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PurposeTo demonstrate the clinical applications and feasibility of online adaptive magnetic resonance image guided radiotherapy (MRgRT) in the pediatric, adolescent and young adult (AYA) population.MethodsThis is a retrospective case series of patients enrolled onto a prospective study. All pediatric (age < 18) and AYA patients (age< 30), treated on the Elekta Unity MR linear accelerator (MRL) from 2019 to 2021 were enrolled onto a prospective registry. Rationale for MRgRT included improved visualization of and alignment to the primary tumor, re-irradiation in a critical area, ability to use smaller margins, and need for daily adaptive replanning to minimize dose to adjacent critical structures. Step-and-shoot intensity-modulated radiation treatment (IMRT) plans were generated for all Unity patients with a dose grid of 3 mm and a statistical uncertainty of < 1% per plan.ResultsA total of 15 pediatric and AYA patients have been treated with median age of 13 years (range: 6 mos - 27 yrs). Seven patients were ConclusionMRgRT was well-tolerated by pediatric and AYA patients. There was no increased use of anesthesia outside of our usual practice. Dosimetric advantages were seen for patients with tumors in critical locations such as adjacent to or involving optic structures, stomach, kidney, bowel, and heart.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

PurposeBrain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.Methods and materialsA multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.ResultsMedian survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).ConclusionsMS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P.01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

PURPOSE Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced ( P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712 ) has begun.

Purpose/Objective(s): The ATM protein is key to DNA double strand break (DSB) repair and ATM inhibitors are potent radiosensitizers. Clinical translation of these agents in combination with radiotherapy (RT) has been limited due to concerns for increased normal tissue toxicity. Pharmacologic Ascorbate (P-AscH-) radiosensitizes cancer cells via generation of a H2O2 flux while acting as a radioprotector in normal tissue via free radicle scavenging. We hypothesized that P-AscH- could open a therapeutic window for the combination of RT and ATM inhibition in colorectal cancer (CRC). Materials/Methods: Multiple human and murine CRC cell lines were used in vitro. Clonogenic survival was assessed after combinations of RT +/- P-AscH and DNA Repair Inhibitors (DRIs). Catalase expression was induced using HCT116 cells expressing a doxycycline-inducible catalase transgene. DSBs were quantified using neutral comet assays. Cell cycle distribution were assessed using flow cytometry. ATM localization/activation were assessed using IF. Normal tissue toxicity in vivo was assessed using IHC following whole-abdominal RT. Survival and tumor growth delay was assessed following 5Gyx3 +/- drug treatment to unilateral flank tumors in syngeneic/xenograft models. Results: DRIs were potent radiosensitizers in most CRC cell lines and the addition of P-AscH- further reduced clonogenic survival. In contrast, P-AscH- did not radiosensitize HUVEC or FHs-74int normal cell lines. P-AscH- significantly increased the number of DSBs in tumors after RT in vitro. P-AscH- simultaneously decreased nuclear localization and activation of pATM after RT and perturbed G2+M phase progression. In vivo, the addition of P-AscH- to RT + KU60019 significantly increased survival delayed tumor growth in syngeneic/xenograft models while ameliorating increased normal bowel toxicity as measured by jejunal crypt density, acute weight loss, rectal injury, and markers of oxidative stress following whole-abdominal RT. The effects of P-AscH were reversed by inducing the overexpression of catalase. Conclusion: P-AscH- improves both aspects of the therapeutic window of RT+ATM inhibition in CRC by simultaneously enhancing tumor efficacy while decreasing RT-mediated bowel toxicity. The effects of P-AscH- on clonogenic survival, initial and persistent DSBs, G2+M phase perturbations, ATM activation/localization, and in vivo survival and tumor growth delay were dependent on H202 flux. Normal tissue protection appears to be related to decreased oxidative stress. Citation Format: Cameron M. Callaghan, Ibrahim M. Abukhiran, Richard V. Van Rheeden, Amanda L. Kalen, Samuel N. Rodman, Michael S. Petronek, Kranti A. Mapuskar, Sarah L. Mott, Mitchell C. Coleman, Prabhat C. Goswami, John M. Buatti, Bryan G. Allen, Douglas R. Spitz, Joseph M. Caster. Pharmacologic ascorbate opens a therapeutic window for ATM inhibition and radiotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 811.

