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1.  Does Family History Of Prostate Cancer Affect Outcomes Following Radiotherapy? 
To examine family history (FH) as a prognostic factor following radiotherapy (RT).
Materials and Methods
Between 1989 and 2007, 1,711 men with clinically localized prostate cancer and complete family history who had received RT (median RT dose = 74 Gy) without androgen deprivation therapy were analyzed. FH was defined as any prostate cancer in a first degree relative. For the biochemical failure (BF) outcome, this sample size has 85% power to detect a hazard ratio of 1.56 for positive versus negative FH.
With a median follow-up of 71 months, there was no significant difference in the distribution of Gleason score (GS) or prostate specific antigen (PSA) based on FH. A positive FH was not an independent predictor of BF, distant metastasis (DM), prostate cancer specific mortality (PCSM), or overall mortality (OM) in Cox proportional multivariable analysis. On further analysis in a Cox proportional multivariable analysis, men with two or more first degree relatives with prostate cancer had a significantly higher likelihood of BF and DM than those with no FH, although there was no difference in PCSM or OM. Men with a positive FH (23%) were more likely to be younger, have a lower PSA, and non-palpable disease. There was no interaction between a positive FH and neither race nor treatment era (pre-PSA vs. PSA era).
A positive FH is not a prognostic factor following RT and should not alter standard treatment recommendations. Patients with two or more first degree relatives with prostate cancer had a higher likelihood of BF and DM, but there was no effect on survival. There was no interaction between a positive FH and African American race or treatment era. A positive FH was however, associated with more favorable PSA values and T-stage that may be the result of earlier screening.
PMCID: PMC3991234  PMID: 24560758
Prostate Cancer; Radiotherapy; Family History
2.  [No title available] 
PMCID: PMC3969841  PMID: 24444524
4.  BCCIP as a prognostic marker for radiotherapy of laryngeal cancer 
Recent studies have shown that BCCIP (BRCA2 & CDKN1A interacting protein) is essential for maintaining the transactivation activity of wild type p53. We analyzed the expression of BCCIP and p53 in a cohort of laryngeal cancer treated with radiotherapy and assessed whether BCCIP and p53, alone or in combination, would correlate with local control and overall survival.
One hundred twenty-three patients treated between 1975 and 2000 for early stage (stage I & II) squamous cell carcinoma of the larynx were included in the study. Treatment consisted of radiation therapy (RT) with standard fields and fractionation to a median dose of 66 GY. Tissue was collected from pre-RT biopsies and constructed in a tissue microarray and BCCIP and p53 expression was determined using immunohistochemistry.
Loss of expression of BCCIP in combination with normal p53 (negative p53 staining) was associated with local recurrence (RR 2.04; 95% CI 0.99–4.56, p=0.05) and poor overall survival (RR 2.09; 95% CI 1.21–4.00, p=0.008) compared to patients who did express BCCIP. Expression of BCCIP or p53 alone was not found to be independently associated with benefits in local control or overall survival.
This study provides clinical evidence that BCCIP contributes to outcomes in patients with laryngeal cancer treated with RT. This benefit may be a result of increased radiosensitivity in patients who have functional BCCIP and p53. These data may be used to identify sub-groups of laryngeal cancer patients who are more likely to be cured with radiotherapy.
PMCID: PMC4283809  PMID: 19046788
5.  Axitinib sensitization of high Single Dose Radiotherapy 
Background and purpose
Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT.
Methods and materials
Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90 days to evaluate the impact of axitinib on SDRT tumor control.
Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1 h before SDRT was critical for radiosensitization.
Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.
PMCID: PMC4278650  PMID: 24794795
Radiosurgery; Stereotactic body radiation therapy; Vascular endothelial growth factor; Acid sphingomyelinase; Ceramide; Anti-angiogenic
6.  Cold spot mapping inferred from MRI at time of failure predicts biopsy-proven local failure after permanent seed brachytherapy in prostate cancer patients: Implications for focal salvage brachytherapy 
Background and purpose
To establish a method to evaluate dosimetry at the time of primary prostate permanent implant (pPPI) using MRI of the shrunken prostate at the time of failure (tf).
To compare cold spot mapping with sextant-biopsy mapping at tf.
Material and methods
Twenty-four patients were referred for biopsy-proven local failure (LF) after pPPI. Multiparametric MRI and combined-sextant biopsy with a central review of the pathology at tf were systematically performed.
