Progress made in treatment of childhood cancer in the past 30 years has been tremendous. We need only examine the survival statistics of 30 years ago and compare them to those of the present to realize the great strides that have been made.
This progress can be ascribed to many different factors, including:
1. A better knowledge of the natural history and course of the disease, leading to earlier and more thorough surgical treatment
2. The development of high-energy radiation, again combined with knowledge of the spread of the disease, which has contributed significantly to the treatment of Hodgkin's disease and the lymphomas
3. The use of intensive, intermittent, short-course chemotherapy, usually with combinations of drugs, both as adjuvant to surgery and radiation or given alone in stage III and stage IV disease, which has markedly increased survival and produced cures in many cases.
The most common neoplastic disease in childhood is acute lymphoblastic leukemia. Before the introduction by Farber in 19481 of specific therapy with folic acid antagonists, the median survival time from the first symptom of the disease until death was between four and five months.2 In 107 cases reported from Memorial Hospital prior to 1948, only one survived more than a year, and that patient died at 14 months.3
With the accession of many new agents,4-13 the discovery by Whiteside14 of the efficacy of intrathecal methotrexate against meningeal leukemia, and the introduction of intensive, intermittent combination chemotherapy,15 the outlook for long-term survival and perhaps cure has altered drastically. In a current series of patients observed following treatment, Pinkel16 and Simone17 are projecting a five-year survival rate of over 50 per cent. These patients were induced into remission with vincristine and prednisone, treated prophylactically with craniospinal irradiation or cranial irradiation and intrathecal methotrexate, and maintained on oral dosages of mercaptopurine daily and cyclophosphamide and methotrexate weekly. Similarly, the recently reported study of Acute Leukemia Group B has shown an overall survival rate of 40 per cent at four years in 426 patients. By life-table analysis, several selected regimens of this multiphasic study are expected to produce more than 50 per cent survivors at five years.18
In previous studies of cases collected from hematologists all over the world, it was demonstrated that cases of acute leukemia surviving five years have a 50 per cent chance of continuing free-ofdisease for an indefinite period of time.19 Of these 158 patients, 93 are living and well with no evidence of disease 10 to 21 years after diagnosis. Since many of the patients in this series had one or more relapses of leukemia prior to five years, it is likely that intensively-treated cases in the recently-reported series who have continued for five years in continuous remission will have a much higher rate of indefinite disease-free survival than the previous less intensively-treated series.
In Burkitt's tumor in Africa,20 Burkitt and O'Conor in 1961 reported a median survival time of as little as four to six months from the first symptom of the disease.21 In contrast, Ziegler22 is now able to report 50 per cent overall long-term survival, and as high as 73 per cent long-term survival in stage I and stage II disease. Since relapses after two years of unmaintained remission are extremely rare in this disease, it is probable that these longterm remissions are nearly synonymous with cure. The treatment consisted of massive doses of cyclophosphamide (40 mg./kg.), repeated every two to three weeks, with intrathecal methotrexate or cytosine arabinoside or both for C.N.S. complications. The combination of vincristine and methotrexate followed by a five-day course of cytosine arabinoside was also used, with or without cyclophosphamide.
The diagnosis of Burkitt's tumor in a nonendemic area such as the United States is difficult; such cases are rare. Previously they were grouped in with the non-Hodgkin's lymphomas. Thirty years ago the survival of the generalized disease was extremely poor (three to six months). Only completely localized, extranodal or nodal lesions treated by surgery or massive irradiation had any chance of long-term survival. Now Carbone23 has recently reported that 9 out of 20 patients with American Burkitt's tumor, treated with repeated massive doses of cyclophosphamide, have survived more than two years; three of these have no evidence of disease at five years. In a larger total series of 29 patients there has been less than four per cent decrease in survival after the first 12 months.
