FLASH radiotherapy for the treatment of symptomatic bone metastases in the thorax (FAST-02): protocol for a prospective study of a novel radiotherapy approach.

BACKGROUND: FLASH therapy is a treatment technique in which radiation is delivered at ultra-high dose rates (≥ 40 Gy/s). The first-in-human FAST-01 clinical trial demonstrated the clinical feasibility of proton FLASH in the treatment of extremity bone metastases. The objectives of this investigation are to assess the toxicities of treatment and pain relief in study participants with painful thoracic bone metastases treated with FLASH radiotherapy, as well as workflow metrics in a clinical setting. METHODS: This single-arm clinical trial is being conducted under an FDA investigational device exemption (IDE) approved for 10 patients with 1-3 painful bone metastases in the thorax, excluding bone metastases in the spine. Treatment will be 8 Gy in a single fraction administered at ≥ 40 Gy/s on a FLASH-enabled proton therapy system delivering a single transmission proton beam. Primary study endpoints are efficacy (pain relief) and safety. Patient questionnaires evaluating pain flare at the treatment site will be completed for 10 consecutive days post-RT. Pain response and adverse events (AEs) will be evaluated on the day of treatment and on day 7, day 15, months 1, 2, 3, 6, 9, and 12, and every 6 months thereafter. The outcomes for clinical workflow feasibility are the occurrence of any device issues as well as time on the treatment table. DISCUSSION: This prospective clinical trial will provide clinical data for evaluating the efficacy and safety of proton FLASH for palliation of bony metastases in the thorax. Positive findings will support the further exploration of FLASH radiation for other clinical indications including patient populations treated with curative intent. REGISTRATION: ClinicalTrials.gov NCT05524064.

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

The MIT D-lab electricity-free PortaTherm™ incubator for remote testing with the QuantiFERON®-TB Gold In-Tube assay.

BACKGROUND: Use of the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT) in remote areas is limited by the need to incubate blood samples within 12 h of collection. PortaTherm™ is a portable, electricity-free, phase-change incubator previously used for field collection of microbiological samples. OBJECTIVE: To determine whether the PortaTherm can be used for the reliable incubation of QFT-GIT samples, thus enabling QFT-GIT use in settings distant from laboratory facilities. METHODS: In a prospective comparative study in Peru, blood samples were collected from 50 participants and processed in three parallel QFT-GIT tests per participant; two were incubated in a conventional incubator; the third was incubated in the PortaTherm. RESULTS: All 150 QFT-GIT tests gave definitive results, and for 46 of the 50 participants all three tests were concordant, eight of which were positive. Four participants had one discordant result: two due to discordance of a conventional incubator QFT-GIT result, and two due to discordant PortaTherm QFT-GIT results. CONCLUSION: The QFT-GIT inter-incubator variability between the PortaTherm and conventional incubator was no greater than the intra-incubator variability for the conventional incubator, indicating that the PortaTherm is a suitable tool for incubating QFT-GIT whole blood samples in remote settings where access to a laboratory or electricity is limited.

Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Although age <1 year at diagnosis has been associated with a worse prognosis in rhabdomyosarcoma (RMS), the relationship of age at diagnosis to clinical presentation and outcome has not been evaluated carefully. We reviewed data from recent Intergroup Rhabdomyosarcoma Study Committee (later called Group, IRSG) trials to examine this relationship in order to estimate prognosis more accurately and further refine treatment. PROCEDURE: We used data from IRS-III, -IV Pilot, and -IV (1983-97, N=2,343) to study the relationship of patient age with clinical features and prognosis in a large cohort of patients treated with contemporary therapy. RESULTS: We showed that, after adjusting for important prognostic factors, age was an independent risk factor for treatment failure and patients could be classified into three failure-risk categories based on age (i.e., <1 year; 1-9 years; >10 years). Infants and adolescents were more likely to have unfavorable features, including alveolar or undifferentiated tumors and advanced Group and Stage, and also had significantly poorer failure-free survival (FFS) than did children aged 1-9 (53 and 51% vs. 72%, P<0.001). Although there was a difference in FFS among age categories, there was no evidence that age influences outcome within the three categories. CONCLUSIONS: Since age relates independently to outcome after adjustment for known risk factors, it is likely that other factors, including perhaps patients' tolerance of protocol-specified therapy, explain this relationship.

Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group.

PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy. PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc). RESULTS: Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy. CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.

Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG.

PURPOSE: To evaluate the outcome and toxicity of hyperfractionated radiotherapy (HFRT) vs. conventionally fractionated radiotherapy (CFRT) in children with Group III rhabdomyosarcoma (RMS). METHODS AND MATERIALS: Five hundred fifty-nine children were enrolled into the Intergroup Rhabdomyosarcoma Study IV with Group III RMS. Sixty-nine were ineligible for the analysis because of incorrect group or pathologic findings. Of the 490 remaining, 239 were randomized to HFRT (59.4 Gy in 54 1.1-Gy twice daily fractions) and 251 to CFRT (50.4 Gy in 28 1.8-Gy daily fractions). The age range was <1-21 years. All patients received chemotherapy. RT began at Week 9 after induction chemotherapy for all but those with high-risk parameningeal tumors who received RT during induction chemotherapy. The patient groups were equally balanced. The median follow-up was 3.9 years. RESULTS: Analysis by randomized treatment assignment (intent to treat) revealed an estimated 5-year failure-free survival (FFS) rate of 70% and overall survival (OS) of 75%. In the univariate analysis, the factors associated with the best outcome were age 1-9 years at diagnosis; noninvasive tumors; tumor size <5 cm; uninvolved lymph nodes; Stage 1 or 2 disease; primary site in the orbit or head and neck; and embryonal histologic features (p = 0.001 for all factors). No differences in the FFS or OS between the two RT treatment methods and no differences in the FFS or OS between HFRT and CFRT were found when analyzed by age, gender, tumor size, tumor invasiveness, nodal status, histologic features, stage, or primary site. Treatment compliance differed by age. Of the children <5 years, 57% assigned to HFRT received HFRT and 77% assigned to CFRT received CFRT. Of the children >or=5 years, 88% assigned to both HFRT and CFRT received their assigned treatment. The reasons for not receiving the appropriate randomized treatment were progressive disease, early death, parent or physician refusal, young age, or surgery. The toxicity assessment revealed more mucositis with HFRT (66%) than with CFRT (46%) (p = 0.03) for the parameningeal patients, and more skin reactions (16%) and nausea/vomiting (13%) with HFRT than with CFRT (7% and 5%, respectively) for patients with nonparameningeal primary tumors (p = 0.03 and p = 0.02, respectively). The analysis by treatment actually received revealed a 5-year FFS rate of 73% and OS rate of 77%, with no difference between CFRT and HFRT. As well, there was no difference in FFS or OS between CFRT and HFRT when analyzed by age, gender, tumor size, tumor invasiveness, modal status, histology, stage or site of primary. The 5-year estimated cumulative incidence of failure for the irradiated patients was local, 13%; regional, 3%; and distant, 13%; with no differences between HFRT and CFRT. The 5-year local failure rate by site was orbit, 5%; head and neck, 12%; parameningeal, 16%; bladder/prostate, 19%; extremity, 7%; and all others, 14%. The 5-year regional failure rate was parameningeal,1%; extremity, 20%; and all others, 5%. The 5-year distant failure rate was orbit, 2%; head and neck, 6%; parameningeal, 11%; bladder/prostate, 15%; extremity, 28%; and all others, 17%. CONCLUSIONS: HFRT, as given in this study, did not improve local/regional control, FFS, or OS compared with CFRT. The risk of local/regional failure was comparable to that of distant failure in children with Group III RMS. The standard of care for Group III RMS continues to be CFRT with chemotherapy.

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.

