Pediatric Annals

ADVANCES IN THE TREATMENT OF CHILDHOOD CANCER-1944 TO 1974

Joseph H Burchenal, MD

Abstract

1. Farber, S.. Diamond, L. K., Mercer. R. D., et al. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroylglutamic acid (aminopterin). New Engl. J. Med. 238 (1948), 787.

2. Tivey. H. Prognosis for survival in the leukemias of childhood. Pediatrics 70(1952), 48.

3. Southam. CM.. Craver. L. F., Dargeon, H. W., and Burchenal, J. H. A study of the natural history of acute leukemia with special reference to the duration of the disease and the occurrence of remissions. Cancer 4 (1951), 39.

4. Pearson, O. H.. Elie), L. P., and Ráwson, - R. W. Regression of Lymphoid Tumors in Man Produced by ACTH and Cortisone. J. R. Moti, ed. In Proceedings of the Clinical ACTH Conference. Philadelphia: Blakiston, 1950, 318.

5. Farber. S.. Schwachman, H.. Toch, R, et al. Effect of ACTH in Acute Leukemia in Childhood. J.R. Moti, ed. In Proceedings of the Clinical ACTH Conference. Philadelphia: Blakiston. 1950, 328.

6. Burchenal, J. H., Murphy. M. L.. Ellison, R. R., et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood 8 (1953), 965.

7. Fernbach. D.J., Sutow. W.W., Thurman, W., and Vietti, T. Clinical evaluation of cyclophosphamide, J. A. M. A. 152(1962), 30.

8. Selawry, O.S. and Delta, B. G. Leurocristine in cancer of children. Proc. Amer. Assoc. Cancer Res. 3(1962), 360.

9. Evans. JS. , Musser, E. A., Mengel, G. D., et. al. Anti-tumor activity of 1-B-D-arabinofura rosy lcytosine hydrochloride. Proc. Soc. Exp. Biol. Med. 106 (1961), 350.

10. Tan, C, Tasaka, H., Yu1 K. -P., et al. Daunomycin, an anti-tumor antibiotic in therapy of neoplastic disease. Cancer 20 (1967), 333.

11. Bonadonna, G. and Monfardini, S. Therapeutic effects of adriamycin in neoplastic disease of children and adults. Proc. Amer. Assoc. Cancer Res. 11 (1970), 10.

12. Hill. JM. . Roberts, J., Loeb. E., et al. 1asparaginase therapy for leukemia and other malignant tumors. J. A. M .A. 202 (1967), 882.

13. Oettgen. H. F.. Old, L.J.. Boyse, E.A., et al. Inhibition of leukemias in man by 1 -asparaginase. Cancer Res. 27(1967), 2619.

14. Whiteside, J. A., Philips. F.S.. Dargeon. HW. , and Burchenal. JH. Intrathecal Amethopterin in neurological manifestations of leukemia. Arch. Intern. Med. 101 (1958), 279.

15. Freireich, E.J., Karon, M., and Frei, E. Potential for eliminating leukemic cells in childhood acute leukemia. Proc. Amer. Assoc. Cancer Res. S (1964), 20.

16. Pinkel, D. Five-year follow-up of "total therapy" of childhood lymphocytic leukemia. J. A. M. A. 276(1971). 648.

17. Simone, J., Aur. R. J. ?.. Hustu, H. O., and Pinkel. D. "Total therapy" studies of acute lymphocytic leukemia in children. Cancer 30 (1972), 1488.

18. Holland. JF. and Glidewell, O. Chemotherapy of acute lymphocytic leukemia of childhood. Cancer 30 1 972) . 1 480.

19. Burchenal. J. H., Dowling, M., and Tan, C. Treatment of acute lymphoblastic leukemia. Ann. Rev. Med. 23 (1972), 77.

20. Burkitt. D. Sarcoma involving jaws in African children. Brit. J. Surg. 46(1958), 218.

21. Burkitt, D. and O'Cono.r. G. Malignant lymphoma in African children. Cancer 14 (1961). 258.

22. Ziegler. J. L. Chemotherapy of Burkitt's lymphoma. Cancer 30 (1972). 1534.

23. Carbone, P.P. Non-Hodgkin's lymphoma; recent observations on natural history and Intensive treatment. Cancer 30 (1972), 1511.

24. Wollner, N., D'Angio, G., Burchenal. J. H.. et al. Treatment of non-Hodgkin's lymphoma In children with multiple drug leukemia regimen and radiation therapy. Proc. Am. Assoc. Cancer Res. 1 4 (1973), 97.

25. Wollner. N., Lieberman, P., Exelby. P.. et al. Non-Hodgkin's Lymphoma in Children. Results of Treatment with LSA2-L2. Protocol presented at International Pediatric Oncology Society Conference, Amsterdam,…

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.

ACUTE LEUKEMIA

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.

BURKITT'S TUMOR

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.

LYMPHOMAS

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

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.

EWING'S TUMOR

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.

RHABDOMYOSARCOMA

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.

BIBLIOGRAPHY

1. Farber, S.. Diamond, L. K., Mercer. R. D., et al. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroylglutamic acid (aminopterin). New Engl. J. Med. 238 (1948), 787.

2. Tivey. H. Prognosis for survival in the leukemias of childhood. Pediatrics 70(1952), 48.

3. Southam. CM.. Craver. L. F., Dargeon, H. W., and Burchenal, J. H. A study of the natural history of acute leukemia with special reference to the duration of the disease and the occurrence of remissions. Cancer 4 (1951), 39.