Radiopharmaceutical therapy (RPT) is an area of projected growth and importance with several agents in clinical use, new agents in late-phase clinical trials, and many others under testing and development. This article proposes a framework for developing pathways of care that can be broadly applied to all RPTs, representing the current status of RPT. It suggests foundational elements for many pathways of care for patients with cancer and concludes with areas in active development and the future horizon for RPT treatment centers. Developing a framework for patient-centered pathways of care is a critical step in establishing RPT as standard therapy for patients with a diverse spectrum of cancers. This expected increase in RPT treatment options will affect a much larger population of patients with complex cancer. It will also require enhanced coordination and collaboration among appropriately qualified personnel with diverse expertise in image acquisition, image interpretation, quantitative imaging, dosimetry calculation, radiation quality assurance and safety as well as oncology care and RPT-induced sequelae and response assessment. The essential role of this evolving RPT care team within multidisciplinary oncology care is a cornerstone of this framework for a patient-centered pathway of care for RPT. Given the status of current RPT practice and the horizon for future applications, this patient-centered pathway of care guidance is timely and should help inform future clinical RPT practice paradigms. A task force was recruited from the Theranostic Working Group of the American Society for Radiation Oncology (ASTRO) in May 2019 with equal representation from the nuclear medicine community. The task force expanded on a framework that was originally conceived by the Working Group for patient-centered care. This framework was developed to incorporate the strengths of both radiation oncologists and nuclear medicine physicians. The manuscript was then developed by the task force and posted on the ASTRO website for a 6-week public comment period ending in July 2020. Comments were adjudicated, and the draft was sent to external organizations for potential endorsement. This document was sent to the ASTRO Board of Directors in October 2020 for approval.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multi-dimensional anatomical imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters has the potential to provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute (NCI) to advance and validate these QI modalities in the context of oncology clinical trials, emphasizing the great clinical need for this technology. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific quantitative information is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how it hopes to enhance the integration of QI into the practice of radiation oncology.

PurposeToidentify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).Methods and materialsA multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed.ResultsThe median survival for the prior/present cohorts was 9.6/12months, respectively (P&nbsp

PURPOSE: Oral mucositis (OM) remains a critical problem; 70% of patients receiving chemoradiation (CRT) for oral cavity or oropharynx cancers (OCC) develop severe OM. Superoxide (O(2)•-) generated by CRT plays a significant role in initiating OM. Pre-clinical studies demonstrated that conversion of (O(2)•-) to O(2) and H(2)O(2) by the superoxide dismutase mimetic GC4419 interdicts this essential step. We hypothesized that GC4419 could safely be administered with CRT and reduce severe OM. PATIENTS AND METHODS: Patients with locally-advanced OCC treated with definitive or post-operative intensity-modulated (IM)RT plus cisplatin received GC4419 by 60-minute IV infusion, ending

