Philip Littman

DECLINES IN IQ SCORES AND COGNITIVE DYSFUNCTIONS IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKAEMIA TREATED WITH CRANIAL IRRADIATION

Intellectual and other neuropsychological dysfunctions have been observed in survivors of childhood acute lymphocytic leukaemia (ALL). The possible relationship of therapy to these dysfunctions was investigated in a prospective study of children with newly diagnosed ALL seen at the Childrens Hospital of Philadelphia. They were evaluated with standardised intelligence tests during the first month of treatment and periodically thereafter. There were two therapy schedules--one using standard drugs for induction and maintenance, the other a more intensive schedule. Central-nervous-system prophylaxis (2400 rad cranial radiation and six doses of intrathecal methotrexate) was given to all. Significant reductions were found in overall IQ score for the majority of children, younger patients being most affected. More extensive testing of surviving children, with and without decline in IQ, all of whom were normal on the first test, revealed patterns of functional deficits and residual strengths that could not be characterised with IQ testing alone. These deficits, which could affect learning and academic performance, were not seen in six children studied years after receiving similar chemotherapy that included intrathecal and oral methotrexate but not cranial irradiation.

Pediatric brain stem gliomas.

Sixty‐two pediatric patients with brain stem glioma diagnosed between 1964 and 1978 have been reviewed. Posterior fossa exploration was performed on 53% of the patients. Pathology was obtained by biopsy in 58% of those explored. Fifty‐four patients had definitive radiation therapy with a median dose of 5000 rads. The actuarial five‐year survival for the entire group is 30%.

Results of radiation therapy given after radical hysterectomy

Two hundred twelve patients with carcinoma of the cervix, Stage I (193 patients) and Stage II (19 patients), were treated by radical hysterectomy at the Hospital of the University of Pennsylvania during the period from 1955–1977. Pathology reports were evaluated for the presence of the following factors thought to indicate an unfavorable prognosis: (1) positive pelvic lymph nodes (31 patients); (2) parametriat extension (22 patients); and (3) infiltration of the margin of resection (14 patients). Fifty‐one high risk patients (HR) with one or more of these pathologic findings have five and ten year survivals of 55% and 30%, respectively. This compares with five‐ and ten‐year survivals of 87% and 85%, respectively, for patients without these findings. Local recurrences were noted in 20/50 (40%) HR patients versus 23/159 (13.2%) non‐HR patients (P < .001). A retrospective analysis revealed that 21 of 50 evaluable HR patients received adjunctive postoperative pelvic irradiation (HR‐XRT). Although the reduction in local recurrence in the treated group approached statistical significance, 5/21 versus 15/29 (0.1 > P > 0.05), the five‐ and ten‐year survival did not differ significantly. Twenty‐four patients initially treated with surgery received definitive radiation therapy for local recurrence. The five‐ and ten‐year survivals from the time of recurrence were 22% and 15%. Our findings suggest that postoperative irradiation may be beneficial in controlling local disease in a subgroup of radical hysterectomy patients who are at high risk for recurrence. Since the ultimate incidence of extra pelvic metastasis for the high risk and the recurrent group is 32% and 67%, respectively, however, it appears that improved survival awaits the development of effective systemic adjuvant therapy.

Treatment of children with neurogenic sarcoma. Experience at the Children's Hospital of Philadelphia, 1958-1984.