Routine brain imaging is unwarranted in asymptomatic patients with rhabdomyosarcoma arising outside of the head and neck region that is metastatic at diagnosis: a report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: To the authors' knowledge, the incidence of brain metastases at the time of diagnosis in children with metastatic rhabdomyosarcoma (RMS) arising outside the head and neck region is unknown, and routine imaging to identify metastatic brain involvement is costly. METHODS: The authors retrospectively reviewed the results of computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head, which was mandated by protocol, in patients with metastatic RMS arising outside the head and neck region who were enrolled on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV; 1991--1997). RESULTS: Of 100 eligible patients with metastatic RMS arising outside the head and neck region, 56 (56%) underwent head CT (n = 51) and/or MRI (n = 11) scans. Seven of these 56 patients (12.5%) had abnormal scans. Three patients with physical findings suggesting head or neck pathology underwent imaging that confirmed the presence of metastases in bone (one patient), orbit (one patient), or lymph nodes (one patient). One patient who presented with seizures had imaging findings consistent with cerebral embolic infarctions. Of three asymptomatic patients, one had bone metastases that also were identified on skeletal survey and one had bone metastases in the base of the skull that were not identified on bone scan. The remaining asymptomatic patient had a retroperitoneal paraspinal tumor with spinal canal extension and subsequently developed leptomeningeal disease dissemination. CONCLUSIONS: Brain metastases are uncommon at the time of initial diagnosis of metastatic RMS arising outside the head and neck region, and the majority of abnormalities detected on head CT or MRI scans are evident clinically or on other imaging studies. Patients with clinical findings suggesting intracranial pathology and those with paraspinal tumors may benefit from brain imaging, but cost savings may be realized by foregoing imaging in patients without these features.

Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease.

PURPOSE: The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy. PATIENTS AND METHODS: Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT). RESULTS: Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P =.42). No significant difference in outcome was noted with HF-RT versus C-RT (P =.85 and P =.90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%. CONCLUSION: VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study.

PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m(2) of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m(2), dactinomycin 1.5 mg/m(2), and cyclophosphamide 2.2 g/m(2) (VAC) and vincristine 1.5 mg/m(2), topotecan 0.75 mg/m(2) daily x 5, and cyclophosphamide 250 mg/m(2) daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P: = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.

Linked linear amplification: a new method for the amplification of DNA.

BACKGROUND: Linked Linear Amplification (LLA) is a new nucleic acid amplification method that uses multiple cycles of primer extension reactions. The presence of nonreplicable elements in LLA primers renders primer extension products unusable as templates for further amplification, leading to linear accumulation of products. Through the use of nested primers, linear reactions can be "linked", providing total amplification yields comparable to those obtained by PCR. METHODS: The LLA model predicts (a) that amplification yield will approach that of PCR as the number of primers increases and (b) that the unique composition of LLA products will give lower carryover amplification efficiency compared with PCR. To test these hypotheses, the human ss-globin gene was amplified by 10-, 14-, or 18-primer LLA and the yield was compared with PCR. Carryover contamination was simulated by reamplifying a dilution series of LLA or PCR products. To demonstrate the clinical utility of the method, LLA coupled with allele-specific oligonucleotide (ASO) capture was used to detect the factor V Leiden mutation in a panel of 111 DNA samples. RESULTS: Fourteen- and 18-primer LLA gave amplification yields comparable to PCR. However, LLA carryover amplification efficiency was four orders of magnitude lower than that of PCR. The LLA-ASO assay detected the correct factor V Leiden genotype in all 111 samples. CONCLUSIONS: LLA is a robust target amplification method that is comparable to PCR in yield. However, LLA is more resistant to false results caused by carryover amplicon contamination.

Clinical oncology clerkship for third-year medical students.