PURPOSE: First line treatment with platinum-based chemotherapy with or without immunotherapy improves survival in metastatic non-small cell lung cancer (NSCLC). Preclinical studies suggest that pharmacological ascorbate (P-AscH-) enhances tumor response to platinum therapy. Hence, we conducted a single-arm phase II study to evaluate the efficacy of P-AscH- in combination with platinum-doublet chemotherapy in patients with advanced stage NSCLC (NCT02420314). METHODS: Chemotherapy naïve advanced stage NSCLC patients with an ECOG PS of 0-2 were enrolled to receive 4-cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks (wks). Ascorbate (75 g) infusions were given twice a wk for 12-wks. The primary endpoint was to assess tumor objective response per RECIST v1.1. The trial was conducted as an optimal Simon two-stage design. After initial therapy, patients could receive maintenance or consolidation treatment. Secondary endpoints were to evaluate tolerability, progression-free survival (PFS) and overall survival (OS). Serum cytokines and chemokines were measured at baseline, C2d1, and C4d21± 7d. RESULTS: Forty subjects were enrolled. The study met its primary endpoint with 38 efficacy evaluable subjects. The objective response rate was 34.2%. All were confirmed partial responses (cPR). Disease control rate was 84.2% (stable disease + cPR). Median duration of follow up was 11.7 months (mo), mPFS was 5.7 mo (95% CI:4.2-6.7), and mOS was 12.5 mo (95% CI:7.5-21.4). Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 (cytopenia) events. These events were not attributed to P-AscH-. Common (≥5%) grade 3 TRAE included transient hypertension (27.5%), lymphopenia (22.5%), fatigue (7.5%), anemia (7.5%) and hypokalemia (5%). Cytokine and chemokines data suggest that protocol regimen elicited an immune response with multiple distinct cytokine signatures. Immunophenotyping of peripheral blood mononuclear cells (n=7) demonstrated a mean fold increase in effector CD8 T cells of 4.9 in patients with PFS ≥ 6 mo compare to 1.6 in patients with PFS < 6 mo. Assessments of serum iron profile and somatic alterations in KRAS, KEAP1, NFE2L2 and STK11 genes are underway. CONCLUSIONS: This phase II trial met the primary objective of improving the tumor response rate in advanced stage NSCLC by adding P-AscH- to platinum-based chemotherapy. P-AscH- appears to alter the host immune response. These promising findings warrant further investigation. Citation Format: Muhammad Furqan, Taher Abu-Hejleh, Kellie L. Bodeker, Laura M. Pietrok, Stacey M. Hartwig, Mikaela M. Tremblay, Micaela G. Fosdick, Jon Houtman, Steven Varga, Casey F. Pulliam, Michael Petronek, Melissa A. Fath, Sarah L. Mott, Aaron D. Bossler, Andrew M. Bellizzi, Jun Zhang, Hariharasudan Mani, Varun Monga, Brian J. Smith, Joseph Cullen, Brett A. Wagner, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen. Pharmacological ascorbate enhances platinum-based chemotherapy responses in metastatic non-small cell lung cancer (NSCLC): A phase II clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT164.

Pharmacological ascorbate (P-AscH-; high dose intravenous infusions of vitamin C generating milli-molar plasma concentrations) has re-emerged as an anti-cancer therapy. Phase 1 clinical trials combining P-AscH- with chemotherapy and ionizing radiation demonstrate safety and promising clinical outcomes in a variety of malignancies. In a first-in-human trial, subjects with newly diagnosed glioblastoma (GBM) and undetectable MGMT promoter methylation were treated with P-AscH-, ionizing radiation, and temozolomide. Results demonstrate median progression-free survival (PFS) of 10 months and median overall survival (OS) of 23 months, comparing favorably to historical GBM patients expressing MGMT. P-AscH-‘s anti-cancer mechanism is dependent upon the presence of redox active labile iron. In the presence of redox active iron, the formation of hydrogen peroxide, which causes oxidative stress and eventual cell death, selectively forms in cancer cells. Treatment with P-AscH- increased cancer cells’ labile iron pool, further enhancing sensitivity to P-AscH-. We investigated the capability of MR imaging (T2* relaxation time) to measure the redox active iron and predict response to P-AscH-. T2* relaxation time is influenced by in-field inhomogeneities, such as redox active paramagnetic iron. The active phase 2 trial evaluating P-AscH-, radiation, and temozolomide for GBM, obtains T2* imaging prior to (baseline) and immediately after ascorbate infusion (NCT02344355). A preliminary analysis of the baseline scan for the first 15 subjects suggests those with faster GBM T2* relaxation times (≤ 58 ms) have more redox active labile iron pools as well as an improved median PFS (11.4 months) compared to those with slower T2* relaxation times (> 58 ms; median PFS of 8.5 months). Pre-clinical studies evaluating the effectiveness of iron nano-particle supplementation in GBM animal models are on-going. (Supported by P01 CA217797, R01 CA169046, U01 CA140206, T32 CA078586, P30 CA086862, as well as the Gateway for Cancer Research grant G-17–1500.)

