Elizabeth I. Thompson

A MULTIDISCIPLINARY STUDY INVESTIGATING RADIOTHERAPY IN EWING'S SARCOMA: END RESULTS OF POG #8346

PURPOSE To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewings sarcoma. METHODS AND MATERIALS Between 1983 and 1988, 184 children with Ewings sarcoma were enrolled onto Pediatric Oncology Group 8346 (POG 8346). A total of 178 (97%) met eligibility criteria; 6 had pathology other than Ewings sarcoma. Induction chemotherapy of cyclophosphamide/doxorubicin (adriamycin )(C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy and C/A, dactinomycin, and vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. Forty patients were randomized to receive SF, whole bone radiation to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy, and the remainder were assigned to IF radiation. RESULTS Of 178 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases at presentation. Their 5-year EFS was 51% (SE 5%) and 23% (SE 7%) respectively. The response rate to induction chemotherapy was 88% (28% complete, 60% partial), but after radiotherapy the response rate increased to 98%. Thirty-seven of the localized patients underwent resection, of whom 16 (43%) required postoperative radiotherapy; the 5-year EFS of these surgical patients was 80% (SE 7%). The remaining 104 localized patients were eligible for randomization or assignment to receive radiotherapy; the 5-year EFS of these patients was 41% (SE 5%), with no significant difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5-year EFS: distal extremity 65% (SE 8%), central 63% (SE 10%), proximal extremity 46% (SE 8%), and pelvic-sacral 24% (SE 10%) (p=0.004). Initial tumor size did not correlate significantly with EFS. Patterns of failure among the 141 localized patients revealed 23% of patients experienced a local failure, while 40% had a systemic failure. The 5-year local control rate for the surgical patients +/- postoperative radiotherapy was 88% (SE 6%), while for the patients undergoing radiotherapy alone it was 65% (SE 7%). There was no difference in local control between those randomized to SF vs. IF. The 5-year local control rate for the patients with pelvic-sacral tumors was 44% (SE 15%), significantly worse than the local control rates for those with central tumors 82% (SE 8%), distal extremity 80% (SE 8%), or proximal extremity 69% (SE 9%) (p=0.023). However, quality of radiotherapy correlated with outcome. Patients who had appropriate radiotherapy had a 5-year local control of 80% (SE 7%), while those with minor deviations had 5-year local control of 48% (SE 14%), and those with major deviations had a local control of only 16% (SE 15%) (p=0.005). The local failure was within an irradiated volume in 62% of patients, outside the irradiated volume in 24% of cases, while the precise location could not be determined in the remaining 14%. CONCLUSIONS As most failures in Ewings sarcoma are systemic, improved EFS requires more effective systemic chemotherapy. Adequate IF radiotherapy requires treatment to appropriate volumes as defined by MRI imaging and full radiation doses. Pretreatment review of radiologic images with a musculoskeletal radiologist to determine appropriate tumor volumes, as well as use of conformal radiotherapy techniques are important for improved outcome.

Efficacy of transfusion therapy for one to two years in patients with sickle cell disease and cerebrovascular accidents.

Since 1974 we have entered 12 children with sickle cell disease and strokes on a transfusion protocol to maintain hemoglobin S less than 20%. Serial arteriography, EEGs, brain or CT scans, and neuropsychologic testing were also obtained. Transfusion has been stopped in ten patients after one to two years. Seven of these ten patients have had second strokes five weeks to 11 months after cessation of transfusion (median three months). Arteriography was normal at the time of the initial stroke in two patients; one of these had a second stroke. Arteriograms did not improve during transfusion therapy. EEGs and brain and CT scans were occasionally useful at the time of the initial stroke but were of little value in following these patients. Neuropsychologic testing indicated severe impairment of sensory-motor and cognitive processes at the time of the initial stroke and was useful in following improvement or deterioration and in designing remedial education programs. We conclude that short-term transfusion therapy will not prevent second strokes once transfusion is stopped and that arteriography is of limited value in these patients.