A model of the shrinking pattern was defined as a Volumetric Change Factor (VCF) as a function of time from time of pPPI (t0). An isotropic expansion to both prostate volume (PV) and seed position (SP) coordinates determined at tf was performed using a validated algorithm using the VCF.
pPPI CT-based evaluation (at 4 weeks) vs. MR-based evaluation: Mean D90% was 145.23 ± 19.16 Gy [100.0–167.5] vs. 85.28 ± 27.36 Gy [39–139] (p = 0.001), respectively. Mean V100% was 91.6 ± 7.9% [70–100%] vs. 73.1 ± 13.8% [55–98%] (p = 0.0006), respectively. Seventy-seven per cent of the pathologically positive sextants were classified as cold.
Patients with biopsy-proven LF had poorer implantation quality when evaluated by MRI several years after implantation. There is a strong relationship between microscopic involvement at tf and cold spots.
PMCID: PMC4081029  PMID: 24231238
Prostate cancer; Prostate permanent implant; Seeds; Local failure; MR-based dosimetry
7.  Differential Effect of Soy Isoflavones in Enhancing High Intensity Radiotherapy and Protecting Lung Tissue in a Pre-Clinical Model of Lung Carcinoma 
Radiotherapy of locally-advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. We have further investigated the role of soy isoflavones to improve the effect of a high intensity radiation and reduce lung damage in a pre-clinical lung tumor model.
Human A549 NSCLC cells were injected i.v. in nude mice to generate a large tumor burden in the lungs. Mice were treated with lung irradiation at 10 Gy and with oral soy. The therapy effect on the tumor cells and surrounding lung tissue was analyzed on lung sections stained with H&E, Ki-67 and Masson’s Trichrome. Pneumonitis and vascular damage were evaluated by measurements of alveolar septa and immunofluorescent staining of vessel walls.
Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels.
These studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while radioprotecting normal lung tissue and support using soy to alleviate radiotoxicity in lung cancer.
PMCID: PMC3840154  PMID: 24021346
Lung cancer; radiation; soy isoflavones
8.  Paralysis following stereotactic spinal irradiation in pigs suggests a tolerance constraint for single-session irradiation of the spinal nerve 
Background and Purpose
Paralysis observed during a study of vertebral bone tolerance to single-session irradiation led to further study of the dose-related incidence of motor peripheral neuropathy.
Materials and Methods
During a bone tolerance study, cervical spinal nerves of 15 minipigs received bilateral irradiation to levels C5–C8 distributed into three dose groups with mean maximum spinal nerve doses of 16.9±0.3Gy(n=5), 18.7±0.5Gy(n=5), and 24.3±0.8Gy(n=5). Changes developing in the gait of the group of pigs receiving a mean maximum dose of 24.3 Gy after 10 – 15 weeks led to the irradiation of two additional animals. They received mean maximum dose of 24.9±0.2 Gy(n=2), targeted to the left spinal nerves of C5 – C8. The followup period was one year. Histologic sections from spinal cords and available spinal nerves were evaluated. MR imaging was performed on pigs in the 24.9Gy group.
No pig that received a maximum spinal nerve point dose ≤19.0Gy experienced a change in gait while all pigs that received ≥24.1Gy experienced paralysis. Extensive degeneration and fibrosis were observed in irradiated spinal nerves from the 24.9Gy animals. All spinal cord sections were normal. Irradiated spinal nerve regions showed increased thickness and hypointensity on MR imaging.
The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model.
PMCID: PMC3840915  PMID: 24060168
spinal nerve; radiation neuropathy; stereotactic ablative radiotherapy; stereotactic body radiation therapy; swine
9.  Motion-Specific Internal Target Volumes for FDG-Avid Mediastinaland HilarLymph Nodes 
Background and Purpose
To quantify the benefit of motion-specific internal target volumes for FDG-avid mediastinal and hilar lymph nodes generated using 4D-PET, vs. conventional internal target volumes generated using non-respiratory gated PET and 4D-CT scans.
