Expression of the SARS-CoV-2 receptor-binding domain by live attenuated influenza vaccine virus as a strategy for designing a bivalent vaccine against COVID-19 and influenza.

Influenza and SARS-CoV-2 are two major respiratory pathogens that cocirculate in humans and cause serious illness with the potential to exacerbate disease in the event of co-infection. To develop a bivalent vaccine, capable of protecting against both infections, we inserted the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein into hemagglutinin (HA) molecule or into the open reading frame of the truncated nonstructural protein 1 (NS1) of live attenuated influenza vaccine (LAIV) virus and assessed phenotypic characteristics of the rescued LAIV-RBD viruses, as well as their immunogenicity in mouse and Syrian hamster animal models. A panel of 9 recombinant LAIV-RBD viruses was rescued using the A/Leningrad/17 backbone. Notably, only two variants with RBD insertions into the HA molecule could express sufficient quantities of RBD protein in infected MDCK cells. Intranasal immunization of mice induced high levels of anti-influenza antibody responses in all chimeric LAIV-RBD viruses, which was comparable to the LAIV virus vector. The RBD-specific antibody responses were most pronounced in the variant expressing RBD194 fragment as a chimeric HA protein. This candidate was further tested in Syrian hamsters and was shown to be immunogenic and capable of protecting animals against both infections.

Development and validation of a 3D-printed bolus cap for total scalp irradiation.

PURPOSE: The goal of total scalp irradiation (TSI) is to deliver a uniform dose to the scalp, which requires the use of a bolus cap. Most current methods for fabricating bolus caps are laborious, yet still result in nonconformity and low reproducibility, which can lead to nonuniform irradiation of the scalp. We developed and validated patient-specific bolus caps for TSI using three-dimensional (3D) printing. METHODS AND MATERIALS: 3D-printing materials were radiologically analyzed to identify a material with properties suitable for use as a bolus cap. A Python script was developed within a commercial treatment planning system to automate the creation of a ready-to-print, patient-specific 3D bolus cap model. A bolus cap was printed for an anthropomorphic head phantom using a commercial vendor and a computed tomography simulation of the anthropomorphic head phantom and bolus cap was used to create a volumetric-modulated arc therapy TSI treatment plan. The planned treatment was delivered to the head phantom and dosimetric validation was performed using thermoluminescent dosimeters (TLD). The developed procedure was used to create a bolus cap for a clinical TSI patient, and in vivo TLD measurements were acquired for several fractions. RESULTS: Agilus-60 was validated as a new 3D-printing material suitable for use as bolus. A 3D-printed Agilus-60 bolus cap had excellent conformality to the phantom scalp, with a maximum air gap of 4 mm. TLD measurements showed that the bolus cap generated a uniform dose to the scalp within a 2.7% standard deviation, and the delivered doses agreed with calculated doses to within 2.4% on average. The patient bolus was conformal and the average difference between TLD measured and planned doses was 5.3%. CONCLUSIONS: We have developed a workflow to 3D-print highly conformal bolus caps for TSI and demonstrated these caps can reproducibly generate a uniform dose to the scalp.

Improved setup and positioning accuracy using a three-point customized cushion/mask/bite-block immobilization system for stereotactic reirradiation of head and neck cancer.

The purpose of this study was to investigate the setup and positioning uncertainty of a custom cushion/mask/bite-block (CMB) immobilization system and determine PTV margin for image-guided head and neck stereotactic ablative radiotherapy (HN-SABR). We analyzed 105 treatment sessions among 21 patients treated with HN-SABR for recurrent head and neck cancers using a custom CMB immobilization system. Initial patient setup was performed using the ExacTrac infrared (IR) tracking system and initial setup errors were based on comparison of ExacTrac IR tracking system to corrected online ExacTrac X-rays images registered to treatment plans. Residual setup errors were determined using repeat verification X-ray. The online ExacTrac corrections were compared to cone-beam CT (CBCT) before treatment to assess agreement. Intrafractional positioning errors were determined using prebeam X-rays. The systematic and random errors were analyzed. The initial translational setup errors were -0.8 ± 1.3 mm, -0.8 ± 1.6 mm, and 0.3 ± 1.9 mm in AP, CC, and LR directions, respectively, with a three-dimensional (3D) vector of 2.7 ± 1.4 mm. The initial rotational errors were up to 2.4° if 6D couch is not available. CBCT agreed with ExacTrac X-ray images to within 2 mm and 2.5°. The intrafractional uncertainties were 0.1 ± 0.6 mm, 0.1 ± 0.6 mm, and 0.2 ± 0.5 mm in AP, CC, and LR directions, respectively, and 0.0° ± 0.5°, 0.0° ± 0.6°, and -0.1° ± 0.4° in yaw, roll, and pitch direction, respectively. The translational vector was 0.9 ± 0.6 mm. The calculated PTV margins mPTV(90,95) were within 1.6 mm when using image guidance for online setup correction. The use of image guidance for online setup correction, in combination with our customized CMB device, highly restricted target motion during treatments and provided robust immobilization to ensure minimum dose of 95% to target volume with 2.0 mm PTV margin for HN-SABR.

