Neurovascular bundle-sparing radiotherapy for prostate cancer using MRI-CT registration: A dosimetric feasibility study.

PURPOSE: Sexual dysfunction after radiotherapy for prostate cancer remains an important late adverse toxicity. The neurovascular bundles (NVB) that lie posterolaterally to the prostate are typically spared during prostatectomy, but in traditional radiotherapy planning they are not contoured as an organ-at-risk with dose constraints. Our goal was to determine the dosimetric feasibility of "NVB-sparing" prostate radiotherapy while still delivering adequate dose to the prostate. METHODS: Twenty-five consecutive patients with prostate cancer (with no extraprostatic disease on pelvic magnetic resonance imaging [MRI]) who that were treated with external beam radiotherapy, with the same primary planning target volume margins, to a dose of 79.2 Gy were evaluated. Pelvic MRI and simulation computed tomography scans were registered using dedicated software to allow for bilateral NVB target delineation on T2-weighted MRI. A volumetric modulated arc therapy plan was generated using the NVB bilaterally with 2 mm margin as an organ to spare and compared to the patient's previously delivered plan. Dose-volume histogram endpoints for NVB, rectum, bladder, and planning target volume 79.2 were compared between the 2 plans using a 2-tailed paired t-test. RESULTS: The V70 for the NVB was significantly lower on the NVB-sparing plan (p <0.01), while rectum and bladder endpoints were similar. Target V100% was similar but V105% was higher for the NVB-sparing plans (p <0.01). CONCLUSIONS: "NVB-sparing" radiotherapy is dosimetrically feasible using CT-MRI registration, and for volumetric modulated arc therapy technology - target coverage is acceptable without increased dose to other normal structures, but with higher target dose inhomogeneity. The clinical impact of "NVB-sparing" radiotherapy is currently under study at our institution.

A comprehensive review of incidence and survival in patients with rare histological variants of prostate cancer in the United States from 1973 to 2008.

BACKGROUND: The American Joint Commission on Cancer (AJCC) identifies five rare variants of prostate adenocarcinoma: mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine including small cell. No prior study has comprehensively detailed incidence and outcomes for all AJCC variants of prostate cancer. METHODS: We used the Surveillance, Epidemiology and End Results (SEER) program to analyze prostate cancers diagnosed from 1973 to 2008. Cases of mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine carcinoma were identified, along with cases of non-variant adenocarcinoma for comparison. Age-adjusted incidence rates (IRs) and overall survival (OS) were evaluated and stratified by race, age, stage and PSA. All IRs represent the number of cases per million people per year. RESULTS: Each variant is rare, with IRs between 0.03 (adenosquamous) and 0.61 (mucinous). There was a significant difference in incidence between Caucasian and African American patients with mucinous adenocarcinoma. Median OS varied ranged from 10.0 months in neuroendocrine carcinoma to 125.0 months in mucinous adenocarcinoma. In all, 5-year OS ranged from 12.6% in neuroendocrine carcinoma to 75.1% in mucinous adenocarcinoma. There was a significant difference in survival between Caucasian and African American patients for mucinous adenocarcinoma (median survival 144.0 vs 99.0 months, P<0.01). African American patients with mucinous adenocarcinoma also presented with more advanced stage disease compared with Caucasian patients. Multivariate analysis demonstrated that African American race was not associated with worse survival when corrected for stage. CONCLUSIONS: There are differences in IRs and OS among rare variants of prostate cancer. For mucinous adenocarcinoma, there are significant differences in incidence and survival between Caucasian and African American patients. These differences should be considered in clinical decision making for patients with these malignancies.

Biochemical control and toxicity after intensity-modulated radiation therapy for prostate cancer.