Materials and Methods
Five patients with FDG-avid tumors metastatic to 11 hilar or mediastinal lymph nodes were imaged with respiratory-correlated FDG-PET (4D-PET) and 4D-CT. FDG-avid nodes were contoured by a radiation oncologist in two ways. Standard-of-care volumes were contoured using conventional un-gated PET, 4D-CT, and breath-hold CT. A second, motion-specific, set of volumes was contoured using 4D-PET. Contours based on 4D-PET corresponded directly to an internal target volume (ITV4D), whereas contours based on un-gated PET were expanded by a series of exploratory isotropic margins (from 5-13 mm) based on literature recommendations on lymph node motion to form internal target volumes (ITV3D).
A 13 mm expansion of the un-gated PET nodal volume was needed to cover the ITV4D for 10 of 11 nodes studied. The ITV3D based on a 13 mm expansion included on average 45 cm3 of tissue that was not included in the ITV4D.
Motion-specific lymph-node internal target volumes generated from 4D-PET imaging could be used to improve accuracy and/or reduce normal-tissue irradiation compared to the standard-of-care un-gated PET based internal target volumes.
PMCID: PMC3903453  PMID: 24044792
4D PET/CT; treatment planning; motion management; lung cancer; internal target volume
10.  Nuclear EGFR as a Molecular Target in Cancer 
The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell’s nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future.
PMCID: PMC3818450  PMID: 23830194
Nuclear EGFR; Cancer; Resistance
11.  Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: Implications for radiation therapy planning 
Background and purpose
This study seeks to: (a) quantify radiologic-pathologic discrepancy for pancreatic adenocarcinoma by comparing tumor size on conventional computed tomography (C-CT) and 3-dimensional CT (3D-CT) to corresponding pathologic specimens; and (b) to identify clinico-pathologic characteristics predictive of radiologic-pathologic discrepancy to assist radiotherapy planning.
Materials and methods
Sixty-three patients with pancreatic adenocarcinoma and preoperative C-CT and volume-rendered 3D-CT imaging within 6 weeks of resection were identified. Maximum tumor diameter (MTD) was measured on pathology, C-CT, and 3D-CT and compared for each patient as well as among different clinico-pathologic subgroups.
There was a trend toward C-CT underestimation of MTD compared to final pathology (p = 0.08), but no significant difference between 3D-CT MTD and pathology (p = 0.54). Pathologic tumor size was significantly underestimated by C-CT in patients with larger pathologic tumor size (>3.0 cm, p = 0.0001), smaller tumor size on C-CT (<3.0 cm, p = 0.003), higher CA19-9 (>90 U/mL, p = 0.008), and location in the pancreatic head (p = 0.015). A model for predicting pathologic MTD using C-CT MTD and CA19-9 level was generated.
3D-CT may allow for more accurate contouring of pancreatic tumors than C-CT. Patients with the above clinico-pathologic characteristics may require expanded margins relative to tumor size estimates on C-CT during radiotherapy planning.
PMCID: PMC4124599  PMID: 22883106
Pancreatic cancer; Resectable; Radiation treatment planning; 3D-CT; SBRT
12.  Compliance with Therapeutic Guidelines in Radiation Therapy Oncology Group Prospective Gastrointestinal Clinical Trials 
This report analyzes the adherence to radiation therapy protocol guidelines in contemporary Radiation Therapy Oncology Group (RTOG) gastrointestinal trials. We aim to provide insight into current standards and compliance of radiation therapy field design and administration.
From 1994 to 2006, the Gastrointestinal Cancer Committee of the RTOG initiated and completed 15 phase I-III clinical trials utilizing radiation therapy in the multimodality treatment of gastrointestinal cancers. In each protocol, details for planning and executing radiation therapy were outlined and each protocol contained scoring criteria for these components of radiation therapy, characterized according to per-protocol, variation acceptable and deviation unacceptable. Review of treatment planning and implementation was performed in all studies following therapy completion.
Radiation therapy planning and implementation was reviewed in 2,309 of 2,312 (99.9%) patients. The mean rate of compliance over all for the 15 protocols was 65% (total of the 2,309 analyzed patients). The mean variation acceptable rate was 21% whereas the mean deviation unacceptable rate was 5%. The mean “other” rate (no RT given or incomplete RT due to death, progression or refusal) was 8%. Two of the 15 trials (13%) had deviation unacceptable rates > 10%. In four studies incorporating pre-treatment review of radiation therapy planning and treatment, compliance with protocol therapy was enhanced.