The purpose of the present prospective clinical trial was to determine the efficacy of [(18)F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity.Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity.IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P.05, paired t test).IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.

As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies. Clin Cancer Res; 22(2); 284–90. ©2016 AACR.

Simple Summary Numerous mechanisms of glioblastoma (GBM) radioresistance have been identified but have not yet resulted in development of effective radiosensitizer that can increase the efficacy of radiotherapy. In this review, the authors review the mechanisms of GBM radioresistance along with current status of radiation treatment and imaging techniques used in GBM diagnosis and radiotherapy. In addition, they summarize the current GBM radiosensitizers that are being investigated or enrolled in clinical trials. This review emphasizes on the importance of developing an effective radiosensitizers to increase the outcome of GBM radiotherapy. The authors highlight the importance of discovering of novel mechanism(s) of GBM radioresistance that will lead in developing an effective radiosensitizer. Abstract Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.

Background Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.

Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH−, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH− decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH− radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH−, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH− in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH− during the radiotherapy “beam on.” Specifically, treatment with P-AscH− increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH−–treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH− in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH− efficacy is warranted in a phase II clinical trial. Significance: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Purpose To evaluate dynamic [ 18 F]-fluorodeoxyglucose (FDG) uptake methodology as a post–radiation therapy (RT) response assessment tool, potentially enabling accurate tumor and therapy-related inflammation differentiation, improving the posttherapy value of FDG–positron emission tomography/computed tomography (FDG-PET/CT). Methods and Materials We prospectively enrolled head-and-neck squamous cell carcinoma patients who completed RT, with scheduled 3-month post-RT FDG-PET/CT. Patients underwent our standard whole-body PET/CT scan at 90 minutes, with the addition of head-and-neck PET/CT scans at 60 and 120 minutes. Maximum standardized uptake values (SUV max ) of regions of interest were measured at 60, 90, and 120 minutes. The SUV max slope between 60 and 120 minutes and change of SUV max slope before and after 90 minutes were calculated. Data were analyzed by primary site and nodal site disease status using the Cox regression model and Wilcoxon rank sum test. Outcomes were based on pathologic and clinical follow-up. Results A total of 84 patients were enrolled, with 79 primary and 43 nodal evaluable sites. Twenty-eight sites were interpreted as positive or equivocal (18 primary, 8 nodal, 2 distant) on 3-month 90-minute FDG-PET/CT. Median follow-up was 13.3 months. All measured SUV endpoints predicted recurrence. Change of SUV max slope after 90 minutes more accurately identified nonrecurrence in positive or equivocal sites than our current standard of SUV max ≥2.5 ( P =.02). Conclusions The positive predictive value of post-RT FDG-PET/CT may significantly improve using novel second derivative analysis of dynamic triphasic FDG-PET/CT SUV max slope, accurately distinguishing tumor from inflammation on positive and equivocal scans.

BACKGROUND: The clinical impact of lymph node dissection extent remains undetermined in the contemporary setting, as reflected in care pattern variations. Despite some series demonstrating a direct relationship between number of lymph nodes identified and detection of nodal involvement, the correlation between lymph node yield and disease control or survival outcomes remains unclear. METHODS: Patients with clinically localized prostate cancer, pre-RP PSA

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H(2)O(2); however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O(2)(.−) and H(2)O(2) are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H(2)O(2). In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%–80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%–20% killing) and adult fibroblasts (20 years old; ∼10%–30% killing). Old fibroblasts also displayed significantly increased (2–4-fold) steady-state levels of O2•−, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%–50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5–7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•− in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•− and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054–67. ©2017 AACR.

