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© 1999 American Society for Clinical Oncology Treatment of Localized Primary Non-Hodgkin's Lymphoma of Bone in Children: A Pediatric Oncology Group StudyFrom the Departments of Pediatrics and Radiation Oncology, Stanford University School of Medicine, and Lucile Salter Packard Children's Hospital at Stanford, Stanford, CA; Department of Statistics, University of Florida, and Pediatric Oncology Group Statistical Office, Gainesville, FL; Department of Pathology, School of Medicine, State University of New York, Syracuse, NY; and Department of Pediatrics, Northwestern University School of Medicine and Children's Memorial Hospital, Chicago, IL. Address reprint requests to Michael P. Link, MD, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5208.
PURPOSE: The treatment of primary lymphoma of bone (PLB) in children has traditionally included radiotherapy to the primary site; more recently, it has included systemic chemotherapy. Because of concern about the untoward effects of treatment in a disease that is curable, we attempted to determine whether radiotherapy can be safely excluded from treatment. PATIENTS AND METHODS: The results of three consecutive Pediatric Oncology Group (POG) studies were examined to determine the impact on outcome of radiotherapy as adjunctive treatment in children and adolescents receiving chemotherapy for early-stage primary lymphoma of bone. RESULTS: From 1983 to 1997, 31 patients with localized PLB were entered onto POG studies of early-stage non-Hodgkin's lymphoma (NHL). Between 1983 and 1986, seven patients were treated with 8 months of chemotherapy with irradiation (XRT) of the primary site. After 1986, patients were treated without XRT; four received 8 months of chemotherapy, and 20 received 9 weeks of chemotherapy. Primary sites were the femur (nine), tibia (eight), mandible (five), mastoid (one), maxilla (one), zygomatic arch (one), rib (one), clavicle (one), scapula (one), ulna (one), talus (one), and calcaneous (one). Histologic classification revealed 21 cases of large-cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. One patient relapsed at a distant site 22 months after completion of therapy. There have been no deaths. CONCLUSION: Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.
A SMALL PROPORTION (~ 5%) of children with early-stage non-Hodgkin's lymphoma (NHL) have a primary site in bone and have traditionally been treated with radiotherapy. In adults, long-term survival is at best 50% for patients with early-stage NHL of bone treated with local irradiation alone.1,2 As is the case for many pediatric malignancies, NHL is a systemic disease. Local therapy alone is not sufficient treatment, even for what seems to be localized disease. The introduction of multiagent chemotherapy has resulted in a substantial improvement in survival, and more than 90% of children with early-stage NHL are now cured.3 Because primary lymphoma of bone (PLB) in children is rare, there is limited information in the literature concerning the appropriate treatment of these patients. Most of the reports are retrospective reviews, and the largest group reported to date consists of 14 patients.4-9 In the past, radiotherapy has played an important role in treatment, both alone and, more recently, in combination with chemotherapy. As an increasing number of children are cured, the focus of treatment shifts to minimizing adverse effects, because the risk of these complications can be significant in long-term survivors. Secondary cancers are a particularly devastating problem observed in survivors of childhood cancers. In 1986, Loeffler et al8 reported two cases of secondary sarcoma in the radiation field among 11 children who had been successfully treated for lymphoma of bone. The focus of recent treatment studies of early-stage NHL in children has been on minimizing early and late toxicities by introducing chemotherapy regimens of lessened intensity and shorter duration. In addition, studies from the Pediatric Oncology Group and elsewhere indicate that local irradiation is unnecessary for NHL arising in primary sites other than bone.10 Because radiotherapy seems to be unnecessary for the treatment of childhood NHL at other sites, we sought to determine whether radiotherapy is a necessary component of treatment of primary NHL of bone. In addition, we sought to determine whether a 9-week chemotherapy regimen of lessened intensity is sufficient for cure.