The fidelity of radiation planning and execution detailed in protocol to actual therapy is heterogeneous, with a mean per-protocol rate of 65%. As clinical trials evolve, available technology should permit efficient pre-treatment review processes, thus facilitating compliance to protocol therapy. These analyses should also permit prospective analysis of outcome measures by compliance to therapy.
PMCID: PMC4106147  PMID: 23084596
13.  Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer* 
Background and Purpose
Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict for rectal bleeding, and genetic factors may be important.
Materials and Methods
A genome-wide association study (GWAS) was performed to identify SNPs associated with development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites.
rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10−8 and 6.9×10−7 respectively). Several other SNPs had p-values trending towards genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0×10−12 in the replication cohort).
This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.
PMCID: PMC3787843  PMID: 23719583
radiogenomics; prostate cancer; rectal toxicity; genome-wide association study
14.  Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia 
Radiotherapy and Oncology  2014;111(1):72-80.
Inhibitors of the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathway are currently in clinical trials. In addition to antiproliferative and proapoptotic effects, these agents also diminish tumor hypoxia. Since hypoxia is a major cause of resistance to radiotherapy, we sought to understand how it is regulated by PI3K/mTOR inhibition.
Whole cell, mitochondrial, coupled and uncoupled oxygen consumption were measured in cancer cells after inhibition of PI3K (Class I) and mTOR by pharmacological means or by RNAi. Mitochondrial composition was assessed by immunoblotting. Hypoxia was measured in spheroids, in tumor xenografts and predicted with mathematical modeling.
Inhibition of PI3K and mTOR reduced oxygen consumption by cancer cell lines is predominantly due to reduction of mitochondrial respiration coupled to ATP production. Hypoxia in tumor spheroids was reduced, but returned after removal of the drug. Murine tumors had increased oxygenation even in the absence of average perfusion changes or tumor necrosis.
Targeting the PI3K/mTOR pathway substantially reduces mitochondrial oxygen consumption thereby reducing tumor hypoxia. These alterations in tumor hypoxia should be considered in the design of clinical trials using PI3K/mTOR inhibitors, particularly in conjunction with radiotherapy.
PMCID: PMC4070024  PMID: 24631147
PI3K; mTOR; Oxidative metabolism; Hypoxia; Reoxygenation
15.  Radiation induces aerobic glycolysis through reactive oxygen species 
Background and purpose
Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype.
Materials and methods
40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state.
Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p = 0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation.
Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used concurrently with radiation, without preventing reoxygenation.
PMCID: PMC3770265  PMID: 23541363
Warburg effect; Radiation; Reoxygenation; Aerobic glycolysis; Reactive oxygen species
16.  Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR-inhibition and radiotherapy sensitivity in head and neck cancer models 
Background and Purpose
EGFR-inhibitor Cetuximab (C225) improves the efficacy of radiotherapy in only a subgroup of HNSCC patients. Identification of predictive tumor characteristics is essential to improve patient selection.
Material and Methods
Response to C225 and/or radiotherapy was assessed with tumor growth delay assays in 4 HNSCC xenograft models with varying EGFR-expression levels. Hypoxia and proliferation was quantified with immunohistochemistry and expression of proteins involved in C225-resistance with western blot.
EGFR-expression did not predict response to C225 and/or radiotherapy. Reduction of hypoxia by C225 was only observed in SCCNij202, which was highly sensitive to C225. Proliferation changes correlated with response to C225 and C225 combined with radiotherapy, as proliferation decreased after C225 treatment in C225-sensitive SCCNij202 and after combined treatment in SCCNij185, which showed a synergistic effect to combined C225-radiotherapy. Furthermore, C225-resistant SCCNij153 tumors expressed high levels of (activated) HER3 and MET.
EGFR-expression is needed for C225-response, but is not sufficient to predict response to C225 with or without radiotherapy. However, basal expression of additional growth factor receptors and effects on proliferation, but not hypoxia, correlated with response to combined C225-radiotherapy treatment and are potential clinically relevant predictive biomarkers.
PMCID: PMC3627829  PMID: 23453541
head and neck cancer; EGFR-inhibition; tumor microenvironment; radiotherapy; tyrosine kinase receptors
17.  Aortic Dose Constraints when Reirradiating Thoracic Tumors 
Background and Purpose
Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors.
Material and Methods
In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm3 of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR).