Purpose To evaluate the utility of 3-dimensional magnetic resonance (3D-MR) proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. Methods and Materials Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium-enhanced MR images at simulation and at boost treatment planning after 17 to 20 fractions of radiation therapy. All patients received standard radiation therapy (RT) with concurrent temozolomide followed by adjuvant temozolomide. Imaging for response assessment consisted of MR scans every 2 months. Progression-free survival was defined by the criteria of MacDonald et al. MRSI images obtained at initial simulation were analyzed for choline/N-acetylaspartate ratios (Cho/NAA) on a voxel-by-voxel basis with abnormal activity defined as Cho/NAA ≥2. These images were compared on anatomically matched MRSI data collected after 3 weeks of RT. Changes in Cho/NAA between pretherapy and third-week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression-free survival, radiation dose and location of recurrence using Cox proportional hazards regression. Results After a median follow-up time of 8.6 months, 50% of patients had experienced progression based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression ( P P P =.03). Most patients received the prescription dose of RT to the Cho/NAA ≥2 volume, where recurrence most often occurred. Conclusion Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk-adaptive therapy based on early spectroscopic findings is suggested.

Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with progressive glioblastoma multiforme after the first adjuvant combined multimodality treatment with radiation and chemotherapy? These recommendations apply to adult patients with progressive glioblastoma after first line combined multimodality treatment with chemotherapy and radiation. When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery. Re-irradiation is recommended in order to maintain or improve a patient’s neurological status and quality of life prior to any further tumor progression.

Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species (ROS) such as O2•−and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses.

A workshop entitled “Lessons Learned from Radiation Oncology Trials” was held on December 7–8, 2011, in Bethesda, MD, to present and discuss some of the recently conducted radiation oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the preclinical data that supported the hypotheses underlying these trials, and to consider possible solutions to these challenges for the design of future clinical trials. Several themes emerged from the discussions: (i) opportunities to learn from null-hypothesis trials through tissue and imaging studies; (ii) value of preclinical data supporting the design of combinatorial therapies; (iii) significance of validated biomarkers; (iv) necessity of quality assurance in radiotherapy delivery; (v) conduct of sufficiently powered studies to address the central hypotheses; and (vi) importance of publishing results of the trials regardless of the outcome. The fact that well-designed hypothesis-driven clinical trials produce null or negative results is expected given the limitations of trial design and complexities of cancer biology. It is important to understand the reasons underlying such null results, however, to effectively merge the technologic innovations with the rapidly evolving biology for maximal patient benefit through the design of future clinical trials. Clin Cancer Res; 19(22); 6089–100. ©2013 AACR.

Purpose: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. Experimental Design: Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8–2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)–modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively. Results: The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. Conclusions: These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress. Clin Cancer Res; 19(14); 3905–13. ©2013 AACR.

To determine the pattern and risk factors for distant metastases in head-and-neck squamous cell carcinoma (HNSCC) after curative treatment with intensity-modulated radiotherapy (IMRT).This was a retrospective study of 284 HNSCC patients treated in a single institution with IMRT. Sites included were oropharynx (125), oral cavity (70), larynx (55), hypopharynx (17), and unknown primary (17). American Joint Committee on Cancer stage distribution includes I (3), II (19), III (42), and IV (203). There were 224 males and 60 females with a median age of 57. One hundred eighty-six patients were treated with definitive IMRT and 98 postoperative IMRT. One hundred forty-nine patients also received concurrent cisplatin-based chemotherapy.The median follow-up for all patients was 22.8 months (range, 0.07-77.3 months) and 29.5 months (4.23-77.3 months) for living patients. The 3-year local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 94.6%, 96.4%, 92.5%, 84.1%, and 68.95%, respectively. There were 45 patients with distant metastasis. In multivariate analysis, distant metastasis was strongly associated with N stage (p = 0.046), T stage (p0.0001), and pretreatment maximum standardized uptake value of the lymph node (p = 0.006), but not associated with age, gender, disease sites, pretreatment standardized uptake value of the primary tumor, or locoregional control. The freedom from distant metastasis at 3 years was 98.1% for no factors, 88.6% for one factor, 68.3% for two factors, and 41.7% for three factors (p0.0001 by log-rank test).With advanced radiation techniques and concurrent chemotherapy, the failure pattern has changed with more patients failing distantly. The majority of patients with distant metastases had no local or regional failures, indicating that these patients might have microscopic distant disease before treatment. The clinical factors identified here should be incorporated in future clinical trials.

