Sanctuary therapy: a randomized trial of 724 children with previously untreated acute lymphoblastic leukemia: A Report from Children's Cancer Study Group.

Between 1972 and 1974, Childrens Cancer Study Group enrolled 724 children with newly diagnosed acute lymphoblastic leukemia on a single randomized clinical trial. Study CCG-101 was designed to test four types of presymptomatic central nervous system and sanctuary therapies consisting of (a) 2400-rad craniospinal radiation therapy (RT) plus 1200-rad extended-field RT, which included the liver, spleen, kidneys, lower abdomen, and gonads; (b) 2400-rad craniospinal RT; (c) 2400-rad cranial RT plus intrathecal methotrexate (i.t. MTX); and (d) i.t. MTX alone. Patients all received a 28-day induction course of vincristine, prednisone, and L-asparaginase and were maintained subsequently on a regimen consisting of daily 6-mercaptopurine, weekly MTX, and monthly pulses of vincristine and prednisone. Patients treated with six doses of i.t. MTX alone had a significantly higher incidence of central nervous system relapse than did patients treated with 2400-rad craniospinal RT plus 1200-rad abdominal RT, 2400-rad craniospinal RT, or 2400-rad cranial RT plus i.t. MTX. There was no significant differences in marrow remission duration or survival of the treatment groups. There appears to be a benefit with regard to length of bone marrow remission and survival for patients with initial white blood counts greater than or equal to 20,000/cu mm treated with cranial RT plus i.t. MTX. The majority of the patients remaining on study have now discontinued maintenance therapy. The 8-year overall estimated survival rate on this study is 56%, and the disease-free survival rate is 52%.

Stature loss following skeletal irradiation for childhood cancer.

A model is presented to predict adult stature in children treated successfully for cancer outside the CNS. The model is based on radiation dose in Gray adjusted for location of therapy and attained stature (GALA); ideal adult stature (IAS), assuming the patient had not developed cancer, calculated by the Roche-Wainer-Thissen (RWT) method (which uses patient stature and weight before developing cancer, and parent stature data); a femur correction if both the acetabula or heads of both femurs were irradiated (FEMUR); and sex. The model was constructed using data from 49 patients with a mean time from completion of therapy to follow-up of 8.9 years (range, 3.3 to 15.4 years). Thirteen patients received no radiotherapy. All model coefficients were highly significant (P less than .001), and the model appears to be an excellent predictor of adult stature, with a multiple correlation coefficient of 0.84 (R2 = .74) between corrected adult stature (CAS) based on the most recent follow-up stature available for the patient projected to final adult stature, compared with the model's predicted adult stature (MPAS), based only on initial data at presentation and subsequent radiation treatment. Patients who did not receive radiotherapy did not have loss of stature, ie, there was no significant difference between IAS and CAS, (P less than .71; n = 13), but patients who received radiotherapy had shorter statures than would be expected from the healthy population model (P less than .0004; n = 36). The magnitude of the loss in stature appears to be well explained by the dose and location of radiation, the stature already achieved at the time of radiotherapy, along with IAS, FEMUR, and sex. We believe this model will help clinicians to predict the growth effects of radiotherapy in children with cancer not involving the CNS.

Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen.

During the period 1976-1981, 3241 children were enrolled on three major studies of acute lymphoblastic leukemia by participating institutions of the Children's Cancer Study Group. Each study included a different method of central nervous system (CNS) prophylaxis: (1) standard therapy with cranial irradiation, 2400 rads, and intrathecal methotrexate at 12 mg/m2 six times during consolidation (CCG-141); (2) a modification of CCG-141 in which the intrathecal methotrexate was initiated during induction (CCG-141A); and (3) a reduced cranial irradiation dose of 1800 rads with intrathecal methotrexate given at the same frequency as a CCG-141A, with or without maintenance intrathecal methotrexate, but with a dosage regimen derived from CNS volume considerations rather than based on body surface area (CCG-160 series). Strategy 3, a change in the intrathecal methotrexate dosage, has resulted in the lowest incidence of CNS leukemia to date (p less than 0.007). The cumulative 3-yr CNS relapse rate has decreased from 8%-10% to 2%-5% in average-risk patients (p less than 0.02; life table estimate) and from 23%-27% to 6% in high-risk patients (p less than 0.0002; life table estimate), despite a reduction in the cranial irradiation dose from 2400 to 1800 rads. Maintenance intrathecal chemotherapy has had a marginal effect among patients randomized to receive this additional therapy (p = 0.06). The overall outcome has been an increase in the continuous complete remission rate (p = 0.04) but not in the estimated 3-yr continuous hematologic remission or survival rates.

