Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges.

Despite radiation therapy (RT) being an integral part of the treatment of most pediatric cancers and the recent discovery of novel molecular-targeted agents (MTAs) in this era of precision medicine with the potential to improve the therapeutic ratio of modern chemoradiotherapy regimens, there are only a few preclinical trials being conducted to discover novel radiosensitizers and radioprotectors. This has resulted in a paucity of translational clinical trials combining RT and novel MTAs. This report describes the opportunities and challenges of investigating RT together with MTAs in preclinical testing for immunotherapy, brain tumors, and sarcomas in pediatric oncology. We discuss the need for improving the collaboration between radiation oncologists, biologists, and physicists to improve the reliability, reproducibility, and translational potential of RT-based preclinical research. Current translational clinical trials using RT and MTAs for immunotherapy, brain tumors, and sarcomas are described. The technologic advances in experimental RT, availability of novel experimental tumor models, advances in immunology and tumor biology, and the discovery of novel MTAs together hold considerable promise for good quality preclinical and clinical multimodality research to improve the current rates of survival and toxicity in children afflicted with cancer.

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.

Clinical implementation, logistics and workflow guide for MRI image based interstitial HDR brachytherapy for gynecological cancers.

Interstitial brachytherapy (IBT) is often utilized to treat women with bulky endometrial or cervical cancers not amendable to intracavitary treatments. A modern trend in IBT is the utilization of magnetic resonance imaging (MRI) with a high dose rate (HDR) afterloader for conformal 3D image-based treatments. The challenging part of this procedure is to properly complete many sequenced and co-related physics preparations. We presented the physics preparations and clinical workflow required for implementing MRI-based HDR IBT (MRI-HDR-IBT) of gynecologic cancer patients in a high-volume brachytherapy center. The present document is designed to focus on the clinical steps required from a physicist's standpoint. Those steps include: (a) testing IBT equipment with MRI scanner, (b) preparation of templates and catheters, (c) preparation of MRI line markers, (d) acquisition, importation and registration of MRI images, (e) development of treatment plans and (f) treatment evaluation and documentation. The checklists of imaging acquisition, registration and plan development are also presented. Based on the TG-100 recommendations, a workflow chart, a fault tree analysis and an error-solution table listing the speculated errors and solutions of each step are provided. Our workflow and practice indicated the MRI-HDR-IBT is achievable in most radiation oncology clinics if the following equipment is available: MRI scanner, CT (computed tomography) scanner, MRI/CT compatible templates and applicators, MRI line markers, HDR afterloader and a brachytherapy treatment planning system capable of utilizing MRI images. The OR/procedure room availability and anesthesiology support are also important. The techniques and approaches adopted from the GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Therapeutic Radiology and Oncology) recommendations and other publications are proven to be feasible. The MRI-HDR-IBT program can be developed over time and progressively validated through clinical experience, this document is expected to serve as a reference workflow guideline for implementing and performing the procedure.

A feasibility study of using advanced external beam techniques to create a vaginal cuff brachytherapy-like endometrial boost plan.

