Biomedical subjects

Susan L Tucker

Publications and source records attributed to Susan L Tucker.

At least 37 records · Page 2Linked to original sources

PubMed2005

Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy.

PURPOSE: To identify the clinical and pathologic factors predictive of locoregional recurrence (LRR) after neoadjuvant chemotherapy, mastectomy, and radiotherapy. METHODS AND MATERIALS: We retrospectively reviewed the hospital records of 542 patients treated on six consecutive institutional prospective trials using neoadjuvant chemotherapy and postmastectomy radiotherapy. The clinical stage (American Joint Committee on Cancer, 1988) was Stage II in 17%, Stage IIIA in 30%, Stage IIIB in 43%, and Stage IV (ipsilateral supraclavicular disease) in 10%. All LRRs were considered events, irrespective of the timing to distant metastases. RESULTS: The median follow-up was 70 months. The 5-year and 10-year actuarial LRR rate was 9% and 11%, respectively. The clinical factors associated with LRR included combined clinical stage, clinical T stage, ipsilateral supraclavicular nodal disease, chemotherapy response, physical examination size after chemotherapy, and no tamoxifen use (p < or = 0.04 for all factors). The pathologic predictors of LRR included the number of positive nodes, dissection of <10 nodes, multifocal/multicentric disease, lymphovascular space invasion, extracapsular extension, skin/nipple involvement, and estrogen receptor-negative disease (p <or = 0.05 for all factors). Multivariate Cox regression analysis revealed that five factors independently predicted for LRR: skin/nipple involvement, supraclavicular nodal disease, no tamoxifen use, extracapsular extension, and estrogen receptor-negative disease (hazard ratio, 2.1-2.8; p < or = 0.02 for all factors). The 10-year LRR rate was only 4% for patients with one or none of these five independent factors, 8% for those with two factors, and 28% for those with three or more factors (p < 0.0001). CONCLUSION: Although the long-term rate of LRR after neoadjuvant chemotherapy, mastectomy, and radiotherapy is low, we identified a number of factors that correlated independently with greater rates of LRR. Patients with three or more of these factors may benefit from research protocols investigating alternative treatment strategies.

Adult↗

PubMed2005

Nasopharyngeal cancer in the Middle East: experience of the American University of Beirut Medical Center.

PURPOSE: To review the data of nasopharyngeal carcinoma (NPC) treated at the American University of Beirut Medical Center and reflect on the characteristics and treatment outcome of NPC in the Middle East compared with those of Western countries and countries in which NPC is endemic. METHODS AND MATERIALS: Between 1966 and 1998, 151 patients with the diagnosis of NPC received definitive radiotherapy at the American University of Beirut Medical Center. Of the 151 patients, 111 were males (gender ratio, 2.78); the median age was 45 years (range, 11-75 years). Most (95%) patients (n = 144) were Lebanese, 4 were Syrians, and 3 were from the Gulf countries. Most (60%) patients (n = 91) had Stage IV disease, 27% had Stage III, and 13% had Stage I or II disease; nodal disease was present in 117 patients (77%). The pathologic type was predominantly lymphoepithelioma or World Health Organization type III (95 patients, 63%). Treatment consisted of definitive radiotherapy alone for 116 patients (77%). All others received induction chemotherapy, primarily with cisplatin-containing regimens. The median radiation dose was 66 Gy (range, 47-73 Gy) to the primary and 67 Gy (range, 49-85 Gy) to involved neck nodes given at 2 Gy/fraction. The average follow-up was 3.02 years (range, 0.1-24.5 years). RESULTS: The 5-year and 10-year disease-free survival (DFS) rate was 46%. Using univariate analyses, the following factors significantly affected DFS: node size (<3 vs. 3-6 vs. >6 cm; p = 0.01), node level (upper vs. mid vs. lower neck; p = 0.004), and duration of radiotherapy (p = 0.002). However, T stage, age, gender, radiation dose, use of chemotherapy, and histologic features had no statistically significant influence on DFS. The actuarial rate of local control at 5 and 10 years was 81% and 73%. T stage, N stage, and histologic features were statistically significant variables for local control in the univariate analyses. Using a Cox regression model, N stage (N1-N2 vs. N3; relative risk 2.09, p = 0.004) was identified as an independent variable for DFS, and N stage and pathologic features were identified as independent variables for local control. The actuarial rate of distant metastases was 32% at both 5 and 10 years. Distant metastases were only affected by N stage (upper-mid vs. lower neck; p = 0.004). Six patients (4%) were reported to have Grade 4 late complications. CONCLUSION: Our results indicate that the characteristics of NPC patients in Lebanon and their parameters of outcome are comparable to those reported in Western series, particularly for the relative frequency and effect of lymphoepithelial histologic type. Because of potential confounding factors, no definite conclusions about induction chemotherapy could be drawn from this retrospective study.