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

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.

Treatment of bladder cancer with interstitial iridium-192 implantation and external beam irradiation.

Although interstitial implantation of invasive carcinoma of the bladder has been shown to be an effective treatment in Europe, there has been little experience with this method in the U.S. During the past 6 years, 14 patients at the Hospital of the University of Pennsylvania with single bladder tumors less than 5 cm and no evidence of carcinoma in situ on random bladder biopsies have been treated by a combination of external beam radiation and iridium wire implant. The iridium wire is inserted by an afterloading technique following tumor exposure via suprapubic cystotomy. Following delivery of the prescribed dose, the sources are removed percutaneously. Three patients with recurrent or high grade T1 lesions and 11 patients with T2-T3A lesions have been treated. With a median follow-up of 22 months (range 17 to 65 months), 9 patients are currently NED, 4 patients have died of disease, and 1 patient has died of intercurrent disease. There have been two isolated bladder recurrences, both non-invasive, one having been treated with cystectomy and one being treated locally. In addition, one patient developed regional failure, two developed distant metastases only, and one developed local recurrence following distant failure. The 2-year actuarial local control rate is 84%, with an overall 2-year actuarial survival of 66%. Complications have been minimal. Bladder implantation by this method is technically simple and produces excellent local control with acceptable morbidity.

Soft-tissue sarcomas of the head and neck in children.

Thirty-two children aged three months to 17 years (median six years) were diagnosed with soft-tissue sarcoma of the head and neck and treated at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania from 1971 to 1981. Thirty-one received chemotherapy and all received radiation therapy (RT). Twenty-five patients had pre-treatment computed tomography (CT) scans, which were used for staging and treatment planning. Doses of radiation therapy ranged from 3000 to 7300 rad to the primary tumor (median 5000 rad). The overall five-year survival of the entire group of 32 patients was 75%. Ten of the 32 patients had invasive cranial parameningeal disease as demonstrated by bony erosion at the skull base, seen on CT in eight and plain radiographs in two patients. Eight of these 10 patients have developed recurrent sarcoma: four in the meninges, two locally, one regionally and one distantly. Five of these 10 children with invasive cranial parameningeal sarcoma received 3000 rad of prophylactic cranial irradiation, begun within the first 12 days of chemotherapy, and none developed meningeal disease. In contrast, only one of the 22 patients without invasive cranial parameningeal disease has relapsed (local recurrence). The data suggest that soft-tissue sarcomas of the head and neck in children without invasion into the base of the skull (invasive cranial parameningeal disease) are usually cured. CT scans are essential for staging. Patients with invasion of the base of the skull may be protected from meningeal relapse by early cranial irradiation, although they still are at high risk for relapse in other sites.

Results of a pilot study of hyperfractionated radiation therapy for children with brain stem gliomas.

