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PURPOSE Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS ACNS0331 (ClinicalTrials.gov identifier: NCT00085735 ) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm ( P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS ( P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.

Purpose To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. Methods and Materials Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. Results Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). Conclusions For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.

Purpose Variability in computed tomography/magnetic resonance imaging (CT/MR) cranial image registration was assessed using a benchmark case developed by the Quality Assurance Review Center to credential institutions for participation in Children's Oncology Group Protocol ACNS0221 for treatment of pediatric low-grade glioma. Methods and Materials Two DICOM image sets, an MR and a CT of the same patient, were provided to each institution. A small target in the posterior occipital lobe was readily visible on two slices of the MR scan and not visible on the CT scan. Each institution registered the two scans using whatever software system and method it ordinarily uses for such a case. The target volume was then contoured on the two MR slices, and the coordinates of the center of the corresponding target in the CT coordinate system were reported. The average of all submissions was used to determine the true center of the target. Results Results are reported from 51 submissions representing 45 institutions and 11 software systems. The average error in the position of the center of the target was 1.8 mm (1 standard deviation=2.2 mm). The least variation in position was in the lateral direction. Manual registration gave significantly better results than did automatic registration ( p = 0.02). Conclusion When MR and CT scans of the head are registered with currently available software, there is inherent uncertainty of approximately 2 mm (1 standard deviation), which should be considered when defining planning target volumes and PRVs for organs at risk on registered image sets.

Background Although radical prostatectomy for localized disease is considered as a standard of care, external-beam radiotherapy and brachytherapy are equally effective. We report on the technique and preliminary results of high-dose-rate (HDR) brachytherapy using a temporary iridium-192 implant technique. Methods The authors reviewed the literature on the techniques, treatment protocols, and results of HDR brachytherapy in the treatment of carcinoma of the prostate, and they report their own protocols, technique, and results. Results The combination of HDR brachytherapy and external irradiation has been well tolerated by all 200 patients in our series, with less than 3% grade 3 late complications and with 95% PSA relapse-free survival with a median follow-up of 24 months. Conclusions HDR brachytherapy may be the most conformal type of irradiation in the treatment of carcinoma of the prostate regardless of tumor size, anatomical distortion, and organ mobility.

BACKGROUND The objective of this study was to evaluate long-term treatment outcome of definitive irradiation by using temporary interstitial implant and limited dose of external beam radiotherapy in treatment of localized prostate carcinoma. METHODS In total, 536 patients with biopsy-proven adenocarcinoma of the prostate, classification T1–T3, underwent staging pelvic lymph node dissection and brachytherapy delivering an average tumor dose of 30 grays (Gy), supplemented by external beam radiation therapy for an additional dose of 36 Gy delivered over 4 weeks. One hundred of 536 (18%) patients had pathologic D1 disease. A total of 181 patients had undergone transurethral prostatectomy before the treatment. Repeat prostate biopsy was performed on 132 patients 18 or more months after treatment. None of the patients received neoadjuvant or adjuvant hormone therapy. RESULTS Cumulative disease free survival (DFS) including biochemical DFS at 10 and 15 years for classification T1B,C was 78% and 72%; for T2A, 78% and 78%; for T2B,C, 68% and 66%; and for T3A–C, 45% and 45%, respectively. Cause specific survival for the entire group at 10 and 15 years was 89% and 87%, respectively. Severe complications occurred only in the early developmental phase of the study. CONCLUSIONS In univariate analysis, the clinical stage, histologic grade, pretreatment PSA level, lymph node status, and results of repeat posttreatment biopsy were all independently significant prognostic factors. However, the authors' study indicates that in multivariate analysis, only two factors emerged with statistical significance—the status of pelvic lymph nodes and the results of posttreatment biopsy. This signifies the importance of local tumor control to achieve ultimate cure and the importance of assessment of pelvic lymph nodes before definitive local therapy other than radical prostatectomy, especially in the high-risk group. Cancer 2001;92:2084–94. © 2001 American Cancer Society.