The purpose of this study was to explore the feasibility of using advanced external beam radiation therapy (EBRT) planning techniques for creating plans that could be used as a possible alternative for high-dose rate (HDR) vaginal cuff brachytherapy (VCBT) boost in treating endometrial cancer. The computed tomography (CT) images of a total of 4 female patients who had endometrial cancer treated with HDR-VCBT were selected for this study. A typical HDR-VCBT target volume, 0.5-cm-thick shell volume around the cylinder applicator in the prescribed treatment length was contoured and used as the planning target volume (PTV) in both the HDR VCBT and the EBRT VCBT-like plans. HDR-VCBT plans were made based on the clinical protocol, 6 Gy given at the cylinder surface. The EBRT plans were generated using either a 7-field intensity-modulated radiation therapy (IMRT) or a 2-arc volumetric-modulated arc therapy (VMAT) techniques for different cylinder sizes and treatment lengths, with the prescription dose of 5 Gy. Organs at risk (OARs) such as bladder, femoral heads, rectum, and sigmoid were also contoured and used in dosimetric evaluations. Dose-to-target metrics included mean dose, the dose covering 90% of target volume (D90) and the percentage of target volume covered by 90% of prescription dose (V90 or V13.5 Gy). Dose to OAR metrics included the maximum dose received by 0.1 cc (D0.1cc), 1.0 cc (D1.0cc), and 2.0 cc (D2.0cc) of OARs. These metrics were calculated and compared between all techniques. After the EBRT plans were normalized to achieve a comparable mean dose to target as HDR-VCBT, the EBRT plans were found to have superior target coverage and increased dose homogeneity compared with HDR-VCBT. V90s of EBRT plans were 95%, compared with 50% to 58% of the HDR plans. However, D0.1cc, D1.0cc, and D2.0cc of OARs were 2% to 38% lower in HDR-VCBT than in EBRT. Although HDR-VCBT plans demonstrated superior normal tissue sparing, both EBRT and HDR-VCBT plans produce plans that met clinical dose constraints on normal tissues. Advanced EBRT techniques such as IMRT and VMAT are capable of making plans, which closely resemble HDR-VCBT. Although the doses of OARs are greater in EBRT than in HDR-VCBT, the prescription dose coverage and dose homogeneity of the EBRT plans are greater than that of HDR-VCBT plans at the similar mean dose, and the OAR dose is still acceptable with EBRT plans. The detailed dosimetric approaches are provided in the study.

Dosimetric impact of cylinder size in high-dose rate vaginal cuff brachytherapy (VCBT) for primary endometrial cancer.

The purpose of this study was to evaluate the dosimetric impact of cylinder size in high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT). Sample plans of HDR VCBT in a list of cylinders ranging from 2.5 to 4 cm in diameter at 0.5 cm incre-ment were created and analyzed. The doses were prescribed either at the 0.5cm depth with 5.5 Gy for 4 fractions or at the cylinder surface with 8.8 Gy for 4 frac-tions, in various treatment lengths. A 0.5 cm shell volume called PTV_Eval was contoured for each plan and served as the target volume for dosimetric evaluation. The cumulative and differential dose volume histograms (c-DVH and d-DVH), mean doses (D-mean) and the doses covering 90% (D90), 10% (D10), and 5% (D5) of PTV_Eval were calculated. In the 0.5 cm depth regimen, the DVH curves were found to have shifted toward the lower dose zone when a larger cylinder was used, but in the surface regimen the DVH curves shifted toward the higher dose zone as the cylinder size increased. The D-means of the both regimens were between 6.9 and 7.8 Gy and dependent on the cylinder size but independent of the treatment length. A 0.5 cm variation of diameter could result in a 4% change of D-mean. Average D90s were 5.7 (ranging from 5.6 to 5.8 Gy) and 6.1 Gy (from 5.7 to 6.4 Gy), respectively, for the 0.5 cm and surface regimens. Average D10 and D5 were 9.2 and 11 Gy, respectively, for the 0.5 cm depth regimen, and 8.9 and 9.7 Gy, respectively, for the surface regimen. D-mean, D90, D10, and D5 for other prescription doses could be calculated from the lookup tables of this study. Results indicated that the cylinder size has moderate dosimetric impact, and that both regimens are comparable in dosimetric quality.

Brachial plexus dose tolerance in head and neck cancer patients treated with sequential intensity modulated radiation therapy.

PURPOSE: We aimed to study the radiation induced brachial plexopathy in patients with head and neck squamous cell carcinoma (HNSCC) treated with Sequential Intensity Modulated Radiation Therapy (S-IMRT). METHODS AND MATERIALS: This IRB approved study included 68 patients with HNSCC treated consecutively. Detailed dose volume histogram data was generated for ipsilateral and contralateral brachial plexus (BP) volumes receiving a specified dose (Vds) i.e. V50-V75 and dose in Gray covering specified percent of BP volume (Dvs) i.e. D5-D30 and maximum point doses (Dmax). To assess BP injury all patients' charts were reviewed in detail for sign and symptoms of BP damage. Post-hoc comparisons were done using Tukey-Kramer method to account for multiple significance testing. RESULTS: The mean and maximum doses to BP were significantly different (p < .05) based on tumor site, nodal status and tumor stage. The mean volume to the ipsilateral BP for V50, V60, V70, and V75 were 7.01 cc, 4.37 cc, 1.47 cc and 0.24 cc, respectively. The mean dose delivered to ≤5% of ipsilateral BP was 68.70 Gy (median 69.5Gy). None of the patients had acute or late brachial plexopathy or any other significant neurological complications, with a minimum follow up of two years (mean 54 months). CONCLUSIONS: In this study cohort, at a minimum of two-years follow up, the mean dose of 68.7Gy, a median dose to 69.5Gy to ≤5% of ipsilateral BP, and a median Dmax of 72.96Gy did not result in BP injury when patients were treated with S-IMRT technique. However, longer follow up is needed.