EWING'S SARCOMA: LOCAL TUMOR CONTROL AND PATTERNS OF FAILURE FOLLOWING LIMITED-VOLUME RADIATION THERAPY

Sixty children with localized osseous Ewings sarcoma were treated between 1978 and 1988 with induction chemotherapy (cyclophosphamide, adriamycin), irradiation and/or surgery, and 10 months of maintenance chemotherapy (cyclophosphamide, adriamycin, dactinomycin, vincristine). Following induction chemotherapy, 43 patients received primary radiation therapy to limited radiation volumes defined by post-chemotherapy residual soft tissue tumor extension and initial osseous tumor extent. Irradiation was defined as low dose at 30-36 Gy (median 35 Gy) for 31 cases with objective response to induction chemotherapy and high dose at 50-60 Gy (median 50.4 Gy) for 12 patients with poor response to induction chemotherapy or with tumors greater than or equal to 8 cm. Overall event-free survival at 5 years is 59% and local tumor control is 68%. Initial failures have been local (12), simultaneous local and distant failures (7), and distant (6). In the surgical resection group, 14 patients had complete resection without radiation therapy, and 3 patients had microscopic residual plus 35-41 Gy; 100% local control has been maintained. In 43 patients with primary radiation therapy group, local tumor control is 58% (p = .004). Despite limited radiation volume, 18/19 local failures occurred centrally within the bone, well within the radiation volume. Imaging response to induction chemotherapy predicted local tumor control in the radiation therapy group: 62% with complete response/partial response versus 17% with no response/progressive disease (p less than 0.01). Local tumor control related strongly to primary tumor size in the radiation therapy group; among 31 cases receiving 35 Gy, local tumor control is 90% for lesions less than 8 cm versus 52% for tumors greater than or equal to 8 cm (p = .054). The central pattern of local failure in this experience suggests the effectiveness of limited radiation volume. The overall local tumor control rate following the tested dose level of 35 Gy appears to be inadequate, although results in selected cases with tumors less than 8 cm in greatest tumor dimension indicate potential efficacy in a yet limited experience.

Chemotherapy as an alternative to laminectomy and radiation in the management of epidural tumor

Nine children with neuroblastoma and five with Ewing sarcoma were found at diagnosis to have epidural extension of tumor. Five children underwent laminectomy prior to referral, with good neurologic recovery in only one. Management in the other nine children did not include laminectomy. All 14 patients were given chemotherapy without radiotherapy. Rapid regression of tumor with neurologic recovery occurred in response to chemotherapy in all patients with neurologic deficits. The responses observed in these children indicate that for chemotherapy-sensitive tumors, effective chemotherapy is a feasible alternative to laminectomy and radiation therapy in the management of epidural disease.

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.

Chest wall resection for ewing's sarcoma of the rib: an unnecessary procedure

Approximately 10% of all cases of Ewings sarcoma arise from a rib. Conventional management has included chest wall resection (3 or more ribs) and radiation therapy. These forms of therapy have led to complications such as scoliosis and local deformity. The addition of radiation therapy can result in damage to the lung and adjacent viscera and also potentiate pulmonary restrictive disease. Between 1971 and 1978, 9 patients were treated with surgery, radiation therapy, and combination chemotherapy (three- or four-drug regimen). Only 2 patients (22%) survive. Since 1979, 14 patients were entered into a new protocol consisting of sequential induction chemotherapy, followed by delayed surgical resection whenever feasible. Three patients had complete resection of their primary lesion at onset. Initially, 7 patients had either biopsy (N = 4) or incomplete chest wall resection N = 3). All 4 patients with biopsy only at diagnosis had excellent responses to induction chemotherapy, allowing delayed resection of the involved rib without chest wall resection. Overall, 12 of 14 patients (86%) treated since 1979 survive, with only 2 receiving radiation therapy for residual disease in the primary rib site.

Serial pulmonary function studies in children treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine

Background. The pulmonary toxicity of bleomycin‐containing chemotherapy combined with mantle radiotherapy in children treated for Hodgkins disease was longitudinally assessed.

Long‐Term Results of Treatment of Children and Adolescents with Hodgkin's Disease

Fifty‐four children and adolescents with Hodgkins disease Stages I–IV were treated with chemotherapy plus radiotherapy from 1967 to 1972. Thirty‐eight patients (70%) remain in continuous complete remission. Nine patients have died, four of progressive disease, three of pneumonitis, one with probable pneumococcal sepsis, and one of acute myelocytic leukemia. Significant retardation of height and crown‐rump length occurred, particularly in boys who received at least mantle or abdominal radiotherapy when younger than age 16 years. Five women have amenorrhea and no patient has clinical evidence of hypothyroidism. The major long‐term effects of therapy in this group of patients has been growth retardation. Future studies to minimize long‐term effects of therapy are necessary but must be carefully designed so that present cure rates are not jeopardized.

Two decades of experience with testicular tumors in children at St Jude Children's Research Hospital

From 1968 to 1988, 24 children and adolescents with malignant testicular tumors were treated at St Jude Childrens Research Hospital. Pure yolk sac tumors (YST) were present in 13 cases; 11 patients had other types of nonseminomatous malignant germ cell tumors. Children with localized and totally resectable disease (stage I) were treated by orchiectomy alone; all others also received chemotherapy. Five of ten patients treated before the implementation of a multiagent chemotherapy protocol in 1979 have died. By contrast, all of the 14 patients treated on this protocol are alive. The improved survival during the past decade is attributable to better diagnostic imaging techniques, the availability of serum tumor markers to monitor disease activity, and more effective chemotherapy. Orchiectomy alone is sufficient treatment for patients with clinical stage I disease who show appropriate reductions in tumor marker levels after surgery. Modern platinum-based chemotherapy provides disease control in patients with higher stage disease.

The survivors of childhood solid tumors

With the improvement in cancer therapy in recent years, the number of cancer survivors is rapidly increasing. Potential late medical and psychosocial sequelae of cancer therapy are reviewed. A practical guide for the primary health care giver is provided.