To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP).
Methods and Materials
Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms.
The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RTwith undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups.
The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer.
To test the hypothesis that small molecule targeting of nucleophosmin (NPM1) represents a rational approach for radiosensitization.
Methods and Materials
Wild type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine if radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived NSCLC tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts.
Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci (IRIF) that co-localize with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is over expressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts.
These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.
The dosimetric impact of dose-probability based PTV margins for liver cancer patients receiving SBRT was compared to standard PTV based on the internal target volume (ITV). Plan robustness was evaluated by accumulating the treatment dose to ensure delivery of the intended plan.
Methods and Materials
Twenty patients planned on exhale CT for 27–50 Gy in 6 fractions using an ITV-based PTV and treated free-breathing were retrospectively evaluated. Iso-toxic, dose-escalated plans were created on mid-position CT, representing the mean breathing position, using a dose-probability PTV. The delivered doses were accumulated using biomechanical deformable registration of the daily cone-beam CT based on liver targeting at the exhale or mean breathing position, for the exhale and mid-position CT plans respectively.
The dose-probability PTVs were on average 38% smaller than the ITV-based PTV enabling an average±standard deviation increase in the planned dose to 95% of the PTV of 4.0±2.8 Gy (9±5%) on the mid-position CT (p<0.01). For both plans, the delivered minimum GTV doses were greater than the planned nominal prescribed dose in all 20 patients and greater than the planned dose to 95% of the PTV in 18 (90%) patients. Nine patients (45%) had one or more GTVs with a delivered minimum dose more than 5 Gy higher with the mid-position CT plan using dose-probability PTV, compared to the delivered dose with the exhale CT plan using ITV-based PTV.
For iso-toxic liver SBRT planned and delivered at the mean respiratory, reduced dose-probability PTV enables a mean escalation of 4 Gy (9%) in 6 fractions over ITV-based PTV. This may potentially improve local control without increasing the risk of tumor under-dosing.
To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity-modulated proton therapy (IMPT).
Methods and Materials
A multi-criteria optimization (MCO) module was utilized to generate series of Pareto-optimal IMPT base plans (BPs), corresponding to defined objectives, for 5 headand- neck and 2 pancreatic cancer cases. A Monte Carlo platform was used to calculate dose and LET distributions for each BP. A custom-designed MCO navigation module allowed the user to interpolate between BPs to produce deliverable Pareto-optimal solutions. Differences among the BPs, were evaluated for each patient, based on dose- and LET-volume histograms and 3D distributions. An LET-based RBE (relative biological effectiveness) model was employed to evaluate the potential clinical benefit when navigating the space of Pareto-optimal BPs.
Mean LET values for the target varied up to 30% among the BPs for the head-and-neck cases, and up to 14% for the pancreatic cancer cases. Variations were more prominent in organs-atrisk (OARs), where mean LET values differed by up to a factor of 2 among the BPs for the same patient. An inverse relation between dose and LET distributions for the OARs was typically observed. Accounting for LET-dependent variable RBE values, a potential improvement on RBE weighted dose of up to 40%, averaged over several structures under study, was noticed during MCO navigation.
We present a novel strategy for optimizing proton therapy to maximize doseaveraged LET in tumor targets while simultaneously minimizing dose-averaged LET in normal tissue structures. MCO BPs show substantial LET variations, leading to potentially significant differences in RBE-weighted doses. Pareto-surface navigation, utilizing both dose and LET distributions for guidance, provides the means for evaluating a large variety of deliverable plans, and aids in identifying the clinically optimum solution.
Linear energy transfer; radiobiological optimization; intensity modulated proton therapy
Hepatocellular carcinoma (HCC) is the 5th most common malignancy worldwide and accounts for nearly 10% of cancer deaths annually . In patients with well-preserved liver function and limited disease, surgical resection offers the best chance of cure. For the 80% of HCC patients with underlying cirrhosis, however, liver transplantation remains the only available curative treatment, and then only in Child-Pugh (C-P) class A or B patients . Even in transplant-eligible patients, the shortage of available donor livers severely limits the number of HCC patients that ultimately undergo transplantation . Thus, for the majority of HCC patients, which present at advanced stage or with significant liver dysfunction, non-surgical interventions remain the only treatment option .