OBJECTIVES To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the radiotherapy of carcinoma of the endometrium. METHODS Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS The main recommendations for the radiotherapy of carcinoma of the endometrium are: 1) For grade 1 and 2 stage IA tumours, follow-up alone is standard as additional treatment. For grade 1 and 2 stage IB tumours, vaginal brachytherapy or follow-up alone are options. For grade 3, stage IB tumours and stage IC disease, there are two treatment options: external pelvic radiotherapy with a brachytherapy boost or vaginal brachytherapy. 2) Treatment for stage II disease can be preoperative when stage II disease has been suggested by a positive endometrial curettage. Postoperative vaginal brachytherapy is given for stage IIA tumours if the penetration of the myometrium is less than 50% or if the tumour is grade 1 or 2. In the case of deep penetration, or higher grade disease, or for stage IIB external radiotherapy with brachytherapy boosting must be undertaken routinely. 3) After surgery, for stage IIIA disease, either external pelvic radiotherapy or abdomino-pelvic radiotherapy is indicated, along with medical treatment in certain patients. For stage IIIB tumours, postoperative external radiotherapy with brachytherapy (if possible) should be undertaken. For stage IIIC tumours, standard treatment is external (pelvic or pelvic and para-aortic) radiotherapy followed or not by a brachytherapy boost. In case of extrauterine sites involved abdomino-pelvic irradiation is recommended. 4) Standard treatment for inoperable stage I and II disease is external radiotherapy and brachytherapy. For patients with inoperable stage III or IV disease, treatment is often symptomatic, combining external radiotherapy and medical treatment.

Children with high-risk acute lymphoblastic leukemia (ALL) who have a slow response to initial chemotherapy (more than 25 percent blasts in the bone marrow on day 7) have a poor outcome despite intensive therapy. We conducted a randomized trial in which such patients were treated with either an augmented intensive regimen of post-induction chemotherapy or a standard regimen of intensive post-induction chemotherapy.Between January 1991 and June 1995, 311 children with newly diagnosed ALL who were either 1 to 9 years of age with white-cell counts of at least 50,000 per cubic millimeter or 10 years of age or older, had a slow response to initial therapy, and entered remission at the end of induction chemotherapy were randomly assigned to receive standard therapy (156 children) or augmented therapy (155). Those with lymphomatous features were excluded. Event-free survival and overall survival were assessed from the end of induction treatment.The outcome at five years was significantly better in the augmented-therapy group than in the standard-therapy group (Kaplan-Meier estimate of event-free survival [+/-SD]: 75.0+/-3.8 vs. 55.0+/-4.5 percent, P0.001; overall survival: 78.4+/-3.7 vs. 66.7+/-4.2 percent, P=0.02). The difference between treatments was most pronounced among patients one to nine years of age, all of whom had white-cell counts of at least 50,000 per cubic millimeter (P0.001). Risk factors for an adverse event in the entire cohort included a white-cell count of 200,000 per cubic millimeter or higher (P=0.004), race other than black or white (P0.001), and the presence of a t(9;22) translocation (P=0.007). The toxic effects of augmented therapy were considerable but manageable.Augmented post-induction chemotherapy results in an excellent outcome for most patients with high-risk ALL and a slow response to initial therapy.

BACKGROUND Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS Complete remission was induced in 97% of patients. The overall event free survival (EFS) ± the standard deviation was 60 ± 4% 6 years after diagnosis, in contrast to 36 ± 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 ± 7%. EFS was best on the NY (67 ± 7%) and the BFM (67 ± 6%) arms. These were significantly better than the EFS on the 2 LSA2-L2 regimens, with an EFS of 53 ± 8% (Regimen B) and 42 ± 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 ± 5% vs. 6 ± 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes. Cancer 1998;82:600-612. © 1998 American Cancer Society.