Multisector dosimetry in the immediate post-implant period: significant under dosage of the prostate base.

PURPOSE: While there are several reports of prostate multisector dosimetry data obtained from CT or MRI scans performed at intervals ranging from 14-70 days after prostate brachytherapy (PB), there are no reports on multisector dosimetry performed in the immediate post-implant period. This study was undertaken to determine the results of prostate multisector dosimetry performed in the immediate post-implant period on day 1 post-implant dosimetry after (125)I PB. MATERIAL AND METHODS: The day 1 post-implant CT-based V100 and D90 were determined for the prostate base (PGB) and compared to doses to the entire gland (PG), mid-gland (PMG), and apex (PA) in 75 patients who underwent (125)I PB to a dose of 144 Gy. Similar multisector dosimetry was also performed on the pre-implant ultrasound volume study scans of these patients. RESULTS: All patients had good quality implants. On day 1 post-implant multisector dosimetry there was significant under dosage of the PGB for both V100 and D90. The average magnitude of under dosage of PGB compared to PMG and PA was 17.2% and 22.7% for V100 and 44.6 Gy and 31.7 Gy for D90, respectively. On pre-implant multisector dosimetry there was no statistically significant under dosage of the PGB for V100, but the PGB D90 was significantly lower compared to PMG and PA, however, the average magnitude of under dosage was small at 12.6 Gy and 4.2 Gy, respectively. CONCLUSIONS: This report demonstrates that similar to other reports on more delayed post-implant multisector dosimetry data, there is significant under dosage of the prostate base in the immediate post-implant period based on day 1 post-implant dosimetry. The clinical significance of this under dosage remains to be defined and further studies are warranted.

A comprehensive quality assurance program for personnel and procedures in radiation oncology: value of voluntary error reporting and checklists.

PURPOSE: This report describes the value of a voluntary error reporting system and the impact of a series of quality assurance (QA) measures including checklists and timeouts on reported error rates in patients receiving radiation therapy. METHODS AND MATERIALS: A voluntary error reporting system was instituted with the goal of recording errors, analyzing their clinical impact, and guiding the implementation of targeted QA measures. In response to errors committed in relation to treatment of the wrong patient, wrong treatment site, and wrong dose, a novel initiative involving the use of checklists and timeouts for all staff was implemented. The impact of these and other QA initiatives was analyzed. RESULTS: From 2001 to 2011, a total of 256 errors in 139 patients after 284,810 external radiation treatments (0.09% per treatment) were recorded in our voluntary error database. The incidence of errors related to patient/tumor site, treatment planning/data transfer, and patient setup/treatment delivery was 9%, 40.2%, and 50.8%, respectively. The compliance rate for the checklists and timeouts initiative was 97% (P<.001). These and other QA measures resulted in a significant reduction in many categories of errors. The introduction of checklists and timeouts has been successful in eliminating errors related to wrong patient, wrong site, and wrong dose. CONCLUSIONS: A comprehensive QA program that regularly monitors staff compliance together with a robust voluntary error reporting system can reduce or eliminate errors that could result in serious patient injury. We recommend the adoption of these relatively simple QA initiatives including the use of checklists and timeouts for all staff to improve the safety of patients undergoing radiation therapy in the modern era.

Cardiac-sparing whole lung IMRT in children with lung metastasis.

