Biomedical subjects

K S Clifford Chao

Publications and source records attributed to K S Clifford Chao.

At least 19 recordsLinked to original sources

PubMed2007

Intensity-modulated radiation therapy in head and neck cancers: an update.

Intensity-modulated radiation therapy (IMRT), an advent of three-dimensional conformal radiotherapy (3D CRT), has excited the profession of radiation oncology more than any other new invention since the introduction of the linear accelerator. Approximately 1000 articles have been published on this topic to date, more than 200 of which focus on head and neck cancer. IMRT is based on computer-optimized treatment planning and a computer-controlled treatment delivery system. The computer-driven technology generates dose distributions that sharply conform to the tumor target while minimizing the dose delivered to the surrounding normal tissues. The high dose volume that tailors to the 3D configuration of the tumor along with the ability to spare the nearby normal tissues allows the option of tumor dose escalation. The head and neck region is an ideal target for this new technology for several reasons. First, IMRT offers the potential for improved tumor control through delivery of high doses to the target volume. Second, because of sharp dose gradients, IMRT results in the relative sparing of normal structures, such as the parotid glands, in the head and neck region. Third, organ motion is virtually absent in the head and neck region so, with proper immobilization, treatment can be accurately delivered. Although this is a relatively new technology, single-institution retrospective studies show better dosimetric profiles compared with conventional radiation techniques, as well as excellent clinical results. Salivary gland sparing using IMRT has also resulted in reduced incidence and severity of xerostomia, and this has been tested in a randomized trial against conventional radiotherapy for early-stage nasopharyngeal cancer. The results do confirm that IMRT does decrease xerostomia compared with conventional radiotherapy.

Head and Neck Neoplasms↗

PubMed2006

Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response.

PURPOSE: Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown. EXPERIMENTAL DESIGN: The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation. RESULTS: We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells. CONCLUSIONS: These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.

Adenocarcinoma↗

PubMed2006

Early detection of chemoradioresponse in esophageal carcinoma by 3'-deoxy-3'-3H-fluorothymidine using preclinical tumor models.

PURPOSE: Early identification of esophageal cancer patients who are responding or resistant to combined chemoradiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemoradiotherapy in experimental models of esophageal carcinoma. EXPERIMENTAL DESIGN: The in vitro and ex vivo tumor uptake of [(3)H]FLT in SEG-1 human esophageal adenocarcinoma cells were studied at various early time points after docetaxel plus irradiation and validated with conventional assessments of cellular proliferation [thymidine (Thd) and Ki-67] and [(18)F]FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [(18)F]FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments. RESULTS: In vitro [(3)H]FLT and [(3)H]Thd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P = 0.005). The [(3)H]FLT tumor-to-muscle uptake ratio in xenografts declined by 75% compared with baseline (P < 0.005) by 2 days after chemoradiotherapy, despite the lack of change in tumor size. In contrast, the decline of [(3)H]FDG uptake was gradual and less pronounced. Tumor uptake of [(3)H]FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [(3)H]FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [(18)F]FLT and [(18)F]FDG tumor uptake. Autoradiographs displayed spatial correlations between [(18)F]FLT uptake and histologic Ki-67 distribution in preliminary studies. CONCLUSIONS: FLT-PET is suitable and more specific than FDG-PET for depicting early reductions in tumor proliferation that precede tumor size changes after chemoradiotherapy.

Animals↗

PubMed2006

Association of activated transcription factor nuclear factor kappab with chemoradiation resistance and poor outcome in esophageal carcinoma.