Object. The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. Methods. Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two cycles of “8-drugs-in-1-day” (8-in-1) chemotherapy prior to radiotherapy and eight additional cycles thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1–15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (> 90%), four partial or subtotal resections (10–90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 cycles of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. Conclusions. The 5-year progression-free and total survival rates for the 13 children were 46 ± 14% and 54 ± 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51–93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

Purpose: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from

Background. Brain stem gliomas remain the childhood brain tumors most resistant to treatment. Treatments with hyperfractionated radiotherapy at doses as high as 7560 cGy have been fairly well tolerated. This study was undertaken to determine the toxicity and possible efficacy of hyperfractionated radiotherapy in children with brain stem gliomas using 100 cGy of radiation twice daily, to a total dose of 7800 cGy. Methods. Sixty-six children (mean age at diagnosis, 7.5 years) with diffuse intrinsic brain stem gliomas were treated. Patients were evaluated for potential toxicity of treatment, progression-free survival, survival, and response to treatment. Results. Objective response to treatment was documented in 20 of 58 (34%) evaluable patients, with 8 (14%) patients having a greater than 50% reduction in tumor size. Overall survival was 35% plus or minus 6% at 1 year and 11% plus or minus 6% at 3 years. Intralesional cystic/necrotic radiographic changes developed in nine patients 6 weeks after radiation, and three of these patients subsequently improved without antitumor intervention. Six of 14 autopsied patients had evidence of probable radiation-induced intralesional necrotic damage, and in 1, necrosis may have played a role in death. Thirty-three of 66 patients were treated with steroids for prolonged periods. Conclusions. The results of this treatment regimen demonstrate that hyperfractionated radiotherapy, as delivered in this study to a total dose of 7800 cGy, is relatively well tolerated, but may result in prolonged steroiduse dependency and possible radiation-associated damage. Objective responses to treatment were seen in 34% of patients, but these results were not better than those seen at lower doses of hyperfractionated radiotherapy. There is no evidence that radiation to 7800 cGy results in improved survival for patients with diffuse intrinsic brain stem gliomas.

Purpose: Childrens Cancer Group 123 was a trial of intensive multidrug chemotherapy as well as cranial irradiation and bulk disease irradiation in children with acute lymphoblastic leukemia with lymphomatous presentation (bulk disease and either T-cell phenotype, high white blood count, or absence of anemia), a poor prognostic group with an increased risk of central nervous system (CNS) and other extramedullary recurrence. Methods and Materials: Three hundred eight patients without CNS disease were randomized among three regimens: A—BFM chemotherapy (designed for high risk ALL patients) with 1800 cGy cranial irradiation; B—LSAZLZ chemotherapy (designed for non-Hodgkins lymphoma patients) with 1800 cGy cranial irradiation and 1500 cGy to nonabdominal bulk disease; C—Reg B without cranial irradiation. All patients received intrathecal methotrexate throughout therapy. Radiation treatment records were reviewed. Results: With a minimum 52-month follow-up, Regimen B and C patients had 5-year actuarial CNS relapses of 7% and 17% ( p = 0.01) and event-free survivals of 53% and 39% ( p = 0.04). Patients with white blood count 3 did not benefit from cranial irradiation. Regimen A patients had the same CNS relapse rate as Regimen B patients but an improved event-free survival. Regimen B and C patients with large mediastinal masses who received their assigned chest radiation had a lower event rate than those who did not ( p = 0.06). Patients whose cranial fields did or did not encompass the entire meningeal surface had equivalent CNS relapse rates. Conclusion: Patients treated with LSAZLZ chemotherapy, a less than optimal regimen, benefited from cranial and mediastinal irradiation. Compliance with radiation volume guidelines was not essential for patients to receive the benefit of cranial irradiation.

The controversy about the treatment of carcinoma of the prostate has increased in the last decade, with most urologists favoring radical prostatectomy rather than primary irradiation. Several reports of persistent tumors in 50% to 90% of patients after external irradiation and permanent iodine-125 implantation of the prostate have been disturbing. From July 1977 to December 1985, 200 patients with adenocarcinoma of the prostate were treated by combining bilateral pelvic lymphadenectomy and temporary interstitial iridium-192 implantation of the prostate, followed by external irradiation. Seventy-four (36%) patients underwent biopsies of the prostate 4 months to 2 years after completion of the irradiation. Only 12 (16%) patients had persistent tumors. Complications were minimized subsequently by dose modifications.

