G.S. Sibley

Bio: G.S. Sibley is an academic researcher from Duke University. The author has contributed to research in topics: Pulmonary function testing & Lung injury. The author has an hindex of 13, co-authored 21 publications receiving 2024 citations.

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck

Abstract: Purpose: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evalaute the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of th ehead and neck (SCCHN). Methods and Materials: Pretreatment tumor pO2 was assessed polagographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measureemnt taken from locally advanced primaries (T3 or T4) or neck nodes ≥ 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66–70 Gy) or twice daily irradiation 91.25 Gy B.I.D. to 70–75 Gy) +/- planned neck dissection (for ≥N2A disease) according to institutiional treatment protocols. Results: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4–60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tmor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.07). Conclusion: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relatiosnhip between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Physical and biological predictors of changes in whole-lung function following thoracic irradiation

Abstract: Purpose: To develop methods of predicting the pulmonary consequences of thoracic irradiation (RT) by prospectively studying changes in pulmonary function following RT. Methods and Materials: 100 patients receiving incidental partial-lung irradiation during treatment of tumors in or adjacent to the thorax had whole-lung function assessed via symptoms and pulmonary function tests (PFTs: FEV 1 -forced expiratory volume I s; DLCO-diffusion capacity) before and repeatedly 6-48 months following RT. All had computed tomography-based three-dimensional (3D) dose calculations with lung density heterogeneity corrections for dose-volume histogram (DVH) and normal tissue complication probability (NTCP) calculations. Functional DVHs (DVfH) based on SPECT (single photon emission computed tomography) lung perfusion scans, and serial transforming growth factor-beta (TGF-β 1 ) levels were available in 50 and 48 patients, respectively. The incidence and severity of changes in whole-lung function were correlated with clinical, physical, and biological factors. Exploratory statistical analyses were performed using chi-square, Pearson correlations, logistic regression, and multiple linear regression. Results: RT-induced symptoms developed in 21 patients. In the overall group, the single best predictor for the development of symptoms was the NTCP (p 30 Gy (p < 0.05). Conclusion: The extent of alteration in whole-lung function (symptoms or PFT changes) appears to be related to both dose-volume and pre-RT PFT parameters. The data suggest that no one variable is likely to be an adequate predictor and that multivariate predictive models will be needed. Additional studies are underway to develop better predictive models that consider physical factors such as the DVH and regional perfusion, as well as biological/clinical factors such as pre-RT PFTs and TGF-β 1 .

Clinical and dosimetric predictors of radiation-induced esophageal toxicity.

Abstract: Purpose: To evaluate the incidence, severity, and clinical/dosimetric predictors of acute and chronic esophageal toxicities in patients with non-small cell lung cancer (NSCLC) treated with high-dose conformal thoracic radiation. Methods and Materials: Ninety-one patients with localized NSCLC treated definitively with high-dose conformal radiation therapy (RT) at Duke University Medical Center (DUMC) were reviewed. Patient characteristics were as follows: 53 males and 38 females; median age 64 yr (range 46–82); stage I—16, II—3, IIIa—40, IIIb—30, X—2; dysphagia pre-RT—6 (7%). Treatment parameters included: median corrected dose—78.8 Gy (range 64.2–85.6); BID fractionation—58 (64%); chemotherapy—43 (47%). Acute and late esophageal toxicities were graded by RTOG criteria. Using 3D treatment planning tools, the esophagus was contoured in a uniform fashion, the 3D dose distribution calculated (with lung density correction), and the dose–volume (DVH) and dose–surface histograms (DSH) generated. At each axial level, the percentage of the esophageal circumference at each dose level was calculated. The length of circumferential esophagus and the maximum circumference treated to doses >50 Gy were assessed. Patient and treatment factors were correlated with acute and chronic esophageal dysfunction using univariate and multivariate logistic regression analyses. Results: There were no acute or late grade 4 or 5 esophageal toxicities. Ten of 91 patients (11%) developed grade 3 acute toxicity. On univariate analysis of clinical parameters, both dysphagia pre-RT ( p = 0.10) and BID fractionation ( p = 0.11) tended toward significantly predicting grade 3 acute esophagitis. None of the dosimetric parameters analyzed significantly predicted for grade 3 acute esophagitis. Twelve of 66 assessable patients (18%) developed late esophageal toxicity. Of the clinical parameters analyzed, only dysphagia pre-RT ( p = 0.06) tended toward significantly predicting late esophageal toxicity. On univariate analyses, the effects of percent organ volume treated >50 Gy ( p = 0.05), percent surface area treated >50 Gy ( p = 0.05), length of 100% circumference treated >50 Gy ( p = 0.04), and maximum percent of circumference treated >80 Gy ( p = 0.01) significantly predicted for late toxicity of all grades. On multivariate analysis, percent organ volume treated >50 Gy ( p = 0.02) and maximum percent of circumference treated >80 Gy ( p = 0.02) predicted for late toxicity. Conclusions: Late esophageal toxicity following aggressive, high-dose conformal radiotherapy is common but rarely severe. Dosimetric variables addressing the longitudinal and circumferential character of the esophagus have biologic rationale and are predictive of late toxicity. Further studies are needed to assess whether these parameters are better predictors than those derived from traditional DVHs.

