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Purpose: Neoadjuvant radiation therapy (RT) improves disease control in various cancers and has become an established oncologic treatment strategy. During 2001 to 2004, we conducted a phase 1 pilot study assessing the role of short-course preoperative RT (PreORT) for men with unfavorable intermediate- and high-risk localized prostate cancer. Herein, we present long-term follow-up toxicity and oncologic outcomes., Methods and Materials: Eligible patients had histologically proven prostate cancer, cT1-T2N0M0 disease, prostate-specific antigen >15 to 35 ng/mL regardless of Gleason score, or prostate-specific antigen 10 to 15 ng/mL with Gleason score ≥7. Patients received 25 Gy in 5 consecutive daily fractions (5 Gy per fraction) to the prostate only, followed by radical prostatectomy within 14 days after RT completion. Primary outcomes were intraoperative morbidity and late genitourinary (GU) and gastrointestinal toxicities., Results: In total, 15 patients were enrolled; 14 patients completed PreORT followed by radical prostatectomy, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range, 6.7-16.3). Late GU toxicity was common, with 2 patients (13.3%) experiencing G2 toxicity and 6 patients (40%) G3 toxicity. There were no patients with G4 to G5 late GU toxicity. Late gastrointestinal toxicity was infrequent, with only 1 patient (6.7%) experiencing transient G2 proctitis. At last follow-up, 8 (53.3%) and 6 (40%) patients experienced biochemical and metastatic disease recurrence, respectively., Conclusions: The use of PreORT in men with high-risk prostate cancer is associated with unexpected high rates of late GU toxicity. Future studies examining the role of RT preradical prostatectomy must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data are essential to fully determine the therapeutic index of PreORT in the management of localized disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The National Comprehensive Cancer Network (NCCN) has recently endorsed the stratification of intermediate-risk prostate cancer (IR-PCa) into favorable and unfavorable subgroups and recommend the addition of androgen deprivation therapy (ADT) to radiation therapy (RT) for unfavorable IR-PCa. Recently, more accurate prognostication was demonstrated by integrating a 22-feature genomic classifier (GC) to the NCCN stratification system. Here, we test the utility of the GC to better identify patients with IR-PCa who are sufficiently treated by RT alone., Methods and Materials: We identified a novel cohort comprising 121 patients with IR-PCa treated with dose-escalated image guided RT (78 Gy in 39 fractions) without ADT. GC scores were derived from tumors sampled in diagnostic biopsies. Multivariable analyses, including both NCCN subclassification and GC scores, were performed for biochemical failure (prostate-specific antigen nadir + 2 ng/mL) and metastasis occurrence., Results: By NCCN subclassification, 33 (27.3%) and 87 (71.9%) of men were classified as having favorable and unfavorable IR-PCa, respectively (1 case unclassifiable). GC scores were high in 3 favorable IR-PCa and low in 60 unfavorable IR-PCa. Higher GC scores, but not NCCN risk subgroups, were associated with biochemical relapse (hazard ratio, 1.36; 95% confidence interval [CI], 1.09-1.71] per 10% increase; P = .007) and metastasis (hazard ratio, 2.05; 95% CI, 1.24-4.24; P = .004). GC predicted biochemical failure at 5 years (area under the curve, 0.78; 95% CI, 0.59-0.91), and the combinatorial NCCN + GC model significantly outperformed the NCCN alone model for predicting early-onset metastasis (area under the curve for 5-year metastasis of 0.89 vs 0.86 [GC alone] vs 0.54 [NCCN alone])., Conclusions: We demonstrated the accuracy of the GC for predicting disease recurrence in IR-PCa treated with dose-escalated image guided RT alone. Our findings highlight the need to evaluate this GC in a prospective clinical trial investigating the role of ADT-RT in clinicogenomic-defined IR-PCa subgroups., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy., Methods and Materials: Men prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse-free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality., Results: Of 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence., Conclusions: Curative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In early 2011, a dialogue was initiated within the Board of Directors (BOD) of the American Society for Radiation Oncology (ASTRO) regarding the future of the basic sciences of the specialty, primarily focused on the current state and potential future direction of basic research within radiation oncology. After consideration of the complexity of the issues involved and the precise nature of the undertaking, in August 2011, the BOD empanelled a Cancer Biology/Radiation Biology Task Force (TF). The TF was charged with developing an accurate snapshot of the current state of basic (preclinical) research in radiation oncology from the perspective of relevance to the modern clinical practice of radiation oncology as well as the education of our trainees and attending physicians in the biological sciences. The TF was further charged