Omar Hustu

A study of “total therapy” of acute lymphocyticleukemia in children†††

A study was designed to test the hypothesis that, following induction of remission and an intensive short-term, high-dosage phase of treatment, continuous maintenance chemotherapy with the use of a combination of 4 antileukemic agents concurrently in conjunction with radiotherapy to the entire craniospinal axis would produce prolonged complete remission in patients with previously untreated acute lymphocytic leukemia. The intensive systemic administration of antileukemic agents resulted in longer complete remissions than described in other studies, and survival was at least equal to that obtained with sequential use of these agents.

Thyroid dysfunction and neoplasia in children receiving neck irradiation for cancer

The reported relationship of radiation exposure and thyroid carcinoma stimulated this retrospective study of 298 patients treated at St. Jude Childrens Hospital with radiation therapy to the neck for childhood cancer to identify patients who developed subsequent thyroid abnormalities. This series includes 153 patients with Hodgkins disease, 95 with acute lymphocytic leukemia, 28 with lymphoepi‐thelioma, and 22 with miscellaneous tumors. Inclusion in the study required 5 years of disease‐free survival following therapy for their original tumor, which included thyroid irradiation. Follow‐up has been 100%. Most patients also received chemotherapy. Seventeen patients were found to have decreased thyroid reserve with normal levels of free triiodothyroxine (T3) or free thyroxin, (T4) and an elevated level of thyroid‐stimulating hormone (TSH). In nine patients hypothyroidism developed, with decreased T3 or T4 levels and an elevated level of TSH. One hyperthyroid patient was identified. Two patients had thyroiditis, and seven had thyroid neoplasms: (carcinoma in two, adenoma in two, colloid nodule in one, and undiagnosed nodules in two). This survey has demonstrated an increased incidence of thyroid dysfunction and thyroid neoplasia when compared to the general population. The importance of long‐term follow‐up for thyroid disease is emphasized in patients who have received thyroid irradiation. The possible role of subclinical hypothyroidism with TSH elevation coupled with radiation darnage to the thyroid gland as a model for the development of neoplastic disease is discussed. Cancer 55:1190‐1194, 1985.

Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity

Results of treatment for osteosarcoma of the extremity have been poor with metastases usually causing death within 2 years following diagnosis. Because of the great risk of development of metastases, 20 patients have received adjuvant chemotherapy with Adriamycin, cyclophosphamide and high‐dose meth‐otrexate‐leucovorin rescue for up to 12 months following amputation for osteosarcoma. Sixteen of these patients are surviving; 11 are free of evident tumor from 6 to 34 months following amputation. Five patients were found to have pulmonary metastases while receiving chemotherapy and three patients developed metastases following completion of chemotherapy. One patient died following her third treatment with high‐dose methotrexate‐leucorovin rescue. Other toxicity included nausea, vomiting, mucosal ulcerations, infections, hematologic abnormalities, changes in kidney and liver functions tests, and minor coagulation abnormalities. The natural history of osteosarcoma may have been modified by the use of these agents for periods exceeding the median time to predicted detection of pulmonary metastases. Microscopic metastases of some patients were eradicated by this adjuvant chemotherapy. For patients who developed metastases, these metastases were delayed in their time of detection and in their number at the time of detection.

Concurrent chemotherapy and radiation therapy in the treatment of childhood and adolescent Hodgkin's disease

A treatment program of combination chemotherapy and concurrent radiotherapy was designed for children and adolescents with all stages of Hodgkins disease. From September, 1967 to April, 1972, 49 patients with previously untreated disease were admitted to the study. They were given 12 weeks of initial chemotherapy in combination with simultaneous radiotherapy at a tumor dose of 3500 to 4000 R. For Stages II‐IV chemotherapy was continued for 1 to 2 years. Forty‐seven patients responded to therapy with complete remissions; two had no response. Of the patients responding, 40 have been in continuous complete remission for periods of 6 to 58 months, four have relapsed, and three have died in remission. Twenty‐six patients have been off all therapy for periods of 4 to 54 months without evidence of active disease. In most instances complications of therapy including drug toxicity, infections and nutritional disturbances have been reversible by modification of chemotherapy and judicious supportive care. We conclude that combination chemotherapy and concurrent irradiation are tolerated by children and adolescents with Hodgkins disease and result in a high frequency of complete remission. Results to date suggest that the majority of children, even those with advanced stages, will have lengthy complete remissions.

The role of surgical resection when combined with chemotherapy and radiation in the management of pelvic rhabdomyosarcoma.