Adolescent↗

PubMed2005

Paget's disease of the breast: there is a role for breast-conserving therapy.

BACKGROUND: The optimal surgical management of Paget's disease of the breast remains to be defined. Mastectomy has been the standard of care, but several institutions have recently advocated breast-conserving surgery, particularly for patients with minimal disease. In an effort to develop rational treatment guidelines, we examined our institutional experience with Paget's disease of the breast. METHODS: Patients with Paget's disease of the breast who had surgical therapy at our institution between 1949 and 1993 were reviewed. In addition to patient and tumor characteristics, charts were reviewed for treatment modalities, locoregional recurrence patterns, and survival. Subgroups were compared for differences in survival in both univariate and multivariate analyses. RESULTS: A total of 104 patients met the study criteria. The most common presenting symptoms were nipple discharge and eczematous changes of the nipple/areola complex. Ninety-seven patients (93.2%) had an underlying invasive or noninvasive cancer associated with Paget's disease. Ninety-two patients (88.5%) underwent mastectomy, and 12 (11.5%) had a breast-conserving procedure. On univariate analysis, patients with age <60 years at diagnosis, stage II disease, positive lymph nodes, invasive disease, or a palpable mass had significantly lower 10-year disease-specific and recurrence-free survival. There were four locoregional recurrences (three after mastectomy and one after breast conservation). There were no significant differences in overall, disease-specific, or recurrence-free survival according to the type of surgery. CONCLUSIONS: Paget's disease of the breast is almost always associated with an underlying breast cancer. Breast-conserving approaches result in local control and survival rates similar to those achieved with mastectomy.

Adult↗

PubMed2005

Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy.

PURPOSE: In this era of dose escalation, the benefit of higher radiation doses for low-risk prostate cancer remains controversial. For intermediate-risk patients, the data suggest a benefit from higher doses. However, the quantitative characterization of the benefit for these patients is scarce. We investigated the radiation dose-response relation of tumor control probability in low-risk and intermediate-risk prostate cancer patients treated with radiotherapy alone. We also investigated the differences in the dose-response characteristics using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition vs. an alternative biochemical failure definition. METHODS AND MATERIALS: This study included 235 low-risk and 387 intermediate-risk prostate cancer patients treated with external beam radiotherapy without hormonal treatment between 1987 and 1998. The low-risk patients had 1992 American Joint Committee on Cancer Stage T2a or less disease as determined by digital rectal examination, prostate-specific antigen (PSA) levels of < or =10 ng/mL, and biopsy Gleason scores of < or =6. The intermediate-risk patients had one or more of the following: Stage T2b-c, PSA level of < or =20 ng/mL but >10 ng/mL, and/or Gleason score of 7, without any of the following high-risk features: Stage T3 or greater, PSA >20 ng/mL, or Gleason score > or =8. The logistic models were fitted to the data at varying points after treatment, and the dose-response parameters were estimated. We used two biochemical failure definitions. The ASTRO PSA failure was defined as three consecutive PSA rises, with the time to failure backdated to the mid-point between the nadir and the first rise. The second biochemical failure definition used was a PSA rise of > or =2 ng/mL above the current PSA nadir (CN + 2). The failure date was defined as the time at which the event occurred. Local, nodal, and distant relapses and the use of salvage hormonal therapy were also failures. RESULTS: On the basis of the ASTRO definition, at 5 years after radiotherapy, the dose required for 50% tumor control (TCD(50)) for low-risk patients was 57.3 Gy (95% confidence interval [CI], 47.6-67.0). The gamma50 was 1.4 (95% CI, -0.1 to 2.9) around 57 Gy. A statistically significant dose-response relation was found using the ASTRO definition. However, no dose-response relation was noted using the CN + 2 definition for these low-risk patients. For the intermediate-risk patients, using the ASTRO definition, the TCD(50) was 67.5 Gy (95% CI, 65.5-69.5) Gy and the gamma50 was 2.2 (95% CI, 1.1-3.2) around TCD(50). Using the CN + 2 definition, the TCD(50) was 57.8 Gy (95% CI, 49.8-65.9) and the gamma50 was 1.4 (95% CI, 0.2-2.5). Recursive partitioning analysis identified two subgroups within the low-risk group, as well as the intermediate-risk group: PSA level <7.5 vs. > or =7.5 ng/mL. Most of the benefit from the higher doses for the low- and intermediate-risk group was derived from the patients with the higher PSA values. For the low-risk group, the dose-response curves essentially plateaued at 78 Gy. CONCLUSION: A dose-response relation was found using the ASTRO definition for low-risk prostate cancer. However, we found only marginal or no dose-response relation when the CN + 2 definition was used. Most of the benefit from the higher doses derived from low-risk patients with higher PSA levels. In all cases, little projected gain appears to exist at doses >78 Gy for these patients. A dose-response relation was noted for the intermediate-risk patients using either the CN + 2 or ASTRO definition. Most of the benefit from the higher doses also derived from the intermediate-risk patients with higher PSA levels. Some room for improvement appears to exist with additional dose increases in this group.

