Carol Greenwald

Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease.

PURPOSE Between May 1980 and September 1990, 85 patients with Hodgkins disease were treated with a regimen designed to increase cure rates while reducing late toxicity. PATIENTS AND METHODS Therapy consisted of five cycles of cyclophosphamide, Oncovin (vincristine; Eli Lilly and Co, Indianapolis, IN), and procarbazine (COP), alternated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and low-dose (20 Gy) regional radiotherapy. Vincristine and cyclophosphamide were administered as tolerated during irradiation and during the 2- to 4-week rest period between radiation volumes. The need for staging laparotomy was defined by clinical presentation. RESULTS The median age at diagnosis was 14 years (range, 4 to 20), and 56% of patients were male. The majority (67%) had stage III or IV disease and 68% (19 of 28) of stage II patients had bulky mediastinal disease. Nodular sclerosing histology predominated (67%). Ninety-three percent of patients were alive without disease with a median follow-up of 4.1 years. Abnormalities were detected on chest roentgenograms and/or pulmonary function tests in 58% and 25% of clinically asymptomatic patients who were tested at least 1 year after completion of therapy. The only symptomatic patient had pulmonary fibrosis after treatment with bleomycin (20 U/m2) and mantle (20 Gy)/lung (13 Gy) irradiation, and developed multiple spontaneous pneumothoraces that required cortical stripping. One patient had congestive heart failure 19 months post-treatment, and two had abnormalities on echocardiograms. Thyroid abnormalities occurred in 21 (27%) patients who were assessable for late toxicity. The majority of female patients have had regular menstrual cycles. Six developed ovarian failure, and 10 have had a total of 17 pregnancies. Other than one documented case of oligospermia, information was not available on male fertility. CONCLUSION The results demonstrate excellent disease control for the COP/ABVD regimen, with acceptable toxicity.

Chemotherapy Dose-Intensification for Pediatric Patients With Ewing's Family of Tumors and Desmoplastic Small Round-Cell Tumors: A Feasibility Study at St. Jude Children's Research Hospital

PURPOSE To evaluate the feasibility of dose-intensification for patients with Ewings family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS From February 1992 to June 1996, we treated 53 consecutive patients on our Ewings protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72%+/-8% and 60%+/-9%, respectively. CONCLUSION Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.

Increased mortality after successful treatment for Hodgkin's disease.

PURPOSE To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkins disease. PATIENTS AND METHODS We studied late events in 387 patients treated for pediatric Hodgkins disease on four consecutive clinical trials at St Jude Childrens Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkins disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkins disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION Compared with age- and sex-matched control populations, survivors of pediatric Hodgkins disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.

Dental abnormalities in children treated for acute lymphoblastic leukemia

The purpose of this study was to define the therapy-associated dental abnormalities in survivors of acute lymphoblastic leukemia (ALL). We reviewed the clinical records and panoramic radiographs of 423 survivors of ALL who were treated on one of four consecutive protocols (1975–1991). Dental abnormalities included root stunting, microdontia, hypodontia, taurodontia (enlarged pulp chambers), and over-retention of primary teeth. The frequency of these factors was determined in relation to age at initiation of treatment (⩽8 years vs >8 years), addition of cranial irradiation, and chemotherapeutic protocol. A total of 423 patients met the study criteria. The abnormalities comprised root stunting in 24.4% (n = 103), microdontia in 18.9% (n = 80), hypodontia in 8.5% (n = 36), taurodontia in 5.9% (n = 25), and over-retention of primary dentition in 4.0% (n = 17). Patients who were ⩽8 years old at diagnosis or who received cranial irradiation therapy developed more dental abnormalities than did those >8 years and those who did not receive cranial irradiation (42 vs 32%). Survivors of childhood ALL often have dental abnormalities that may affect their quality of life. Dental evaluation at diagnosis and frequent follow-up may help to ensure appropriate preventive measures and minimize dental and periodontal disease.

Predominance of Pilocytic Histology in Dorsally Exophytic Brain Stem Tumors

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

Treatment of children with peripheral primitive neuroectodermal tumor or extraosseous Ewing's tumor with Ewing's-directed therapy.

