Extraneural Metastases of Diffuse Midline Glioma, H3 K27M-Mutant at Diagnosis: Case Report, Review of the Literature, and Identifying Targetable Alterations.

Extraneural metastases are rare in pediatric high-grade gliomas and little is known about the genomic profiles of tumors that disseminate beyond the central nervous system. We describe a pediatric patient with H3 K27M-mutant diffuse midline glioma of the brain and spine with biopsy-confirmed osseous metastases present at diagnosis and suspected metastatic parenchymal pulmonary disease. Several potentially clinically and/or therapeutically relevant genomic alterations were identified, including H3F3A and TP53 mutations as well as MET, CDK6, EMSY, and PIK3CG amplifications. Sequencing is critical to improve our understanding of the molecular drivers of distant metastases and discover therapeutic targets that penetrate all disease sites.

Palliative radiation therapy for children with cancer.

Radiation therapy (RT) is often used as a palliative treatment for children with recurrent malignant disease to ameliorate or prevent symptoms. However, no guidelines exist regarding the clinical indications or dose fractionation for palliative RT. The goal of this report is to provide guidelines for the use of palliative RT in children with cancer. In this guideline, appropriate indications for palliative RT, recommended dose-fractionation schedules, relevant toxicities, and avenues for future research are explored. RT is an effective palliative treatment for bone, brain, liver, lung, abdominopelvic and head-and-neck metastases, spinal cord compression, superior vena cava syndrome, and bleeding. Single-fraction regimens (8 Gy in one fraction) for children with short life expectancy are recommended for simple, uncomplicated bone metastases and can be considered for some patients with lung or liver metastases. A short, hypofractionated regimen (20 Gy in five fractions) may be used for other indications to minimize overall burden of therapy. There are little data supporting use of more prolonged fractionation regimens, though they may be considered for patients with very good performance status. Future research should focus on response and outcomes data collection, and to rigorously evaluate the role of stereotactic body RT in well-designed, prospective studies.

Rhabdomyosarcoma.

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials.

Impact of local control and surgical lymph node evaluation in localized paratesticular rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

Paratesticular rhabdomyosarcoma (PT-RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT-RMS. We analyzed patients with localized PT-RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients ≥10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five-year event-free survival (EFS) was 92.0% (95% CI 88.4%-95.6%). Sampling ≥7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant (P = .068). Age (P = .28), N-stage (P = .39), T-stage (P = .11) and pathologic node involvement (P = .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS (P = .027) though not overall survival (P = .13). In conclusion, outcomes for patients with PT-RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease.

A Fully Automated Multiplex Assay for Diagnosis of Lyme Disease with High Specificity and Improved Early Sensitivity.

Lyme borreliosis is a tick-borne disease caused by the Borrelia burgdorferisensu lato complex. Bio-Rad Laboratories has developed a fully automated multiplex bead-based assay for the detection of IgM and IgG antibodies to B. burgdorferi The BioPlex 2200 Lyme Total assay exhibits an improved rate of seropositivity in patients with early Lyme infection. Asymptomatic subjects from endemic and nonendemic origins demonstrated a seroreactivity rate of approximately 4% that was similar to other commercial assays evaluated in this study. Coupled to this result was the observation that the Lyme Total assay retained a high first-tier specificity of 96% while demonstrating a relatively high sensitivity of 91% among a well-characterized CDC Premarketing Lyme serum panel. The Lyme Total assay also performs well under a modified two-tier algorithm (sensitivity, 84.4 to 88.9%; specificity, 98.4 to 99.5%). Furthermore, the new assay is able to readily detect early Lyme infection in patient samples from outside North America.

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

PURPOSE: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. METHODS: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. RESULTS: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . CONCLUSIONS: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. TRIAL REGISTRATION: NCT02607124.

Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report.

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.

Sentinel lymph node biopsy in head and neck rhabdomyosarcoma.

Head and neck rhabdomyosarcoma lymph node staging is challenging due to varied patterns of lymphatic drainage and the suboptimal predictive value of available imaging modalities. Furthermore, regional relapse rates are unacceptably high, and the toxicity of empiric radiation is undesirable in the pediatric and young adult population. In an attempt to improve locoregional control without excess morbidity, we have adopted routine sentinel lymph node biopsy in head and neck rhabdomyosarcoma, which is safe and feasible in pediatric patients. Of six procedures reported here, pathologic findings led to intensification of regional and/or systemic therapy in two patients.

Debulking surgery of pituitary adenoma as a strategy to facilitate definitive stereotactic radiosurgery.