Aged↗

PubMed2005

Mortality risk from squamous cell skin cancer.

PURPOSE: To identify nonmelanoma skin cancer patients with squamous cell carcinoma (SCC) who are at greatest risk of disease-specific mortality. PATIENTS AND METHODS: Prospectively enrolled patients with a minimum of one pathologically confirmed skin SCC lesion, definitive treatment of the SCC lesion(s) resulting in no evidence of disease, and at least 2 months of follow-up after definitive treatment were eligible for the present longitudinal analysis. They received comprehensive clinical, pathologic evaluations and follow-up for patterns of failure and mortality. RESULTS: We enrolled 210 patients (187 men and 23 women) with a total of 277 skin SCC lesions and a median enrollment age of 68 years (range, 34 to 95 years). Median follow-up of surviving patients was 22 months. Three-year overall and disease-specific survival (DSS) rates were 70% and 85%, respectively. In univariate analyses, the clinical-pathologic factors associated with adverse DSS were local recurrence at presentation (P = .05), invasion beyond subcutaneous tissues (P = .009), perineural invasion (P = .002), lesion size (P = .0003), and depth of invasion (P = .05). Statistical models identified a homogeneous high-risk group of patients with lesions > or = 4 cm, perineural invasion, and deep invasion beyond subcutaneous structures. Three-year DSS was 100% for patients with no risk factors versus 70% for patients with at least one risk factor. CONCLUSION: Lesion size > or = 4 cm and histologic evidence of perineural invasion and deep invasion beyond subcutaneous structures were the clinical-pathologic factors most significantly associated with disease-specific mortality in skin SCC.

Adult↗

PubMed2005

Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy.

PURPOSE: The American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition has recently been compared with various alternative definitions. We assessed the effect of using an alternative failure definition on the dose-response characteristics of high-risk prostate cancer treated with radiotherapy alone. METHODS AND MATERIALS: This study included 363 high-risk prostate cancer patients treated with external beam radiotherapy alone from 1987 to 1999. These patients have one or more of the following: 1992 American Joint Committee on Cancer (AJCC) digital rectal examination (DRE) stage > or = cT3, prostate-specific antigen (PSA) > 20 ng/mL, and/or biopsy Gleason score > or = 8. We previously reported the dose response based on the ASTRO definition for these patients. In this study, a biochemical failure is defined as a PSA rise > or = 2 ng/mL above the current nadir PSA (CN + 2). The failure date is defined as the time at which the event occurred (i.e., the call date). RESULTS: Using CN + 2, the tumor control probability (TCP) continues to decrease with time as opposed to reaching a plateau as with the ASTRO definition. At 5 years, TCD50 (95% CI), the dose to achieve 50% tumor control, for high-risk prostate cancer, is 70.4 (68.0-72.9) Gy using CN + 2 [ASTRO: 75.5 (70.7-80.2) Gy]. The relative slope, gamma50 (95% CI) is 1.8 (0.8-2.8) [ASTRO: 1.7 (0.7-2.7)]. Recursive partitioning again identified two subgroups: PSA < vs. > or = 13 ng/mL (ASTRO: PSA < or = vs. > 20 ng/mL). The difference in TCD50 between the two subgroups is about 20 Gy at 5 years (ASTRO: about 15 Gy at 5 years). CONCLUSION: This analysis using the CN + 2 failure definition continues to show a dose response for the high-risk group of patients. However, the dose-response characteristics differ from those estimated using the ASTRO definition. We observed that the position (TCD50) and steepness (gamma50) of the dose-response curve changed with time as long as the TCP continued to decrease. This suggests that the dose response characteristics derived from data with longer follow-up may be different from those derived with shorter follow-up using the CN + 2 or similar failure definitions which do not back-date the failure. These changes in dose-response characteristics as well as the time dependence of dose response should be noted when investigators design dose escalation trials for the high-risk prostate cancer patients.

