Hodgkin's disease in children: treatment with MOPP and low-dose, extended field irradiation without laparotomy. Late results and toxicity

The 10 year results of a trial of bimodal treatment of Hodgkin's disease in children with 6 cycles of MOPP and low-dose extended field irradiation, without staging laparotomy, were for 57 children in all stages as follows: survival 85%, relapse-free survival 80%, and survival-free of second relapse 86%. There were three fatal toxic events, two due to viral infection and one to a second malignant tumor (NHL). Three other patients developed a second malignant tumour, and one developed a thyroid adenoma. No patient developed acute leukemia. These results are compared with the results of treatment of surgically staged children by extended field irradiation alone, with bimodal treatment reserved for relapse or advanced disease at diagnosis. Initial bimodal treatment improved the overall 10 year survival free from a second relapse rate by 20% (86% vs. 66%). No major difference in treatment toxicity between these two groups has emerged during the first 10 years of follow-up. We conclude that, except for favourable CS-1 presentations, children with Hodgkin's disease confined to the lymphatic system should be given bimodal treatment, but that the least morbid effective combination remains to be determined.     

Second malignant tumours in childhood Hodgkin's disease

This study was undertaken to determine the treatment-specific incidence of second malignant tumours (SMT) in childhood Hodgkin's disease. The institutional databases at The Hospital for Sick Children, the Princess Margaret Hospital, and the Toronto-Bayview Regional Cancer Centre were reviewed for the years 1958–1993. Three hundred and forty-three consecutive newly diagnosed children were evaluated. The overall 30 year cumulative SMT incidence was 31%. The 20 year SMT incidence was greater for patients who relapsed (n = 129), 27%, compared with patients who remained relapse free (n = 214), 13%. For patients with stage 1–3B disease who remained relapse free, the 10 year SMT rate was 7% for patients who were surgically staged and treated with extended field radiation treatment (EF RT) (35 G), compared with 3% in clinically staged patients treated with MOPP (six cycles) and EF RT (25–30 G). To date there is no significant difference in the oncogenicity of these treatment protocols. However, EF RT alone was less effective in disease control. For stages 1–3B, 62% of patients relapsed after EF RT alone compared with 18% after bimodal treatment. Therefore treatment intensification due to relapse was more frequent in the former group. The overall 10 year SMT incidence for patients treated with these protocols was 11% and 3%, respectively. The 20 year SMT incidence following EF RT alone was 24%. We conclude that SMTs were a common late complication in childhood Hodgkin's disease and are a limiting factor in the achievement of cure. The incidence of SMTs was increased in children who required retreatment and was minimal in children who remained in a first complete remission. Therefore the initial treatment strategy in childhood Hodgkin's disease must be to minimize the risk of relapse, in order to avoid the morbidity and mortality associated with both relapse and SMT induction, and to achieve this objective with a primary treatment protocol of low oncogenicity. © 1996 Wiley-Liss, Inc.     

Chemotherapy and irradiation in childhood Hodgkin's disease.

Eighty children aged less than 16 years with newly diagnosed Hodgkin''s disease were treated between 1974 and 1982. Complete remission occurred in 95%, with actuarial five year overall survival of 94%, and relapse free survival of 82%: median follow up was 4.8 years. Sixty one children were staged clinically while 19 had staging laparotomies before treatment. Most received combined modality treatment with Ch1VPP chemotherapy (chlorambucil, vinblastine, procarbazine, and prednisolone) followed by irradiation of initial bulk disease. Nodular sclerosis predominated in both sexes, accounting for 60% of the total. Girls with stage IV disease, nodal sclerosis histology, and bulky mediastinal masses had a relatively poor prognosis. Ten children have relapsed, and three prolonged (6 to 7 years) second remissions have been observed. Four died of disease, and one from infection. Clinical staging, avoiding splenectomy, reduced the risk of serious infections. Our current policy is to treat stage IA disease with local irradiation and all other stages with chemotherapy, adding irradiation for bulky mediastinal disease.     