Can We Predict Radiation-Induced Changes in Pulmonary Function Based on the Sum of Predicted Regional Dysfunction?

Abstract: PURPOSE: To determine whether changes in whole-lung pulmonary function test (PFT) values are related to the sum of predicted radiation therapy (RT)-induced changes in regional lung perfusion. PATIENTS AND METHODS: Between 1991 and 1998, 96 patients (61% with lung cancer) who were receiving incidental partial lung irradiation were studied prospectively. The patients were assessed with pre- and post-RT PFTs (forced expiratory volume in one second [FEV1] and diffusion capacity for carbon monoxide [DLCO]) for at least a 6-month follow-up period, and patients were excluded if it was determined that intrathoracic recurrence had an impact on lung function. The maximal declines in PFT values were noted. A dose-response model based on RT-induced reduction in regional perfusion (function) was used to predict regional dysfunction. The predicted decline in pulmonary function was calculated as the weighted sum of the predicted regional injuries: equation where Vd is the volume of lung irradiated to dose d, and Rd is t...

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Abstract: Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

Hypoxia in cancer: significance and impact on clinical outcome

Abstract: Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a “Janus face” in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O2 sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX) or exogenous bioreductive drugs. In many—albeit not in all—studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.

The unique physiology of solid tumors: opportunities (and problems) for cancer therapy

Abstract: The physiology of solid tumors differs from that of normal tissues in a number of important aspects, the majority of which stem from differences between the two vasculatures. Compared with the regular, ordered vasculature of normal tissues, blood vessels in tumors are often highly abnormal, distended capillaries with leaky walls and sluggish flow. Tumor growth also requires continuous new vessel growth, or angiogenesis. These physiological differences can be problems for cancer treatment; for example, hypoxia in solid tumors leads to resistance to radiotherapy and to some anticancer drugs. However, these differences can also be exploited for selective cancer treatment. Here we review four such areas that are under active investigation: (a) hypoxia-selective cytotoxins take advantage of the unique low oxygen tension in the majority of human solid tumors. Tirapazamine, a drug in the final stages of clinical trials, is one of the more promising of these agents; (b) leaky tumor blood vessels can be exploited using liposomes that have been sterically stabilized to have a long intravascular half-life, allowing them to selectively accumulate in solid tumors; (c) the tumor microenvironment is a stimulus to angiogenenesis, and inhibition of angiogenesis can be a powerful anticancer therapy not susceptible to acquired drug resistance; and (d) we discuss attempts to use gene therapy activated either by the low oxygen environment or by necrotic regions of tumors.

American Society of Clinical Oncology Treatment of Unresectable Non–Small-Cell Lung Cancer Guideline: Update 2003

Abstract: The American Society of Clinical Oncology (ASCO) previously published evidencebased guidelines for the treatment of unresectable non–small-cell lung cancer (NSCLC) [1]. ASCO guidelines are updated periodically by the responsible Expert Panel (Appendix) [2]. For the 2003 update, a methodology similar to that applied in the original ASCO practice guidelines for treatment of unresectable NSCLC was used. Pertinent information published from 1996 through March 2003 was reviewed. The MEDLINE database (1996 through October 2002; National Library of Medicine, Bethesda, MD) was searched to identify relevant information from the published literature for this update. A series of searches was conducted using the medical subject headings, “carcinoma, non–small-cell lung,” “diagnostic imaging,” “neoplasm staging,” “mediastinoscopy,” “bone neoplasms,” “brain neoplasms,” “liver neoplasms,” “adrenal gland neoplasms,” “non–small-cell lung cancer,” “radionuclide imaging,” “bisphosphonates,” “radiotherapy,” “smoking,” “chemoprevention,” and the text words “chemotherapy,” “bone scan,” “PET,” and “zoledronic acid.” These terms were combined with the study design–related subject headings or text words “meta-analysis” and “randomized controlled trial.” Search results were limited to human studies and English-language articles. The Cochrane Library was searched in October 2002 using the phrase “lung cancer.” Directed searches based on the bibliographies of primary articles were also performed. Randomized trials published in the literature since October 2002, as well as data presented at ASCO Annual Meetings, were added to the evidence for these guidelines at the discretion of members of the Expert Panel. The entire update committee met once to discuss strategy and assign responsibilities for the update. A writing committee subsequently met to further review the literature searches, collate different sections of the update, and refine the manuscript. A draft update was circulated to the full Expert Panel for review and approval. The final document was also reviewed by ASCO’s Health Services Research Committee and the ASCO Board of Directors. Each recommendation from the 1997 guideline is listed below, and is followed by an updated (2003) recommendation, if applicable. “No change” is indicated if a particular recommendation has not been revised. A summary of the evidence follows thereafter. In order to preserve the framework of the 1997 guideline, information and recommendations regarding major topics, such as fluorodeoxyglucose positron emission tomography (FDGPET), have been divided and distributed to the appropriate section of the text. ASCO considers adherence to these guidelines to be voluntary. The ultimate determination regarding their application is to be made by the physician in light of each From the American Society of Clinical Oncology, Alexandria, VA.

The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence

Abstract: Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.