Cirrhosis; Bone Marrow-Derived Stromal Cell Therapy; Hepatocellular Carcinoma; Radiation Induced Liver Disease
We investigated the outcome of suppression of renin angiotensin system (RAS) using Captopril combined with an antioxidant (EUKarion-207) for mitigation of radiation-induced lung damage in rats.
Materials and Methods
The thoracic cavity of female Sprague-Dawley (SD) rats was irradiated with single dose of 11 Gy. Treatment with Captopril at a dose of 40 mg/kg/day in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week (wk) post-irradiation (PI) and continuing until 14 wks PI. Breathing rate was monitored until the rats were sacrificed at 32 wks PI when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine, Transforming Growth Factor (TGF)-β1, and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG) levels and lipid peroxidation was measured by a T-BARS assay.
The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-OHdG and malondialdehyde levels, and levels of activated macrophages and the cytokine TGF-β1 at 32 wks. Almost complete mitigation of these radiation effects was observed by combining Captopril and EUK-207.
Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 wks PI following treatment given 1–14 wks PI. Overall the combination of Captopril and EUK-207 was more effective than the individual drugs used alone.
Radiation; Lung; Mitigation; Captopril; EUK-207
The first fifteen consecutive patients treated with multi-field optimization intensity modulated proton therapy (MFO-IMPT) were able to complete treatment with no need for treatment breaks and no hospitalizations. Ten patients presented with SCC and 5 with ACC. There were no treatment-related deaths and with a median follow-up of 28 months, the overall clinical complete response rate was 93.3%. Early clinical outcomes warrant further investigation of proton therapy in the management of head and neck malignancies.
We report the first clinical experience and toxicity of multi-field optimization (MFO) intensity-modulated proton therapy (IMPT) for patients with head and neck tumors.
Fifteen consecutive patients with head and neck cancer underwent MFO-IMPT with active scanning beam proton therapy. Patients with SCC had comprehensive treatment extending from the base of the skull to the clavicle. The dose for chemoradiation therapy and radiation therapy alone was 70 Gy and 66 Gy, respectively. The robustness of each treatment plan was also analyzed to evaluate sensitivity to uncertainties associated with variations in patient setup and the effect of uncertainties with proton beam range in patients. Proton beam energies during treatment ranged from 72.5 to 221.8 MeV. Spot sizes varied depending on the beam energy and depth of the target, and the scanning nozzle delivered the spot scanning treatment “spot-by-spot” and “layer-by-layer”
Ten patients presented with squamous cell carcinoma (SCC) and 5 with adenoid cystic carcinoma (ACC). All 15 patients were able to complete treatment with MFO-IMPT with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths and with a median follow-up of 28 months (range: 20-35), the overall clinical complete response rate was 93.3% (95%, confidence interval 68.1% to 99.8%). Xerostomia occurred in all 15 patients as follows; Grade 1 - ten patients, Grade 2 - four patients, and Grade 3 - one patient. Mucositis within the planning target volumes was seen during the treatment of all patients; Grade 1 - one patient, Grade 2 - eight patients, and Grade 3 - six patients. No patient experienced Grade 2 or higher anterior oral mucositis.
This is the first clinical report of MFO-IMPT for head and neck tumors. Early clinical outcomes are encouraging and warrant further investigation of proton therapy in prospective clinical trials.
To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3β, as a neuroprotectant of radiation-induced, CNS (brain) necrosis in a mouse model.
Methods and Materials
Cohorts of mice were treated with SB415286 or DMSO prior to irradiation with a single 45-Gy fraction targeted to the left hemisphere (brain) using the Leksell Perfexion Gamma Knife. The onset and progression of radiation necrosis were monitored longitudinally by non-invasive in vivo, small-animal MRI, beginning 13 weeks post-irradiation. MRI-derived necrotic volumes for SB415286- and DMSO-treated mice were compared. MRI results were supported by correlative histology.