The majority of children with brain stem gliomas develop progressive disease within 18 months of diagnosis and treatment. Radiotherapy (RT) is of transient benefit in most patients and higher total doses of RT have been related to improved survival. The amount of RT which can be given is limited by the tolerance of the surrounding brain. Hyperfractionated RT theoretically allows higher doses of RT to be tolerated by the brain. Sixteen children with brain stem gliomas were treated on a hyperfractionated RT schedule, receiving 120 cGy of RT twice daily, to a total dose of 6480 cGy. All patients tolerated treatment well. Eleven of 15 (73%) evaluable patients had a response to treatment and two (13%) others had stable disease. One patient developed progressive disease during treatment. All patients were tapered off steroids by the completion of treatment. Thirteen of 16 (81%) patients developed progressive disease at a median of 7 months after diagnosis and three remain in remission 8, 12, and 15 months following diagnosis. These results were similar to those of historical controls. Two patients were surgically explored at time of relapse and 5 have had an autopsy. No acute or subacute neurologic toxicity was seen; but long-term detrimental effects on brain could not be assessed. The implications of this study are that escalations of the dose of hyperfractionated RT can be entertained for children with brain stem gliomas.

Central nervous system (CNS) prophylaxis in children with low risk acute lymphoblastic leukemia (ALL).

Five hundred four children with low risk acute lymphocytic leukemia (previously untreated, age 3 to 6 years with white blood counts less than 10,000/mm3 at diagnosis) were randomized into two different central nervous system prophylaxis regimens. One regimen (250 patients) consisted of cranial radiation and intrathecal methotrexate (IT MTX). The second regimen (254 patients) consisted of IT MTX only. Median follow-up time for surviving patients is currently 54 months from randomization. Life table analysis of central nervous relapse, marrow relapse, disease-free survival, and survival shows very similar outcome for both treatment groups. The results indicate that maintenance IT MTX as described in this report can be substituted for cranial radiation in children with low risk ALL.

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.

Intracranial ependymomas in children.

Between 1970 and 1988, 51 children with intracranial ependymal tumors (33-infratentorial, 18-supratentorial received initial treatment at the University of Pennsylvania. Therapy consisted of total or near total tumor resection in 15 patients and partial resection or biopsy in 36. Postoperative irradiation alone was given to 18, chemotherapy to 4, and a combination of these two modalities to 26. Patients have been followed for a median period of 7.75 years. The 5-year actuarial survival and progression-free survival (PFS) rates are 46% and 30%, respectively. Of the 30 patients who have progressed, 29 did so locally and one died before the site of failure could be determined. Six patients also had disease outside the primary site at relapse; three of them had received craniospinal irradiation. Local control was significantly better for patients whose tumor dose exceeded 4500 cGy (32% vs. 0%, p = .01) and for Caucasian patients (34% vs. 15%, p =.05). Survival was better for patients who were over 4 years of age at diagnosis (55% vs. 30%, p = .04), for patients who received local radiation doses above 4500 cGy (51% vs. 18%, p = .01), and for Caucasian patients (43% vs. 14%, p = .01). Extent of resection, histology, location, the use of cranial or craniospinal irradiation, and the use of chemotherapy did not significantly impact on survival. We conclude that the inability to control local disease remains the single most important factor leading to treatment failure. Older age, higher local radiation dose, and Caucasian race appear to be the only favorable prognostic factors.

Nonsurgical management of children with recurrent or unresectable fibromatosis.

At The Children's Hospital of Philadelphia, since 1971, six children 3 months to 17 years of age with fibromatosis have been treated with a combination of vincristine, actinomycin D, and cyclophosphamide (VAC). The first three patients also received radiation therapy (5,500 rads). Locally recurrent tumors developed in four of the children after previous operative removal; the other two had tumors that could not be removed initially. The tumors arose in the neck (three patients), pelvis (two patients), or foot (one patient). In the three patients treated with VAC alone, complete disappearance of tumor was confirmed at second operation in two, and greater than 75% shrinkage on CT scans occurred in the third, all at 4 to 6 months after VAC was started. In two of the three patients who received VAC plus radiation therapy, complete disappearance of tumor occurred at 13 and 16 months; the third had no response. Five of the six patients are free of recurrent fibromatosis at 1, 2, 4, and 11 years after VAC was begun; the sixth has required multiple operations during the last 6 years. We conclude that combination chemotherapy with VAC can produce regression of fibromatosis in some children with recurrent or unresectable lesions. The administration of VAC should be considered for children with fibromatosis in whom operative removal is not feasible, would prove mutilating, or is unlikely to produce long-term control of the disease.