In patients with pituitary adenomas (PA) who are unable to undergo complete surgical resection, radiation therapy (RT), specifically stereotactic radiosurgery (SRS), results in excellent local control. However, the utility of radiosurgery may be limited by the proximity of the lesion to the optic chiasm (OC). We evaluate the efficacy of debulking surgery in increasing the PA-OC separation to convert patients into SRS candidates. From 2007 to 2015, 31 patients with PA < 2 mm from the OC underwent debulking surgery followed by RT within 2 years of resection. Coronal and sagittal T1-pre- and post-contrast sequences were used to determine PA-OC separation. Time interval between postoperative and pre-radiotherapy MRI scans and type of radiation therapy were analyzed. Functional tumor status, tumor characteristics [cavernous sinus (CS) or suprasellar (SS) involvement, chiasm/nerve encasement (NE)], and presence of ≥ 2 of these characteristics (multiple factors, MF) was also noted. Surgery converted 9 of 31 patients (29%) to SRS candidates. Median time from surgery to pre-RT planning MRI was 8 months (range 2-20). Of the 31 patients initially ineligible for SRS, 6 became eligible immediately after surgery, and another 3 were deemed eligible on follow-up. Mean PA-OC separation was 0.3 mm preoperative, 1.4 mm postoperative, and 2.1 mm at time of SRS (p = 0.002). Preoperative SS, NE, and MF involvement predicted pre-RT separation < 2 mm. Debulking surgery of unresectable pituitary tumors is a successful strategy for converting select radiosurgery-ineligible patients to radiosurgery candidates. Absence of preoperative SS, NE, and MF predicts for successful conversion.

Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/m2 ) to the combination of vincristine and dactinomycin (VAC). The goal of Children's Oncology Group ARST0331 for subset 2 low-risk patients was to reduce the total cumulative cyclophosphamide dose without compromising FFS. METHODS: Therapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/m2 ) followed by 12 cycles of vincristine and dactinomycin over 46 weeks. Patients with group II or III tumors received radiotherapy, except for girls with group III vaginal tumors who enrolled before September 2009 and achieved a complete response with chemotherapy with or without delayed surgical resection. RESULTS: Among 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02). CONCLUSIONS: The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331. PROCEDURE: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m2 ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy. RESULTS: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with

Hypofractionated stereotactic radiotherapy for unifocal and multifocal recurrence of malignant gliomas.

To evaluate the efficacy and safety of stereotactic radiotherapy (SRT) for unifocal and multifocal recurrence of malignant gliomas. Between June 2007 and October 2010, 35 consecutive patients with 47 recurrent lesions were treated with salvage SRT at the University of Cincinnati. Thirty-three patients treated had a diagnosis of high grade glioma, four Grade III and twenty-nine Grade IV, while two patients initially were diagnosed with grade II tumors but recurred as high grade lesions. All patients had previously received a median dose of 59.4 Gy. Twenty-six patients were treated for a single lesion, and nine patients were treated for multiple lesions. Using SRT, patients were re-treated with a median total dose of 30 Gy in a median of five fractions. Median survival from diagnosis was 22 months and median survival following SRT was 8.6 months. The median survival following SRT for those patients treated for multifocal recurrence was 7.9 versus 10 months for those treated for unifocal recurrence (p = 0.7). Multivariate analysis showed local control of the SRT treated lesion(s) 6 months after SRT was associated with a significant improvement in survival (p ≤ 0.01). All patients tolerated their treatment well and completed their prescribed SRT as planned. Three patients (9 %) were felt to possibly have developed radiation necrosis following therapy. SRT was both well tolerated and efficacious with the local control provided by SRT resulting in improved overall survival. This benefit also seems to be apparent for patients with multi-focal recurrence.

FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01): Protocol for the First Prospective Feasibility Study.

BACKGROUND: In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. OBJECTIVE: FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. METHODS: Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm × 7.5 cm up to 7.5 cm × 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. RESULTS: FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. CONCLUSIONS: The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. TRIAL REGISTRATION: : ClinicalTrials.gov NCT04592887; http://clinicaltrials.gov/ct2/show/NCT04592887. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41812.

Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases: The FAST-01 Nonrandomized Trial.