with making suggestions as to critical areas of biological basic research investigation that might be most likely to maintain and build further the scientific foundation and vitality of radiation oncology as an independent and vibrant medical specialty. It was not within the scope of service of the TF to consider the quality of ongoing research efforts within the broader radiation oncology space, to presume to consider their future potential, or to discourage in any way the investigators committed to areas of interest other than those targeted. The TF charge specifically precluded consideration of research issues related to technology, physics, or clinical investigations. This document represents an Executive Summary of the Task Force report., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT., Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used., Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G(2)-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7., Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Prostate cancer patients exhibit variability in normal tissue reactions and biochemical failure. With the use of image-guided radiotherapy (IGRT), there is a greater likelihood that the differences in normal tissue and tumor response are due to biological rather than physical factors. We tested the hypothesis that prospectively scored acute toxicity is associated with biochemical failure-free rate (BFFR) in prostate cancer patients treated with IGRT., Methods and Materials: We retrospectively analyzed BFFR in 362 patients with localized prostate cancer treated with IGRT. We compared BFFR with prospectively collected Radiation Therapy Oncology Group (RTOG) maximum acute gastrointestinal (GI) and genitourinary (GU) toxicity scores. Median follow-up for all patients was 58.3 months after total radiotherapy doses of 75.6-79.8 Gy., Results: Patients reporting RTOG acute GU or GI toxicity scores of ≥ 2 were considered "sensitive" (n = 141, 39%) and patients reporting scores <2 were considered "nonsensitive" (n = 221, 61%). When calculating biochemical failure (BF) using the American Society for Therapeutic Radiology and Oncology definition at 5 years, 76% (CI 70-82%) of the "nonsensitive" patients were failure free, compared with only 53% (CI 43-62%) of the "sensitive" patients (log-rank test, p < 0.0001). This difference was also observed using the Phoenix definition; "nonsensitive" 5-year BFFR was 81% (CI 74-86%) vs. "sensitive" BFFR was 68% (CI 58-76%; log-rank test p = 0.0012). The difference in BF between cohorts remained significant when controlled for radiation dose (75.6 vs. 79.8 Gy), prognostic stratification (T category, prostate-specific antigen, and Gleason score), and prostate volume., Conclusions: This study unexpectedly shows that prostate cancer patients who develop ≥ Grade 2 RTOG acute toxicity during radiotherapy are less likely to remain BFF at 5 years. These results deserve further study and, if validated in other large IGRT cohorts, additional models would be required to study interaction between normal tissue and tumor biology in prostate cancer patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Rational design of targeted radiotherapy (RT) in prostate cancer (Pca) hinges on a better understanding of spatial patterns of recurrence. We sought to identify pathological factors predictive for site of local recurrence (LR) after external beam RT., Methods and Materials: Prospective databases were reviewed to identify men with LR after RT from 1997 through 2009. Patients with biochemical failure and biopsy-confirmed Pca more than 2 years after RT were evaluated. Prediction for site of recurrence based on the following pretreatment factors was determined on independent and cluster-sextant basis: presence of malignancy, dominant vs. nondominant percentage core length (PCL) involvement, PCL ≥ or <40%, and Gleason score. Sites of dominant PCL were defined as sextants with peak PCL involvement minus 10%, and >5% for each patient., Results: Forty-one patients with low-intermediate risk Pca constituted the study cohort. Median time to biopsy after RT was 51 months (range, 24-145). Of 246 sextants, 74 were involved with tumor at baseline. When sextants are treated as independent observations the presence of malignancy (77% vs. 22%, p = 0.0001), dominant PCL (90% vs. 46%, p = 0.0001), and PCL ≥40% (89% vs. 68 %, p = 0.04) were found to be significant predictors for LR, although PCL ≥40% did not retain statistical significance if sextants were considered correlated. The vast majority of patients (95%) recurred at the original site of dominant PCL or PCL ≥40%, and 44% also recurred in regions of nondominant PCL <40% (n = 8) and/or benign sampling (n = 14) at baseline., Conclusions: LR after RT predominantly occurs in regions bearing higher histological tumor burden but are not isolated to these sites. Our data highlights the value of spatially resolved baseline pathological sampling and may assist in the design of clinical trials tailoring RT dose prescriptions to subregions of the prostate gland., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells., Methods and Materials: Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis., Results: IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK alpha subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21(waf/cip) as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further., Conclusions: We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21(waf/cip) and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21(waf/cip) pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose: Pretreatment hemoglobin (Hb) level has been reported to be an important prognostic factor for local control and survival in various malignancies. However, in many settings, the adverse effect of a low Hb may be related to more advanced disease. The purpose of this analysis was to assess the influence of pretreatment Hb on local control in a large series of patients with a localized cancer (T1/T2 glottic cancer, AJCC 1992) treated in a standard fashion., Materials and Methods: Between January 1981 and December 1989, 735 patients (median age 63; 657 males, 78 females) with T1/T2 glottic cancer were treated with radiation therapy (RT). The standard RT prescription was 50 Gy in 20 fractions over 4 weeks (97% of patients). Factors studied for prognostic importance for local failure included pretreatment Hb, age, sex, T category, anterior commissure involvement, subglottic extension, and tumor bulk (presence of visible tumor vs. subclinical disease)., Results: With a median follow-up of 6.8 years (range 0.2-14.3), 131 patients have locally relapsed for an actuarial 5-year relapse-free rate of 81.7%. The 5-year actuarial survival was 75.8%. The mean pretreatment hemoglobin level was 14.8 g/dl and was similar in all prognostic categories. On multivariate analysis, using the Cox proportional hazards model, pretreatment Hb predicted for local failure after RT. The hazard ratio (HR) for relapse was calculated for various Hb levels. For example, the HR for a Hb of 12 g/dl vs. a Hb of 15 g/dl was 1.8 (95% confidence interval 1.2-2.5). Previously established factors, including gender, T category, subglottic extension, as well as tumor bulk, were also prognostically important for local control., Conclusions: This analysis, in a large number of similarly treated patients, indicates that pretreatment Hb is an independent prognostic factor for local control in patients with T1/T2 carcinoma of the glottis treated with RT. The underlying biology of this observation needs to be explored, and using this information, it may be possible to develop strategies to improve treatment outcome.

Purpose: Changes in wild-type p53 protein function occur in the majority of human tumors, and may alter genomic stability and the cellular response to ionizing radiation. Whether oncoproteins can render tumor cells both radioresistant and metastatic, may have implications for clinical strategies designed to improve local tumor control. In the studies reported here, we tested the hypothesis that acquired radioresistance correlates with metastatic potential within a large panel of transformed rat embryo cell (REF) lines following transfection with activated H-ras, mutant p53, and HPV16-E7 alleles., Methods and Materials: Rat embryo cells (REF cells) were transfected using the calcium-phosphate technique with an activated H-ras gene alone, or in combination with human papillomavirus HPV16-E7 and/or human or murine mutant p53 sequences. Other rat embryo cell clones expressing transfected HPV-E7 and activated ras sequences subsequently acquired endogenous p53 gene mutations during culture in vitro. The relative expression of p21ras and p53 protein for each REF transformant was determined by Western blot analysis following transfection. REF clones were phenotypically characterized at early passage (i.e., passages 5-7) and late passage (i.e., passages 10-20) for their: (a) relative tumor growth rate, and (b) their ability to undergo spontaneous metastasis following intramuscular injection into the hind legs of SCID mice. In vivo phenotypic end points were then compared to previously measured parameters of in vitro radiosensitivity for each cell line. Additionally, the expression of the cellular protease, plasminogen activator, was determined for a number of metastatic and nonmetastatic cell lines., Results: We found no evidence that selected oncogene-transfected REF transformants that were radioresistant in culture had a greater spontaneous metastatic potential than nonradioresistant REF transformants. Neither the level of expression of the p21ras protein nor that of the p53 protein was correlated with the spontaneous metastatic phenotype when tested at early passage. The metastatic phenotype appeared to be independent of p53 genotype. The majority of metastatic REF clones tested (7 out of 9 clones) expressed plasminogen activator following oncogene transfection, in contrast to nonmetastatic REF transformed cell lines., Conclusions: Our results suggest that (a) intrinsic radioresistance does not correlate with spontaneous metastatic potential in oncogene-expressing REF transformant cell lines, and (b), novel clinical strategies designed to overcome oncogene-mediated radioresistance could potentially impact on overall survival, as gains in local tumor control may not be offset by a greater risk of distant metastasis.