Purpose The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans. Methods and Materials Pre- and post-Week 1 treatment [18F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [18F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6–T7 vertebrae that straddled the field edge were measured for all patients. Results Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and Conclusions The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [18F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [18F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity.

The growth of functional and metabolically informative imaging is eclipsing anatomic imaging alone in clinical practice. The recognition that magnetic resonance (MR) and positron emission tomography (PET)-based treatment planning and response assessment are essential components of clinical practice and furthermore offer the potential of quantitative analysis being important. Extracting the greatest benefit from these imaging techniques will require refining the best combinations of multimodality imaging through well-designed clinical trials that use robust image-analysis tools and require substantial computer based infrastructure. Through these changes and enhancements, image-based biomarkers will enhance clinical decision making and accelerate the progress that is made through clinical trial research.

Purpose: A ketogenic diet (KD) is a high fat, low carbohydrate diet that forces cells to utilize mitochondrial fatty acid oxidation for energy production. It has been previously shown that cancer cells have defects in mitochondrial oxidative metabolism resulting in increased oxidative stress relative to non-malignant cells. Because radiation and platinum based chemotherapy also induce oxidative damage, we hypothesized that a KD may enhance radiation and platinum chemotherapy efficacy in head and neck cancer. The KD's ability to enhance radiation and chemotherapy efficacy were assessed in murine head and neck cancer xenograft models. The safety and tolerability of a KD in combination with standard of care radiation and platinum-based chemotherapy in head and neck cancer patients was assessed in a phase I clinical trial. Methods: Mice bearing FaDu human head and neck cancer xenografts were fed either standard mouse chow or commercially prepared KD and treated with varying combination of cetuximab (CTX), cisplatin, and/or radiation (IR) and tumor growth was measured via calipers. Tumor homogenates and mice serum were harvested to test for markers including glutathione, 4HNE, PCNA, and IL6. Based on this study and other previously published pre-clinical studies, a phase I clinical trial in locally advanced head and neck cancer combining standard radiation and chemotherapy while consuming a KD was initiated. Subjects consumed a KD by PEG or nasogastric-tube and were also allowed to orally consume water, sugar-free drinks approved by the dietician, and approved snacks and meals approved by the dietician. Oxidative stress markers including protein carbonyl and glutathione were assessed. Results: Mice bearing xenografts treated with KD + IR + CTX had significantly increased survival relative to mice treated with IR + CTX. Collected tumor homogenates in KD + IR + CTX treated mice demonstrated increased 4HNE modified proteins relative to tumor homogenates from IR +CTX mice. In the phase I clinical trial, a total of twelve subjects were enrolled in the study. Four subjects completed five weeks of the KD as per protocol. Median follow-up from completion of RT was 13.1 months (range 8.0-26.7 months). Of the eight subjects that did not tolerate the diet, median number of days subjects stayed on diet was 5.5 (range: 2-8 days). Reasons for discontinuation included “stress of diet compliance” (1), grade 2 nausea (3), and grade 3 fatigue (1). Three subjects were removed for dose limiting toxicities: grade 4 hyperuricemia (2) and grade 3 acute pancreatitis (1). Median weight loss was 2.95% for the KD group and 7.92% for subjects that did not tolerate the diet. Subject serums demonstrated increased oxidative stress as they continued the diet. Conclusions: KD shows promise as adjuvant treatment in mouse xenograft model of head and neck cancer but in our small study there was difficulty with compliance and tolerability when combined with standard of care radiation and chemotherapy. Citation Format: Daniel MA, Carryn Anderson, Samuel N. Rodmann, Kayla Follmer, Visarut Buranasudja, Kellie Bodeker, Jessica R. Parkhurst, Michael McCormack, Andrew Davis, Douglas R. Spitz, John Buatti, Bryan G. Allen, Melissa A. Fath. Ketogenic diet with concurrent chemoradiation in head and neck squamous cell carcinoma: Pre-clinical and phase I trial results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-252.