PURPOSE: The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor kappaB (NF-kappaB), a transcriptional factor, is constitutively activated or treatment induced in esophageal cancer and may influence treatment outcomes. PATIENTS AND METHODS: Pre- and post-treatment cancer specimens from patients enrolled onto a clinical trial were studied for the expression of activated NF-kappaB protein and it was correlated with histologic features, pathologic response, metastatic potential, overall survival (OS), and disease-free survival (DFS). RESULTS: Forty-three patients undergoing the same therapy on a protocol were studied. Twenty-one (72%) of 29 patients achieving less than complete pathologic response (pathCR) had NF-kappaB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-kappaB positive cancer (P = < .001). Activated NF-kappaB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-kappaB positive patients developed metastases compared to none of 22 NF-kappaB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-kappaB positive patients had died compared to only one (5%) of 22 NF-kappaB negative patients (P = .0013). Observations were similar for DFS (P = .0006). In a multivariate model (using baseline stage, pathCR or less than pathCR, age, presence of metastatic lymph nodes in the surgical specimen, and NF-kappaB expression) NF-kappaB activation was the only independent predictor of DFS (P = .010) and OS (P = .015). CONCLUSION: Our data suggest that esophageal cancers with activated NF-kappaB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-kappaB regulated pathways may uncover potential therapeutic targets.

Adult↗

PubMed2006

Importance of patient examination to clinical quality assurance in head and neck radiation oncology.

BACKGROUND: When quality assurance programs in clinical radiation oncology focus mainly on the technical aspects of treatment, they tend to underplay questions of therapeutic process and outcome. We determined the value of clinical peer review in radiation therapy for head and neck cancer that involved head and neck examination. METHODS: Data were collected prospectively on 134 consecutive patients with preliminary radiation therapy (RT) plans. Peer review was performed that included head and neck examination and imaging review to confirm target localization. RESULTS: Peer review led to changes in treatment plans for 66% of patients. Most changes were minor, but 11% of changes were major and thought to be of a magnitude that could potentially affect therapeutic outcome or normal tissue toxicity. Most changes involved target delineation based on physical findings CONCLUSIONS: Peer review of radiation target localization in RT plans led to changes that could potentially affect rates of cancer control or complication in about 10% of patients. We suggest that the accuracy of head and neck radiation oncology treatment plans might be increased by co-examination by another head and neck cancer specialist, typically a radiation oncologist or head and neck surgeon, to confirm RT target volumes.

Clinical Competence↗

PubMed2006

Functional imaging for early prediction of response to chemoradiotherapy: 3'-deoxy-3'-18F-fluorothymidine positron emission tomography--a clinical application model of esophageal cancer.

Pathologic complete response after neoadjuvant chemoradiation therapy is associated with increased survival in esophageal cancer. Early detection of response or nonresponse to neoadjuvant chemoradiation might allow individualization of treatment strategies and avoidance of unnecessary treatment. Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) permits detection of changes in tumor proliferation before any change in tumor size occurs, and FDG-PET findings have been correlated with outcomes in esophageal cancer. However, FDG-PET may fail to distinguish between residual tumor and inflammation and between complete response and partial response with substantial residual tumor burden. PET with the nucleoside analogue 3'-deoxy-3'-18F-fluorothymidine (FLT) has been found to be more accurate than FDG-PET in visualizing early changes in tumor proliferation. In a recent study in experimental models of esophageal cancer, FLT-PET was more accurate than FDG-PET in detecting early changes in proliferation following docetaxel and radiation therapy in human SEG-1 cells and mouse SEG-1 xenografts, including having a much stronger correlation with histologic findings. Clinical studies are needed to determine if FLT-PET can distinguish among degrees of response to neoadjuvant chemoradiation in patients with esophageal cancer.

Combined Modality Therapy↗

PubMed2006

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy.

PURPOSE: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.

Antigens, Neoplasm↗

PubMed2006

Effect of regression of enlarged neck lymph nodes on radiation doses received by parotid glands during intensity-modulated radiotherapy for head and neck cancer.

