Pediatric Hodgkin's disease is one of the most curable of childhood malignancies today. Despite availability of effective chemotherapy and radiotherapy, there remain several areas of controversy in staging and treatment of this disease. With increasing numbers of survivors morbidity from treatment related complications seems to exceed that due to the disease itself(1). The current focus is to decrease therapy related complications with newer strategies without jeopardizing the efficacy of presently available treatment(2). The second area of current research is to develop novel and more aggressive regimens for the small subgroup of patients with advanced disease and unfavorable features who may fail treatment.

With universal use of systemic chemo-therapy for pediatric patients it has become less important to precisely define all areas of occult disease. Surgical staging was more important in the era when exact radiotherapy fields had to be determined. Staging laparotomy with splenec-tomy has the attendant risks of post splenectomy sepsis(3) and more recently concern for increased incidence of leukemia(4). With improving imag-ing modalities most patients can be clinically staged using CT scans and gallium scans to define extent of disease. Infra-diaphragmatic involve-ment particularly minimal or occult disease may however still be missed occasionally by both these imaging modalities(5). Bipedal lymph-angiography although a better way to delineate retro-peritoneal nodes is rarely used now since it is invasive and technically difficult in children. In the era of effective chemotherapy regimens, staging laparotomy is almost never used in children and treatment is assigned based on clinical staging. German investigators report that the likelihood of abdominal involvement at laparotomy in patients with neither enlarged pulmonary hilar nor abdominal nodes is only 8%(6).

Pathological confirmation of biopsied tissue is essential. Neoplastic cells in Hodgkin's cells are usually positive for CD30 and CD15 antigens. In histologically and clinically typical cases immunophenotyping need not be performed routinely, if not easily available. However, if the pathologist is uncertain about the diagnosis or in clinically atypical cases like extranodal presentations or unusually aggressive disease this may be required. Certain disorders may mimic Hodgkin's on routine histological sections. These include anaplastic large cell lymphoma, T cell/histiocyte rich large B cell lymphoma and prog-ressive transformation of germinal centers (PTGC)(7). Most cases of lymphocyte depleted Hodgkin's disease are now identified by modern immunological methods to be actually Non Hodgkin's lymphoma. Bone marrow involve-ment is very rare in early stage disease and bilateral aspirate and biopsy should be performed only for patients with "B" symp-toms or those with stage III/IV disease(5).

Several adverse prognostic factors have been identified to guide therapy. These include the presence of "B" symptoms (unexplained persis-tent or recurrent fever >38.3°C, drenching night sweats, unexplained loss of >10% of body weight), bulk disease (mediastinal mass >1/3 of the thoracic diameter, nodal aggregate >10 cm), presence of hilar lymphadenopathy and >3 nodal areas of involvement. Therapy is stratified based on disease stage (using the Ann Arbor classi-fication) and presence or absence of adverse prognostic factors. Treatment modifications are made based on response to treatment.

Radiation therapy was discovered to be the first effective treatment for Hodgkin's disease. However, high dose radiation (36-45 Gy) led to serious long term sequelae in growing children including growth disturbances, impaired heart, lung, thyroid and ovarian function and occur-rence of secondary malignancies in the irradiated filed. With the discovery of effective chemo-therapy regimens the standard of care shifted to combined modality therapy(8). Survival rates comparable to developed countries have been demons- trated from several countries using this approach(9,10). By combining chemotherapy with radiation, high dose extended field radiotherapy could be replaced by low dose involved field therapy(20-25Gy) without losing efficacy. Effective chemotherapy regimens used in children around the world have included cycles of MOPP (nitrogen mustard, vincristine, prednisone and procarbazine), COPP (replacing cyclophosphamide for nitrogen mustard), ABVD (doxorubicin, bleomycin, vinblastine and DTIC), alternating MOPP/ABVD or COPP-ABVD and more recently hybrid COPPABV. The use of the hybrid COPP-ABV regimen was based on the Goldie-Coldman hypothesis that drug resistance was reduced by the earliest possible introduction of active single agents(11).

Presently used regimens have several therapy related toxicities leading to significant late com-plications(12-14). After 6 cycles of MOPP there is usually persistent azoospermia in most male patients and there is a 3%-6% risk of secondary leukemias (mostly from nitrogen mustard). Six cycles of ABVD is associated with the risk of chronic cardiomyopathy (cumulative doxorubi-cin dose of 300 mg/m2) and impaired lung func-tion with Bleomycin (cumulative dose of 120 mg/m2). Breast cancer is the most common solid tumor occurring in female Hodgkin's survivors with 94% of these tumors occurring in the irradiated field(13). Current trials in pediatrics are therefore looking to decrease toxicity from chemotherapy and radiotherapy.