Recent studies by Wollner24,25 have produced striking results in the nonHodgkin's lymphomas, nodal or extranodal, in children by using a massive dose of cyclophosphamide (40 mg. /kg. I.V.), followed immediately by a regimen used for acute lymphoblastic leukemia. This regimen consists of vincristine, prednisone, and daunomycin induction, intrathecal methotrexate for prophylaxis of C.N.S. involvement, radiation therapy to any localized disease, three courses of cytosine arabinoside and thioguanine, followed by thrice-weekly 1-asparaginase for four weeks as consolidation, and then sixweek cycles of maintenance therapy. Thirty-two of 35 patients (19 with lymphosarcoma and 16 with reticulum cell sarcoma) - 27 in stage III and IV - had complete regression of all measurable tumor, and 29 remain with no evidence of disease from 3 to over 28 months from the start of treatment. Studies from the same hospital, before the initiation of this massive combination treatment regimen, had shown 14 of 18 patients relapsing at a median of four months.26
In Hodgkin's disease 30 years ago, even in stage I and II disease, repeated palliative radiotherapy resulted in occasional long-term survival, but rarely in cures. The generalized disease was synonymous with a sentence of death. The great improvements in massivedose and extended-field radiotherapy initiated by Easson, Peters, and Kaplan have increased the cure rate tremendously in localized disease. The epochmaking development by De Vita27,28 of the intermittent intensive combination chemotherapy program with nitrogen mustard, vincristine (Oncovin), procarbazine, and prednisone (MOPP), in two-week courses, every month for six months, has revolutionized the treatment of stage III and IV Hodgkin's disease.
Wilms' tumor is one of the common solid tumors in infants and children; it may be present at birth. Klapproth,29 surveying the literature, found the cure rate between 1940 and 1958 to be between 17 and 23 per cent. In 1966, Farber30 was able to report that by the use of early radical surgery, locallyadministered radiotherapy, and actinomycin D, 47 out of 53 patients with no demonstrable metastases on admission were alive with no evidence of tumors from two to nine years later. In 18 of 31 patients who had pulmonary metastases, radiotherapy and actinomycin D destroyed the tumor. These 18 patients were alive and well with no evidence of disease two years or more following therapy. Thus, the cure rate with multidisciplinary therapy in both early and far-advanced Wilms' tumor has improved immeasurably in the past 30 years.
Treated either by surgery or radiation, a five-year survival of approximately 10 per cent was to be expected in Ewing's tumor 30 years ago, and most patients showed evidence of metastases within two years. Recently, Hustu31 reported 11 of 15 patients surviving with no evidence of disease 4 to over 91 months after diagnosis. These patients were treated with massive local irradiation to the primary tumor and with prophylactic vincristine and cyclophosphamide once weekly for four to six doses, as tolerated, and then every two weeks for two years. Similarly, the recent studies of Rosen et al.,32 using massive local radiation to the primary Ewing's tumor and a fourdrug adjuvant chemotherapy protocol consisting of actinomycin D, adriamycin, cyclophosphamide, and vincristine, repeated every three months, showed 12 out of 12 patients without evidence of disease 10 to 37 months from the start of therapy.
The disappointing results of radiation or surgical treatment of rhabdomyosarcoma in children, with an overall survival rate of about 10 per cent, have changed markedly in recent years. Pratt33 reported 20 children with embryonal rhabdomyosarcoma treated with multidisciplinary therapy consisting of surgery, radiotherapy, and combination chemotherapy. Fifteen of the 20 developed complete regression of the tumor and seven are now tumorfree from 2 to 39 months on maintenance combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide. In rhabdomyosarcoma of the head and neck, Donaldson34 reported no evidence of disease in 14 of 19 children with the use of surgical excision, when possible, combined with radiation and combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide. Twelve of these children have been disease-free for more than two years.
In the treatment of neuroblastoma, marked palliation and temporary complete remissions can be achieved with chemotherapy, but long-term remissions or cures are rare, except in patients under one year of age. Similarly, in osteogenic sarcoma, the use of supra-lethal doses of methotrexate by continuous infusion, followed by rescue with leucovorin, has produced occasional striking regressions. But again it is too early to discuss definitive results. In brain tumors, although certain of the nitrosoureas have been shown to cross the blood-brain barrier, and methotrexate has been used intrathecally and intraventricularly, progress has been less impressive than with the previously mentioned group of tumors.
Thus, there has been tremendous progress in the treatment of childhood tumors in the past 30 years, due to the development of multidisciplinary therapy and intensive intermittent combination chemotherapy. But much remains to be done to achieve the goal of the complete control of childhood cancer.
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