Mice treated with SB415286 showed significant protection from radiation-induced necrosis, as determined by in vivo MRI with histologic validation. MRI-derived necrotic volumes were significantly smaller at all post-irradiation time points in SB415286-treated animals. While the irradiated hemispheres of the DMSO-treated mice demonstrated many of the classic histologic features of RN, including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, and tissue loss, the irradiated hemisphere of the SB415286-treated mice consistently showed only minimal tissue damage. These studies confirmed that treatment with a GSK-3β inhibitor dramatically reduced delayed time-to-onset necrosis in irradiated brain.
The unilateral cerebral hemispheric stereotactic radiosurgery mouse model, in concert with longitudinal MRI monitoring, provides a powerful platform for studying the onset and progression of radiation necrosis and for developing and testing new neuroprotectants. SB415286’s effectiveness as a neuroprotectant for necrosis motivates potential clinical trials of it or other GSK-3β inhibitors.
Magnetic resonance imaging; Radiation necrosis; Neuroprotection; Small animal models; Radiotherapy
This pilot study investigates the role of DAB2IP and EZH2 as prognostic biomarkers in high-risk prostate cancer patients receiving definitive radiation therapy.
Methods and Materials
Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Clinical endpoints evaluated were freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Log-rank test and Cox regression were used to determine significance of biomarker levels with clinical outcome.
Fifty-four patients with high-risk prostate cancer (stage ≥T3a, or Gleason score ≥8, or PSA ≥20) treated with radiation therapy from 2005-2012 at our institution were evaluated. Nearly all patients expressed EZH2 (98%), whereas 28% of patients revealed DAB2IP-reduction and 72% retained DAB2IP. Median follow up was 34.0 months for DAB2IP-reduced patients, 29.9 months for DAB2IP-retained patients, and 32.6 months in the EZH2 study. DAB2IP reduction portended worse outcome compared to DAB2IP-retained patients, including FFBF (4-year: 37% vs. 89%, p = 0.04), CRFS (4-year: 50% vs. 90%, p = 0.02), and DMFS (4-year: 36% vs. 97%, p = 0.05). Stratified EZH2 expression trended toward significance for worse FFBF and CRFS (p = 0.07). Patients with reduced DAB2IP or highest intensity EZH2 expression exhibited worse FFBF (4-year: 32% vs. 95%, p = 0.02), CRFS (4-year: 28% vs. 100%, p < 0.01), and DMFS (4-year: 39% vs. 100%, p = 0.04) compared to the control group.
DAB2IP loss is a potent biomarker that portends worse outcome despite definitive radiotherapy for patients with high-risk prostate cancer. EZH2 is expressed in most high-risk tumors and is a less potent discriminator of outcome in this study. DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk prostate cancer population.
Biochemical failure; Castration resistance; DAB2IP; EZH2; Prostate cancer
To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy.
Methods and Materials
The rectum, bladder and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SDTOT) was calculated.
The population mean ± 1 standard deviation of κ, CIgen and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08 and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08 and 20% ± 5% for rectum, and 0.33 ± 0.20, 0.26 ± 0.17 and 82% ± 42% for sigmoid. Dosimetric variability was: for bladder, CV = 31% ± 19% (SDTOT = 72 ± 64 Gy) for D0.1cc and CV = 16% + 10% (SDTOT = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SDTOT = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SDTOT = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SDTOT = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SDTOT = 4 ± 4 Gy) for D2cc.
Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.
The goal of the Proton Priority System (PROPS) is to guide the allocation of proton therapy treatment at Blinded Institution. The PROPS score is a priority points framework that assigns higher scores to patients thought to more likely benefit from proton therapy.
We present the principles and rationale of PROPS and the distribution of weighted PROPS scores by patient characteristics. We perform multivariable logistic regression to evaluate the association between PROPS scores and receipt of proton therapy, adjusted for insurance status, gender, race, geography, and the domains that inform the PROPS score.