Importance: To our knowledge, there have been no clinical trials of ultra-high-dose-rate radiotherapy delivered at more than 40 Gy/sec, known as FLASH therapy, nor first-in-human use of proton FLASH. Objectives: To assess the clinical workflow feasibility and treatment-related toxic effects of FLASH and pain relief at the treatment sites. Design, Setting, and Participants: In the FAST-01 nonrandomized trial, participants treated at Cincinnati Children's/UC Health Proton Therapy Center underwent palliative FLASH radiotherapy to extremity bone metastases. Patients 18 years and older with 1 to 3 painful extremity bone metastases and life expectancies of 2 months or more were eligible. Patients were excluded if they had foot, hand, and wrist metastases; metastases locally treated in the 2 weeks prior; metal implants in the treatment field; known enhanced tissue radiosensitivity; and implanted devices at risk of malfunction with radiotherapy. One of 11 patients who consented was excluded based on eligibility. The end points were evaluated at 3 months posttreatment, and patients were followed up through death or loss to follow-up for toxic effects and pain assessments. Of the 10 included patients, 2 died after the 2-month follow-up but before the 3-month follow-up; 8 participants completed the 3-month evaluation. Data were collected from November 3, 2020, to January 28, 2022, and analyzed from January 28, 2022, to September 1, 2022. Interventions: Bone metastases were treated on a FLASH-enabled (≥40 Gy/sec) proton radiotherapy system using a single-transmission proton beam. This is consistent with standard of care using the same prescription (8 Gy in a single fraction) but on a conventional-dose-rate (approximately 0.03 Gy/sec) photon radiotherapy system. Main Outcome and Measures: Main outcomes included patient time on the treatment couch, device-related treatment delays, adverse events related to FLASH, patient-reported pain scores, and analgesic use. Results: A total of 10 patients (age range, 27-81 years [median age, 63 years]; 5 [50%] male) underwent FLASH radiotherapy at 12 metastatic sites. There were no FLASH-related technical issues or delays. The average (range) time on the treatment couch was 18.9 (11-33) minutes per patient and 15.8 (11-22) minutes per treatment site. Median (range) follow-up was 4.8 (2.3-13.0) months. Adverse events were mild and consistent with conventional radiotherapy. Transient pain flares occurred in 4 of the 12 treated sites (33%). In 8 of the 12 sites (67%) patients reported pain relief, and in 6 of the 12 sites (50%) patients reported a complete response (no pain). Conclusions and Relevance: In this nonrandomized trial, clinical workflow metrics, treatment efficacy, and safety data demonstrated that ultra-high-dose-rate proton FLASH radiotherapy was clinically feasible. The treatment efficacy and the profile of adverse events were comparable with those of standard-of-care radiotherapy. These findings support the further exploration of FLASH radiotherapy in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04592887.

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy.

BACKGROUND AND PURPOSE: Emerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group. MATERIALS AND METHODS: All patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis. RESULTS: There were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively. CONCLUSIONS: PD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.

Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients: A Multicenter Trial.

PURPOSE: The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. METHODS AND MATERIALS: Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. RESULTS: Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P = .04) and private versus public insurance (P < .001). Both patient (P = .008) and parent (P = .006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001). CONCLUSIONS: In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

Results of phase I study of a multi-modality treatment for newly diagnosed glioblastoma multiforme using local implantation of concurrent BCNU wafers and permanent I-125 seeds followed by fractionated radiation and temozolomide chemotherapy.

Previously we demonstrated median survival of 69 weeks after combination therapy of permanent, low-activity I-125 seeds and BCNU wafers for recurrent glioblastoma multiforme (GBM). We designed this prospective phase I trial to assess efficacy of this combination treatment for newly diagnosed GBM. Patients with newly diagnosed GBMs deemed amenable to gross total resection were included. This dose-escalation study of I-125 seeds included three 6-patient cohorts, receiving increasing doses of 3000, 6000, and 9000 cGy, and a maximal number of BCNU wafers placed surgically. Postoperatively patients underwent standard fractionated radiation to 5,940 cGy followed by temozolomide chemotherapy. During enrollment of the first 6-patient cohort, the trial was stopped when 3 of 5 patients developed radiation toxicity. Five patients (median age 55 years, range 46-64 years) completed postoperative radiation; Karnofsky Performance Status ranged from 70 to 90. This lowest-dose cohort received I-125 seeds at 3,000 cGy and maximal BCNU wafer placement, and reached endpoint (median 26 weeks follow-up). Two patients developed local disease progression (median 34.4 weeks). The 3 patients who developed radiation toxicity, which was documented on follow-up MRI and confirmed by MRI spectroscopy (median 20 weeks), underwent treatment with steroids and bevacizumab. Our phase I study was closed during enrollment of the first 6-patient cohort because of the high incidence (60 %) of early radiation toxicity. We do not recommend the seed-wafer therapy for newly diagnosed GBM patients but rather reserve this as salvage therapy for select patients with recurrent GBM.

Long-term effects of total skin electron beam therapy for mycosis fungoides on hair and nail loss and regrowth.

OBJECTIVE: To better document the risk of permanent hair and nail loss after total skin electron beam therapy (TSEBT) for mycosis fungoides (MF). METHODS: Interviews and evaluations were conducted in 13 patients with MF treated with TSEBT alone and two patients treated with concomitant TSEBT and chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Evaluated parameters included time to hair and nail loss and regrowth, the density of hair regrowth, and quality of hair and nail regrowth. RESULTS: Most patients had complete loss of scalp hair during treatment, and new growth appeared about 2 months following treatment completion. After 18 months, most patients felt their hair had regrown to about 70% of baseline thickness without cosmetically obvious alopecia. The patients treated with TSEBT and concomitant chemotherapy had substantially less scalp hair regrowth with persistent cosmetically obvious alopecia. Some lost eyebrows and eyelashes, but complete or near-complete regrowth generally occurred. Most patients lost their nails following TSEBT, with complete regrowth noted by most patients 5 months after treatment. New nails were most often normal, but a few patients developed post-therapy nail dystrophies. CONCLUSION: This data can be used to better inform patients of likely long-term changes of hair and nails following TSEBT.

Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group.

BACKGROUND: The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children's Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection. PROCEDURES: We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies. RESULTS: Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively. CONCLUSIONS: To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of ≤ 4.8 g/m².