Management of childhood lymphomas—Hodgkin's disease and non-Hodgkin's lymphomas

Hodgkin's disease can be cured in greater than 70% of the children diagnosed. Overall 5-year survival rates now approach 90% and approximotely 80% for 10-year survival. Combination chemotherapy along with irradiation has decreased the relapse rate in all stages of Hodgkin's disease. Intensive chemotherapy and irradiation therapy is associated with long-term complications including development of second malignant tumors. Optimum therapy is the minimum therapy associated with uncomplicated care. In 80 to 90% of children with non-Hodgkin's lymphoma the disease is widerspread when obvious clinically at diagnosis, and the first site of relapse is commonly the bone marrow or central nervous system (CNS). Combined chemotherapy, irradiation and CNS prophylaxis has resulted in 50% to 80% 3-year, disease-free survival. Patients with mediast'nal or extensive intrabdominal disease have a poor prognosis.     

Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.     

Hodgkin's Disease in Children in the West Midlands, 1957–1986: A Large Population-Based Study

One hundred forty-one children were diagnosed with Hodgkin's disease between 1957 and 1986 in the West Midlands Health Authority Region (1991 population, 1.I million children). Eighty-seven were boys and 54 were girls, representing a significant male:female ratio of 1.5:1 (P < 0.01). The average age-standardized incidence rate was 3.6 per million per year with a significant increase in the older age group (≥ 10 years) in the second half of the period (P= 0.02). The mixed cellularity subtype was more common in those younger than 10 years, with nodular sclerosing disease being seen more in those ≤ 10 years. Overall survival at 5 years was 76% (65% at 10 years) with a significant difference (P < 0.001) in survival between the first and last decades. There were six second malignancies, five of which could have been treatment related. A positive history of cancer in close relatives was found in 11 patients, and higher social class war found in more older than younger children. These findings support the hypothesis that Hodgkin's disease may have a viral etiology and may be linked with socioeco-nomic conditions.     

Intracranial Hodgkin's disease in two patients with familial Hodgkin's disease

Intracranial Hodgkin's disease is very rare and is often a terminal event. The case of a 33-year-old man who relapsed in the anterior pituitary gland without other evidence of disease 6 months after extended field radiation therapy for Stage IIA Hodgkin's disease is presented. He remains well with no evidence of disease five years after surgery and chemotherapy for intracranial relapse. The case of a 16-year-old boy with a dural relapse of Hodgkin's disease associated with positive cerebrospinal fluid cytology is also presented. These two patients are members of different families each with multiple cases of Hodgkin's disease. Central nervous system involvement with Hodgkin's disease may be more frequent in familial Hodgkin's disease in which immune deficiency is common. Med. Pediatr. Oncol. 28:255–258. © 1997 Wiley-Liss, Inc.     

Treatment of childhood Hodgkin's disease with ABVD without radiotherapy

Seventeen previously untreated children with Hodgkin's disease were treated with six courses of the combination adriamycin, bleomycin, vinblastine, and DTIC (ABVD), without radiotherapy, from 1984–1987. In all patients, complete remission was attained. After a median follow-up period of 73.5 months (range 59–98 months), five patients had a relapse after 4, 5, 11, 21, and 34 months, respectively, from attainment of complete remission. In 12 patients with stages I and II, two relapses occurred. Three out of five patients with stage III and stage IV developed a relapse. Based upon these results, we conclude that ABVD might be an appropriate treatment for newly diagnosed children with Hodgkin's disease stages I and II. However, for children with stages III and IV, more intensive treatment is needed. Radio-therapy should be withheld for children with refractory disease, residual disease, or relapse. © 1996 Wiley-Liss, Inc.     

Pediatric hodgkin's disease in costa rica: Twelve years' experience of primary treatment by chemotherapy alone,without staging laparotomy