4. Pearson, O. H.. Elie), L. P., and Ráwson, - R. W. Regression of Lymphoid Tumors in Man Produced by ACTH and Cortisone. J. R. Moti, ed. In Proceedings of the Clinical ACTH Conference. Philadelphia: Blakiston, 1950, 318.

5. Farber. S.. Schwachman, H.. Toch, R, et al. Effect of ACTH in Acute Leukemia in Childhood. J.R. Moti, ed. In Proceedings of the Clinical ACTH Conference. Philadelphia: Blakiston. 1950, 328.

6. Burchenal, J. H., Murphy. M. L.. Ellison, R. R., et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood 8 (1953), 965.

7. Fernbach. D.J., Sutow. W.W., Thurman, W., and Vietti, T. Clinical evaluation of cyclophosphamide, J. A. M. A. 152(1962), 30.

8. Selawry, O.S. and Delta, B. G. Leurocristine in cancer of children. Proc. Amer. Assoc. Cancer Res. 3(1962), 360.

9. Evans. JS. , Musser, E. A., Mengel, G. D., et. al. Anti-tumor activity of 1-B-D-arabinofura rosy lcytosine hydrochloride. Proc. Soc. Exp. Biol. Med. 106 (1961), 350.

10. Tan, C, Tasaka, H., Yu1 K. -P., et al. Daunomycin, an anti-tumor antibiotic in therapy of neoplastic disease. Cancer 20 (1967), 333.

11. Bonadonna, G. and Monfardini, S. Therapeutic effects of adriamycin in neoplastic disease of children and adults. Proc. Amer. Assoc. Cancer Res. 11 (1970), 10.

12. Hill. JM. . Roberts, J., Loeb. E., et al. 1asparaginase therapy for leukemia and other malignant tumors. J. A. M .A. 202 (1967), 882.

13. Oettgen. H. F.. Old, L.J.. Boyse, E.A., et al. Inhibition of leukemias in man by 1 -asparaginase. Cancer Res. 27(1967), 2619.

14. Whiteside, J. A., Philips. F.S.. Dargeon. HW. , and Burchenal. JH. Intrathecal Amethopterin in neurological manifestations of leukemia. Arch. Intern. Med. 101 (1958), 279.

15. Freireich, E.J., Karon, M., and Frei, E. Potential for eliminating leukemic cells in childhood acute leukemia. Proc. Amer. Assoc. Cancer Res. S (1964), 20.

16. Pinkel, D. Five-year follow-up of "total therapy" of childhood lymphocytic leukemia. J. A. M. A. 276(1971). 648.

17. Simone, J., Aur. R. J. ?.. Hustu, H. O., and Pinkel. D. "Total therapy" studies of acute lymphocytic leukemia in children. Cancer 30 (1972), 1488.

18. Holland. JF. and Glidewell, O. Chemotherapy of acute lymphocytic leukemia of childhood. Cancer 30 1 972) . 1 480.

19. Burchenal. J. H., Dowling, M., and Tan, C. Treatment of acute lymphoblastic leukemia. Ann. Rev. Med. 23 (1972), 77.

20. Burkitt. D. Sarcoma involving jaws in African children. Brit. J. Surg. 46(1958), 218.

21. Burkitt, D. and O'Cono.r. G. Malignant lymphoma in African children. Cancer 14 (1961). 258.

22. Ziegler. J. L. Chemotherapy of Burkitt's lymphoma. Cancer 30 (1972). 1534.

23. Carbone, P.P. Non-Hodgkin's lymphoma; recent observations on natural history and Intensive treatment. Cancer 30 (1972), 1511.

24. Wollner, N., D'Angio, G., Burchenal. J. H.. et al. Treatment of non-Hodgkin's lymphoma In children with multiple drug leukemia regimen and radiation therapy. Proc. Am. Assoc. Cancer Res. 1 4 (1973), 97.

25. Wollner. N., Lieberman, P., Exelby. P.. et al. Non-Hodgkin's Lymphoma in Children. Results of Treatment with LSA2-L2. Protocol presented at International Pediatric Oncology Society Conference, Amsterdam, October 1973.

26. Wollner. N. Personal communication, 1973.

27. DeVita, V.T., Serpick. A., and Carbone, P. Combination chemotherapy in the treatment of advanced Hodgkin' s disease. Ann. Intern. Med. 73 (1970). 881.

28. DeVita, V.T., Canellos. G. P., and Moxley, J. A decade of combination chemotherapy of advanced Hodgkin 's disease. Cancer 30 (1973), 1495.

29. Klapproth, H.J. Wilms' tumor ; A report of 45 cases and an analysis of 1 ,351 cases reported in the world literature from 1940 to 1956. J. Urol. 81 (1959). 663.

30. Farber, S. Chemotherapy in the treatment of leukemia and Wilms' tumor. J. A. M. A. 198 (1966), 154.

31. Hustu. H.O., Plnkel, D., and Pratt, C. Treatment of clinically localized Ewing's sarcoma with radiotherapy and combination chemotherapy. Cancer 30 (1973). 1522.

32. Rosen. G.. Wollner, N.. Tan, C. et al. Disease-free survival in children with Ewing's sarcoma treated with radiation therapy and adjuvant four-drug sequential therapy. Cancer 33 (1974). 384-393.

33. Pratt, C.B.. Hustu. H.O.. Fleming, I.D., and Pinkel, D. Coordinated treatment of childhood rhabdomyosarcoma with surgery, radiotherapy, and combination chemotherapy. Cancer Res. 32 (1972). 606.

34. Donaldson, S.. Castro. J., Wilbur, J.. and Jesse. R. Rhabdomyosarcoma of head and neck in children. Cancer 31 (1973), 26.

10.3928/0090-4481-19740501-05

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