Effect of interfractional shoulder motion on low neck nodal targets for patients treated using volumetric-modulated arc therapy (VMAT).

VMAT is an important tool in the treatment of head and neck cancers, many of which also require treatment to the supraclavicular lymph nodes. However, full VMAT arcs treating this nodal region necessarily cause entrance beam to pass through patients' shoulders. Thus, interfractional variations in shoulder position may cause unwanted dose perturbations. To assess this possibility, six patients undergoing treatment at our institution for head and neck cancers with associated supraclavicular lymph node treatment were imaged with in-room CT-on-rails during the course of their treatments. This allowed for the establishment of a true record of the actual shoulder position during selected treatment fractions. Then, a full VMAT plan and a plan with VMAT arcs superior to the shoulder and a static anteroposterior field inferiorly were copied onto the patients' weekly image sets. The average one-dimensional shoulder motion was generally within 10 mm of the simulated position, with some notable exceptions. The standard deviation in week-to-week shoulder position relative to simulation was 4.3 mm and 4.2 mm in the SI and AP dimensions, respectively. The average nodal target mean dose across all fractions sampled was within 5% of planned for all patients and both plans. Similarly, the average D95 for the nodal target was within 5% of planned across all fractions sampled, with the single exception of the full VMAT plan for one patient. In most cases, the standard deviation in both target mean dose and D95 was smaller with the VMAT+static AP field plan than it was with the full VMAT plan.

Development of Cross-Reactive Live Attenuated Influenza Vaccine Candidates against Both Lineages of Influenza B Virus.

BACKGROUND: Influenza viruses continue to cause a significant social and economic burden globally. Vaccination is recognized as the most effective measure to control influenza. Live attenuated influenza vaccines (LAIVs) are an effective means of preventing influenza, especially among children. A reverse genetics (RG) system is required to rapidly update the antigenic composition of vaccines, as well as to design LAIVs with a broader spectrum of protection. Such a system has been developed for the Russian LAIVs only for type A strains, but not for influenza B viruses (IBV). METHODS: All genes of the B/USSR/60/69 master donor virus (B60) were cloned into RG plasmids, and the engineered B60, as well as a panel of IBV LAIV reassortants were rescued from plasmid DNAs encoding all viral genes. The engineered viruses were evaluated in vitro and in a mouse model. RESULTS: The B60 RG system was successfully developed, which made it possible to rescue LAIV reassortants with the desired antigenic composition, including hybrid strains with hemagglutinin and neuraminidase genes belonging to the viruses from different IBV lineages. The LAIV candidate carrying the HA of the B/Victoria-lineage virus and NA from the B/Yamagata-lineage virus demonstrated optimal characteristics in terms of safety, immunogenicity and cross-protection, prompting its further assessment as a broadly protective component of trivalent LAIV. CONCLUSIONS: The new RG system for B60 MDV allowed the rapid generation of type B LAIV reassortants with desired genome compositions. The generation of hybrid LAIV reassortants with HA and NA genes belonging to the opposite IBV lineages is a promising approach for the development of IBV vaccines with broad cross-protection.

Influenza vaccine: progress in a vaccine that elicits a broad immune response.

