Tailoring treatment to prognosis for childhood localized non-Hodgkin's lymphoma.

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, 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 1983 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. 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. 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. 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. 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 involvedfield radiotherapy (IF-RT) combined with an effective drug regimen. 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. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 7 MARCH 1 2008