Adenocarcinoma↗

PubMed2004

Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis.

BACKGROUND: Cytokines have been implicated in diverse processes that are relevant to pancreatic carcinoma, including cachexia, asthenia, and tumor growth. The objective of this study was to examine the association between serum levels of proinflammatory and antiinflammatory or angiogenic cytokines and the outcomes of patients with pancreatic carcinoma. METHODS: Serum cytokine levels were measured by enzyme-linked immunosorbent assay from 51 patients with pancreatic carcinoma and from 48-62 healthy volunteers. Cytokine levels were compared with disease manifestations and overall survival. RESULTS: Circulating levels of vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-1alpha (IL-1alpha), and IL-1beta were not elevated significantly in patients with pancreatic carcinoma, but levels of IL-6, IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) were elevated significantly (P <0.05). Cytokine levels were dichotomized based on an analysis of null Martingale residuals. Patients who had IL-6 levels > 5.2 pg/mL or IL-10 levels >9.8 pg/mL had significantly worse survival compared with patients who had lower IL-6 or IL-10 levels (P <0.05). IL-8 levels were not associated with survival differences. Patients who had IL-1RA levels <159 pg/mL had significantly worse survival compared with patients who had higher IL-1RA levels (P <0.05). Higher IL-6, IL-10, and IL-8 levels were associated with poor performance status and/or weight loss. In multivariate analysis, only T4 tumors and high IL-6 levels were selected as independent prognostic factors for poor survival. CONCLUSIONS: Circulating levels of several cytokines were high in patients with pancreatic carcinoma, and their association with weight loss and poor performance status suggested that they may be involved in these disease manifestations. Furthermore, serum cytokine levels, in particular IL-6, may be a useful prognostic marker.

Adult↗

PubMed2004

Comparison of rectal dose-wall histogram versus dose-volume histogram for modeling the incidence of late rectal bleeding after radiotherapy.

PURPOSE: To compare the fits of normal-tissue complication probability (NTCP) models based on rectal dose-wall histograms (DWHs) vs. dose-volume histograms (DVHs) when the two are used to analyze a common set of late rectal toxicity data. METHODS AND MATERIALS: Data were analyzed from 128 prostate cancer patients treated with 3-dimensional conformal radiotherapy (3D-CRT) at The University of Texas M.D. Anderson Cancer Center (UTMDACC). The DVH for total rectal volume, including contents, was obtained for each patient from the treatment-planning system. A DWH was also computed, using the outer rectal contour plus an autogenerated inner contour that corresponds to an assumed 3-mm rectal wall thickness. The endpoint for analysis was Grade 2 or higher late rectal bleeding within 2 years of treatment; all patients had at least 2 years of follow-up. Four different NTCP models were fitted to the response data by using either the DVH or the DWH to describe the dose distribution to rectum or rectal wall, respectively. The 4 models considered were the Lyman model, the mean dose model, the parallel-architecture model, and a model based on the volume of a organ receiving more than a specified dose (the "cutoff-dose" model). RESULTS: For each of the models, the fit to the late rectal bleeding data was slightly improved when the analysis was based on the rectal DWH instead of on the DVH. In addition, the results of the cutoff dose and parallel architecture models were consistent with one another for the DWH data but not for the DVH data. For the DWH data, both models predict a 50% or higher incidence of Grade 2 or worse late rectal bleeding within 2 years if 80% or more of the rectal wall is exposed to doses greater than 32 Gy. A 50% or higher incidence of rectal bleeding is also predicted if the mean dose to rectal wall exceeds 53.2 Gy. CONCLUSIONS: A consistent, although modest, improvement occurs in the fits of NTCP models to the UTMDACC 2-year late rectal bleeding data when the fit is based on the rectal dose-wall histogram instead of on the dose-volume histogram for entire rectum, including contents.