PURPOSE: To demonstrate the dosimetric advantages of cardiac-sparing (CS) intensity modulated radiation therapy (IMRT) in children undergoing whole lung irradiation (WLI). METHODS AND MATERIALS: Chest CT scans of 22 children who underwent simulation with 3-dimensional (n=10) or 4-dimensional (n=12) techniques were used for this study. Treatment planning was performed using standard anteroposterior-posteroanterior (S-RT) technique and CS-IMRT. Left and right flank fields were added to WLI fields to determine whether CS-IMRT offered any added protection to normal tissues at the junction between these fields. The radiation dose to the lung PTV, cardiac structures, liver, and thyroid were analyzed and compared. RESULTS: CS-IMRT had 4 significant advantages over S-RT: (1) superior cardiac protection (2) superior 4-dimensional lung planning target volume coverage, (3) superior dose uniformity in the lungs with fewer hot spots, and (4) significantly lower dose to the heart when flank RT is administered after WLI. CONCLUSIONS: The use of CS-IMRT and 4-dimensional treatment planning has the potential to improve tumor control rates and reduce cardiac toxicity in children receiving WLI.

Intra-operative pubic arch interference during prostate seed brachytherapy in patients with CT-based pubic arch interference of < or =1cm.

PURPOSE: There are only a few reports on the frequency of intra-operative pubic arch interference (I-PAI) during prostate seed brachytherapy (PB). MATERIALS AND METHODS: Two hundred and forty-three patients with a CT-based pubic arch interference (PAI) of < or =1 cm and a prostate volume of < or =50-60 cc underwent PB. Those patients requiring needle repositioning by > or =0.5 cm on the template were scored as having I-PAI. The incidence of I-PAI and its impact on biochemical control were analyzed. RESULTS: Intra-operative PAI was encountered in 47 (19.3%) patients. Forty two patients (17.3%) had I-PAI in 1-2 needles, two (0.8%) had I-PAI in four needles and three patients (1.2%) had I-PAI in six needles. Overall, 1.4% of needles required repositioning due to I-PAI. BMI>27 kg/m(2) and wider (>75 mm) pubic bone separation at mid ramus (PS-ML) were associated with a lower incidence of I-PAI. At a median follow-up of 50.1 months, the 3- and 5-year bPFS was 97.3% and 95.2%, respectively. The 5-year bPFS rates for patients with and without I-PAI were 95.6% and 95%, respectively (p=0.28). CONCLUSIONS: The use of CT-based PAI of < or =1cm as a selection criterion for PB is a simple and reliable method for minimizing the incidence of I-PAI and maintaining excellent biochemical control rates.

Phase I study of intraoperative radiotherapy with photon radiosurgery system in children with recurrent brain tumors: preliminary report of first dose level (10 Gy).

PURPOSE: To describe the preliminary results after intraoperative radiotherapy (IORT) with the photon radiosurgery system in children with recurrent brain tumors treated at the first dose level (10 Gy) of a Phase I protocol. METHODS AND MATERIALS: A Phase I IORT dose escalation protocol was initiated at Children's Memorial Hospital to determine the maximal tolerated IORT dose in children with recurrent brain tumors. RESULTS: Fourteen children have received IORT thus far. Eight had been previously irradiated. Thirteen children had ependymoma. The median follow-up was 16 months. Three patients (21%) developed radiation necrosis on follow-up MRI scans 6 to 12 months after IORT. They had not been previously irradiated and had received 10 Gy to a depth of 5 mm. One required surgery and the other two had resolution of their lesions without treatment. All 3 patients were asymptomatic at the last follow-up. No other late toxicity was observed at the last follow-up visit. Eight patients (57%) had tumor control within the surgical bed after IORT. CONCLUSION: Our findings have demonstrated the safety and feasibility of IORT to a dose of 10 Gy to 2 mm in children with previously irradiated brain tumors. IORT to a dose of 10 Gy at 5 mm was associated with a greater complication rate.

Acute neurological complications following gamma knife surgery for vestibular schwannoma. Case report.

