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Tailoring Treatment to Prognosis for Childhood Localized Non-Hodgkin's Lymphoma

Greehey Children's Cancer Research Institute; Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, TX

Risk-adapted treatment for cancer. Hardly a revolutionary concept, you say. But when I was a young investigator at St Jude Children's Research Hospital three decades ago, sitting down at my desk to write a new protocol for a clinical trial testing the idea, the concept was previously untested and entirely unproven. I asked the question whether or not it would be possible to actually reduce the intensity of treatment for a group of children with non-Hodgkin's lymphoma (NHL), defined by their risk, ie, their prognosis. I based the risk assessment on their initial disease extent, using an NHL staging system I had developed,¹ which has become known as the Murphy (or St Jude) System. The aim of the trial (NHL-78) was to achieve a high cure rate (80% to 90%) for children and adolescents with stage I and II NHL while simultaneously reducing the acute toxicity and risk for adverse long-term late effects by reducing the intensity of treatment. The end results of the trial were published in the first volume of the Journal of Clinical Oncology in 1983² and have been selected for reprinting as part of this special Silver Anniversary series.

It is important to place this trial within the historic context of then-contemporaneous approaches to treatment of pediatric malignancies, particularly leukemias and lymphomas, both NHL and Hodgkin's disease (HD). NHL was viewed as a highly lethal disease, with few long-term survivors from the era before the 1970s. Reports first began to appear in the early to mid 1970s of improved survival rates in pediatric NHL resulting from combined modality approaches.^3-5 By this time, irradiation had become firmly established as a modality essential for cure of HD, and, despite the absence of controlled randomized trials of the role of irradiation for pediatric NHL, it was considered to be essential for success.⁶ Application of intensive "leukemia-like " multiple-drug regimens to NHL, combined with irradiation to involved fields and prophylactic treatment of the CNS, became established practice.

Around the same time, there arose the first concerns about acute toxicities of treatment and the adverse long-term effects of radiation and cytotoxic chemotherapy on children. In that era, before hyperalimentation and growth factors, severe mucositis and neutropenia posed significant risks. The experience with pediatric HD survivors treated with standard dose (35 to 40 Gy) extended-field radiation was also just beginning to be appreciated with alarm, prompting Donaldson and her coworkers at Stanford to begin in 1970 an age-adjusted protocol combining lower doses of radiation (15 and 20 Gy, depending on bone age) combined with six cycles of MOPP (mechlorethamine, onocovin, procarbazine, and prednisone) chemotherapy.⁷ In the first randomized test of a reduction in therapy for pediatric cancer, pioneering investigators of the National Wilms' Tumor Study Group (NWTS) originated the concept of grouping patients by extent of disease and testing whether less aggressive therapies would not worsen results in children at relatively low risk of failure. In NWTS-1, conducted from 1969 to 1974, it was shown that routine postoperative radiation therapy was not needed in babies with Group I tumors, limited to the kidney and completely excised.⁸ Against this contemporary backdrop, I designed NHL-78, the first trial to attempt a reduction of therapy for pediatric NHL, a departure from standard practice at the time.

The immediately antecedent NHL trial I had conducted at St Jude, NHL-75, was the first stratified and randomized test of involved-field radiotherapy (IF-RT) combined with an effective drug regimen.⁹ After staging, children and adolescents with stages I and II disease received three-drug induction and IF-RT (30 to 35 Gy) with curative intent, which was then standard treatment. Children with advanced stages III and IV received the same three-drug combination plus a fourth drug, doxorubicin, and were randomly assigned to receive IF-RT or not. I justified the randomization for IF-RT in advanced stage patients on the paucity of any evidence whatsoever that irradiation to bulky tumor masses, in combination with chemotherapy, was beneficial, given the fact that the major cause of treatment failure in NHL was relapse in unirradiated areas. Children with stages II to IV were also randomly assigned to prophylactic treatment of the CNS, while children with stage I or with completely resected stage II GI primaries received none. All patients then completed 2 years of oral two-drug maintenance with daily 6-mercaptopurine and weekly methotrexate. Ninety percent of the stage I to II patients survived, and there was no benefit but added toxicity observed from the addition of large volume conventional dose IF-RT to chemotherapy in stages III and IV.