Purpose: Brachytherapy plays a major role in the treatment of patients with carcinoma of the cervix. However, routine intracavitary brachytherapy may not be feasible or adequate to treat locally advanced disease. The purpose of this retrospective study (spanning a 20-year period) was to determine the outcome of interstitial low-dose-rate brachytherapy in the treatment of bulky or locally advanced cervical cancer. The long-term survival and safety of this technique were evaluated, along with its impact on local and locoregional control, disease-free survival, and complications. Methods and Materials: A total of 185 previously untreated patients with cervical cancer were treated between 1977 and 1997. According to the International Federation of Gynecology and Obstetrics classification, 21 patients had Stage IB (barrel), 77 Stage II, 77 Stage III, and 10 Stage IV disease. All patients were treated by a combination of external megavoltage irradiation to the pelvis to a dose of 5040 cGy followed by interstitial-intracavitary implants to a dose of 40–50 Gy to the implanted volume in two applications. Results: Clinical local control was achieved in 152 (82%) of the 185 patients. A 5-year disease-free survival rate of 65%, 67%, 49%, and 17% was achieved for patients with Stage IB, II, III, and IV disease, respectively. Eighteen (10%) of the 185 patients developed Radiation Therapy Oncology Group Grade 3 or 4 late complications. Conclusion: Patients with locally advanced cervical cancer, or with distorted anatomy, may be treated adequately with interstitial brachytherapy to achieve excellent locoregional control and a reasonable chance of cure with acceptable morbidity.

Addition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% ± 1% and 89% ± 1%, respectively. EFS was improved on DDI compared with either DI (log-rank P = .04; Kaplan-Meier [KM] P = .04; relative risk [RR] = 1.38) or DIVPI (log-rank P = .04; KM P = .01; RR = 1.39).There was no difference in EFS for the DI and DIVPI regimens (log-rank P = .96; KM P = .75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI ( P = .17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.

Purpose: We evaluated treatment outcomes of patients with mostly locally advanced primary and recurrent cancer of the nasopharynx managed with interstitial and intraluminal brachytherapy. Methods and Materials: This is a retrospective analysis of 56 patients with cancer arising from the nasopharynx treated with interstitial and intracavitary afterloading brachytherapy from 1978 to 1997. Patients were divided into three treatment groups: 15 patients with primary cancer (Group 1), 34 patients with recurrent or persistent disease (Group 2), and 7 patients with cancer in the nasopharynx who had history of previous definitive radiation therapy to the nasopharynx for head and neck cancer (Group 3). Fifty-three percent of patients in Group 1 had 1992 AJCC Stage IV disease, and 49% of patients in Groups 2 and 3 had extensive disease (defined as T3, T4, or parapharyngeal extension). Group 1 received megavoltage radiation to 50–60 Gy followed by a boost to the primary site and neck (in cases of persistent neck disease) with a combination of interstitial and intracavitary brachytherapy (mean dose 33–37 Gy). Five patients received chemotherapy, and 6 patients received hyperthermia. Groups 2 and 3 patients were treated with brachytherapy implants (mean dose 50–58 Gy) without external beam radiation. Twenty-five patients received chemotherapy either before or during radiation, and 21 patients received hyperthermia. Results: The overall survival at 2, 5, and 10 years for patients in Group 1 was 79%, 61%, and 61%, respectively, and for patients in Groups 2 and 3 combined was 48%, 30%, and 20%, respectively. Cause-specific survival at 2, 5, and 10 years was 87%, 74%, and 74%, respectively, for patients in Group 1; and 82%, 60%, and 60%, respectively, for patients in Groups 2 and 3. Local control at 2, 5, and 10 years was 93%, 93%, and 77%, respectively, for patients in Group 1; and 81%, 59%, and 49%, respectively, for patients in Groups 2 and 3. Control in the neck at 2, 5, and 10 years was achieved in 93%, 93%, and 93% of patients, respectively, in Group 1; and 88%, 81%, and 81%, respectively, for patients in Groups 2 and 3. Disease-free survival was 87%, 74%, and 62%, respectively, for patients in Group 1, and 56%, 41%, and 34%, respectively, for patients in Groups 2 and 3. There were 4 peri-operative deaths. One death (2%) was attributable to the development of late complications. Forty-five percent of patients experienced some form of late complications. Conclusion: Interstitial afterloading brachytherapy can provide effective treatment for nasopharyngeal cancers, especially for locally persistent/recurrent and locally extensive lesions.