BACKGROUND: A two-week elective clerkship in clinical oncology is offered to third-year medical students. METHODS: Two students at a time participated in the rotation and spent time with attendings in a one-to-one setting in outpatient clinics in the cancer specialties. The students also attended multidisciplinary tumor boards. Grand rounds, peer review conferences, and problem-case conferences were attended by the students as well. The students met with an attending for one-hour, twice-per-week to discuss pertinent oncologic cases and problems. The exposure to clinical oncology for two weeks is intended to educate the students relative to the presentation, evaluation, treatment, prognosis, and follow-up for a variety of cancers. RESULTS: The rotation has been highly successful as measured by its popularity and by consistently high course evaluations from the medical students. CONCLUSION: The overall quality of the learning experience for the rotation has been rated by the students as the highest among all courses in their four-year curriculum.

Issues in the local control of rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is a heterogeneous disease consisting of several different histologies arising from a variety of anatomic sites. Approximately half of the children who die of this tumor have failure at the primary site of involvement, making local control an important component of therapy. PROCEDURE: Published literature and newly analyzed data from the Intergroup Rhabdomyosarcoma Study Group (IRSG) regarding local control of RMS were reviewed. Information regarding the role of various local control modalities for different primary disease sites is presented along with new directions for clinical research. RESULTS: Local control rates for RMS average 80% for group III tumors, with large variations seen for different anatomic sites. Important gains in functional outcome for certain sites such as gynecologic system and bladder/prostate have been achieved by optimizing the use of the various treatment modalities. Local control at other sites such as the chest and extremities remains a problem. CONCLUSIONS: Advances in surgical and radiotherapy techniques coupled with multiagent chemotherapy are providing improved local control with decreasing morbidity. Optimal outcome is dependent on close collaboration between surgical, radiotherapy, and pediatric oncology specialists.

Treatment of optic nerve sheath meningioma with three-dimensional conformal radiation.

PURPOSE: To report a patient recovering vision after three-dimensional conformal radiotherapy for optic nerve sheath meningioma. METHODS: Radiotherapy was delivered by a three-dimensional conformal technique in 28-180-cGy fractions. RESULTS: Visual acuity improved from 20/200 to 20/30, and the visual field defect resolved. CONCLUSION: Visual loss from optic nerve sheath meningioma can be reversed by three-dimensional conformal radiotherapy.

Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV.

PURPOSE: To compare failure-free survival (FFS) and survival for patients with local or regional embryonal rhabdomyosarcoma treated on the Intergroup Rhabdomyosarcoma Study (IRS)-IV with that of comparable patients treated on IRS-III. PATIENTS AND METHODS: Patients were retrospectively classified as low- or intermediate-risk. Low-risk patients were defined as those with primary tumors at favorable sites, completely resected or microscopic residual, or orbit/eyelid primaries with gross residual disease and tumors less than 5 cm at unfavorable sites but completely resected. Intermediate-risk patients were all other patients with local or regional tumors. RESULTS: Three-year FFS improved from 72% on IRS-III to 78% on IRS-IV for patients with intermediate-risk embryonal rhabdomyosarcoma (P =.02). Subset analysis revealed two groups that benefited most from IRS-IV therapy. FFS at 3 years for patients with resectable node-positive or unresectable (group III) embryonal rhabdomyosarcoma arising at certain favorable sites (head and neck [not orbit/eyelid or parameningeal] and genitourinary [not bladder or prostate]) improved from 72% on IRS-III to 92% on IRS-IV (P =.01). Similarly, 3-year FFS for patients with completely resected tumor or with only microscopic disease remaining (group I or II) at unfavorable sites improved from 71% on IRS-III to 86% on IRS-IV (P =.04). Only patients with unresectable embryonal rhabdomyosarcoma (group III) at unfavorable sites had no improvement in outcome on IRS-IV (3-year FFS for IRS-III and IRS-IV, 72% and 75%, respectively; P =.31). CONCLUSION: IRS-IV therapy benefited certain subgroups of patients with intermediate-risk embryonal rhabdomyosarcoma. A doubling of the intensity of cyclophosphamide (or ifosfamide equivalent) dosing per cycle between IRS-III and IRS-IV is thought to be a key contributing factor for this improvement.

Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme.