This is a prospective and nonrandomized study in which 86 children with previously untreated Hodgkin's disease (HD) were clinically staged (CS) and treated with chemotherapy (CT) alone. Fifty-two (CS IA-38, IIA-7, IIB-3, IIIA-4) received six courses of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP). Ten (CS IA with peripheral nodes) received only three courses of CVPP with a reinforcement of C on day 8. Twenty-four (CS IIIB-18, IVA-2, IVB-4) received six courses of CVPP alternating with six courses of epirubicine, bleomycine, and vincristine (EBO). Surgical staging was not performed in any patient. Two patients (CS IIIB) had partial remission and died from progressive disease. Seventy out of 86 children have not relapsed and are in complete remission with a median follow-up of 65 months (range 13-156 months); 14 children relapsed seven to 37 months from diagnosis (median 16 months); one of them (IV B) died of disease. Thirteen are in second and third remission (median 55 months). Actuarial five year survival rates and relapse-free survival rates are 100% and 90% for CS I to IIIA and 81% and 60% for CS 1MB and IV, respectively. As a result of this study, we can conclude that in developing countries most of the children with HD staged by noninvasive diagnostic techniques can be cured with CT alone as primary treatment and thus will not suffer from the late effects of radiotherapy (RT) and the morbidity of laparotomy and splenectomy. RT alone or with other CT combinations should be considered for children who develop relapse of HD. © 1994 Wiley-Liss, Inc.     

Morbus Hodgkin as a second malignancy in acute lymphoblastic leukaemia (author's transl)]

19 months after the clinical manifestation of acute lymphoblastic leukaemia, Hodgkin's disease, stage Ia, of the cervical lymphnodes developed in a 10 year old girl during continuous complete remission of leukaemia under chemotherapy. After a regional irradiation and after completing the antileukamic therapy the patient is at present off therapy, healthy and without signs of relapse of both malignant systemic diseases. The coincidence of acute lymphoblastic leukaemia in children with other malignant neoplasias is rare. The expected frequency of second malignancies and the theories concerning oncogenesis are shortly reviewed.     

Unusual secondary tumors after childhood lymphoid malignancy

Second malignant neoplasms (SMN) in individuals who survived childhood cancer have been reported with increasing frequency during the last decades. The overall probability of developing second malignancy for children treated for cancer was estimated at about 2–5% at 25 years. In children, the tumors most often associated with the development of SMN are retinoblastoma and Hodgkin's disease. We report two cases of unusual second tumors in two patients cured of lymphoid malignancy: one boy cured of acute lymphoblastic leukemia developed mediastinal ganglioneuroma nine years later and one girl had gastric carcinoma seven years after Hodgkin's disease. Both developed a tumor in nonirradiated areas. Gastric carcinoma and ganglioneuroma are not reported as recurrent SMN in survivors after childhood cancer, with one single case of gastric carcinoma and one of ganglioneuroblastoma having been reported as second tumor in survivors after childhood cancer. © 1995 Wi1ey-Liss Inc.     

Detection of Epstein-Barr virus in Reed-Sternberg cells of Hodgkin's disease arising in children

Nonisotopic in situ hybridization has been used to investigate the role of Epstein-Barr virus (EBV) in the aetiology of pediatric Hodgkin's disease. Sections from 24 cases arising in children under the age of 15 years were hybridised with digoxigenin-labelled probes for both EBV and cytomegalovirus, and reactive sites were identified by a sensitive three-layer immunoperoxidase technique. EBV was identified in Reed-Sternberg and mononuclear Hodgkin's cells in five samples (21%). No samples were positive when the cytomegalovirus probe was employed. The specific identification of EBV in the malignant cells of Hodgkin's disease arising in children lends further support for a role of EBV in the aetiology of this disorder. © 1993 Wiley-Liss, Inc.     

Late orthopedic effects in children with Wilms' tumor treated with abdominal irradiation

Between 1970 and 1984, 31 children with biopsy-proven Wilms' tumor received nephrectomy, chemotherapy, and abdominal irradiation and were followed beyond skeletal maturity. Three patients (10%) developed late orthopedic abnormalities requiring intervention. Ten children received orthovoltage irradiation, and all cases requiring orthopedic intervention or developing a scoliotic curve of >20d? were confined to this group, for a complication frequency of 50%. Those children who developed a significant late orthopedic abnormality (SLOA) as defined were treated to a higher median dose (2,890 cGy) and a larger field size (150 cm²) than those who did not (2,580 cGy and 120 cm²). Age at irradiation, sex, and initial stage of disease did not appear to influence the risk of developing an SLOA. No child who received megavoltage irradiation developed an SLOA despite treatment up to 4,000 cGy or to field sizes of 400 cm². We conclude that modern radiotherapy techniques rarely lead to significant late orthopedic abnormalities previously associated with abdominal irradiation in children with Wilms' tumor.     