The median time interval between treatments was 30 months (range, 1–185 months). The median follow-up of patients alive at analysis was 42 months (range, 14–70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses ≥120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047).
Grade 5 aortic toxicities were observed with composite doses ≥120.0 Gy (NIDR ≥90.0 Gy) to 1 cm3 of the aorta.
PMCID: PMC3921976  PMID: 23453540
reirradiation; aortic toxicity; radiation toxicity; lung cancer
18.  Developing a class solution for Prostate Stereotactic Ablative Body Radiotherapy (SABR) using Volumetric Modulated Arc Therapy (VMAT) 
Radiotherapy and Oncology  2014;110(2):298-302.
Background and purpose
To develop a class solution for prostate Stereotactic Ablative Radiotherapy (SABR) using Volumetric Modulated Arc Therapy (VMAT).
Materials and methods
Seven datasets were used to compare plans using one 360° arc (1FA), one 210° arc (1PA), two full arcs and two partial arcs. Subsequently using 1PA, fifteen datasets were compared using (i) 6 mm CTV–PTV margins, (ii) 8 mm CTV–PTV margins and (iii) including the proximal SV within the CTV. Monaco™ 3.2 (Elekta™) was used for planning with the Agility™ MLC system (Elekta™).
Highly conformal plans were produced using all four arc arrangements. Compared to 1FA, 1PA resulted in significantly reduced rectal doses, and monitor units and estimated delivery times were reduced in six of seven cases. Using 6 mm CTV–PTV margins, planning constraints were met for all fifteen datasets. Using 8 mm margins required relaxation of the uppermost bladder constraint in three cases to achieve adequate coverage, and, compared to 6 mm margins, rectal and bladder doses significantly increased. Including the proximal SV required relaxation of the uppermost bladder and rectal constraints in two cases, and rectal and bladder doses significantly increased.
Prostate SABR VMAT is optimal using 1PA. 6 mm CTV–PTV margins, compatible with daily fiducial-based IGRT, are consistently feasible in terms of target objectives and OAR constraints.
PMCID: PMC3969574  PMID: 24332021
Image Guided RadioTherapy (IGRT); Prostate cancer; Stereotactic Ablative Body Radiotherapy (SABR); Volumetric Modulated Arc Therapy (VMAT)
19.  Second primary cancers after radiation for prostate cancer: A systematic review of the clinical data and impact of treatment technique 
Radiotherapy and Oncology  2014;110(2):213-228.
The development of a radiation induced second primary cancer (SPC) is one the most serious long term consequences of successful cancer treatment. This review aims to evaluate SPC in prostate cancer (PCa) patients treated with radiotherapy, and assess whether radiation technique influences SPC. A systematic review of the literature was performed to identify studies examining SPC in irradiated PCa patients. This identified 19 registry publications, 21 institutional series and 7 other studies. There is marked heterogeneity in published studies. An increased risk of radiation-induced SPC has been identified in several studies, particularly those with longer durations of follow-up. The risk of radiation-induced SPC appears small, in the range of 1 in 220 to 1 in 290 over all durations of follow-up, and may increase to 1 in 70 for patients followed up for more than 10 years, based on studies which include patients treated with older radiation techniques (i.e. non-conformal, large field). To date there are insufficient clinical data to draw firm conclusions about the impact of more modern techniques such as IMRT and brachytherapy on SPC risk, although limited evidence is encouraging. In conclusion, despite heterogeneity between studies, an increased risk of SPC following radiation for PCa has been identified in several studies, and this risk appears to increase over time. This must be borne in mind when considering which patients to irradiate and which techniques to employ.
PMCID: PMC3988985  PMID: 24485765
Prostate cancer; Second primary cancer; Systematic review
20.  Spinal cord tolerance to single-session uniform irradiation in pigs: implications for a dose-volume effect 
Background and Purpose
This study was performed to test the hypothesis that spinal cord radiosensitivity is significantly modified by uniform versus laterally non-uniform dose distributions.
Materials and Methods
A uniform dose distribution was delivered to a 4.5–7.0cm length of cervical spinal cord in 22 mature Yucatan minipigs for comparison with a companion study in which a laterally non-uniform dose was given[1]. Pigs were allocated into four dose groups with mean maximum spinal cord doses of 17.5±0.1 Gy(n=7), 19.5±0.2 Gy(n=6), 22.0±0.1 Gy(n=5), and 24.1±0.2 Gy(n=4). The study endpoint was motor neurologic deficit determined by a change in gait within one year. Spinal cord sections were stained with a Luxol fast blue/periodic acid Schiff combination.