Confidence Intervals↗

PubMed2004

Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy.

PURPOSE: To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. PATIENTS AND METHODS: We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation. RESULTS: Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage > or = IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P < or = .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage > or = IIIB disease, clinical T4 tumors, and four or more positive nodes (P < or = .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively. CONCLUSION: After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.

Adult↗

PubMed2004

Modulation of rodent spinal cord radiation tolerance by administration of platelet-derived growth factor.

PURPOSE: To examine the role of platelet-derived growth factor (PDGF) for ameliorating radiation myelopathy of the cervical spinal cord in a rodent model. METHODS AND MATERIALS: After developing the technique for cannulation of the basal cistern, initial animal experiments were conducted to test the feasibility of intrathecal continuous infusion of PDGF in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of PDGF. Subsequently, the dose-modification factor was determined in a larger group of rats. Irradiation was given in 2 fractions (16 Gy followed by 14-24 Gy) and animals were examined for the development of paresis. RESULTS: The initial dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (100% in saline-treated control rats, 25% with the most effective dose of PDGF, up to 100% with less effective doses). The most effective dose of PDGF was 0.014 mug per day. Subsequent experiments revealed a median effective dose (ED(50)) of 35.6 Gy (95% confidence interval, 34.7-36.5 Gy) for animals receiving this dose of PDGF in contrast to 33.8 Gy (33.4-34.3 Gy) for the control group (p = 0.003). The dose-modification factor obtained with this dose of PDGF was 1.05. CONCLUSIONS: Intrathecal administration of PDGF concomitant to irradiation of the cervical spinal cord in rats was feasible. Treatment with PDGF significantly increased the tolerance of the spinal cord. The PDGF experiments should be viewed as a proof of principle that brief therapeutic intervention in the earliest phase of damage induction can reduce late effects in the spinal cord. They form the basis for further studies of growth factor administration in this particular model.

Animals↗

PubMed2004

Correlation of gross tumor volume excursion with potential benefits of respiratory gating.

PURPOSE: To test the hypothesis that the magnitude of thoracic tumor motion can be used to determine the desirability of respiratory gating. METHODS AND MATERIALS: Twenty patients to be treated for lung tumors had computed tomography image data sets acquired under assisted breath hold at normal inspiration (100% tidal volume), at full expiration (0% tidal volume), and under free breathing. A radiation oncologist outlined gross tumor volumes (GTVs) on the breath-hold computed tomographic images. These data sets were registered to the free-breathing image data set. Two sets of treatment plans were generated: one based on an internal target volume explicitly formed from assessment of the excursion of the clinical target volume (CTV) through the respiratory cycle, representing an ungated treatment, and the other based on the 0% tidal volume CTV, representing a gated treatment with little margin for residual motion. Dose-volume statistics were correlated to the magnitude of the motion of the center of the GTV during respiration. RESULTS: Patients whose GTVs were >100 cm(3) showed little decrease in lung dose under gating. The other patients showed a correlation between the excursion of the center of the GTV and a reduction in potential lung toxicity. As residual motion increased, the benefits of respiratory gating increased. CONCLUSION: Gating seems to be advantageous for patients whose GTVs are <100 cm(3) and for whom the center of the GTV exhibits significant motion, provided residual motion under gating is kept small.

Humans↗

PubMed2004

Dosimetric uncertainties of three-dimensional dose reconstruction from two-dimensional data in a multi-institutional study.