Purpose: We report the treatment and outcome of patients with peripheral primitive neuroectodermal tumor (PNET) and extraosseous Ewings tumor (EOE) using Ewings-directed therapy, including an ifosfamide and etoposide window. Methods: Seventeen pediatric patients with peripheral PNET (n = 14) or EOE (n = 3) were enrolled between 1988 and 1992 on our institutional Ewings protocol. Induction therapy comprised a 9-week “window” of ifosfamide and etoposide, followed by 9 weeks of therapy with cyclophosphamide and Adriamycin (Adria Laboratories, Columbus, OH). Response assessment after 17 weeks was followed by surgery and/or radiotherapy (doses based on tumor size and response to induction), repeat evaluation, and maintenance chemotherapy with alternating courses of vincristine/dactinomycin, ifosfamide/etoposide, and cyclophosphamide/Adriamycin for a total of 45 weeks. Results: At diagnosis, 8 patients had large lesions (>8 cm) and 3 had pulmonary metastases (1 with large tumor). Surgical resection was performed at diagnosis for 9 patients and after induction therapy for 5. During window therapy, all of the 9 evaluable patients responded (8 partial, 1 objective), and no patient without measurable disease developed disease progression. Responses were maintained or improved during subsequent induction in six of the patients with residual disease. Fourteen patients received local radiotherapy. At 49 to 94 months after diagnosis, 12 patients are disease-free (1 in second remission), 4 have died, and 1 is alive with disease. The five-year overall and progression-free survival rates are 77 ± 13% and 62 ± 16%, respectively. Conclusion: The use of consistent Ewings-directed combined-modality therapy for patients with soft tissue peripheral PNET/EOE results in survival similar to that of patients with osseous Ewings tumor. The combination of ifosfamide and etoposide appears active and should be incorporated in future treatment protocols.

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors.

PURPOSE We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

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.

Local control in synchronous bilateral Wilms tumor.

PURPOSE To evaluate the role of radiation therapy (RT), chemotherapy (CT), and surgery in the local control of synchronous bilateral Wilms Tumor (WT). METHODS AND MATERIALS Between 1962 to 1993, 45 children were treated for bilateral WT; 38 patients with synchronous tumors were reviewed. Initial surgery depended on the era of treatment and included unilateral nephrectomy (N)/partial nephrectomy (PN) and contralateral PN in 6, unilateral N/PN alone in 7, and biopsy only in 25. Chemotherapy (CT) consisted of vincristine, actinomycin-D, and adriamycin in 32 and vincristine/ actinomycin-D in 6. Radiation therapy (RT) was given to 32 patients. Treatment included both kidneys in 20, unilateral kidney plus contralateral renal bed in 9, unilateral kidney in 2, and unilateral renal bed in 1. Follow-up was 16 months to 25 years (median: 6.3 years). RESULTS Local control (LC) has been maintained in 66 out of 76 sites (87%). For Stage I-II disease with initial N/PN, LC was 10 out of 12 with RT and 11 out of 11 without RT; for Stage III with initial N/PN, LC was 8 out of 9 with RT and 1 out of 1 without RT. Initial CT and RT was followed by delayed N/PN for 20 sites; LC was 15 out of 17 in post induction Stage I-II and 1 out of 3 in postinduction Stage III. In 23 sites undergoing biopsy and chemotherapy, LC was 19 out of 20 with RT and 1 out of 3 without RT. Seven of 23 sites had a complete response (CR) after induction CT, and LC was maintained in four out of four with RT and one out of three without RT. Univariate Cox Regression analysis demonstrated that sites receiving two drugs had a statistically significant increase in loco-regional relapse when compared to sites receiving three drugs (p = 0.004). Major morbidities related to multimodality therapy have included renal failure in one patient and small bowel obstruction requiring lysis of adhesions in two patients. CONCLUSIONS Local control does not seem to be compromised by renal conservation therapy. Local control is excellent in sites treated with radiation therapy in combination with three drug chemotherapy.

Fractures in children treated with radiotherapy for soft tissue sarcoma.

There is a clear association between multimodal therapy for bone tumors and the development of skeletal complications; however, this has not been addressed in children with soft tissue sarcomas. We reviewed records of the 70 children treated for soft tissue sarcoma of the lower extremity at St. Jude Childrens Research Hospital between 1962 and 1991. Of the 12 patients who received radiation after surgical excision of their tumors, three subsequently developed fractures. Two of the three had also received chemotherapy. Our findings indicate that, although the risk of fracture after therapy for soft tissue sarcoma may be multifactorial, radiation may play a significant role. Minimizing the size of surgical incisions, improving radiotherapy techniques, maximizing chemotherapy, and emphasizing physical therapy and appropriate follow up can all serve to decrease long-term toxicities. Such optimal use of therapy could subsequently reduce side effects, such as osteoporosis and muscle and bone atrophy, that predispose patients to fractures.