INTRODUCTION: The licensed seasonal influenza vaccines predominantly induce neutralizing antibodies against immunodominant hypervariable epitopes of viral surface proteins, with limited protection against antigenically distant influenza viruses. Strategies have been developed to improve vaccines' performance in terms of broadly reactive and long-lasting immune response induction. AREAS COVERED: We have summarized the advancements in the development of cross-protective influenza vaccines and discussed the challenges in evaluating them in preclinical and clinical trials. Here, the literature regarding the current stage of development of universal influenza vaccine candidates was reviewed. EXPERT OPINION: Although various strategies aim to redirect adaptive immune responses from variable immunodominant to immunosubdominant antigens, more conserved epitopes are being investigated. Approaches that improve antibody responses to conserved B cell epitopes have increased the protective efficacy of vaccines within a subtype or phylogenetic group of influenza viruses. Vaccines that elicit significant levels of T cells recognizing highly conserved viral epitopes possess a high cross-protective potential and may cover most circulating influenza viruses. However, the development of T cell-based universal influenza vaccines is challenging owing to the diversity of MHCs in the population, unpredictable degree of immunodominance, lack of adequate animal models, and difficulty in establishing T cell immunity in humans. ABBREVIATIONS: cHA: chimeric HA; HBc: hepatitis B virus core protein; HA: hemagglutinin; HLA: human leucocyte antigen; IIV: inactivated influenza vaccine; KLH: keyhole limpet hemocyanin; LAH: long alpha helix; LAIV: live attenuated influenza vaccine; M2e: extracellular domain of matrix 2 protein; MHC: major histocompatibility complex; mRNA: messenger ribonucleic acid; NA: neuraminidase; NS1: non-structural protein 1; qNIV: quadrivalent nanoparticle influenza vaccine; TRM: tissue-resident memory T cells; VE: vaccine effectiveness; VLP: virus-like particles; VSV: vesicular stomatitis virus.

Safety, Immunogenicity, and Protective Efficacy of a Chimeric A/B Live Attenuated Influenza Vaccine in a Mouse Model.

Influenza A and B viruses cause significant morbidity and mortality worldwide. Current influenza vaccines are composed of three or four strains: A/H1N1, A/H3N2, and B (Victoria and Yamagata lineages). It is of great interest if immunization against both type A and B influenza viruses can be combined in a single vaccine strain, thus reducing the cost of vaccine production and the possibility of strain interference within the multicomponent vaccine. In the current study, we developed an experimental live cold-adapted influenza intertype reassortant (influenza A and B) vaccine on the live attenuated influenza vaccine (LAIV) A/Leningrad/134/17/57 backbone. Hemagglutinin (HA) and neuraminidase (NA) functional domains were inherited from the influenza B/Brisbane/60/2008 strain, whereas their packaging signals were substituted with appropriate fragments of influenza A virus genes. The recombinant A/B virus efficiently replicated in eggs and Madin-Darby Canine Kidney (MDCK) cells under optimal conditions, temperature-sensitive phenotype was maintained, and its antigenic properties matched the influenza B parental virus. The chimeric vaccine was attenuated in mice: after intranasal immunization, viral replication was seen only in nasal turbinates but not in the lungs. Immunological studies demonstrated the induction of IgG antibody responses against the influenza A and B virus, whereas hemagglutination inhibition (HAI) and neutralizing antibodies were detected only against the influenza B virus, resulting in significant protection of immunized animals against influenza B virus challenge. IFNγ-secreting CD8 effector memory T cells (CD44+CD62L-) were detected in mouse splenocytes after stimulation with the specific influenza A peptide (NP366); however, the T-cell response was not sufficient to protect animals against infection with a high-dose mouse-adapted A/California/07/2009 (H1N1pdm09) virus, most probably due to the mismatch of key T-cell epitopes of the H1N1 virus and the LAIV backbone. Overall, generation of the chimeric A/B LAIV virus on a licensed LAIV backbone demonstrated prospects for the development of safe and efficacious vaccine candidates that afford combined protection against both type A and type B influenza viruses; however, further optimization of the T-cell epitope content within the LAIV backbone may be required.

The attachment of a DNA-binding Sso7d-like protein improves processivity and resistance to inhibitors of M-MuLV reverse transcriptase.