Dose-response curves for uniform versus non-uniform spinal cord irradiation were nearly identical with ED50's (95% confidence interval) of 20.2 Gy(19.1–25.8) and 20.0 Gy(18.3–21.7), respectively. No neurologic change was observed for either dose distribution when the maximum spinal cord dose was ≤17.8 Gy while all animals experienced deficits at doses ≥21.8Gy.
No dose-volume effect was observed in pigs for the dose distributions studied and the endpoint of motor neurologic deficit; however, partial spinal cord irradiation resulted in less debilitating neurologic morbidity and histopathology.
PMCID: PMC3526692  PMID: 22985780
dose-volume effect; spinal cord tolerance; normal tissue tolerance; stereotactic spinal radiosurgery; swine
21.  Proton therapy radiation pneumonitis local dose–response in esophagus cancer patients 
This study quantifies pulmonary radiation toxicity in patients who received proton therapy for esophagus cancer.
We retrospectively studied 100 esophagus cancer patients treated with proton therapy. The linearity of the enhanced FDG uptake vs. proton dose was evaluated using the Akaike Information Criterion (AIC). Pneumonitis symptoms (RP) were assessed using the Common Toxicity Criteria for Adverse Events version 4.0 (CTCAEv4). The interaction of the imaging response with dosimetric parameters and symptoms was evaluated.
The RP scores were: 0 grade 4/5, 7 grade 3, 20 grade 2, 37 grade 1, and 36 grade 0. Each dosimetric parameter was significantly higher for the symptomatic group. The AIC winning models were 30 linear, 52 linear quadratic, and 18 linear logarithmic. There was no significant difference in the linear coefficient between models. The slope of the FDG vs. proton dose response was 0.022 for the symptomatic and 0.012 for the asymptomatic (p = 0.014). Combining dosimetric parameters with the slope did not improve the sensitivity or accuracy in identifying symptomatic cases.
The proton radiation dose response on FDG PET/CT imaging exhibited a predominantly linear dose response on modeling. Symptomatic patients had a higher dose response slope.
PMCID: PMC3696882  PMID: 23127772
Radiation pneumonitis; Proton therapy; Positron emission tomography
22.  Review of clinical brachytherapy uncertainties: Analysis guidelines of GEC-ESTRO and the AAPM☆ 
Radiotherapy and Oncology  2014;110(1):199-212.
Background and purpose
A substantial reduction of uncertainties in clinical brachytherapy should result in improved outcome in terms of increased local control and reduced side effects. Types of uncertainties have to be identified, grouped, and quantified.
A detailed literature review was performed to identify uncertainty components and their relative importance to the combined overall uncertainty.
Very few components (e.g., source strength and afterloader timer) are independent of clinical disease site and location of administered dose. While the influence of medium on dose calculation can be substantial for low energy sources or non-deeply seated implants, the influence of medium is of minor importance for high-energy sources in the pelvic region. The level of uncertainties due to target, organ, applicator, and/or source movement in relation to the geometry assumed for treatment planning is highly dependent on fractionation and the level of image guided adaptive treatment. Most studies to date report the results in a manner that allows no direct reproduction and further comparison with other studies. Often, no distinction is made between variations, uncertainties, and errors or mistakes. The literature review facilitated the drafting of recommendations for uniform uncertainty reporting in clinical BT, which are also provided. The recommended comprehensive uncertainty investigations are key to obtain a general impression of uncertainties, and may help to identify elements of the brachytherapy treatment process that need improvement in terms of diminishing their dosimetric uncertainties. It is recommended to present data on the analyzed parameters (distance shifts, volume changes, source or applicator position, etc.), and also their influence on absorbed dose for clinically-relevant dose parameters (e.g., target parameters such as D90 or OAR doses). Publications on brachytherapy should include a statement of total dose uncertainty for the entire treatment course, taking into account the fractionation schedule and level of image guidance for adaptation.
This report on brachytherapy clinical uncertainties represents a working project developed by the Brachytherapy Physics Quality Assurances System (BRAPHYQS) subcommittee to the Physics Committee within GEC-ESTRO. Further, this report has been reviewed and approved by the American Association of Physicists in Medicine.