Among 1,529 adult patients considered for proton therapy prioritization during our Center's ramp up phase of treatment availability, PROPS scores varied by age, diagnosis, site and other PROPS domains. In adjusted analyses, receipt of proton therapy was lower for patients with non-Medicare relative to Medicare health insurance [commercial vs. Medicare: adjusted odds ratio (OR) 0.47 95% CI (0.34 – 0.64); managed care vs. Medicare: OR 0.40 95% CI (0.28 – 0.56); Medicaid vs. Medicare: OR 0.24 95% CI (0.13 – 0.44)]. PROPS score and age were not significantly associated with receipt of proton therapy.
PROPS is a rationally designed and transparent system for allocation of proton therapy slots based on the best available evidence and expert opinion. Because the actual allocation of treatment slots depends mostly on insurance status, payers may consider incorporating PROPS, or its underlying principles, into proton therapy coverage policies.
Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT).
Materials and Methods
Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses.
Of the 32 patients, the majority were male (n = 19, 59%), 65 years or older (n = 21, 66%), and had tumors located in the pancreatic head (n = 27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8months (95% confidence interval [CI], 15.7–22.0). An MTV of 26.8 cm3 or greater (hazard ratio [HR] 4.46, 95% CI 1.64–5.88, P<.003) and TLG of 70.9 or greater (HR3.08,95%CI 1.18–8.02,P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19–22.21, P = .029) and TLG (HR 3.34, 95% CI 1.07–10.48, P = .038) remained independently associated with overall survival in separate multivariate analyses.
Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy.
Radiation therapy (RT) techniques for prostate cancer are evolving rapidly, but the impact of these changes on risk of second cancers, which are an uncommon but serious consequence of RT, are uncertain. We conducted a comprehensive assessment of risks of second cancer according to RT technique (>10 MV vs ≤10 MV and 3-dimensional [3D] vs 2D RT) and modality (external beam RT, brachytherapy, and combined modes) in a large cohort of prostate cancer patients.
Methods and Materials
The cohort was constructed using the Surveillance Epidemiology and End Results-Medicare database. We included cases of prostate cancer diagnosed in patients 66 to 84 years of age from 1992 to 2004 and followed through 2009. We used Poisson regression analysis to compare rates of second cancer across RT groups with adjustment for age, follow-up, chemotherapy, hormone therapy, and comorbidities. Analyses of second solid cancers were based on the number of 5-year survivors (n = 38,733), and analyses of leukemia were based on number of 2-year survivors (n = 52,515) to account for the minimum latency period for radiation-related cancer.
During an average of 4.4 years' follow-up among 5-year prostate cancer survivors (2DRT = 5.5 years; 3DRT = 3.9 years; and brachytherapy = 2.7 years), 2933 second solid cancers were diagnosed. There were no significant differences in second solid cancer rates overall between 3DRT and 2DRT patients (relative risk [RR] = 1.00, 95% confidence interval [CI]: 0.91-1.09), but second rectal cancer rates were significantly lower after 3DRT (RR = 0.59, 95% CI: 0.40-0.88). Rates of second solid cancers for higher- and lower-energy RT were similar overall (RR = 0.97, 95% CI: 0.89-1.06), as were rates for site-specific cancers. There were significant reductions in colon cancer and leukemia rates in the first decade after brachytherapy compared to those after external beam RT.
Advanced treatment planning may have reduced rectal cancer risks in prostate cancer survivors by approximately 3 cases per 1000 after 15 years. Despite concerns about the neutron doses, we did not find evidence that higher energy therapy was associated with increased second cancer risks.
Nuclear factor kappa-B (NF-κB), a transcriptional factor that has been shown to be constitutively active in cervical cancer, is part of an important pathway leading to treatment resistance in many tumor types. The purpose of our study was to determine whether expression of NF-κB in pre-treatment specimens and specimens taken shortly after treatment initiation correlated with outcome in cervical cancer patients treated with definitive chemoradiation.
Eighteen patients with locally advanced cervical cancer were enrolled on a study in which cervical biopsies were obtained before radiation therapy and 48 hours after treatment initiation. Matched biopsies from 16 of these patients were available and evaluated for the nuclear expression of NF-κB protein using immunohistochemical staining.