Reverse transcriptases (RTs) are a standard tool in both fundamental studies and diagnostics. RTs should possess elevated temperature optimum, high thermal stability, processivity and tolerance to contaminants. Here, we constructed a set of chimeric RTs, based on the combination of the Moloney murine leukaemia virus (M-MuLV) RT and either of two DNA-binding domains: the DNA-binding domain of the DNA ligase from Pyrococcus abyssi or the DNA-binding Sto7d protein from Sulfolobus tokodaii. The processivity and efficiency of cDNA synthesis of the chimeric RT with Sto7d at the C-end are increased several fold. The attachment of Sto7d enhances the tolerance of M-MuLV RT to the most common amplification inhibitors: NaCl, urea, guanidinium chloride, formamide, components of human whole blood and human blood plasma. Thus, fusing M-MuLV RT with an additional domain results in more robust and efficient RTs.

Daily computed tomography image guidance: Dosimetric advantages outweigh low-dose radiation exposure for treatment of mediastinal lymphoma.

CT-guided treatment delivery can improve target localization in mediastinal lymphoma patients treated with "butterfly" intensity-modulated radiotherapy and deep-inspiration breath hold. Although daily CT imaging adds additional radiation exposure, its use may be justified given the greater normal tissue sparing enabled by PTV margin reduction.

Decreased heart dose with deep inspiration breath hold for the treatment of gastric lymphoma with IMRT.

We hypothesized that deep inspiration breath-hold (DIBH) and computed-tomography image-guided radiotherapy (CT-IGRT) may be beneficial to decrease dose to organs at risk (OARs), when treating the stomach with radiotherapy for lymphoma. We compared dosimetric parameters of OARs from plans generated using free-breathing (FB) versus DIBH for 10 patients with non-Hodgkin lymphoma involving the stomach treated with involved site radiotherapy. All patients had 4DCT and DIBH scans. Planning was performed with intensity modulated radiotherapy (IMRT) to 30.6 Gy in 17 fractions. Differences in target volume and dosimetric parameters were assessed using a paired two-sided t-test. All heart and left ventricle parameters including mean dose, V30, V20, V10, and V5 were statistically significantly lower with DIBH. For IMRT-FB plans the average mean heart dose was 4.9 Gy compared to 2.6 Gy for the IMRT-DIBH group (p < 0.001). There was a statistically significant decrease in right kidney dose with DIBH. For lymphoma patients treated to the stomach with IMRT, DIBH provides superior OAR sparing compared to FB-based planning, most notably reducing dose to the heart and left ventricle. This strategy could be considered when treating other gastric malignancies.

Predictors of Radiation-Induced Liver Disease in Eastern and Western Patients With Hepatocellular Carcinoma Undergoing Proton Beam Therapy.

PURPOSE: To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS: This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving <1 GyE; the standard liver volume (SLV) was calculated using body surface area. Possible correlations of clinicodosimetric parameters with RILD were examined. RESULTS: The mean pretreatment LV was 85% of SLV, and patients with a history of hepatectomy (P < .001) or hepatitis B virus infection (P = .035) had significantly smaller LV/SLV. Nineteen (14%) patients developed RILD. Multivariate logistic regression analysis identified ULV/SLV (P = .001), gross tumor volume (P = .001), and Child-Pugh classification (P = .002) as independent RILD predictors, and mean liver dose and target-delivered dose were not associated with RILD occurrence. A "volume-response" relationship between ULV/SLV and RILD was consistently observed in both eastern and western cohorts. In Child-Pugh class-A patients whose ULV/SLV were ≥50%, 49.9%-40%, 39.9%-30% and <30%, the RILD incidences were 0%, 6%, 16%, and 39% (P < .001), respectively. For the Child-Pugh class-B group, the RILD incidences in patients with ≥60%, 59.9%-40%, and <40% of ULV/SLV were 0%, 14%, and 83% (P = .006), respectively. CONCLUSIONS: The ULV/SLV, not mean liver dose, independently predicts RILD in patients with HCC undergoing PBT. The relative and absolute contraindications for Child-Pugh class-A patient's ULV/SLV are <50% and <30%, and <60% and <40% for Child-Pugh class-B patients, respectively. Our results indicate that the likelihood of hepatic complications for PBT is dictated by similar metrics as that for surgery.

Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma.