Observing no benefit from added IF-RT in advanced state NHL, I began to wonder if it was necessary at all, but I lacked the temerity in 1978 to drop it altogether for localized lymphomas and risk throwing the baby out with the bathwater. I also faced a dilemma of comparatively too few patients with localized NHL at St Jude, insufficient enough to conduct a randomized study. So I chose to design a prospective single-arm pilot trial, testing a number of variables simultaneously: reducing the dose of IF-RT (20 Gy), halving the dose of cyclophosphamide, shortening the duration of treatment, and limiting CNS prophylaxis to only those children with tumors in the head and neck. The therapy was remarkably well tolerated and proved to be effective, resulting in 85.7% disease-free survival.²

While my colleagues and I at St Jude were embarking on this pilot trial of less intense treatment for localized NHL, investigators of the Children's Cancer Study Group opened a large trial (CCG-551) in April 1977, which treated all children and adolescents without regard to disease extent, randomly assigning them to either a four-drug COMP (cyclophosphamide, oncovin, methotrexate, and prednisone) regimen or the intensive 10-drug LSA₂-L₂ regimen developed at Memorial Sloan-Kettering. All patients also received irradiation to involved fields (30 Gy for localized disease, with larger volumes, like the whole abdomen, receiving 20 Gy). Both regimens were effective for localized stage I and II disease, resulting in a 2-year failure-free survival of 89% (COMP) versus 84% (LSA₂-L₂,).¹⁰ Our results compared quite favorably to those reported by the Children's Cancer Study Group and were achieved with less intense and less costly treatment.

The success of this small St Jude trial paved the way for a series of larger multi-institutional trials of localized NHL conducted by the Pediatric Oncology Group (POG) during the 1980s and 1990s aimed at further reductions in therapy. The trials were driven by increasing concerns regarding the long-term deleterious effects of childhood cancer therapy, coupled with increasing concern for the large numbers of probably cured survivors. The POG trials began with a small, multi-institutional pilot trial (8202), essentially replicating our trial and confirming that our single institution St Jude results were not a fluke, followed by two large randomized trials (8314 and 8719), designed to study the importance of local radiation and the duration of treatment, respectively.^11,12 The results of these large trials conclusively demonstrated that this subgroup of children and adolescents with stage I and II NHL with a favorable prognosis can be readily identified by clinical evaluation and staging and successfully treated with therapy that is less intense than usual. In fact, the POG trials demonstrated that a 9-week chemotherapy regimen without irradiation is adequate for most (90%) children and adolescents with early stage-nonlymphoblastic NHL. Localized lymphoblastic lymphomas, a small histologically defined subgroup comprising only 15% of all localized NHL in the pediatric age range, were shown to benefit from maintenance chemotherapy, while for other histologic subtypes, maintenance was ineffective.¹²

Throughout the ensuing years, the importance of both histology and stage have become established in assignment of treatment for pediatric (and adult) NHL, and the lack of benefit from local radiotherapy has been further substantiated. Sequential progress has been attributable to well-organized pediatric clinical cooperative group trials, conducted not only by the POG and CCG—which have now merged to form the Children's Oncology Group —but also by significant contributions from other national pediatric clinical trials groups, notably the German BFM (Berlin-Frankfurt-Münster) and the French SFOP (Société Françoise d'Oncologie Pédiatrique) groups.

