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Proton beam radiotherapy unavoidably exposes healthy tissue to stray radiation emanating from the treatment unit and secondary radiation produced within the patient. These exposures provide no known benefit and may increase a patient's risk of developing a radiogenic cancer. The aims of this study were to calculate doses to major organs and tissues and to estimate second cancer risk from stray radiation following craniospinal irradiation (CSI) with proton therapy. This was accomplished using detailed Monte Carlo simulations of a passive-scattering proton treatment unit and a voxelized phantom to represent the patient. Equivalent doses, effective dose and corresponding risk for developing a fatal second cancer were calculated for a 10-year-old boy who received proton therapy. The proton treatment comprised CSI at 30.6 Gy plus a boost of 23.4 Gy to the clinical target volume. The predicted effective dose from stray radiation was 418 mSv, of which 344 mSv was from neutrons originating outside the patient; the remaining 74 mSv was caused by neutrons originating within the patient. This effective dose corresponds to an attributable lifetime risk of a fatal second cancer of 3.4%. The equivalent doses that predominated the effective dose from stray radiation were in the lungs, stomach and colon. These results establish a baseline estimate of the stray radiation dose and corresponding risk for a pediatric patient undergoing proton CSI and support the suitability of passively-scattered proton beams for the treatment of central nervous system tumors in pediatric patients.

The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6 MV conventional and intensity-modulated photon therapies.

Although sarcoma surgery is very important for cancer control, it is not always possible or practical to offer in some situations, including sarcoma recurrences, metastatic disease and/or unacceptable loss of function. We review some pragmatic approaches and examples of how to balance indications, risks and alternatives to control cancer in young people with sarcomas that are no longer using ‘front-line’ therapy. Radiotherapy combined with chemotherapy and outpatient ‘continuation’ chemotherapy regimens using drugs that cause less alopecia can improve function and quality of life. Some effective strategies to help cope when cure is not possible may include tumor ablation techniques performed in interventional radiology and percutaneous nerve blocks. Family centered care and effective problem solving of difficult issues can be greatly facilitated by consultation with a multidisciplinary team experienced in the management of very difficult cases. Treatment of young people with recurrent, relapsed and/or metastatic sarcoma still remains an art very much in the realm of compassion not protocol and persistent advocacy is required for the young person for whom cure may not be possible. A reduction of suffering and assistance in writing more chapters of a rich life narrative is the goal.

Purpose Chemotherapy during radiation and/or bone-seeking radioisotope therapy (153-samarium; 1 mCi/kg) during radiation may improve osteosarcoma cancer control. Patients and Methods We analyzed our preliminary radiation experience in high-risk, metastatic, and/or recurrent patients during a consecutive period of 20 months (May 2005–December 2006). Results Thirty-nine high-risk osteosarcoma patients had radiotherapy; 119 sites were irradiated. A median four sites were irradiated per patient (range 1–14). The median radiation dose and number of fractions of radiation was 30 Gy in 10 fractions (range 10–70 Gy in 4–35 fractions). Chemotherapy, most commonly ifosfamide or methotrexate, was used in 80% (100/119) radiotherapy courses. Of 38 painful sites, 29 had improvement (76%), 4 had no change (10%), and 5 had more pain (13%). Objective and potentially durable responses were documented using PET-CT and bone scans with persistent and sustained reduction of standard uptake values (SUVs; initial SUV of indication lesion 9.5 became

Purpose: ERCC4 ( XPF ) plays a role in both recombinant DNA repair and nucleotide excision repair, which involve repairing radiation-induced genetic damage. We hypothesized that two ERCC4 single-nucleotide polymorphisms are associated with normal-tissue toxicity in patients treated with radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). Methods and Materials: A retrospective review of the medical records of 130 patients with OPSCC who were prospectively recruited into a molecular epidemiologic study was performed to determine whether a long-term percutaneous feeding gastrostomy (LPFG) tube (a tube required for more than 180 days) had been used during and after definitive radiotherapy. We determined the genotype of the ERCC4 G1244A and T2505C polymorphisms using standard polymerase chain reaction-restriction fragment-length polymorphism techniques on DNA extracted from peripheral blood lymphocytes. Results: Of 130 patients, 100 (77%) were evaluable for the ERCC4 G1244A polymorphism in exon 8, and 122 (94%) were evaluable for the ERCC4 T2505C polymorphism in exon 11. The ERCC4 G1244A polymorphism was associated with a decreased need for LPFG, but this was not statistically significant (adjusted odds ratio=0.53; 95% confidence interval, 0.10–2.78). Sixteen (32%), 9 (14%), and 1 (10%) of patients with the wild-type homozygous TT genotype of ERCC4 T2505C, the heterozygous TC genotype, and the homozygous CC polymorphic genotype, respectively, required LPFG. These results suggest that the ERCC4 2505C allele was associated with a reduced need for LPFG (adjusted odds ratio=0.20; 95% confidence interval, 0.06–0.67). Furthermore, the need for LPFG was reduced by having more than 1 ERCC4 2505C allele and further for having both the ERCC4 1244A and 2505C polymorphic alleles, but this was not statistically significant. In addition, the actual time of gastrostomy dependence was associated with the T2505C polymorphism based on the Kaplan-Meier method ( p = 0.03). Conclusions: Our findings suggest that the ERCC4 T2505C polymorphism may be associated with improved recovery from radiation treatment toxicity in patients with OPSCC. Further study with larger sample sizes and prospective measure of radiotherapy-induced toxicity is warranted.

Summary Background It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. Methods Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test–Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756. Findings After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0·0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. Interpretation Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases. Funding No external funding was received.

Purpose: To examine, in the setting of total body irradiation (TBI) for the preparation of pediatric hematopoietic stem cell transplantation (HSCT), whether TBI dose can be reduced without compromising the efficacy of a regimen consisting of fludarabine and radiotherapy; and whether there is any increased risk of pulmonary toxicity due to the radiosensitizing effect of fludarabine. Methods and Materials: A total of 52 pediatric patients with hematologic malignancies received TBI-based conditioning regimens in preparation for allogeneic HSCT. Twenty-three patients received 12 Gy in 4 daily fractions in combination with cyclophosphamide, either alone or with other chemotherapeutic and biologic agents. Twenty-nine patients received 9 Gy in 3 fractions in conjunction with fludarabine and melphalan. Clinical and radiation records were reviewed to determine engraftment, pulmonary toxicity (according to Radiation Therapy Oncology Group criteria), transplant-related mortality, recurrence of primary disease, and overall survival. Results: The two groups of patients had comparable pretransplant clinical characteristics. For the 12-Gy and 9-Gy regimens, the engraftment (89% and 93%; p = 0.82), freedom from life-threatening pulmonary events (65% and 79%; p = 0.33), freedom from relapse (60% and 73%; p = 0.24), and overall survival (26% and 47%; p = 0.09) were not statistically different. Conclusions: The addition of fludarabine and melphalan seems to allow the dose of TBI to be lowered to 9 Gy without loss of engraftment or antitumor efficacy.