Pineal region tumors of childhood.

The incidence, response to treatment, and outcome of children with pineal region neoplasms is poorly characterized. Since 1975, in one institution, 25 consecutive patients with pineal tumors have undergone biopsy prior to further treatment. This constituted 11% (25/234) of all brain neoplasms seen over this time period. Specific tumors diagnosed included pineal parenchymal tumors ( pineoblastomas , pineocytomas ) in eight patients (32%); germ cell tumors (embryonal cell carcinomas, teratomas, germinomas) in eight patients (32%); glial tumors (astrocytoma, ganglioglioma ) in eight patients (32%); and ganglioneuroblastoma in one patient (4%). Clinical parameters, computed tomographic findings and CSF markers (alphafetoprotein and human chorionic gonadotropin) were unreliable in discriminating between specific tumor types. Response to treatment and patterns of disease relapse were dependent on the type of tumor present. Five of eight children with pineal parenchymal tumors had disease recurrence, and in all leptomeningeal dissemination occurred prior to or concurrent with local relapse. Three of eight children with germ cell tumors and two of eight patients with glial tumors suffered a relapse; in all five children recurrence was initially local. Findings suggest that pineal region neoplasms are not infrequent in childhood; that these tumors vary greatly in histologic type; that contrary to other reports germinomas do not constitute the majority of pineal tumors; and that histologic confirmation is necessary prior to treatment for appropriate management.

Improved relapse-free survival in medulloblastoma utilizing modern techniques.

Between 1969 and 1979, 22 patients with medulloblastoma were treated by the same surgical group and radiation therapy group. The patients were divided into two groups because of the clinical availability in December 1974 of the computed tomographic (CT) scanner and of the operating microscope used in the initial surgical procedure. There were 11 patients in each group. The percentage of patients with a relapse-free survival in the group treated between 1969 and 1974 (Group 1) was 38% at 4 years. The survival in the 11 patients treated between 1974 and 1979 (Group 2) was 84% at 4 years. This improvement is statistically significant (P less than or equal to 0.001). All patients received the same dose of radiation. Efforts to minimize the tumor burden by total surgical resection did not increase postoperative morbidity or mortality. These results are discussed, along with the relative impact of the CT scan, total resection at operation, and increased focus for radiation therapy on the improved outcome.

Prognostic importance of cellular differentiation in medulloblastoma of childhood.

Medulloblastoma is the most common intracranial primitive neuroectodermal malignancy of childhood. Certain parameters are predictive of survival in children with medulloblastoma; however, tumor histology is of unclear prognostic value. A classification system, proposed by Rorke for all central nervous system (CNS) neoplasms composed of primitive neuroepithelial cells, was utilized in a review of 38 consecutive patients with newly diagnosed medulloblastoma. The classification is based on the concept that medulloblastoma is not unique to the cerebellum but is similar to tumors that may arise elsewhere in the CNS consequent to neoplastic transformation of primitive neuroepithelial cells. Cells forming the tumors may remain in the undifferentiated state or they may exhibit differentiation along glial, and/or ependymal, and/or neuronal lines. For purposes of simplification, the cases were divided into two major groups: those primitive neuroectodermal tumors (PNET's) which showed no evidence of cellular differentiation (PNET-U) and those that were differentiated (PNET-D). There were 20 cases in the PNET-U group and 18 in the PNET-D group. The 4-year survival rate was 70% for PNET-U, compared to 32% for PNET-D (p = 0.004). Only one of 10 children with PNET-D with differentiation along more than one cell line survived. Other factors, including age at diagnosis, tumor metastasis (TM) stage, and extent of surgical resection, were analyzed and were of prognostic importance; but histological features remained statistically significant within each subgroup.

The role of surgery in localized neuroblastoma.

A 30-year experience with 83 patients, median age two years, with Children's 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.

Treatment strategies for infants with malignant sacrococcygeal teratoma.

Twelve children with malignant sacrococcygeal teratoma containing embryonal carcinoma, were treated at the Children's 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.