Inconsistencies in the treatment planning process leading to dosimetric uncertainties may affect conclusions drawn from interinstitutional radiation oncology clinical trials. The purpose of this study was to assess the dosimetric uncertainties resulting from the process of reconstructing three-dimensional dose distributions from two-dimensional treatment plan information provided by participating institutions in a randomized clinical trial. This study was based on American College of Radiology Protocol #427, Locally Advanced Multi-Modality Protocol; a multi-institutional phase II randomized study involving radiation therapy for patients with inoperable non-small cell lung cancer. Several sources of dosimetric uncertainty were identified and analyzed, including image quality of hard-copy computed tomography (CT) images, slice spacing of CT scans, treatment position, interpretations of target volumes by radiation oncologists, the contouring of normal anatomic structures, and the use of common beam models for all dose calculations. Each source of uncertainty was investigated using a set of plans, with the ideal characteristics of digital images with 3-mm axial slice spacing and a flat couch, consisting of eight cases from Vanderbilt University Medical Center with electronically transferred CT data. The target volume DVH values were dependent on the additional uncertainty introduced by differences in delineation of the target volumes by the participating radiation oncologists. The DVH values for the lungs and heart were dependent on image quality and treatment position. Esophagus DVH values were not dependent on any of the sources of uncertainty. None of the structure DVH values were dependent on slice thickness or variations in the contouring of normal anatomic structures. Reconstruction of three-dimensional dose distributions from two-dimensional treatment plan information may be useful in cases for which digital CT data is not available or for historical data review. However, dosimetric accuracy will depend on image quality of the treatment planning CT data and consistency in the delineation of tumor volumes.

Body Burden↗

PubMed2004

Cluster models of dose-volume effects.

PURPOSE: Describe cluster models, normal-tissue complication probability models in which both the number and the spatial location of radiation-sterilized functional subunits play a role in defining complication probability. METHODS AND MATERIALS: Computer simulation was used to determine the maximum size cluster of sterilized subunits associated with a given dose distribution. Complications were associated with large clusters. RESULTS: Cluster models showed a volume effect, as increasing effect for constant dose when the volume increased or constant effect when the dose was reduced with increasing volume. Cluster models gave similar results to existing models when tissues were irradiated uniformly. With inhomogeneous dose distributions, on the other hand, different spatial distributions of "hot spots" may lead to different predictions of complication probability by cluster models. The result was that a higher complication probability resulted when hot spots were contiguous (clustered) than when they were dispersed, even if both situations are characterized by the same dose-volume histogram. A potential advantage of cluster models is to provide an easy, internally consistent way to predict complications arising from the inhomogeneous dose distributions that sometimes arise with intensity-modulated radiotherapy. CONCLUSION: Cluster models offer a new way to quantify complication probability in treatment situations in which a wide variety of hot-spot distributions occur.

Animals↗

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

Dose-volume response analyses of late rectal bleeding after radiotherapy for prostate cancer.

PURPOSE: To compare the fits of various normal tissue complication probability (NTCP) models to a common set of late rectal toxicity data, with the aim of identifying the best model for predicting late rectal injury after irradiation. METHODS AND MATERIALS: Late toxicity data from 128 prostate cancer patients treated on protocol with three-dimensional conformal radiotherapy at The University of Texas M.D. Anderson Cancer Center (UTMDACC) were analyzed. The dose-volume histogram for total rectal volume, including contents, was obtained for each patient, and the presence or absence of Grade 2 or worse rectal bleeding within 2 years of treatment was scored. Five different NTCP models were fitted to the data using maximum likelihood analysis: the Lyman model, the mean dose model, a parallel architecture model, and models based on either a cutoff dose or a cutoff volume. RESULTS: All five of the NTCP models considered provided very similar fits to the UTMDACC rectal bleeding data. In particular, none of the more highly parameterized models (the four-parameter parallel model, three-parameter Lyman model, or three-parameter cutoff dose and volume models) provided a better fit than the simplest of the models, the two-parameter NTCP model describing rectal bleeding as a probit function of mean dose to rectum. CONCLUSION: No dose-volume response model has yet been identified that provides a better description of the UTMDACC rectal toxicity data than the mean dose model. Because this model has relatively low predictive accuracy, the need to identify a better model remains.

Dose-Response Relationship, Radiation↗

PubMed2004

T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for locoregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiotherapy.