So, where do we stand now, 25 years later, in relation to further refinements in curative therapies for pediatric NHL and other pediatric malignancies? While lessening treatment intensity for favorable stage groups of NHL has proven successful, intensified treatments for patients with extensive disease have markedly improved their survival rates.^13,14 Currently, we can expect to cure the great majority of all children and adolescents with NHL, regardless of disease extent. These advances have occurred in parallel with the major advances achieved in curative treatments for acute lymphoblastic leukemia (ALL), HD, Wilms' tumor, bone and soft tissue sarcomas, and other forms of pediatric cancer. Further gains are likely to come not from reductions (or intensification) of treatments for entire groups of patients, but rather from attempts to identify at diagnosis patients destined to fare well (or poorly) and treat them appropriately. An outstanding example of a successful approach of this kind has been provided by the report of the POG trial 9201 for children with lesser risk ALL, defined by age (between 1 and 9 years), WBC count less than 50 x 10⁹/L, blast cell DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt CNS leukemia. POG 9201 was designed to treat this favorable prognostic subgroup of ALL patients with less intensive treatment, sparing them exposure to alkylating agents, anthracyclines, epipodophyllotoxins, and radiation. Using a comparatively simple, nontoxic antimetabolite-based regimen, a 6-year overall survival of 97.2% was achieved.¹⁵ By accurately profiling the genetic characteristics of the malignant cells, combined with clinical features of age and disease extent or rate of response to chemotherapy, the goal of curative treatments for all pediatric cancers with few serious, late secondary effects may be achievable.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Murphy SB: Prognostic features and obstacles to cure of childhood non-Hodgkin's lymphoma. Semin Oncol 4:265-271, 1977[Medline]

2. Murphy SB, Hustu HO, Rivera G, et al: End results of treating children with localized non-Hodgkin's lymphomas with a combined modality approach of lessened intensity. J Clin Oncol 1:326-330, 1983[Abstract]

3. Wollner N, Burchenal JH, Lieberman PL, et al: Non-Hodgkin's lymphoma in children: A comparative study of two modalities of therapy. Cancer 37:123-134, 1976[CrossRef][Medline]

4. Aur RJA, Hustu HO, Simone JV, et al: Therapy of localized and regional lymphosarcoma of childhood. Cancer 27:1328-1331, 1971[CrossRef][Medline]

5. Murphy SB: Management of childhood non-Hodgkin's lymphoma. Cancer Treat Rep 61:1161-1173, 1977[Medline]

6. Glatstein E, Kim H, Donaldson SS, et al: Non-Hodgkin's lymphomas VI: Results of treatment in childhood. Cancer 34:204-211, 1974[CrossRef][Medline]

7. Donaldson SS: Pediatric Hodgkin's disease—focus on the future, in Van Eys J, Sullivan MP (eds): Status of the curability of childhood cancers. New York, NY, Raven Press, 1980, pp 235-249

8. D'Angio GJ, Beckwith JB, Breslow NE, et al: Wilm's Tumor: An update. Cancer 45:1791-1798, 1980[Medline]

9. Murphy SB, Hustu HO: A randomized trial of combined modality therapy of childhood non-Hodgkin's lymphoma. Cancer 45:630-637, 1980[CrossRef][Medline]

10. Anderson JR, Wilson JF, Jenkin RDT, 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 306:559-566, 1983

11. 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]

12. 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[Abstract/Free Full Text]

13. Reiter A, Schrappe M, Parwaresch R, et al: Non-Hodgkin's lymphomas of childhood and adolescence: Results of a treatment stratified for biologic subtypes and stage—A report of the Berlin-Frankfurt- Münster Group. J Clin Oncol 13:359-372, 1995[Abstract/Free Full Text]

14. Patte C, Auperin A, Michon J, et al: The Société Françoise d'Oncologie Pédiatrique LMB89 protocol: Highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97:3370-3379, 2001[Abstract/Free Full Text]

15. Chauvenet AR, Martin PL, Devidas M, et al: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: A report from Children's Oncology Group Study P9201. Blood 110:1105-1111, 2007[Abstract/Free Full Text]

Related Article

• End results of treating children with localized non-Hodgkin's lymphomas with a combined modality approach of lessened intensity
  SB Murphy, HO Hustu, G Rivera, and CW Berard
  JCO 1983 1: 326-330 [Abstract]

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Google Scholar Articles by Murphy, S. B. PubMed PubMed Citation Articles by Murphy, S. B. Related Articles Related Article