OBJECTIVES: The regression of enlarged neck lymph nodes during intensity-modulated radiotherapy (IMRT) may increase actual radiation doses to the parotid glands of patients with head-and-neck cancer. We investigated the changes in the lymph nodes volume during IMRT and the effect of these changes to the parotid gland doses. METHODS: Ten head and neck cancer patients with enlarged neck lymph nodes were enrolled in this study. Computed tomography (CT) imaging was repeated to evaluate the change in lymph nodes volume after initial 45 Gy, and the second part of IMRT (21 Gy) was then replanned to reflect the change of nodal tumor volume. The dosimetric benefit of parotid sparing with replanning was compared with that of no replanning. RESULTS: The enlarged neck lymph nodes in all patients pushed the parotid glands outward in pretreatment CT images. After 45 Gy of IMRT, nodal regression caused the parotid glands to shift inward into the high-dose area. When compared with those without replanning, we found modification of IMRT plan after 45 Gy significantly reduced radiation dose to parotid glands (mean reduction of 2.95 +/- 1.10 Gy to the left and 3.23 +/- 1.37 Gy to the right, respectively; P < 0.001). CONCLUSIONS: Excessive parotid gland doses secondary to the regression of enlarged neck nodes could be mitigated by replanning after 45 Gy. However, recontouring of large lymph nodes that regress during therapy has a risk of under-dosing extracapsular extension of lymph node metastases. Therefore, recontouring should be done with extreme caution.

Adult↗

PubMed2006

Additional value of PET/CT over PET in assessment of locoregional lymph nodes in thoracic esophageal squamous cell cancer.

UNLABELLED: The aim of this study was to compare the value of reviewing combined 18F-FDG PET/CT images with that of reviewing side-by-side PET and CT images in the diagnosis of locoregional lymph node metastases in patients with esophageal squamous cell cancer. METHODS: From November 2003 to December 2005, 45 patients with thoracic esophageal squamous cell cancer underwent 18F-FDG PET/CT before surgery. The results of reviewing combined PET/CT images and side-by-side PET and CT images for the diagnosis of locoregional lymph node metastases were compared prospectively in relation to pathologic findings. RESULTS: All patients underwent successful surgery, and pathologic examination confirmed nodes positive for metastasis in 32 patients and 82 of 397 excised nodal groups. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT were 93.90% (77/82 nodal groups), 92.06% (290/315), 92.44% (367/397), 75.49% (77/102), and 98.31% (290/295), respectively, whereas those of PET were 81.71% (67/82), 87.30% (275/315), 86.15% (342/397), 62.62% (67/107), and 94.83% (275/290), respectively. P values were 0.032, 0.067, 0.006, 0.063, and 0.037, respectively. The differences in sensitivity, accuracy, and negative predictive value between PET and PET/CT were statistically significant. CONCLUSION: PET/CT improves the sensitivity, accuracy, and negative predictive value of 18F-FDG imaging in the assessment of locoregional lymph nodes in thoracic esophageal squamous cell cancer and provides data of diagnostic significance.

Adult↗

PubMed2005

Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes.

PURPOSE: To determine the optimal clinical target volume margins around the gross nodal tumor volume in head-and-neck cancer by assessing microscopic tumor extension beyond cervical lymph node capsules. METHODS AND MATERIALS: Histologic sections of 96 dissected cervical lymph nodes with extracapsular extension (ECE) from 48 patients with head-and-neck squamous cell carcinoma were examined. The maximum linear distance from the external capsule border to the farthest extent of the tumor or tumoral reaction was measured. The trends of ECE as a function of the distance from the capsule and lymph node size were analyzed. RESULTS: The median diameter of all lymph nodes was 11.0 mm (range: 3.0-30.0 mm). The mean and median ECE extent was 2.2 mm and 1.6 mm, respectively (range: 0.4-9.0 mm). The ECE was <5 mm from the capsule in 96% of the nodes. As the distance from the capsule increased, the probability of tumor extension declined. No significant difference between the extent of ECE and lymph node size was observed. CONCLUSION: For N1 nodes that are at high risk for ECE but not grossly infiltrating musculature, 1 cm clinical target volume margins around the nodal gross tumor volume are recommended to cover microscopic nodal extension in head-and-neck cancer.

Adult↗

PubMed2005

Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.