After median follow-up of 43 months, there were 9 total treatment failures. Nuclear staining for NF-κB was positive in 3 of 16 (19%) pre-treatment biopsies and 5 of 16 (31%) post-radiation biopsies. Pre-treatment expression of NF-κB nuclear staining correlated with increased rates of local-regional failure (100% vs. 23%, p = .01), distant failure (100% vs. 38%, p = .055), disease-specific mortality (100% vs. 31%, p = .03) and overall mortality (100% vs. 38%, p = .055). Best rates of local-regional failure (0%) and highest rates of overall survival (80%) were seen in the 5 patients where the expression of NF-κB was negative in pre-treatment samples but changed to positive in the samples obtained 48 hours after treatment initiation.
Our data suggest that pre-treatment nuclear expression of NF-κB may be associated with a poor outcome for cervical cancer patients treated with chemoradiation. Although these data require validation in a larger group of patients, the results support the continued study of the relationship between NF-κB and outcome in patients treated for carcinoma of the cervix.
radiation; chemotherapy; cervical cancer; nuclear transcription factor kappa b
To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.
Methods and Materials
Twenty patients were treated using the gated RapidArc technique on a Varian TrueBeam STx Linac. One to seven metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created corresponding to each implanted marker. The gating signal was generated from the RPM system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all the implanted markers were detected and their 3D positions in the patient were estimated using in-house developed software. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.
The 3D distance between the markers and their ITV is 0.8 ± 0.5 mm on average (range: 0 to 1.7 mm), and is 2.1 ± 1.2 mm at 95th percentile (range: 0 to 3.8 mm). On average a margin of 0.6 mm (left-right), 0.8 mm (anterior-posterior), 1.5 mm (superior-inferior) is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.
To our knowledge, this is the first clinical report on intrafraction verification of respiratory gated RapidArc treatment in SABR. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam on. This emphasizes the need for gating techniques with beam-on/off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.
intrafraction; treatment verification; respiratory gating; gated RapidArc; beam-level images
Post-operative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma (RMS) having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if non-compliance with RT protocol guidelines, influenced local-regional control.
All operative bed recurrences among 695 Group II RMS patients on IRS I-IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as > 10% or 6–10% of the prescribed dose (40–60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (pre-operative tumor volume and 2–5 cm margin), respectively. No RT was a major deviation.
Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46 – 41%), followed by dose (17/46 – 37%), volume (9/46 – 20%), dose and volume deviation (1/46 – 2%). Only 7 operative bed recurrences occurred on IRS IV (5% local-regional failure) with only 3 RT protocol deviations. 63 (76%) patients with a recurrence died of disease despite retrieval therapy, including 13 of 19 non-irradiated children.
Over half the operative bed recurrences were associated with non-compliance; omission of RT was the most common protocol deviation. Three-fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II RMS.
Rhabdomyosarcoma; Radiation Therapy; Group II; Protocol Compliance; Recurrence
In dose painting, in which functional imaging is used to define biological targets for radiation therapy dose escalation, changes in spatial distributions of biological properties during treatment can compromise the quality of therapy. The goal of this study was to assess the spatiotemporal stability of 2 potential dose painting target—dhypoxia and proliferation—in canine tumors during radiation therapy.
Methods and Materials
Twenty-two canine patients with sinonasal tumors (14 carcinoma and 8 sarcoma) were imaged before hypofractionated radiation therapy with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) for hypoxia and 3′-deoxy-3′-18F-fluorothymidine (FLT) PET/CT for proliferation. The FLT scans were repeated after 2 fractions and the Cu-ATSM scans after 3 fractions. Midtreatment PET/CT images were deformably registered to pretreatment PET/CT images. Voxel-based Spearman correlation coefficients quantified the spatial stability of Cu-ATSM and FLT uptake distributions between pretreatment and midtreatment scans. Paired t tests determined significant differences between the patients’ respective Cu-ATSM and FLT correlations coefficients. Standardized uptake value measures were also compared between pretreatment and midtreatment scans by use of paired t tests.