Twenty‐four children aged 3 months to 18 years (median, 12 years) were treated for neurogenic sarcoma at the Childrens Hospital of Philadelphia Cancer Research Center from 1958 through 1984. Sixteen patients had neurofibromatosis (NF). The tumors arose in an extremity or in the trunk (15 patients), the retroperitoneum‐pelvis (6), or other sites (3). Twelve children underwent grossly complete excision of localized sarcoma; of them, five had no known residual tumor and seven had proven microscopic residual disease. Ten of the remaining 12 patients had grossly visible, residual localized disease, and two had lung metastases. After operation, nine were treated on a protocol with local radiation therapy (4000–6000 rad) plus vincristine, actinomycin D, and cyclophosphamide with or without Adriamycin (doxorubicin). The other 15 were treated variably. At 3 years, the proportion of tumor‐free survivors was 9 of 24 (37.5%). The significant favorable factors were the initial surgical removal of all gross tumor (9 of 12 with tumor excision were tumor‐free survivors at 3 years compared to none of 12 with gross residual sarcoma; P < 0.01), and a tumor mitotic rate under one per high‐power field. No significant correlation was found between tumor‐free survival expectancy and age, race, sex, the presence of NF, the site and size of the primary tumor, or use of the chemoradiotherapy regimen. More effective treatment programs are needed for children with neurogenic sarcoma, especially for those with unresectable tumors. Cancer 59:1–5, 1987.

The somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation

A group of children with acute lymphocytic leukemia was studied to investigate if a reduction in daily dose fraction of cranial radiation would reduce the incidence of somnolence syndrome. Thirty-one evaluable patients received 100 rad X 18 cranial radiation therapy. Sixty-six similar evaluable patients were given 180 rad X 10. Both groups received the same chemotherapy including intrathecal methotrexate. Clinically detectable somnolence appeared in 58% of ech group without significant differences in the overall frequency or severity of somnolence (p greater than 0.5). This study failed to substantiate a radiation dose fraction size dependence for somnolence syndrome in children with acute lymphocytic leukemia.

The role of surgery in localized neuroblastoma

A 30-year experience with 83 patients, median age two years, with Childrens Cancer Study Group (CCSG) Stages I, II, and III localized neuroblastoma was studied to determine factors that influence outcome. In addition, histology was reclassified in all patients based on the Shimada system, which is divided into five subtypes according to age and cytohistologic criteria. A multivariant survival analysis was carried out and patients were considered to have failed if they relapsed or died from any cause. Initial analysis determined that CCSG stage, Shimada histologic classification, and presence of disease in lymph nodes were statistically significant predictors of failure. Histology was the most important factor with Shimada subtypes 1, 2, and 4 having good outcome and 3 and 5 poor outcome. The latter three variables were combined to create four prognostic groups that had distinctly different rates of survival. Further analysis showed that after controlling for prognostic groups, extent of surgery was a statistically significant predictor. Patients who had more complete surgical resection had better disease-free survival.

Malignant fibrous histiocytoma of soft tissue in childhood

Seven children aged 6 months to 11 years with malignant fibrous histiocytoma, a type of sarcoma of soft tissues, have been treated at the Childrens Hospital of Philadelphia from January 1975 through July 1983. The primary tumor arose in the head and neck region in three patients, the chest wall in two patients and the pelvis or buttock in one patient each. Operative management consisted of complete tumor removal in the two patients with chest wall tumors, and biopsy only in the remaining five children. Afterward, all seven patients were treated with a multiple‐agent chemotherapy program consisting of vincristine, dactinomycin, and cyclophosphamide for two years, with or without Adriamycin (doxorubicin). The five patients with residual tumor also received radiation therapy (RT) in doses of 1500 to 5500 rad. The two children with localized, completely excised sarcoma are continuously free of tumor at 1.4 and 9 years after initiation of treatment. Of the five with residual sarcoma, three had a complete response to radiation and chemotherapy, and two of them are free of recurrence at 4 and 5 years, respectively. In the three remaining children, the tumor spread regionally into the central nervous system or distantly into the lungs, subcutaneous tissues, and liver. Childhood malignant fibrous histiocytoma of soft tissue appears to be similar to childhood rhabdomyosarcoma in its modes of spread and response to management. Operative removal is the key to successful therapy. The roles of multiple‐agent chemotherapy and RT remain to be defined. Adriamycin appears to be the most promising single agent. In the absence of concrete data, it seems prudent to follow the same guidelines for irradiation as those used for other soft tissue sarcomas of childhood.