PURPOSE: We investigated the factors that affect salivary function after head-and-neck radiotherapy (RT), including parotid gland dose-volume effects, potential compensation by less-irradiated gland tissue, and functional recovery over time. METHODS AND MATERIALS: Sixty-five patients with head-and-neck tumors were enrolled in a prospective salivary function study. RT was delivered using intensity-modulated RT (n = 45), forward-planning three-dimensional conformal RT (n = 14), or three-dimensional conformal RT with an intensity-modulated RT boost (n = 6). Whole salivary flow was measured before therapy and at 6 months (n = 61) and 12 months (n = 31) after RT. A wide variety of dose-volume models to predict post-RT salivary function were tested. Xerostomia was defined according to the subjective, objective, management, analytic (SOMA) criteria as occurring when posttreatment salivary function was < 25% of the pretreatment function. Multivariate logistic regression analysis was used to assess the combined effect of dose-volume, patient-, and treatment-related factors. RESULTS: A significant correlation was observed between the relative quality-of-life scores and relative stimulated saliva values at 6 months after RT (Spearman's correlation coefficient [R(s)] = 0.46, p < 0.001). The dose-volume factors were by far the strongest correlates with stimulated saliva flow, although other factors showed modest significance in multimetric models (chemotherapy, gender, and Karnofsky performance status). Several fitted dose-volume models provided a good mathematical description of the data. Significant noise in the salivary measurements (repeated measurement coefficient of variation was 27% in normal subjects) precluded selection of any one of the models presented solely on the basis of the objective fit criteria. Nevertheless, the mean dose-exponential model, in which each parotid gland's relative salivary gland function equaled exp(-A x mean gland dose), with A equal to 0.054/Gy (68% confidence interval 0.052-0.059), provided a good representation of the data and was incorporated into our multimetric analysis. Using that model, we estimated that a mean parotid dose of 25.8 Gy, on average, was likely to reduce a single parotid gland's flow to 25% of its pretreatment value, regardless of the treatment delivery method. Significant correlations were observed between a logistic multivariate model (incorporating the mean dose-exponential equation, gender, and Karnofsky performance status) and stimulated saliva flow at 6 months (R(s) = 0.73), stimulated saliva flow at 12 months (R(s) = 0.54), and quality-of-life score at 6 months (R(s) = 0.35) after RT. CONCLUSION: Stimulated parotid salivary gland dose-volume models strongly correlated with both stimulated salivary function and quality-of-life scores at 6 months after RT. The mean stimulated saliva flow rates improved from 6 to 12 months after RT. Salivary function, in each gland, appeared to be lost exponentially at a rate of approximately 5%/1 Gy of mean dose. Additional research is necessary to distinguish among the models for use in treatment planning. The incidence of xerostomia was significantly decreased when the mean dose of at least one parotid gland was kept to < 25.8 Gy with conventional fractionation. However, even lower mean doses imply increased late salivary function.

Adult↗

PubMed2005

Intensity-modulated radiotherapy: is xerostomia still prevalent?

Conformal radiation with intensity-modulated radiotherapy (IMRT) is a technique that potentially can minimize the dose to salivary glands and thereby decrease the incidence of xerostomia. Precise target determination and delineation is most important when using salivary gland-sparing techniques of IMRT. Reduction of xerostomia can be achieved by sparing the salivary glands on the uninvolved oral cavity and keeping the mean parotid gland dose of less than 26 to 30 Gy as a planning criterion if the treatment of disease is not compromised and parotid function preservation is desired.

Carcinoma, Squamous Cell↗

PubMed2005

Technology insight: PET and PET/CT in head and neck tumor staging and radiation therapy planning.

The evolving utilization of functional imaging, mainly 2-[18F]fluoro-2-deoxyglucose (18FDG) imaging, with positron emission tomography (PET) and PET/CT, is profoundly altering head and neck tumor staging approaches, radiation treatment planning, and follow-up management. Tumor-node-metastasis staging with PET/CT has improved the characterization of patient disease versus CT, MRI, or PET alone, thereby affecting patient disease management. Therefore, the utilization of PET/CT is appropriate for head and neck cancer staging in the initial presentation and in the recurrent setting. In the setting of radiation therapy treatment planning, PET-directed tumor volume contouring is not ready for clinical practice without further technological improvements in imaging specificity/sensitivity and resolution. Patient or organ motion might interfere with the accuracy of anatomical co-alignment, and variability in defining the threshold of imaging signals on PET images can affect the contour of the biological tumor volume. The use of PET/CT for staging and detecting both primary and recurrent head and neck cancer is valuable; however, its application in radiation treatment planning should be viewed as investigational.