With the development of combined chemotherapy and radiation therapy for embryonal rhabdomyosarcoma, the role and extent of surgical resection of these pelvic tumors need to be defined. Thirty-six children with pelvic genitourinary rhabdomyosarcoma seen at St. Jude Childrens were managed on protocols combining surgical resection and radiation, and chemotherapy. Ten children presented with cervical—vaginal tumors, which were managed with combined therapy; the surgical resection was histovaginectomy in eight and pelvic exenteration in one. Eight of the ten are free of disease from 1 to 14 years. Twelve children presented with bladder and prostate tumors, which were resected with segmental cystectomy in four cases, biopsy in five, and pelvic exenteration in three. All received combination therapy and six of the twelve are surviving free of disease from 6 months to 16 years. Fourteen children presented with paratesticular rhabdomyosarcoma. Chemotherapy was combined with radical orchiectomy in all cases. Retroperitoneal node dissection was done in nine and five had inguinal node dissection. Nine of the 14 are surviving NED from 2 to 16 years. One patient died, free of disease, with complications of combination therapy. The results of this review supports the approach of combining chemotherapy, radiation, and complete surgical resection.

Testicular relapse in children with acute nonlymphoblastic leukemia.

The clinical course and other distinctive features of five children who developed a testicular relapse 4 months to 25 months after the diagnosis of acute nonlymphoblastic leukemia (ANLL) are described. the chief presenting feature at relapse was painless testicular enlargement, as is also seen in children with acute lymphoblastic leukemia who relapse in the testes. By French–American–British convention, the malignant cells were classified as M4 (myelomonoblastic) in four cases and M2 (myeloblastic) in one. All children received a course of multiagent reinduction chemotherapy and all but one received local irradiation to the testes. Only one of these children, whose relapse was a late event after elective cessation of therapy, is a long‐term survivor. A comparison with six previously published cases shows similar clinical characteristics and outcome. Given the poor responses of such patients to conventional treatment, it seems worthwhile to consider the use of intensive reinduction chemotherapy with concomitant bilateral testicular irradiation followed by remission intensification and an autologous or allogenic marrow transplant.

Local-regional non-rhabdomyosarcomatous soft tissue sarcomas of the head and neck

Between 1962 and 1987, 112 consecutive patients were treated at St. Jude Childrens Research Hospital for soft tissue sarcomas of the head and neck region; 18 of these children (16%) had histologic subtypes other than rhabdomyosarcoma. We evaluated the impact of surgery, postoperative chemotherapy, and irradiation on local control and survival in these cases. Three patients who had complete resection of tumors and received no further treatment are alive without disease at 36, 42, and 162 months. Local control was achieved in 1 of 2 patients with microscopic residual tumor and 4 of 9 patients with gross residual tumor who were treated with irradiation (2500-5040 cGy). Chemotherapy was the only postoperative treatment in three patients; only one achieved lasting local control. One patient was treated with irradiation only; his primary site showed no tumor cells at autopsy following an automobile accident. Overall, local control was achieved in 50% of patients; the disease-free survival rate at 3 years was 44%. The prognosis for patients with nonresectable tumors remains unsatisfactory because of the difficulty in securing local control. A revised therapeutic approach to these patients is presented.

CESSATION OF THERAPY DURING REMISSION IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

Combination chemotherapy and preventive central nervous system (CNS) therapy for childhood ALL have resulted in 5-year leukemia-free survival in about one-half of the patients. However, the risk of side effects and fatal infection is significant so chemotherapy was stopped after 2-3 years of complete remission.Therapy was stopped in a total of 123 patients with ALL; 104 were in initial complete remission, 19 had relapsed at least once. All were treated with similar chemotherapy but differing preventive CNS therapy. None of 7 patients given 500 or 1200 rads to the craniospinal axis has relapsed after 5-7 years. Of 8 patients given no preventive CNS therapy, 6 relapsed after stopping therapy, 5 with CNS involvement. The remaining patients received 2400 rads to the cranium with intrathecal MTX or 2400 rads craniospinal irradiation. Of 85 patients irradiated between 1967 and 1970, 10 have relapsed, all in the first year and most of the remainder have been off therapy 2 years or more. Of 23 given irradiation in 1970-71, 2 have relapsed. Thus, the frequency of relapse is 12 of 115 in patients who received preventive CNS irradiation and 6 of 8 given no preventive therapy.We conclude: 1) in children with ALL given preventive CNS therapy and combination chemotherapy who remain in complete remission for 2-3 years, about 10-12% relapse after stopping therapy and 2) the risk of relapse after stopping therapy is greatest in the first year and is greater in patients given no preventive CNS therapy. (Supported by NCI Grant CA-08480 and ALSAC).