INTRACRANIAL INVOLVEMENT IN HODGKIN'S DISEASE

The authors report 3 cases of Hodgkin's disease with intracranial involvement. The patients were 4, 12, and 15 years old (male/female = 1/2). Initially, they were treated with ABVD or COPP chemotherapies and low-dose involved field radiotherapy. Intracranial recurrences occurred 27, 40, and 42 months after initial diagnosis, respectively. Two patients experienced convulsions and the other complained of diplopia. The metastatic lesions were located supratentorially with CT or MRI. Despite initial response achieved following systemic chemotherapy and external irradiation to cranial lesions, all patients died with disseminated disease. In patients with intracranial involvement of Hodgkin's disease, prolonged disease-free survival may be achieved by combined modality treatment.     

Cerebral non-Hodgkin's lymphoma discovered when treating Hodgkin's disease

Case report of the appearance of a highly malignant cerebral non-Hodgkin's lymphoma of a diffuse large cell type, type B, occurring at the immediate onset of chemotherapy for a stage IV (mediastino-pulmonary) Hodgkin's disease (nodular sclerosis) diagnosed in a 16-year-old boy. The treatment of this cerebral lymphoma associated primary chemotherapy with high dose methotrexate, high dose aracytine, etoposide, and ifosfamide. The chemotherapy proved to be highly efficient, producing complete remission. Thoracic and abdominal irradiation for Hodgkin's disease was performed concomitantly with chemotherapy for the non-Hodgkin's lymphoma. This treatment was followed by 36 Gy of cerebral irradiation. Thirty-six months after the discovery of the cerebral non-Hodgkin's lymphoma the patient was still disease-free and doing well. © 1993 Wiley-Liss, Inc.     

Comprehensive treatment of advanced neuroblastoma involving autologous bone marrow transplant

Encouraging results are reported with high-dose chemotherapy and total body irradiation followed by autologous bone marrow transplantation in the treatment of advanced neuroblastoma. However, relapse remains a significant problem. We used high-dose chemotherapy, surgery, intraoperative radiation and an autologous bone marrow transplant treated in vitro to remove tumor cells followed by 13-cis-retinoic acid to treat 36 children with advanced neuroblastoma. This comprehensive treatment appears to improve the survival rate of patients with advanced neuroblastoma, including those with N-myc amplification and bony involvement. The disease-free survival rate was 66% (95% confidence interval, 49–84%) at 3 years. All patients who received 13-cis-retinoic acid developed cheilitis, but no bone marrow depression occurred in these patients. Five patients developed hemolytic uremic syndrome (HUS) post-transplant. This may have been related to the procedure used for total body irradiation. Patients who had their kidneys shielded during this procedure did not develop this syndrome. Patients who received local irradiation at the primary site showed no evidence of relapse in this region, indicating that such therapy may help to prevent a relapse. These data suggest a high rate of 3 year disease-free survival with this treatment strategy. The nonrandomized nature of the study and use of multiple modalities precludes analysis of the specific contribution of each.     

HODGKIN'S DISEASE AS A SECOND MALIGNANT NEOPLASM IN CHILDHOOD: Report of a Case and Review of the Literature

There is a known association between lymphoid malignancy and Hodgkin's disease(HD), but the development of HD in children who have been treated for leukemia or lymphoma is very uncommon. Hodgkin's disease is, after retinoblastoma, the most common primary tumor that is associated with development of second malignant neoplasm. For reasons that remain to be determined, HD is very rare as a second malignancy [1, 2, 3]. We report the caseofa eight-year-old girl whodevelopedHD 6 years aftertreatment forcommon acute lymphoblastic leukemia (ALL). This case promptedus to review the published literature for cases of secondary HD in childhood. Our experience suggests that we should follow strictly our patients with ALL and be ready to intervene with invasive diagnostic procedures at the least suspicion of a second or recurrent neoplasm. The most frequent causes of second tumors are radiotherapy, genetic susceptibility and prior treatment with certain chemotherapeutic agents, suchas nitrogen mustards. It is likely that any typeof immunodeficiency, even without symptoms, might play a role in the development of second tumors in childhood.     