Female↗

PubMed2005

Current imaging paradigms in radiation oncology.

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.

Humans↗

PubMed2004

Sinonasal malignancies with neuroendocrine differentiation: patterns of failure according to histologic phenotype.

BACKGROUND: Sinonasal neuroendocrine tumors are rare malignancies that are represented by a spectrum of histologies, including esthesioneuroblastoma (ENB), sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and small cell carcinoma (SmCC). The authors reviewed their institutional experience to determine whether sinonasal neuroendocrine tumors of different histologies have distinct clinical characteristics that warrant individualized treatment approaches. METHODS: The authors treated 72 adults with pathologically proven, nonmetastatic, primary sinonasal neuroendocrine tumors from 1982 to 2002. There were 31 patients with ENB, 16 patients with SNUC, 18 patients with NEC, and 7 patients with SmCC. Patients with ENB usually were treated with local therapy alone (surgery and/or radiotherapy); only 3 of 31 patients (9.7%) received treatment (radiation) to regional lymphatics, and only 5 of 31 patients (16.1%) received chemotherapy. In contrast, patients with non-ENB histologies usually received chemotherapy (10 of 16 patients with SNUC, 12 of 18 patients with NEC, and 5 of 7 patients with SmCC), and nonsurgical locoregional therapy was used more frequently (6 of 16 patients with SNUC, 4 of 18 patients with NEC, and 5 of 7 patients with SmCC). RESULTS: The median follow-up for surviving patients was 81.5 months (range, 6-266 months). The Kaplan-Meier estimate of overall survival at 5 years was 93.1% for patients with ENB, 62.5% for patients with SNUC, 64.2% for patients with NEC, and 28.6% for patients with SmCC (P = 0.0029; log-rank test). The local control rate at 5 years also was superior for patients who had ENB (96.2%) compared with patients who had SNUC (78.6%), NEC (72.6%), or SmCC (66.7%) (P = 0.04). The regional failure (RF) rate at 5 years was 8.7% for patients with ENB, 15.6% for patients with SNUC, 12.9% for patients with NEC, and 44.4% for patients with SmCC. Additional late events increased the RF rate for patients with ENB to 31.9% at 10 years. The distant metastasis rate at 5 years was 0.0% for patients with ENB, 25.4% for patients with SNUC, 14.1% for patients with NEC, and 75.0% for patients with SmCC. CONCLUSIONS: This spectrum of malignancies with neuroendocrine features shares a common site of origin within the head and neck, but their natural histories appear to diverge into two main groups: ENB and non-ENB. Patients with ENB had excellent local and distant control rates with local therapy alone. Given the higher rates of systemic failure for patients with SNUC, NEC, and SmCC, the authors favor the use of combined-modality therapy for these patients.

Adolescent↗

PubMed2004

Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.