The authors describe an acute facial and acoustic neuropathy following gamma knife surgery (GKS) for vestibular schwannoma (VS). This 39-year-old woman presenting with tinnitus underwent GKS for a small right-sided intracanalicular VS, receiving a maximal dose of 26 Gy and a tumor margin dose of 13 Gy to the 50% isodose line. Thirty-six hours following treatment she presented with nausea, vomiting, vertigo, diminished hearing, and a House-Brackmann Grade III facial palsy. She was started on intravenous glucocorticosteroid agents, and over the course of 2 weeks her facial function returned to House-Brackmann Grade I. Unfortunately, her hearing loss persisted. A magnetic resonance (MR) image obtained at the time of initial deterioration demonstrated a significant decrease in tumor enhancement but no change in tumor size or peritumoral edema. Subsequently, the patient experienced severe hemifacial spasms, which persisted for a period of 3 weeks and then progressed to a House-Brackmann Grade V facial palsy. During the next 3 months, the patient was treated with steroids and in time her facial function and hearing returned to baseline levels. Results of MR imaging revealed transient enlargement (3 mm) of the tumor, which subsequently returned to its baseline size. This change corresponded to the tumor volume increase from 270 to 336 mm3. The patient remains radiologically and neurologically stable at 10 months posttreatment. This is the first detailed report of acute facial and vestibulocochlear neurotoxicity following GKS for VS that improved with time. In addition, MR imaging findings were indicative of early neurotoxic changes. A review of possible risk factors and explanations of causative mechanisms is provided.

Efficacy of irradiation and external hyperthermia in locally advanced, hormone-refractory or radiation recurrent prostate cancer: a preliminary report.

PURPOSE: To present a preliminary report on the feasibility, efficacy, and toxicity of irradiation (RT) and hyperthermia (HT) in patients with locally advanced, hormone-refractory prostate cancer (LAHRPC) who may or may not have received prior RT. METHODS AND MATERIALS: Between 1997 and 2002, 13 consecutive patients with LAHRPC or RT-recurrent prostate cancer were treated with RT and HT on a Phase I-II protocol. Eight patients had RT-recurrent LAHRPC (Group A) and 5 had LAHRPC without prior RT (Group B). All patients had large and clinically symptomatic tumors. The median RT dose was 39.6 Gy and 66.6 Gy in Groups A and B, respectively. External deep HT was delivered using a BSD-2000 Sigma-60 applicator. The median number of HT treatments was 8 in group A and 10 in group B. RESULTS: The median follow-up was 14 and 13 months for Groups A and B, respectively. All patients achieved a complete or partial response (CR/PR) and complete palliation of symptoms. Eleven patients had follow-up CT scans that demonstrated a CR in six and a PR in five. Two patients, who died of metastasis, did not have CT scans and had a PR on digital rectal examination. Two patients demonstrated a biochemical CR. The median duration of the CR/PR among Group A patients was 12 months after therapy. Three patients in Group A developed tumor recurrence at 9, 17, and 27 months after repeat RT to doses of 39.6, 36, and 50 Gy, respectively. At last follow-up, no Group B patient developed local recurrence. Grade 1-2 rectal bleeding was noted in 3 patients. RT and HT were generally well tolerated by all patients who had not previously undergone RT. Of the 8 patients who had, 6 (75%) tolerated retreatment well with minimal or no complications. Two patients in the repeat RT group had severe complications. One patient with lymphoma and factor XI deficiency developed Grade 4 hemorrhagic cystitis. Another previously irradiated patient developed a rectovesical fistula 4 months after retreatment, after disappearance of a large, invasive, and necrotic tumor. CONCLUSION: This preliminary report demonstrates the feasibility and efficacy of RT and HT in patients with LAHRPC, who may or may not have received prior RT. Presently, such patients who have undergone previous RT have no effective treatment options. RT and HT were generally well tolerated by patients who were not previously undergone RT. Of those who had been, most (6 of 8) tolerated retreatment well with minimal or no complications. The high-risk factors for treatment- and tumor regression-related side effects include the presence of large necrotic tumors, previous RT with a large dose/fraction, and the presence of bleeding disorders. Despite the size of these large tumors, RT and HT resulted in significant tumor shrinkage, rapid serum prostate-specific antigen decline, durable treatment responses, and durable palliation of symptoms. Additional clinical studies are warranted.