BACKGROUND: The purpose of this study was to assess the ability of intensity-modulated radiation therapy (IMRT) to achieve favorable disease-control rates while minimizing parotid gland doses in patients treated for small primary tumors of the oropharynx. METHODS AND MATERIALS: We retrospectively identified all patients who received IMRT as treatment for a small (<4 cm) primary tumor of the oropharynx between October 2000 and June 2002. Tumor characteristics, IMRT parameters, and patient outcomes were assessed. RESULTS: Fifty-one patients met the criteria for our study. All patients had treatment to gross disease with margin (CTV1), and all but 1 had treatment to the bilateral necks. The most common treatment schedule (39 patients) was a once-daily fractionation of prescribed doses of 63-66 Gy to the CTV1 and 54 Gy to subclinical sites, delivered in 30 fractions. Twenty-one patients (40%) had gastrostomy tubes placed during therapy; in 4 patients, the tube remained in place for more than 6 months after completion of IMRT. The median follow-up was 45 months. The 2-year actuarial locoregional control, recurrence-free, and overall survival rates were 94%, 88%, and 94%, respectively. CONCLUSIONS: These preliminary data suggest that treatment with IMRT results in favorable locoregional control of small primary oropharynx tumors. IMRT did not appear to have a more favorable acute toxicity profile in this group with respect to the use of a feeding tube; however, the mean dose of radiation delivered to the parotid gland by IMRT was decreased, because 95% of patients had a mean dose of <30 Gy to at least one gland.

Two-field versus three-field irradiation technique in the postoperative treatment of head-and-neck cancer.

PURPOSE: We have increasingly used a two-field noncoplanar "caudal tilt" technique (CTT) for irradiating postlaryngectomy and pharyngectomy patients to avoid matchline problems that can be encountered with the classic three-field head-and-neck radiation technique (3FT). This report compares the clinical outcomes of patients treated with postoperative radiation (PORT) using either 3FT or CTT. METHODS AND MATERIALS: We conducted a retrospective review of the medical records of all patients with laryngeal or hypopharyngeal cancers consecutively treated with PORT between 1997 and 2002. Three-dimensional dosimetric planning was carried out for all patients. RESULTS: Of 91 patients, 39 were treated with 3FT and 52 with CTT. The median follow-up was 34 months. Estimated rates of 2-year locoregional control, disease-free survival, and overall survival for patients treated with 3FT and CTT were, respectively, 92% and 85% (p=0.241), 62% and 55% (p=0.497), and 77% and 72% (p=0.616). There were no significant differences in the incidence of acute or late side effects in the two groups. CONCLUSIONS: "Caudal tilt" technique is often used as an alternative to 3FT for postoperative radiotherapy in cases of greater medical and technical complexity. Despite its use in more challenging cases, CTT provides similar long-term clinical outcomes compared with standard 3FT, when computerized three-dimensional dosimetry is used to assure adequate dosimetry throughout the treated volume.

Treatment planning system evaluation for mesothelioma IMRT.

BACKGROUND AND PURPOSE: Malignant pleural mesothelioma (MPM) has been treated with extrapleural pneumonectomy (EPP) followed by IMRT. IMRT improved radiation dose distributions to the complex operative bed, and preliminary results suggested improved local control compared with conventional treatment planning. IMRT was initially developed on the Corvus treatment planning system. Other treatment planning systems are also IMRT-capable. Treatment plans from several systems were compared to determine the feasibility of using IMRT in a multi-institution trial. PATIENTS AND METHODS: Treatment plans were generated on Corvus, Eclipse, and Pinnacle for a right-sided MPM after EPP using 6 MV X-rays. Tissue heterogeneity corrections were used in dose calculation. Plans were optimized such that the clinical target volume received 50 Gy in 25 fractions. Dose distributions to the target and normal structures were evaluated. The treatment time and delivery efficiency were estimated. RESULTS: Treatment plans could be calculated by all three planning systems without system failure. Larger volumes received 60Gy in Corvus plans (40%, 17% and 8% for Corvus, Pinnacle and Eclipse, respectively). Corvus used the most monitor units (2786 versus 1451 and 1813 for Pinnacle and Eclipse), and treated the most segments (1050 versus 267 and 173 for Pinnacle and Eclipse). Doses to spinal cord, lung, heart, liver, and contralateral kidney were acceptable for all planning systems. CONCLUSIONS: IMRT plans can be calculated for MPM targets by at least three commonly available treatment planning systems. Pinnacle- and Eclipse-based plans seem more efficient, and may be delivered in a shorter time than Corvus-based plans.