OBJECTIVE: Brachytherapy with temporary implants may prolong survival in patients with recurrent glioblastoma multiforme (GBM), but it is associated with relatively high costs and morbidity. This study reports the time to progression and survival after permanent implantation of iodine-125 seeds for recurrent GBM and examines factors predictive of outcome. METHODS: Forty patients with recurrent GBM were treated with maximal resection plus permanent placement of iodine-125 seeds into the tumor bed. A total dose of 120 to 160 Gy was administered, and patients were followed up with magnetic resonance imaging scans every 2 to 3 months. RESULTS: Actuarial survival from the time of implantation was 47 weeks, with 7 of 40 patients still alive at a median of 59 weeks after implantation. Survival was significantly better for patients younger than 60 years, and a trend for longer survival was demonstrated with gross total resection and tumors with a low MIB-1 (a nuclear antigen present in all cell cycles of proliferating cells) staining index. Median time to progression was 25 weeks and, on multivariate analysis, was favorably influenced by gross total resection and patient age younger than 60 years. After implantation, 27 of 30 patients with failure had a local component to the failure. No patient developed symptoms attributable to radiation necrosis or injury. CONCLUSION: Permanent iodine-125 implants for recurrent GBM result in survival comparable with that described in previous reports on temporary implants, but with less morbidity. Results are most favorable for patients who are younger than 60 years, and who undergo gross total resection. Despite this aggressive treatment, most patients die as a consequence of locally recurrent disease.

Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III.

PURPOSE: To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT). PATIENTS AND METHODS: Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D +/- cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment. RESULTS: Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P =.03) and overall survival rates (82% v 52%, respectively; (P =.02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P =.01; overall survival, 95% v 86%; P =.23). CONCLUSION: Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy.

What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma arising in the abdominal wall? A report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: The aim of this study was to define clinical features and determine the best therapy for patients with rhabdomyosarcoma (RMS) of the abdominal wall. METHODS: We examined the demographic, clinical features, therapy (especially surgical), and outcome of 34 patients. Patients received combination chemotherapy after complete surgical resection (group I, n = 14; 41%); resection with microscopic residual followed by local irradiation (RT; group II, n = 8; 24%); partial resection or biopsy only plus RT with gross locoregional residual tumor (group III, n = 4; 12%); or biopsy only plus RT with metastatic disease (group IV, n = 8; 24%). Patients with group I or group II tumors had undergone partial abdominal wall resection (ie, involved muscle only with preservation of peritoneum, n = 11) or complete abdominal wall resection (n = 7). Four additional patients had groin lesions. RESULTS: Thirty-four children or adolescents with abdominal wall RMS (about 1% of all patients) were treated on Intergroup Rhabdomyosarcoma Study I (IRS-I) through IRS-IV. Overall, adolescents comprised 14 of 34 eligible patients (41%), and 10 of 14 (71%) adolescents had alveolar or undifferentiated tumors versus 8 of 20 (40%) younger children (P= .07). Failure-free survival (FFS) rate and survival rate at 5 years was 65%. Treatment outcome was poorer for patients with group III-IV tumors (P = .01), adolescents (P = .09) and patients with alveolar or undifferentiated sarcomas (P = .12). CONCLUSION: Patients with localized tumors appear to fare better if they undergo complete abdominal wall resection (long-term survival rate, 100%) versus partial resection (long-term survival rate, 62% [P = .12]).

Modification of a linear accelerator table top for non-coplanar conformal brain radiotherapy.

The use of non-coplanar conformal therapy necessitates the use of unusual beam projections that may not be accomplished with a conventional linear accelerator table top. Modification of the table top can increase the available combinations of gantry and couch rotation. A standard Philips table top, supplied with an SL 75-5 linear accelerator, was modified to increase available combinations of gantry and couch rotation. This was accomplished by shortening the length and decreasing the width of the table top. The modified table top increases the combinations of gantry and couch angles significantly, simplifying the delivery of non-coplanar conformal therapy without significant compromise to routine treatment. The modification of a standard linear accelerator table top has increased the available combinations of gantry and couch rotation to accommodate non-coplanar conforrmal radiotherapy.

Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group.

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 LSA-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.