Delayed craniospinal irradiation for a first isolated central nervous relapse of acute lymphoblastic leukemia: report on 14 cases

BACKGROUND: Children developing an isolated central nervous system (CNS) relapse as first recurrence of their acute lymphoblastic leukemia (ALL) are considered to have a systemic relapse as well. They are mostly treated with intensive chemotherapy and craniospinal irradiation. In most treatment schedules, irradiation is given early after induction treatment. Because craniospinal irradiation affects a large portion of hematopoietic bone marrow systemically, treatment is often delayed owing to aplasias. Also, dose reductions are frequently needed. Children receiving simultaneously irradiation and chemotherapy are prone to (often severe) neurotoxicity. This study reports on children with a first isolated CNS relapse of their ALL receiving chemotherapy for 40 weeks. Treatment ends with the administration of irradiation given after cessation of chemotherapy. PROCEDURE: Fourteen children, with blasts and >5 cells/mm(3) in two consecutive samples of cerebrospinal fluid and a blast percentage <5% in their bone marrow were treated according to an intensive systemic and site-specific chemotherapy. Craniospinal irradiation was administered after cessation chemotherapy. RESULTS: Event-free-survival was 57% (confidence interval 35-89%), freedom from relapse was 61.5%; follow-up ranges from 2.0 to 15.1 years (median 11.7 years). One child died from septicemia during induction. Five children experienced a second relapse and died from their malignancy. Two children [with a t(9;22) or a rearranged MLL gene] relapsed prior to radiotherapy. Outcome was related to duration of first remission, age at relapse, and identification as a high-risk patient at initial diagnosis. No neurologic complications were noted during and after treatment. CONCLUSIONS: Delayed irradiation for isolated CNS relapse in children with ALL gives favorable survival rates, without significant toxicity. Neurotoxicity was absent.     

Benign proliferative lesions mimicking recurrence of Hodgkin's disease

Salvage treatment in patients with recurrent Hodgkin's disease is more effective when tumor burden is minimal. That is why more intensive follow-up strategies, including frequent imaging tests, have been recently developed for the detection of early relapse. However, as screening procedures become more sensitive, there is an increasing risk of false-positive results, demonstrating nonmalignant proliferative disorders. We describe three young patients who had lymphocyte-predominant or mixed-cellularity Hodgkin's disease and were in clinical complete remission for 2.5–3 years after a combined treatment with chemotherapy and radiation. Imaging tests revealed new gallium-avid lymphadenopathy in the chest in two cases. Pathologically enlarged pelvic lymph nodes were identified in another case, after a diagnosis of recurrent disease in axilla. Those findings were interpreted as relapse, and the patients underwent thoracotomy and laparotomy, respectively, for histologic confirmation. The results showed progressively transformed germinal centers and sarcoid-like lesions, two benign proliferative disorders. When patients with Hodgkin's disease in remission show new lymphadenopathy, even with positive gallium scan, it seems mandatory to obtain tissue for histologic examination, even through invasive procedures such as laparotomy and thoracotomy, to avoid wrong diagnosis and unnecessary treatment. Med. Pediatr. Oncol. 28:187–190 © 1997 Wiley-Liss, Inc.     

Non-Hodgkin's lymphoma: current management

Around 100 new cases of non-Hodgkin's lymphoma are diagnosed each year in the UK, accounting for 7% of childhood cancer. Immunophenotype and stage are used to determine treatment, current treatment resulting in more than 70% long-term survival. The extent of disease at diagnosis is the most important prognostic factor. Patients with localized disease have an excellent prognosis regardless of histology, with a 5-year survival rate of around 90%. The use of intensive multi-agent chemotherapy has improved the outcome for patients with more advanced disease. However, children who relapse after intensive treatment have a poor outcome despite aggressive attempts at salvage treatment. Future advances in treatment require multinational trials in order that treatment can be refined to reduce toxicity for those children with an expected good outcome, and to develop new strategies for children who relapse.