Results of radiotherapy for T2N0 glottic carcinoma: does the "2" stand for twice-daily treatment?

PURPOSE: Radiotherapy (RT) is often the therapy of choice for patients with Stage T2 glottic carcinoma. This retrospective study updated the results of RT for patients treated at our center. The primary focus of this study was whether a policy of using hyperfractionated RT for these patients resulted in a therapeutic gain. METHODS AND MATERIALS: A search of the database of patients treated in the Department of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center was performed to identify patients with Stage T2 glottic carcinoma treated with RT alone between 1970 and 1998. A total of 230 patients formed the study cohort. RESULTS: The median follow-up for all patients was 82 months. Of the 230 patients, 180 were treated with parallel-opposed fields, and the median field size was 30 cm(2). Eighty-one patients (36%) were treated with twice-daily fractionation to 74-80 Gy. Eighty-nine patients (38%) were treated with 32-75 Gy at 2-Gy per fraction once daily, and 57 patients (25%) were treated with 2.06-2.26 Gy, once daily, to 66-70 Gy. The 2- and 5-year actuarial local control rate was 75% and 72%, respectively. After salvage therapy, the ultimate 5-year local control and disease-specific survival rate was 91% and 92%, respectively. The presence of subglottic extension and treatment with a daily dose of < or =2 Gy were associated with poorer local control (p <0.01) on both univariate and multivariate analyses. The 5-year local control rate for patients treated with twice-daily and once-daily RT was 79% and 67%, respectively (p = 0.06). CONCLUSION: The 5-year local control rates with hyperfractionated RT for Stage T2 glottic carcinoma approach 80%. Patients treated with twice-daily fractionation to a median dose of 77 Gy had an improvement in local control compared with patients treated with 70 Gy in 35 fractions. The Radiation Therapy Oncology Group is testing these two fractionation schedules in a randomized study. High control rates were also seen in selected patients treated with hypofractionated schedules, leaving the question of the optimal schedule for patients with Stage T2 disease unanswered.

The effect of titanium stabilization rods on spinal cord radiation dose.

The purpose of this study was to investigate the dosimetric effect of a titanium-rod spinal stabilization system on surrounding tissue, especially the spinal cord. Ion chamber dosimetry was performed for 6- and 18-MV photon beams in a water phantom containing a titanium-rod spinal stabilization system. Isodose curves were obtained in the phantom with and without rods. To assess the ability of a treatment planning system to reproduce the effects of the stabilization system on the radiation dose delivered to surrounding tissue, dose distributions were calculated after appropriate modifications were made in the computed tomography number-to-density conversion table to account for the increased density of the titanium rods. The resultant heterogeneity-corrected plans were compared with uncorrected plans. At a 7-cm depth in the water phantom, corresponding to the depth of the spinal cord, the beam was attenuated by 4% under the rods alone and by 13% rods under the rods with screws for the 6-MV photon beam as compared with curves generated in the absence of rods. The beam was attenuated by 3% and 11%, respectively, for the 18-MV beam. Using anteroposterior (18-MV) and posteroanterior (6-MV) photon beams, with and without heterogeneity correction for the rods, the corrected isodose plan showed an approximately 2% beam attenuation 4 cm anterior to the rods as compared with the uncorrected plan. No significant difference in the spinal cord dose was observed between the 2 plans, however. The titanium-rod spinal stabilization system tested in this study caused a decrease in the dose delivered distal to the rods but did not significantly affect the dose delivered to the spinal cord.

Dosage along the matchline between upper head-and-neck IMRT fields and conventional supraclavicular fields.

There is concern about dose along the matchline when upper head-and-neck fields are treated with IMRT and the lower (supraclavicular) field is treated with a conventional fixed beam. An anatomical phantom was scanned and planned with IMRT upper head-and-neck fields and a fixed-beam supraclavicular field. The plans were fused and dose was calculated to points along the matchline. These doses were compared with thermolaminescent dosimetry measurements in the phantom, as the phantom was treated according to the plans.

New equations for matching a low neck field to oblique upper neck fields with collimator rotation in a 3-field monoisocentric setup for head-and-neck cancers.