6006Background: Intensity-modulated radiotherapy (IMRT) plus cisplatin is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4...

BACKGROUND: The authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed. METHODS: Sixty-two cervical cancer patients underwent dynamic contrast-enhanced (DCE) MRI before and during early radiation/chemotherapy (2-2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE-MRI and 3-dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow-up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis. RESULTS: SI(10%) and 3D volume 2-2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0-6.5 [P = .04] and HR, 1.9; 95% CI, 1.1-3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0-3.5 [P = .03] and HR, 1.9; 95% CI, 1.2-2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death. CONCLUSIONS: MRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy. Cancer 2010. © 2010 American Cancer Society.

Hypo-fractionated radiation schemes may be used for patients with a poor prognosis and limited survival without compromising response. Hyper-fractionation and accelerated fractionation have not been shown to be superior to conventional fractionation and are not recommended. Brachytherapy or stereotactic radiosurgery as a boost to external beam radiotherapy have not been shown to be beneficial and are not recommended in the routine management of newly diagnosed malignant glioma.

Adjuvant radiation treatment is often offered for lacrimal sac tumors. However, due to the adjacent critical structures, conventional radiation technique may result in severe side effects. We have treated two patients with lacrimal sac tumors using optically guided stereotactic radiotherapy. One patient with lacrimal sac melanoma was treated with optical-guidance intensity-modulated radiotherapy (IMRT). The other with mixed transitional and squamous cell carcinoma was treated with optical-guidance 3-D conformal radiation. Dose volume analysis revealed excellent target coverage and sparing of critical structures. Both patients tolerated the treatment well with no significant acute or late side effects. One patient died of metastatic melanoma 30 months after radiation; another died of coexisting disease 41 months after radiation. Both had no clinical evidence of local recurrence at the time of death. Our report show that optically guided stereotactic radiotherapy is well tolerated. It offers excellent tumor coverage and sparing of critical structures. It can be used for tumors adjacent to radiation sensitive critical structures such as skull base tumors.

Purpose To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-d-glucose (2DG); whether 2-[ 18 F]-fluoro-2-deoxy-d-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. Methods and Materials Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. Results Use of CIS + 2DG enhanced cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. Conclusions These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.

To test the hypothesis that radiation dose to key sites in the upper aerodigestive tract is associated with long-term functional outcome after (chemo)radiotherapy for head-and-neck cancers.This study examined the outcome for 27 patients treated with intensity-modulated radiotherapy for definitive management of their head-and-neck cancer who were disease free for at least 1 year after treatment. Head-and-neck cancer-specific quality of life (QoL) was assessed before treatment and at 1 year after treatment. Type of diet tolerated, presence of a feeding tube, and degree of weight loss 1 year after treatment were also used as outcome measures. Radiation doses delivered to various points along the upper aerodigestive tract, including base of tongue, lateral pharyngeal walls, and laryngeal structures, were determined from each treatment plan. Radiation doses for each of these points were tested for correlation with outcome measures.Higher doses delivered to the aryepiglottic folds, false vocal cords, and lateral pharyngeal walls near the false cords correlated with a more restrictive diet, and higher doses to the aryepiglottic folds correlated with greater weight loss (p0.05) 1 year after therapy. Better posttreatment speech QoL scores were associated with lower doses delivered to structures within and surrounding the larynx.Our data show an inverse relationship between radiation dose delivered to laryngeal structures and speech and diet and QoL outcomes after definitive (chemo)radiation treatment. These findings suggest that efforts to deliver lower doses to laryngeal structures may improve outcomes after definitive (chemo)radiation therapy.