Survival in the low-dose region of in vitro radiation survival curves for human tumor cell lines may be correlated with the expected clinical radiocurability of tumors of similar histopathological type. The present investigation examined this hypothesis using a series of transplantable murine solid tumors. The in vivo radioresponse of the tumors following fractionated dose (10 fractions of 2 Gy given at 4 hr intervals) and single dose (20 Gy) radiation treatment was measured by growth delay and tumor cell survival assays. The measurements of tumor cell survival were initiated either immediately or 8 hr after the end of radiation treatment. There was no evidence for repair of potentially lethal damage in vivo in any of the tumors. The measurements of in vivo response were compared to parameters of in vitro radiation survival curves for the same tumor cell lines, which were measured concurrently. The tumor cell survival following 10 fractions of 2 Gy correlated best with the measured in vitro survival at 2 Gy, although good correlations were also observed with two parameters calculated from the in vitro data; the value of alpha from fitting the linear-quadratic (LQ) model and the mean inactivation dose (MID). Correlations were also observed between specific growth delay measured in vivo following 10 fractions of 2 Gy and these in vitro parameters. Despite the correlations observed, the measured survival values following 10 fractions of 2 Gy in vivo did not agree quantitatively with the theoretical values predicted from the in vitro survival data assuming equal effect for each fraction. This discrepancy indicates that other factors also contribute to the overall response of a tumor to fractionated irradiation. Nevertheless, these findings support the idea that intrinsic radiosensitivity plays a significant role in determining the overall response of a tumor to fractionated irradiation and provides strong support for the concept of testing the in vitro radiation sensitivity of biopsy specimens as a predictive assay of clinical radiocurability.

Recent studies have suggested that differences in the initial low-dose region of the radiation survival curves for human tumor cells might explain the differences in clinical response of tumors to fractionated radiation treatment. In this study, which is described in two companion papers, we investigated this hypothesis directly using animal model systems. In the present paper we determined in vitro radiation survival curves for eight murine tumor cell lines of varying histopathological type and: (a) measured survival at the 2 Gy and 8 Gy dose levels, (b) fitted parameters to the linear quadratic and two component multi-target equation models of cellular survival and (c) calculated mean inactivation doses. We found that the choice of the data fitting procedure affected the absolute value, relative ranking, and power to discriminate between the cell lines of these calculated parameters. A detailed statistical study indicated that the measured surviving fraction at 2 Gy (SF2) was the best discriminant of intrinsic radiosensitivity between the eight tumor cell lines. When these same cell lines were assayed for intracellular glutathione (GSH) levels, no correlation was found between levels of GSH and the SF2 value. Determining the SF2 value may be the method of choice to describe the low-dose region of the radiation survival curve, as it precludes the necessity of choosing a model to fit the survival data, it has excellent discriminatory powers, and it represents the survival in the radiotherapeutically relevant region of the in vitro radiation survival curve. Furthermore, as demonstrated in the companion paper, it correlates with cell survival in the tumors following 10 fractions of 2 Gy given in vivo.