PURPOSE Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.

Childhood acute lymphoblastic leukemia (ALL) was considered a fatal condition 40 years ago, but is curable in more than 70% of patients today. The survival rate is being improved by increasing the intensity of chemotherapy early in treatment. Risk factors for potential neurobehavioral sequelae from the most effective therapies continue to be defined. We present early findings from the first largescale longitudinal study of neurobehavioral functioning (CCG-105NP) in childhood ALL patients from a randomized clinical trial (CCG-105). More than 200 patients (age range 1–18 years at diagnosis, x= 5.7 years) with intermediate risk ALL were enrolled in the CCG-105NP study. These children had been randomized to: (a) one of four systemic chemotherapy approaches testing Childrens Cancer Group (CCG) versions of Berlin-Frankfurt-Munster (BFM) intensive and prolonged induction/consolidation (I/C) and delayed intensification (Dl), separated and together; and (b) CNS-directed therapy using intrathecal methotrexate (IT MTX) alone throughout treatment versus 1800 cGy cranial irradiation (CXRT) and IT MTX during I/C and DI. They were examined at 9, 21, and 48 months after diagnosis. Comprehensive assessments included tests of early cognitive and motor development for pre-school patients, and intelligence, attention, visual-spatial perception, fine motor coordination, memory, language, school achievement, and social behaviour for school-age children and adolescents. At 9 months after diagnosis, preliminary data analyses possibly associated DI with fine motor difficulties in children 3–6.5 years of age. In addition, there were significant differences in cognitive and motor functioning between children who received CXRT and those in the same age range in the non-CXRT group. These test findings suggest that gross motor abilities and attentional processes were affected as early as 9 months after diagnosis. All treatment subgroup mean scores were in the average range. Longitudinal analyses of data from serial evaluations of patients will determine the persistence of these findings and the timing and occurrence of specific long-term neurobehavioral sequelae. Mediating factors such as age at diagnosis, gender, family socioeconomic status, and parental education levels, as well as any interaction effects within the context of the clinical trial, will be analyzed more precisely than in previous studies. This could serve as a basis for future intervention efforts. These analyses of data are currently in progress.

Purpose : This study attempted to determine if central nervous system (CNS) disease at diagnosis is a poor prognostic factor in children with acute lymphoblastic leukemia (ALL) and whether 6 Gy of spinal irradiation is an adequate dose for these patients. Methods and Materials : Previously the Children's Cancer Group (CCG) treated patients with ALL and CNS disease at diagnosis with cranio (24 Gy)-spinal (12 Gy) irradiation, as well as systemic and intrathecal chemotherapy. In a series of CCG trials completed in 1989 the spinal dose was empirically reduced to 6 Gy for patients receiving systemic chemotherapy with an intensive consolidation phase to limit hematopoietic toxicity. The spinal dose was left at 12 Gy for patients treated with a less intensive consolidation phase. Results : With a median follow-up for surviving patients of 74 months, the 5-year event-free survival for 53 patients with CNS disease at diagnosis was 69 ± 13% (±2 standard deviations), similar to the value obtained for 3364 patients without CNS disease, 67 ± 2%. Corresponding values for 5-year survival were 77 ± 12% and 80 ± 1%, and for freedom from isolated first CNS relapse, 90 ± 9% and 94 ± 1%. Event-free survival, survival, and freedom from isolated first CNS relapse in the 6-Gy group were as good as in the 12-Gy group. Conclusion : CNS disease at diagnosis is not a poor prognostic factor for children with ALL who are treated with intensive systemic chemotherapy, craniospinal irradiation, and intrathecal chemotherapy. Six Gy is an adequate dose of spinal irradiation for these patients.