The data from three consecutive studies of early-stage NHL in children and young adults (< 21 years old) conducted by the Pediatric Oncology Group between 1983 and 1997 were reviewed for those patients who had PLB. Patients underwent a staging evaluation, including history and physical examination, complete blood count, percutaneous aspiration and/or biopsy of bone marrow from the iliac crest, lumbar puncture for examination of a cytocentrifuged specimen of cerebrospinal fluid, posteroanterior chest radiography, radionuclide bone scanning, and, if indicated, computerized tomography or magnetic resonance imaging. Patients were assigned a clinical stage according to a system described previously.11 The histology was reviewed centrally, and the diagnostic specimens were classified according to the Working Formulation for Clinical Usage.12 All previously untreated children and young adults younger than 21 years old who met criteria for early-stage disease (stages I and II) were eligible for these studies. The first study, conducted between 1983 and 1986, was designed to determine whether radiotherapy could be safely omitted from treatment in children with early-stage NHL. All patients received 9 weeks of induction chemotherapy and 24 weeks of continuation therapy. Patients were randomly assigned to receive radiotherapy to a dose of 27 Gy during induction therapy or to receive chemotherapy alone without irradiation. The results demonstrated that there was no significant difference in outcome whether or not radiotherapy was administered.10 However, patients with bone lymphoma on that study were specifically excluded from the randomization because the use of radiotherapy was considered the standard of care for patients with bone lymphoma at the time, and all received 37.5-Gy irradiation to the primary site. The second study was conducted between 1987 and 1992 and was designed to determine whether 24 weeks of continuation chemotherapy could be safely omitted from the treatment of early-stage NHL. All patients received the identical 9 weeks of induction chemotherapy as administered in the first study. Patients were randomly assigned to receive either 24 weeks of continuation chemotherapy after the 9-week induction phase or no further therapy. No patient received radiotherapy, including those with a primary tumor arising in bone. The results demonstrated that 9 weeks of chemotherapy alone are sufficient treatment for children with early-stage nonlymphoblastic lymphoma; however, patients with localized lymphoblastic lymphoma had inferior outcome and benefit from 24 weeks of continuation therapy.3 Our most recent study was initiated in 1992 and was designed to determine which factors predict outcome in children with early-stage NHL. In this nonrandomized study, patients with nonlymphoblastic lymphoma are treated with 9 weeks of chemotherapy alone, and patients with lymphoblastic lymphoma are treated with 9 weeks of induction and 24 weeks of continuation therapy, for a total of 33 weeks of chemotherapy. Radiotherapy is not prescribed for any patient in this study. The chemotherapy regimens used in the three studies are described in Table 1. Induction/consolidation chemotherapy consisted of four drugs given for 9 weeks, and continuation chemotherapy consisted of daily oral mercaptopurine and weekly oral methotrexate given for 24 weeks. Central nervous system prophylaxis was prescribed only for patients with primary tumors in the head and neck region. The protocols were approved by the institutional review board at each participating center, and all patients or their parents gave informed consent.
In summary and by design, the following three treatment regimens were used for children with primary lymphoma of bone in the three studies: 8 months of systemic chemotherapy (9 weeks of induction therapy with 24 weeks of continuation therapy) with involved-field radiotherapy (37.5 Gy); 8 months of chemotherapy alone (9 weeks of induction therapy with 24 weeks of continuation therapy); or 9 weeks of chemotherapy alone (induction therapy with no continuation therapy).
Between April 1983 and April 1997, among 567 children with early-stage non-Hodgkin's lymphoma, 31 children with PLB (5.5%) were entered onto these three studies. Patient characteristics are listed in Table 2. There were 18 males and 13 females. Twenty-six children had stage I disease (involvement of the primary site only) and five had stage II disease (four patients had involvement of the primary site and regional lymph nodes, and one patient had two discrete osseous sites, one in each side of the mandible). Their ages ranged from 1 to 20 years (median age, 13 years). The primary site was the femur in nine patients, tibia in eight patients, mandible in five patients, and mastoid, maxilla, zygomatic arch, rib, clavicle, scapula, ulna, talus, and calcaneous in one patient each.
The histologic classification revealed 21 cases of large-cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. Immunophenotyping was performed in 12 of the 31 cases. B-lineage markers were expressed in six patients with large-cell lymphoma and two patients with lymphoblastic lymphoma, T-cell markers were expressed in two patients with large-cell lymphoma and one patient with NHL not further classifiable, and monocyte/ macrophage markers were expressed in one patient with large-cell lymphoma. Seven patients received 8 months of chemotherapy with involved-field radiation, four patients received 8 months of chemotherapy alone, and 20 patients received 9 weeks of chemotherapy alone. All 31 patients achieved complete remission, and there has been only one treatment failure, which occurred in a patient with a lymphoblastic lymphoma of the ulna treated with 9 weeks of chemotherapy without continuation therapy or irradiation. He developed a relapse in the testicle 1 year after completion of therapy without evidence of recurrence at the primary site. This patient was successfully treated with additional chemotherapy and remains in a second complete remission 4 years after relapse. There have been no other treatment failures, no significant complications from therapy, and no deaths. The projected survival and event-free survival rates at 5 years for children with early-stage PLB were 100% and 95% (SE, 7%), respectively, as shown in Fig 1. The maximum follow-up was 12 years, and 15 patients have been followed for more than 3 years. Of note, the seven patients who received radiotherapy have been followed for 6 to 12 years after attaining remission (median, 9 years) with no reported sequelae.