Spatial distributions of Cu-ATSM and FLT uptake were stable through mid-treatment for both sarcomas and carcinomas: the population mean ± standard deviation in Spearman correlation coefficient was 0.88 ± 0.07 for Cu-ATSM and 0.79 ± 0.13 for FLT. The patients’ Cu-ATSM correlation coefficients were significantly higher than their respective FLT correlation coefficients (P=.001). Changes in Cu-ATSM SUV measures from pretreatment to midtreatment were histology dependent: carcinomas experienced significant decreases in Cu-ATSM uptake (P<.05), whereas sarcomas did not (P>.20). Both histologies experienced significant decreases in FLT uptake (P<.05).
Spatial distributions of Cu-ATSM were very stable after a few fractions of radiation therapy. FLT spatial distributions were generally stable early in therapy, although they were significantly less stable than Cu-ATSM distributions. Canine tumors had significantly lower proliferative activity at midtreatment than at pretreatment, and they experienced histology-dependent changes in Cu-ATSM uptake.
To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer.
Methods and Materials
Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days’) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival.
Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the two arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer.
Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.
Quantify the accuracy of a clinical proton treatment planning system (TPS) as well as Monte Carlo (MC) based dose calculation through measurements. Assess the clinical impact in a cohort of patients with tumors located in the lung.
A lung phantom and ion chamber array were used to measure the dose to a plane through a tumor embedded in lung and to determine the distal fall-off of the proton beam. Results were compared with TPS and MC calculations. Dose distributions in 19 patients (54 fields total) were simulated using MC and compared to the TPS algorithm.
MC increases dose calculation accuracy in lung tissue compared to the TPS and reproduces dose measurements in the target to within ±2%. The average difference between measured and predicted dose in a plane through the center of the target is 5.6% for the TPS and 1.6% for MC. MC recalculations in patients show a mean dose to the clinical target volume on average 3.4% lower than the TPS, exceeding 5% for small fields. For large tumors MC also predicts consistently higher V5 and V10 to the normal lung, due to a wider lateral penumbra, which was also observed experimentally. Critical structures located distal to the target can show large deviations, though this effect is very patient-specific. Range measurements show that MC can reduce range uncertainty by a factor ~2: the average(maximum) difference to the measured range is 3.9mm(7.5mm) for MC and 7mm(17mm) for the TPS in lung tissue.
Integration of Monte Carlo dose calculation techniques into the clinic would improve treatment quality in proton therapy for lung cancer by avoiding systematic overestimation of target dose and underestimation of dose to normal lung. Additionally, the ability to confidently reduce range margins would benefit all patients through potentially lower toxicity.
This study aimed to investigate whether high dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC).
Methods and Materials
Patients with medically inoperable/unresectable NSCLC treated with definitive radiotherapy (RT) in prospective studies were eligible for this study. PA involvement was defined on the basis of pre-treatment chest computed tomography (CT) and positron emission tomography CT fusion (PET/CT). PA was contoured according to RTOG 1106 atlas and dose volume histograms were generated.
A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiotherapy. Radiation dose ranged 60-85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤ 2, 3, 4, and 5 had 1-year overall survival and median survival of 67% and 25.4 months (95% CI, 15.7-35.1), 62% and 22.2 months (95% CI, 5.8-38.6), 90% and 35.8 months (95% CI, 28.4-43.2), and 50% and 7.0 months, respectively (P = 0.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of RT. Maximum and mean doses to PA were not significantly associated with OS. V45, V50, V55, and V60 of PA were correlated significantly with a worse OS (P < 0.05). Patients with V45 > 70%, or V60 > 37% had significantly worse OS (13.3 vs. 37.9 P < 0.001, and 13.8 vs. 37.9 months, P = 0.04, respectively).
Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.
Non-small cell lung cancer; Pulmonary artery; High dose radiation; Survival
To report the mature data of a prospective Phase II trial designed to evaluate the efficacy of an epidermal growth factor receptor inhibitor cetuximab (CTX) added to the concurrent therapy of weekly paclitaxel/carboplatin (PC) and daily radiation therapy (RT).
Methods and Materials
From 2005 to 2009, a total of 43 patients were enrolled in the study. The median follow-up was 31 months (range, 9–59 months). All patients had Stage III/IV disease at presentation, and 67% had oropharyngeal primaries. The weekly IV dose schedules were CTX 250 mg/m2 (400 mg/m2 IV loading dose 1 week before RT), paclitaxel 40 mg/m2, and carboplatin AUC 2. RT was given at 1.8 Gy per day to 70.2 Gy. Intensity-modulated RT was used in 70% of cases.