In the 1980's a group of French investiga-tors tailored therapy in children using ABVD or MOPP/ABVD based on disease stage(15). Patients with favorable early stage disease received 4 cycles of ABVD or MOPP/ABVD whereas those with advanced stage disease were administered 6 cycles. Subsequent dose of in-volved field radiation used was based on the degree of response. In a more recent study (MDH 90) French investigators have had preliminary success using a new combination of drugs, VBVP (vinblastine, bleomycin, etoposide and prednisone) followed by 20Gy in 85% of their early stage patients(16). This chemotherapy regimen is devoid of alkylating agents (known to increase the risk of secondary malignancies) and anthracyclines (known to be cardiotoxic).

A series of consecutive trials have been conducted by the German-Austrian group with modification of therapy based on the extent of disease. In their most recent DAL-HD-90 study(17) Stage I and IIA patients received induction with only 2 cycles of OPPA in girls (vincristine, prednisone and procarbazine and adriamycin) and OEPA in boys (the gonadotoxic procarbazine was replaced with etoposide). After a similar induction children with higher stages received in addition 2-4 cycles of COPP. All patients received involved field RT after comple-tion of chemotherapy with an additional boost to sites of residual disease.

A major issue, which may particularly be of relevance to developing countries in the context of limited resources, is whether radiation can be omitted in a subset of patients. This is especially important for female patients who are at an increased risk of developing breast cancer in the irradiated field. Several non-randomized studies including those from developing countries have reported success using only chemotherapy without radiation(18,19). Only recently has this been studied in a randomized manner in children. A recently closed US Children's Cancer Group (CCG) study is the first pediatric study to compare chemotherapy alone with combined modality therapy. Stage I-III patients received 4-6 cycles of COPP-ABV hybrid. A different more aggressive regimen was given to Stage IV patients. Patients achieving complete remission (CR) at the end of chemotherapy were random-ized to either receive or not receive radiation. All patients who achieved partial response (RR) got irradiated. Results from this study are still pending. Preliminary data suggests that radiation therapy does reduce the relapse rate but there is no impact on overall survival since those that relapse after chemotherapy alone can mostly be salvaged with further therapy (unpublished observations). It is possible that intensification of chemotherapy may allow elimination of radiotherapy(20); however, this hypothesis was not tested in this CCG study.

Patients with advanced stage disease have a less favorable prognosis. It is speculated that this may be a result of upfront underdosing of effective agents and not from the development of drug resistance(21). Attempts have been made to increase the number of chemotherapy cycles(22) or through the use of low dose total nodal irradiation(23). Neither measure has shown significant benefit. Event free survival for Stage IV patients on a CCG study from the early 1990's was only 67%(22). Recently, time intensive and dose intensive regimens with growth factor support have been used with success in advanced stage disease in adults(24). This is now being studied in children (personal communication).

Another diagnostic dilemma that may arise is the presence of a residual mass (particularly in the mediastinum) at the completion of therapy. This may represent fibrous scar tissue or persistent tumor. A gallium scan is a particularly useful test in this regard. Several studies show that persistence of gallium positivity at the end of therapy is predictive of residual active disease(25,26). The residual mass may ultimately need to be biopsied for pathological confirma-tion. Occasionally, a phenomenon of thymic rebound may occur usually 2-3 months after completion of therapy. This may manifest as an increasing mediastinal mass with new gallium positivity on imaging and may require biopsy to differentiate tumor recurrence from regenerating thymic tissue. A thallium scan(27) or a Positron Emission Tomography (PET) scan(28) may also be useful for differentiating tumor from thymic rebound.

Children with Hodgkin's disease require long-term follow up. Cardiac function should be followed using echocardiography or MUGA scans since cardiac dysfunction can appear several years after anthracycline therapy(29). Pulmonary function including diffusion capacity should be monitored following bleomycin use(30). Thyroid profile should be followed closely since an asymptomatic patient with an elevated TSH is an indication to start thyroid replacement therapy(31). Skeletal growth measurements with growth charts should be maintained and sexual maturation should be monitored. Screening for second malignancy(32) is necessary and in female patients, breast exami-nations and consideration for an early mammo-gram are required, if the breast tissue was in the irradiated field(33).

Shipra Kaicker,
Kara Kelly,
Division of Pediatric Oncology,
Department of Pediatrics,
College of Physicians and Surgeons at Columbia University, New York, NY.

Correspondence to:
Kara Kelly,
Division of Pediatric Oncology,
Harkness Pavilion 5,
180 Fort Washington Ave,
New York, NY 10032,
E-mail: [email protected]