PURPOSE: Many patients receiving fractionated radiotherapy (RT) for head-and-neck cancer have marked anatomic changes during their course of treatment, including shrinking of the primary tumor or nodal masses, resolving postoperative changes/edema, and changes in overall body habitus/weight loss. We conducted a pilot study to quantify the magnitude of these anatomic changes with systematic CT imaging. METHODS AND MATERIALS: Fourteen assessable patients were enrolled in this pilot study. Eligible patients had to have a pathologic diagnosis of head-and-neck cancer, be treated with definitive external beam RT, and had have gross primary and/or cervical nodal disease measuring at least 4 cm in maximal diameter. All patients were treated using a new commercial integrated CT-linear accelerator system (EXaCT) that allows CT imaging at the daily RT sessions while the patient remains immobilized in the treatment position. CT scans were acquired three times weekly during the entire course of RT, and both gross tumor volumes (GTVs: primary tumor and involved lymph nodes) and normal tissues (parotid glands, spinal canal, mandible, and external contour) were manually contoured on every axial slice. Volumetric and positional changes relative to a central bony reference (the center of mass of the C2 vertebral body) were determined for each structure. RESULTS: Gross tumor volumes decreased throughout the course of fractionated RT, at a median rate of 0.2 cm(3) per treatment day (range, 0.01-1.95 cm(3)/d). In terms of the percentage of the initial volume, the GTVs decreased at a median rate of 1.8%/treatment day (range, 0.2-3.1%/d). On the last day of treatment, this corresponded to a median total relative loss of 69.5% of the initial GTV (range, 9.9-91.9%). In addition, the center of the mass of shrinking tumors changed position with time, indicating that GTV loss was frequently asymmetric. At treatment completion, the median center of the mass displacement (after corrections for daily setup variation) was 3.3 mm (range, 0-17.3 mm). Parotid glands also decreased in volume (median, 0.19 cm(3)/d range, 0.04-0.84 cm(3)/d), and generally shifted medially (median, 3.1 mm; range, 0-9.9 mm) with time. This medial displacement of the parotid glands correlated highly with the weight loss that occurred during treatment. CONCLUSION: Measurable anatomic changes occurred throughout fractionated external beam RT for head-and-neck cancers. These changes in the external contour, shape, and location of the target and critical structures appeared to be significant during the second half of treatment (after 3-4 weeks of treatment) and could have potential dosimetric impact when highly conformal treatment techniques are used. These data may, therefore, be useful in the development of an adaptive RT scheme (periodic adjustment of the conformal treatment plan) that takes into account such treatment-related anatomic changes. In theory, such a strategy would maximize the therapeutic ratio of RT.

Adult↗

PubMed2004

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.

BACKGROUND: Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control. METHODS: Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43). RESULTS: After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment. CONCLUSIONS: Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.

Adolescent↗

PubMed2004

Intensity-modulated radiation therapy for oropharyngeal carcinoma: impact of tumor volume.

PURPOSE: To assess the therapeutic outcomes in oropharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT) and analyze the impact of primary gross tumor volume (GTV) and nodal GTV (nGTV) on survival and locoregional control rates. METHODS AND MATERIALS: Between February 1997 and September 2001, 74 patients with squamous cell carcinoma of the oropharynx were treated with IMRT. Thirty-one patients received definitive IMRT; 17 also received platinum-based chemotherapy. Forty-three patients received combined surgery and postoperative IMRT. The median follow-up for all patients was 33 months (range, 9-60 months). Fifty-two patients (70.3%) had Stage IV disease, 17 patients (23%) had Stage III, 3 patients (4.1%) had Stage II, and 2 patients (2.7%) had Stage I tumors. The mean prescription dose was 70 and 66 Gy, respectively, for the definitive and postoperative cohorts. The daily fraction dose was either 1.9 or 2 Gy, five times weekly. The GTV and/or nGTV were determined and derived using the Computational Environment for Radiotherapy Research, a free software package developed at Washington University. The mean GTV was 30.5 +/- 22.3 cm(3), and the mean nGTV was 23.2 +/- 20.6 cm(3). RESULTS: Ten locoregional failures were observed. Six patients died of disease and three died of concurrent disease. Distant metastasis developed in 6 patients. The 4-year estimate of overall survival was 87%, and the 4-year estimate of disease-free survival was 81% (66% in the definitive vs. 92% in the postoperative RT group). The 4-year estimate of locoregional control was 87% (78% in the definitive vs. 95% in the postoperative RT group); the 4-year estimate of distant metastasis-free survival was 90% (84% in the definitive vs. 94% in the postoperative group). Multivariate analysis showed that GTV and nGTV were independent risk factors determining locoregional control and disease-free survival for definitive oropharyngeal IMRT patients. The worst late toxicities documented were as follows: 32 patients with Grade 1 and 9 with Grade 2 xerostomia; 2 with Grade 1 and 1 with Grade 2 skin toxicity; 3 with Grade 1 late mucositis; and 3 with Grade 1 trismus. Seventeen patients required gastrostomy tube placement. CONCLUSION: IMRT is an effective treatment modality for locally advanced oropharyngeal carcinoma. The GTV and nGTV are the most important factors predictive of therapeutic outcome.

Adult↗