PURPOSE: To help define the clinical and pathologic predictors of locoregional recurrence (LRR) in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy without radiotherapy for early-stage disease. METHODS AND MATERIALS: We retrospectively reviewed the outcomes of all 132 patients with Stage I or II breast cancer treated in prospective institutional trials with neoadjuvant chemotherapy and mastectomy without radiotherapy between 1974 and 2001. The clinical stage (American Joint Committee on Cancer 1988) at diagnosis was I in 5%, IIA in 46%, and IIB in 49% of patients. The median age at diagnosis was 49 years. All patients were treated with either a doxorubicin-based neoadjuvant regimen or single-agent paclitaxel. The total LRR rates were calculated by the Kaplan-Meier method, and comparisons were made with two-sided log-rank tests. The median follow-up was 46 months. RESULTS: The actuarial LRR rate at both 5 and 10 years was 10%. Factors that correlated positively with LRR included clinical Stage T3N0 (p = 0.0057), four or more positive lymph nodes at surgery (p = 0.0001), age < or =40 years at diagnosis (p = 0.0001), and no use of tamoxifen. In the patients who did not receive tamoxifen, estrogen receptor-positive disease correlated positively with LRR (p = 0.0067). The 5-year LRR rate for the 42 patients with clinical Stage T1 or T2 disease and one to three positive lymph nodes at surgery was 5% (only two events). CONCLUSIONS: For patients with clinical Stage II breast cancer, T3 primary disease, four or more positive lymph nodes after chemotherapy, and age < or =40 years old predicted for LRR. For most patients with clinical T1 or T2 disease and one to three positive lymph nodes, the 5-year risk for LRR was low, and the routine inclusion of postmastectomy radiotherapy does not appear to be justified.

Adult↗

PubMed2004

Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer.

The deregulated expression of cyclin E as measured by the overexpression of its low molecular weight (LMW) isoforms is a powerful predictor of poor outcome in patients with breast cancer. The mechanism by which these LMW forms give tumor cells a growth advantage is not known and is the subject of this article. In this article, we provide the pathobiological mechanisms of how these LMW forms are involved in disease progression. Specifically, we show that overexpression of the LMW forms of cyclin E but not the full-length form in MCF-7 results in (a) their hyperactivity because of increased affinity for cdk2 and resistance to inhibition by the cyclin-dependent kinase inhibitors p21 and p27, (b) resistance to the growth inhibiting effects of antiestrogens, and (c) chromosomal instability. Lastly, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. Collectively, the biochemical and functional differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. These properties of the LMW forms cyclin E suggest that they are not just surrogate markers of poor outcome but bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.

Adult↗

PubMed2004

Characterization of rectal normal tissue complication probability after high-dose external beam radiotherapy for prostate cancer.

PURPOSE: Conformal radiotherapy (RT) has allowed radiation dose escalation to improve the outcome of prostate cancer. With higher doses, concern exists that rectal injury may increase. This study analyzed the utility and limitations of the widely used Lyman-Kutcher- Burman (LKB) normal tissue complication probability model in projecting the hazards of rectal complication with high-dose RT. METHODS AND MATERIALS: A total of 128 patients were included in this study. These patients were treated with three-dimensional conformal RT alone at the University of Texas M.D. Anderson Cancer Center between 1992 and 1999. Patients were treated to 46 Gy with a four-field box technique followed by a six-field arrangement to boost the total dose to 78 Gy. All doses were delivered at 2 Gy/fraction to the isocenter. The minimal follow-up was 2 years. The end point for analysis was Grade 2 or worse rectal bleeding by 2 years. The LKB model was fitted to the data using the maximal likelihood method. RESULTS: Of the 128 patients, 29 experienced Grade 2 or worse rectal bleeding by 2 years. For the entire cohort, the parameters obtained from the fit of the LKB model were as follows: the volume factor was n = 3.91 (95% confidence interval [CI] 0.031 to infinity ), dose associated with 50% chance of complication for uniform whole rectal irradiation [TD50(1)] was 53.6 Gy (95% CI 50.0-75.1), and a determinant of the steepness of the dose-response curve, (m), was 0.156 (95% CI 0.036-0.271). A statistically significant difference was found in the rate of postradiation rectal bleeding in patients with hemorrhoids vs. those without hemorrhoids. The parameters obtained for the patients without hemorrhoids were as follows: n = 0.746 (95% CI 0.026 to infinity ), TD50(1) 56.7 Gy (95% CI 49.9-75.2), and m 0.092 (95% CI 0.019-0.189). CONCLUSION: Our analysis suggests a dose response for rectal bleeding probability along with a volume effect. We found that the LKB model might have limited utility in determining a large volume effect. We further suggest that LKB model should be used with caution in clinical practice.

Dose-Response Relationship, Radiation↗