PURPOSE To quantify the residual marrow lymphoblast fraction that best defines patients at high risk for relapse, and the optimal time for assessment during remission induction. PATIENTS AND METHODS The residual lymphoblast percentage was evaluated on day 7 (n = 220) and day 14 (n = 205) during a four- or five-drug induction in patients with poor prognostic factors. The rate of cytoreduction was related to event-free survival (EFS) and other factors. RESULTS On the New York (NY) regimen, 68%, 14%, and 18%, and on the Berlin-Frankfurt-Munster (BFM) regimen, 56%, 15%, and 29% of patients had M1 (< 5% blasts), M2 (5-25%), or M3 (> 25%) responses on day 7 (P = .075). On day 14, the corresponding values were 87%, 6%, 7% on NY and 84%, 8%, 8% on BFM. For patients who achieved remission by day 28 and a day-7 marrow rating of M1, M2, or M3, the 6-year EFS rate was 78%, 61%, and 49% (P < .001). The day-14 ratings predicted for a 72%, 32%, or 40% EFS (P < .001). Patients with 5% to 10% blasts day 7 had three times as many events as those with less than 5% and had no better EFS than those with 11% to 25% blasts. Patients with a WBC count more than 200,000/microL at diagnosis and an M1 day 7 marrow had an EFS rate of 69%, while for those with M2 or M3, the EFS rate was 41%. Day-7 marrow had greater prognostic significance than the day-14 evaluation. For slow responders on day 7, the day-14 marrow provided additional information. EFS for patients who achieved M1 by day 14 was 65%. EFS decreased to 20% for those still M2 or M3 on day 14. Day-7 and -14 evaluations had significance for patients of all ages and WBC levels. CONCLUSION Marrow aspiration on day 7 of therapy provided more useful information than that on day 14. However, day-14 marrow provided additional information for patients with a poor day-7 response. The rate of cytoreduction is a powerful, independent prognostic factor that can identify patients with a slow early response who are at risk for a short remission duration.

PURPOSE In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study. PATIENTS AND METHODS Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation. RESULTS Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site. CONCLUSIONS There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.

Endocurietherapy (brachytherapy) is the placing of radioactive sources directly into or near a solid tumor. This technique delivers a concentrated dose of radiation to a restricted volume while minimizing radiation effects on normal tissue. We have treated 11 patients (nine sarcomas, one carcinoma, and one Wilms') with endocurietherapy procedures as part of their multimodality treatment program. Six were treated as part of the primary management, and the other five were treated for recurrent or metastatic disease. Temporary afterloaded implants using ribbons embedded with radioactive iridium192 (Ir192) seeds delivered typical tumor doses of 4,000 cGy. Six patients, including four primary cases and two recurrent cases, are currently classified as no evidence of disease (NED) without further local regional treatment (follow-up of 11-62 months; median, 38 months), and one patient treated for metastasis also remains locally controlled. Two patients are classified as alive with disease (AWD), two died of disease (DOD), and one is now NED after surgical salvage. Special considerations were given to gonadal shielding, radioprotection techniques, and psychosocial issues in this pediatric population.

Two hundred patients with biopsy proven adenocarcinoma of prostate with Stages A to C were treated between July 1977 and December 1985. All patients underwent bilateral retroperitonea 1 pelvic lymph node dissection for staging and transperineal afterloading Iridium-192 implant to prostate; delivering minimum tumor dose of 30 to 40 Gy over 40-60 hours. In addition, all patients with Stage B and C disease also received external megavoltage radiation to prostate to doses of 30 to 40 Gy over 34 to 44 weeks. Local tumor control was defined by digital examination only when there was complete resolution of previously palpable nodules, masses or induration. This was achieved in 191/200 (95.5%) patients with minimum followup of 4 years (median 6.8 years). 74 patients had been rebiopsied at an average time interval of 2 years after completion of treatment. Only 12 (16%) patients had positive biopsies. The overall 5 year actuarial survival of entire group is 95%. Disease free survival has been correlated with stage and histology. Treatment related moderate to severe complications such as cystitis, proctitis, rectal ulcerations or fistulae occurred in 14% of patients initially (in first 100 cases). This has been critically analyzed in detail and several modifications and corrections have been introduced in the original treatment protocol resulting in complication rate of less than 4% without significant change in overall local tumor control.