which confirms that favourable-risk Hodgkin disease can be cured with therapy which excludes alkylating agents and doxorubicin (in the first study) and etoposide and bleomycin in the second.11,36
Poor prognosis Hodgkin disease in childhood
Stage IV disease has the most dismal outcome. As only 8–16 per cent of children have stage IV disease, the absolute number in published series is often small. The results of several studies demonstrate that these patients fare significantly worse than those with less advanced disease. For instance, the EFS of such cases was only 55 per cent in the British study,54 61 per cent in the first French study,49 67 per cent in the CCG study,46 and 69 per cent in the Boston series.55 The German–Austrian group obtained the best results in two consecutive multicentric studies. They were based on surgical staging and chemotherapy with two cycles of OPPA and four cycles of COPP, as previously described. Radiation therapy was given to involved nodes (25 Gy) and involved extra-lymphatic organs (12–15 Gy).56
In 1987 an intergroup study for stage IV was initiated within the SIOP group (International Society of Paediatric Oncology), attempting to reproduce the good German results internationally and to limit the radiation dose to 20 Gy after a good response to chemotherapy. The study included 115 children from six countries. The 5-year overall survival was 90 per cent and the disease-free survival was 85 per cent, similar to the 81 per cent observed in the previous German studies. These results confirm that OPPA–COPP chemotherapy followed by 20 Gy is a valid therapeutic approach for stage IV in children.57
Patients with refractory or relapsed disease form the second group with a poor prognosis. Attempts have been made to improve the efficacy of chemotherapy by incorporating new drugs into standard regimens or using dose intensification with stem cell rescue.
Etoposide, which has already been mentioned, has been included by several teams in thirdline conventional therapy after MOPP and anthracycline-containing regimens. The MIME (methyl GAG, ifosfamide, methotrexate, and etoposide) and MINE [derived from MIME but with an increased dose of ifosfamide and VP16, and vinorelbine (Navelbine)] regimens have yielded response rates of 66 per cent and 75 per cent, respectively, in disease refractory to standard chemotherapy.58,59
The relative resistance of tumour cells to cytotoxics can be overcome by administering very high doses of drugs with bone marrow or peripheral stem cell support. Encouraging results have been obtained in adults, with protracted responses in refractory disease. The paediatric experience is limited, as the number of children who enter this high-risk group is small. However, as their outcome is comparable to that of adults, they should be treated according to the same modality. In the Stanford experience, idiopathic lung injury syndrome occurred in 44 per cent of the patients and a quarter of them died from pulmonary failure. The high-dose regimens consisted of cyclophosphamide and etoposide combined with carmustine, chloroethylcyclohexylnitrosurea, or fractionated total body irradiation.60 Interstitial pneumonitis was also observed in two out of 22 patients61 and two out of 53 patients62 in the other two series The toxicity of high-dose regimens remains the major constraint to widening the indications for transplantation in high-risk patients.
An unanswered question: How should one treat lymphocytepredominant Hodgkin disease?
Lymphocyte-predominant Hodgkin disease (LPHD) is reported to present typically as early stage disease, with slow progression and an excellent outcome with standard therapy.63,64 In contrast with tumour cells of the classical Hodgkin/Reed–Sternberg type, the tumour cells of LPHD express B-cell antigens such as CD20 and rarely express CD15 or CD30, supporting the fact that LPHD is a malignant B-cell lymphoma of germinal center origin. A tendency towards more secondary non–Hodgkin lymphomas is noted, but this remains equivocal. On the basis of what is proposed for stage I follicular lymphoma, a ‘watch and wait’ strategy, in which no immediate therapy is given, could be tested for patients who are without residual disease after surgery; the main advantage of this approach is the avoidance of unwanted effects of radiotherapy or chemotherapy. The use of rituximab (anti-CD20 antibody) is attractive, and a phase II study revealed an overall response rate of 100 per cent.65 Larger studies are warranted to prove the long-term efficacy and tolerability of this therapy. Overall, the question of how to treat such patients, either by reducing treatment intensity or following a ‘watch and wait’ approach, remains unanswered.
Conclusion
The results of recent studies suggest that the cure rate whose curve was constantly rising between 1960 and 1980 has reached a plateau. Since 1980, efforts have been directed towards curing the disease with a minimal amount of morbidity. Combined modality therapy is clearly a strategy allowing the administration of less toxic truncated chemotherapy and low-dose limited-field radiation therapy. It will be difficult to improve drastically upon the present. The efforts currently deployed to cure patients with chemotherapy without recourse to procarbazine and adriamycin are encouraging in favourable cases.
We hope that during the next decade progress in the field of biology will help us to understand the aetiology and pathogenesis of Hodgkin disease and its apparent heterogeneity, and help us to continue refining therapy at a reduced cost.
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