PMCID: PMC3969715  PMID: 24299968
Brachytherapy; Dosimetry; Uncertainties; Treatment planning
23.  Coxsackie- and adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer 
Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie- and adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC.
Materials and methods
Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR-knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays.
CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial-mesenchymal transition.
We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC.
PMCID: PMC3845342  PMID: 23022172
Coxsackie-adenovirus receptor; treatment resistance; NSCLC; cancer stem cells; molecular markers
24.  Effects of Lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation 
Background and Purpose
Inflammatory and fibrogenic processes play a crucial role in the radiation-induced injury in the lung. The aim of the present study was to examine whether additive LPS exposure in the lung (to simulate respiratory infection) would affect pneumonitis or fibrosis associated with lung irradiation.
Material and Methods
Wildtype C57Bl/6J (WT-C57) and TNFα, TNFR1 and TNFR2 knockout (−/−) mice, in C57Bl/6J background, were given whole thorax irradiation (10Gy) with or without post-irradiation intratracheal administration of LPS (50μg/mice). Functional deficit was examined by measuring breathing rate at various times after treatment. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to analyse the protein expression and m-RNA of Interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNFα) and Transforming Growth Factor beta (TGFβ) in the lung at various times after treatment. Inflammatory cells were detected by Mac-3 (macrophages) and Toluidine Blue (mast cells) staining. Collagen content was estimated by hydroxyproline (total collagen) and Sircol assay (soluble collagen). Levels of oxidative damage were assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG) staining.
LPS exposure significantly attenuated the breathing rate increases following irradiation of WT-C57, TNFR1−/− and TNFR2−/− mice and to a lesser extent in TNFα−/− mice. Collagen content was significantly reduced after LPS treatment in WT-C57, TNFR1−/− and TNFα−/− mice and there was a trend in TNFR2−/− mice. Similarly there were lower levels of inflammatory cells and cytokines in the LPS treated mice.
This study reveals a mitigating effect of early exposure to LPS on injury caused by irradiation on lungs of C57Bl mice. The results suggest that immediate infection post irradiation may not impact lung response negatively in radiation-accident victims, however, further studies are required in different animal models, and with specific infectious agents, to confirm and extend our findings.
PMCID: PMC3632095  PMID: 22985778
TNF alpha −/−; TNFR1−/− and TNFR2−/− mice; lung; radiation; lipopolysaccharide (LPS); pneumonitis; fibrosis
25.  A semiautomatic CT-based ensemble segmentation of lung tumors: comparison with oncologists’ delineations and with the surgical specimen 
To assess the clinical relevance of a semiautomatic CT-based ensemble segmentation method, by comparing it to pathology and to CT/PET manual delineations by five independent radiation oncologists in non-small cell lung cancer (NSCLC).
Materials and Methods
For twenty NSCLC patients (stage Ib – IIIb) the primary tumor was delineated manually on CT/PET scans by five independent radiation oncologists and segmented using a CT based semi-automatic tool. Tumor volume and overlap fractions between manual and semiautomatic-segmented volumes were compared. All measurements were correlated with the maximal diameter on macroscopic examination of the surgical specimen. Imaging data is available on
High overlap fractions were observed between the semi-automatically segmented volumes and the intersection (92.5 ± 9.0, mean ± SD) and union (94.2 ± 6.8) of the manual delineations. No statistically significant differences in tumor volume were observed between the semiautomatic segmentation (71.4 ± 83.2 cm3, mean ± SD) and manual delineations (81.9 ± 94.1 cm3; p = 0.57). The maximal tumor diameter of the semiautomatic-segmented tumor correlated strongly with the macroscopic diameter of the primary tumor (r = 0.96).
Semiautomatic segmentation of the primary tumor on CT demonstrated high agreement with CT/PET manual delineations and strongly correlated with the macroscopic diameter considered the “gold standard”. This method may be used routinely in clinical practice and could be employed as a starting point for treatment planning, target definition in multi-center clinical trials or for high throughput data mining research. This method is particularly suitable for peripherally located tumors.
PMCID: PMC3749821  PMID: 23157978
CT; Auto-segmentation; Inter-observer variability; NSCLC delineation

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