Treatment strategies for infants with malignant sacrococcygeal teratoma

Twelve children with malignant sacrococcygeal teratoma containing embryonal carcinoma, were treated at the Childrens Hospital of Philadelphia between 1971 and 1980. Their ages at diagnosis ranged from 2 days to 23 mo; 8 of the 12 (67%) were girls. Five of the 12 patients presented with localized tumors which were grossly completely excised. Four received no further therapy, and all 4 recurred with histologically documented embryonal carcinoma. Despite subsequent treatment with radiation therapy (RT) and chemotherapy (vincristine, actinomycin D, and cyclophosphamide, collectively called VAC, in all 4 plus adriamycin in 3, only 1 has survived free of disease, 8 yr from diagnosis. The other 3 died of tumor (2) or pneumonia after pulmonary RT (1). The fifth patient in this group received VAC with adriamycin (total dose, 350 mg/sq m) and died of autopsy-proven cardiotoxicity without tumor. The remaining 7 patients presented with either unresectable local tumor (3) or distant metastases (4). One of these 7 died 6 days after biopsy with massive liver metastases. The other 6 children were treated after operation with VAC (5) or vincristine and actinomycin D (1) chemotherapy, and 5 also received RT to the pelvis. One has survived free of disease at 6 yr after treatment with VAC and adriamycin and pelvic RT, but the other 5 died of tumor (2) or of pneumonia after pulmonary RT (3). Surgery alone is inadequate for successful management of children with malignant sacrococcygeal teratoma. Chemotherapy with VAC, with or without adriamycin, can be effective when combined with radiation, but fatal pulmonary toxicity can result from such combined therapy. The optimal therapeutic program for children with malignant sacrococcygeal teratoma is still evolving.

Management of Hodgkin-s disease in children and adolescents

Between 1970 and 1980, 66 children or adolescents with Hodgkin‐s disease were treated at the Children‐s Hospital of Philadelphia. Since 1977, prepubertal patients and postpubertal patients with Stage IIA massive mediastinal disease or Stage IIB‐IVB disease were clinically staged and treated with six courses of chemotherapy and 2000 rad involved‐field irradiation. Postpubertal patients with Stage IA or IIA disease were staged pathologically and treated with 3600‐4400 rad extended‐field irradiation. At four years, actuarial survival in 27 patients with Stage IA or IIA disease is 100%; relapse‐free survival is 86% in 16 patients treated with combined modality and 70% in 11 patients treated with irradiation. Among 39 patients with Stage IIB‐IVB disease, 34 received combined modality; at five years, survival is 86% and relapse‐free survival is 60%. In the majority of cases relapses in patients treated with combined modality could be better explained by chemotherapy failure rather than by insufficient radiation. Clinical staging and combined modality therapy may offer advantages for prepubertal patients and those postpubertal patients at high risk of relapse when treated with irradiation alone. The complications of laparotomy and splenectomy are avoided; however, with 2000 rad and limited‐field irradiation, hypothyroidism does occur and growth disturbances may appear.

Interstitial radiation therapy in the treatment of childhood soft-tissue sarcomas

Between 1971 and 1985, 12 children and adolescents aged 0.7 to 19 years (median 4.7 years) with localized residual soft-tissue sarcomas (STS) underwent interstitial radiation therapy (IRT) at our institution. Eight received IRT as a component of initial therapy, and four were treated for recurrent or persistent disease. Tumor sites were head and neck (6), pelvis (4), extremity (1), and retroperitoneum (1). The radionuclides employed were Iridium-192 (9), Iodine-125 (2), and Californium-252 (1). The median prescribed dose in the Iridium-192 group was 3960 cGy (1955-7300). Seven of eight children receiving IRT during initial therapy have maintained local control, and six remain without evidence of disease for a median follow-up time of 5.8 years (2.0-16.0). One of the four patients treated for recurrent disease is free of disease after salvage surgery, and the other three are dead of disease. Multidisciplinary evaluation of the nine patients with more than 2 years of follow-up revealed functional and cosmetic effects of IRT to be minimal. IRT can be an effective method of delivering high dose irradiation in childhood sarcomas while reducing the deleterious effects in adjacent normal tissues.