All patients completed the planned RT dose, 74% without any treatment breaks. The planned CTX and PC cycles were completed in 70% (91% with at least seven of planned nine cycles) and 56% (93% with at least seven of planned eight cycles) of patients, respectively. Toxicity included Grade 3 mucositis (79%), rash (9%), leucopenia (19%), neutropenia (19%), and RT dermatitis (16%). The complete response (CR) rate at the completion of therapy was 84%. The estimated 3-year local regional control rate was 72%. Six patients with an initial CR subsequently experienced a local recurrence, 10 patients experienced distant progression. The median overall survival and disease-free survivals have not been reached. The 3-year actuarial overall survival and disease-free survival were 59% and 58%, respectively.
The addition of CTX to weekly PC and daily RT was well tolerated and resulted in encouraging local control and survival rates.
We surveyed how radiation oncologists think about and incorporate a palliative cancer patient’s life expectancy (LE) into their treatment recommendations.
Methods and Materials
A 41-item survey was e-mailed to 113 radiation oncology attending physicians and residents at radiation oncology centers within the Boston area. Physicians estimated how frequently they assessed the LE of their palliative cancer patients and rated the importance of 18 factors in formulating LE estimates. For 3 common palliative case scenarios, physicians estimated LE and reported whether they had an LE threshold below which they would modify their treatment recommendation. LE estimates were considered accurate when within the 95% confidence interval of median survival estimates from an established prognostic model.
Among 92 respondents (81%), the majority were male (62%), from an academic practice (75%), and an attending physician (70%). Physicians reported assessing LE in 91% of their evaluations and most frequently rated performance status (92%), overall metastatic burden (90%), presence of central nervous system metastases (75%), and primary cancer site (73%) as “very important” in assessing LE. Across the 3 cases, most (88%–97%) had LE thresholds that would alter treatment recommendations. Overall, physicians’ LE estimates were 22% accurate with 67% over the range predicted by the prognostic model.
Physicians often incorporate LE estimates into palliative cancer care and identify important prognostic factors. Most have LE thresholds that guide their treatment recommendations. However, physicians overestimated patient survival times in most cases. Future studies focused on improving LE assessment are needed.
To establish optimal intensity-modulated radiation therapy (IMRT) techniques for treating the left breast and regional nodes, using moderate deep-inspiration breath hold.
Methods and Materials
We developed four IMRT plans of differing complexity for each of 10 patients following lumpectomy for left breast cancer. A dose of 60 Gy was prescribed to the boost planning target volume (PTV) and 52.2 Gy to the breast and supraclavicular, infraclavicular, and internal mammary nodes. Two plans used inverse-planned beamlet techniques: a 9-field technique, with nine equispaced axial beams, and a tangential beamlet technique, with three to five ipsilateral beams. The third plan (a segmental technique) used a forward-planned multi-segment technique, and the fourth plan (a segmental blocked technique) was identical but included a block to limit heart dose. Dose–volume histograms were generated, and metrics chosen for comparison were analyzed using the paired t test.
Mean heart and left anterior descending coronary artery doses were similar with the tangential beamlet and segmental blocked techniques but higher with the segmental and 9-field techniques (mean paired difference of 15.1 Gy between segmental and tangential beamlet techniques, p < 0.001). Substantial volumes of contralateral tissue received dose with the 9-field technique (mean right breast V2, 58.9%; mean right lung V2, 75.3%). Minimum dose to ≥95% of breast PTV was, on average, 45.9 Gy with tangential beamlet, 45.0 Gy with segmental blocked, 51.4 Gy with segmental, and 50.2 Gy with 9-field techniques. Coverage of the internal mammary region was substantially better with the two beamlet techniques than with the segmental blocked technique.
Compared to the 9-field beamlet and segmental techniques, a tangential beamlet IMRT technique reduced exposure to normal tissues and maintained reasonable target coverage.
Breast cancer; IMRT; Radiotherapy; Treatment planning; Dosimetry