With a monoisocentric 3-field technique for treating head-and-neck cancer, collimator rotation may be needed for the upper lateral fields to avoid cephalad-positioned shoulders or to avoid unnecessary arytenoid irradiation while maintaining more anterior coverage. For patients with unilateral lymphadenopathy, lateral oblique-opposed boost fields can be used to encompass the primary tumor and ipsilateral lymph nodes without junctioning through gross disease. When initial collimated lateral fields are also rotated with a gantry angle to produce oblique boost fields, however, the resulting matchline with a low anterior neck (LAN) boost field is no longer nondivergent. This can be corrected by manual adjustment of collimator and gantry angles for the LAN field using 3D treatment planning software. The goal of this study was to derive mathematical formulas to simplify this process. We used a transformation matrix to define formulas that could predict the appropriate modifications to the LAN boost field. Output from the formulas was (1) visually tested within 3D treatment planning software and (2) verified using a solid water head-and-neck phantom and radiographic film dosimetry to confirm that a nondivergent matchline was obtained in several clinical scenarios. When evaluated with 3D treatment planning software, the formulas accurately predicted the appropriate gantry and collimator angles of the LAN boost field for a variety of possible beam combinations. When evaluated with film dosimetry, the formulas were shown to accurately predict the appropriate gantry and collimator angles of the LAN boost field to within the +/- 2 mm/1 degrees tolerance specifications of the linear accelerator and acceptable for routine clinical use. The presented formulas are simple and geometrically precise. They predict the necessary manipulations of the LAN boost field to maintain a geometrically precise matchline, as verified by 3D treatment planning software, phantom dosimetry, and actual patient setups.

Verification techniques and dose distribution for computed tomographic planned supine craniospinal radiation therapy.

A modified 3-field technique was designed with opposed cranial fields and a single spinal field encompassing the entire spinal axis. Two methods of plan verifications were performed before the first treatment. First, a system of orthogonal rulers plus the thermoplastic head holder was used to visualize the light fields at the craniospinal junction. Second, film phantom measurements were taken to visualize the gap between the fields at the level of the spinal cord. Treatment verification entailed use of a posterior-anterior (PA) portal film and placement of radiopaque wire on the inferior border of the cranial field. More rigorous verification required a custom-fabricated orthogonal film holder. The isocenter positions of both fields when they matched were recorded using a record-and-verify system. A single extended distance spinal field collimated at 42 degrees encompassed the entire spinal neuraxis. Data were collected from 40 fractions of craniospinal irradiation (CSI). The systematic error observed for the actual daily treatments was -0.5 mm (underlap), while the stochastic error was represented by a standard deviation of 5.39 mm. Measured data across the gapped craniospinal junction with junction shifts included revealed a dose ranging from 89.3% to 108%. CSI can be performed without direct visualization of the craniospinal junction by using the verification methods described. While the use of rigorous film verification for supine technique may have reduced the systematic error, the inability to visualize the supine craniospinal junction on skin appears to have increased the stochastic error compared to published data on such errors associated with prone craniospinal irradiation.

Adaptive radiotherapy for head and neck cancer--dosimetric results from a prospective clinical trial.

PURPOSE: To conduct a clinical trial evaluating adaptive head and neck radiotherapy (ART). METHODS: Patients with locally advanced oropharyngeal cancer were prospectively enrolled. Daily CT-guided setup and deformable image registration permitted mapping of dose to avoidance structures and CTVs. We compared four planning scenarios: (1) original IMRT plan aligned daily to marked isocenter (BB); (2) original plan aligned daily to bone (IGRT); (3) IGRT with one adaptive replan (ART1); and (4) actual treatment received by each study patient (IGRT with one or two adaptive replans, ART2). RESULTS: All 22 study patients underwent one replan (ART1); eight patients had two replans (ART2). ART1 reduced mean dose to contralateral parotid by 0.6 Gy or 2.8% (paired t-test; p=0.003) and ipsilateral parotid by 1.3 Gy (3.9%) (p=0.002) over the IGRT alone. ART2 further reduced the mean contralateral parotid dose by 0.8 Gy or 3.8% (p=0.026) and ipsilateral parotid by 4.1 Gy or 9% (p=0.001). ART significantly reduced integral body dose. CONCLUSIONS: This pilot trial suggests that head and neck ART dosimetrically outperforms IMRT. IGRT that leverages conventional PTV margins does not improve dosimetry. One properly timed replan delivers the majority of achievable dosimetric improvement. The clinical impact of ART must be confirmed by future trials.