These 31 patients represent the largest group reported in the literature of children with primary lymphoma of bone treated in a standardized fashion. It seems that primary lymphoma of bone accounts for approximately 5% of cases of early-stage NHL in children, which is consistent with previously published data.4-6,8,13,14 The majority of cases occur in the lower extremities and are of large-cell histology. The development of risk-based treatment for children with cancer has resulted in the use of more aggressive therapy for those with malignancies associated with a higher relapse hazard. Less intensive regimens are used for children with malignancies with a higher cure rate, resulting in fewer side effects and complications of therapy. The protocols on which these children with PLB were treated sought to reduce the toxicity associated with traditional treatment regimens without sacrificing the excellent outcomes that had been reported. As increasing numbers of survivors of childhood cancer live well into adulthood, the incidence of long-term complications of therapy is expected to increase. To maximize the quality of life in these patients, those toxicities that may have profound adverse affects on their lives must be minimized. In addition to the more common untoward effects of therapy, such as compromised musculoskeletal development with irradiation, the appearance of secondary malignancies represents a particularly devastating complication.8,15 In a review of secondary malignancies developing in patients treated for childhood cancer, acute leukemia was the most common secondary malignancy observed in patients treated without irradiation, whereas bone sarcoma in the radiated field was the most common secondary malignancy in irradiated children.16 The elimination of these complications, by the omission of radiotherapy in particular, has been an important objective of more recent treatment regimens. The results to date are gratifying. Two thirds of the children in this series were treated with only 9 weeks of chemotherapy, and only seven received radiotherapy to the primary site. Only one child has relapsed. All 31 patients are alive without sequelae. Further follow-up is needed to fully evaluate the outcome for children with PLB, but the results from these three studies demonstrate that such children can be treated successfully with chemotherapy regimens of lessened intensity and duration without irradiation.
Supported in part by grant nos. CA-33603, CA-29139, CA-07431, and CA-30969 from the National Cancer Institute.
1. Ostrowski ML, Unni KK, Banks PM, et al: Malignant lymphoma of bone. Cancer 58:2646-2655, 1986[Medline] 2. Mendenhall NP, Jones JJ, Kramer BS, et al: The management of primary lymphoma of bone. Radiother Oncol 9:137-145, 1987[Medline]
3.
Link MP, Shuster JJ, Donaldson SS, et al: Treatment of children and young adults with early stage non-Hodgkin's lymphoma. N Engl J Med 337:1259-1266, 1997 4. Coppes MJ, Patte C, Couanet D, et al: Childhood malignant lymphoma of bone. Med Pediatr Oncol 19:22-27, 1991[Medline] 5. Furman WL, Fitch S, Hustu HO, et al: Primary lymphoma of bone in children. J Clin Oncol 7:1275-1280, 1989[Abstract]
6.
Haddy TB, Keenan AM, Jaffe ES, et al: Bone involvement in young patients with non-Hodgkin's lymphoma: Efficacy of chemotherapy without local radiotherapy. Blood 72:1141-1147, 1988 7. Howat AJ, Thomas H, Waters KD, et al: Malignant lymphoma of bone in children. Cancer 59:335-339, 1987[Medline]
8.
Loeffler JS, Tarbell NJ, Kozakewich H, et al: Primary lymphoma of bone in children: Analysis of treatment results with adriamycin, prednisone, Oncovin (APO), and local radiation therapy. J Clin Oncol 4:496-501, 1986 9. Jereb B, Wollner N, Kosloff C, et al: The role of local radiation in the treatment of non-Hodgkin lymphoma in children. Med Pediatr Oncol 9:157-166, 1981[Medline] 10. Link MP, Donaldson SS, Berard CW, et al: Results of treatment of childhood localized non-Hodgkin's lymphoma with combination chemotherapy with or without radiotherapy. N Engl J Med 322:1169-1174, 1990.[Abstract] 11. Murphy SB: Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities from lymphomas in adults. Semin Oncol 7:332-339, 1980[Medline] 12. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute-sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982[Medline] 13. Anderson JR, Wilson JF, Jenkin DT, et al: Childhood non-Hodgkin's lymphoma: The results of a randomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2). N Engl J Med 308:559-565, 1983[Abstract] 14. Freeman C, Berg JW, Cutler SJ: Occurrence and prognosis of extranodal lymphomas. Cancer 29:252-260, 1972[Medline] 15. Tucker MA, D'Angio GJ Boice JD, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317:588-593, 1987[Abstract] 16. Meadows AT, Baum E, Fossati-Bellani F, et al: Second malignant neoplasm in children: An update from the Late Effects Study Group. J Clin Oncol 3:532-538, 1985[Abstract] Submitted June 22, 1998; accepted October 5, 1998. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