Intensity modulated radiation therapy (IMRT) has achieved widespread use for prostate cancer; however, in relation to this use, outcomes studies are still relatively sparse. We report a single-institutional experience in outcomes analysis with the use of IMRT for the primary management of prostate cancer. One hundred thirty consecutive patients with adenocarcinoma of the prostate were treated at a single institution using IMRT with curative intent. Thirty-six (28%) patients were classified as low-risk, 69 (53%) as intermediate-risk, and 25 (19%) as high-risk. The median dose prescription was 76 Gy to the planning target volume. Sixty-five (50%) patients received androgen deprivation therapy (ADT) for a median 4 months, starting 2 months prior to IMRT. Biochemical failure was defined as PSA < post-treatment nadir+2. Gastrointestinal (GI) and Genitourinary (GU) toxicity were defined by RTOG criteria. Median follow-up was 53 months. By NCCN risk category, 4-year biochemical control was 97%, 94%, and 87% for low, intermediate, and high-risk patients, respectively. Among disease factors, multivariable analysis demonstrated the strongest association between biochemical control and Gleason score < or =6 (p=0.0371). Therapy was well tolerated with no Grade 4 toxicity and limited grade 3 GI or GU toxicity. Acute Grade 3+ GI and GU toxicity rates were 0% and 2%, and maximal late Grade 3+ GI and GU toxicity rates were 5% and 6%, respectively. Late rectal toxicity was associated with higher volumes of RT to the rectum. By last follow-up late Grade 3+ toxicity was 2% for both GI and GU systems. In conclusion, patients treated with IMRT for prostate cancer have excellent rates of biochemical control and low rates of severe toxicity of treatment.

Grade migration in prostate cancer: an analysis using the Surveillance, Epidemiology, and End Results registry.

To utilize the Surveillance, Epidemiology, and End Results (SEER) registry to examine trends in grade assignment. Data from 411 325 patients from 1984 to 2003 were analyzed for grade migration and for cause-specific survival (CSS) as a function of grade. There has been a significant grade migration during the study period (P<0.001), principally from well-differentiated (WD) to moderately differentiated (MD) disease. Five-year CSS of MD and WD patients have converged, suggesting a decreasing role of grade as a prognostic factor. A grade migration from WD to MD assignment has occurred, suggesting that prognostic categorizations based on grade across eras may be difficult to interpret.

'Insignificant' prostate cancer on biopsy: pathologic results from subsequent radical prostatectomy.

'Insignificant' prostate cancer is defined as disease of virulence insufficient to threaten survival. In this review, which describes nine articles and two abstracts discussing almost 800 cases, we discuss the correlation of such 'insignificant' biopsy findings in the context of subsequent radical prostatectomy data. From our review, minimal disease on biopsy does not reliably predict minimal disease in the subsequent prostatectomy specimen, in terms of the size and grade of tumor, extracapsular extension or positive margins. Thus, reasoned accounting should be made of other data before undertaking a course of radiation therapy as monotherapy, particularly prostate-specific antigen kinetics and potential molecular markers.

Comparison of late gastrointestinal and genitourinary toxicity of prostate cancer patients undergoing intensity-modulated versus conventional radiotherapy using localized fields.

To compare late genitourinary (GU) and gastrointestinal (GI) toxicity of radiotherapy (RT) to localized fields for prostate cancer delivered using intensity-modulated RT (IMRT) versus conventional RT (ConvRT). The records of 461 patients were reviewed; 355 patients received IMRT and 106 received ConvRT. Late GU and GI toxicity were compared. Late GU toxicity rates were not significantly different (P=0.166); however, late GI toxicity rates were lower with IMRT (P=0.001). Regression analyses demonstrated that only IMRT use (P=0.006) predicted reduction in late GI toxicity but no factors correlated with late GU toxicity. IMRT did not influence late GU toxicity but was associated with a reduction of late GI toxicity over ConvRT.

Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques.

The purpose of this study was to assess the efficacy and toxicity of intensity-modulated radiation therapy (IMRT) in the treatment of gastric cancer. Seven patients with gastric cancer were treated with IMRT. Six patients (all Stage III) received post-operative chemoradiotherapy with concurrent 5-fluorouracil and leucovorin. One received planned pre-operative radiation, though did not proceed to surgery. All patients were planned to receive 50.4 Gy in 1.8 Gy fractions. IMRT planning was compared with opposed anterior-posterior: posterior-anterior (AP/PA) and 3-field conventional three-dimensional plans. When compared with either AP/PA or 3-field plans, IMRT significantly reduced the volume exceeding the threshold dose of the liver and at least one kidney. Target coverage with IMRT was excellent, with 98+/-1% of the target receiving >or=100% of the dose. Compared with AP/PA and 3-field plans, IMRT plans had a greater percentage of target receiving the prescribed dose, but also a greater volume receiving >110% of the dose. IMRT was well tolerated; no patients developed acute gastrointestinal toxicity greater than grade 2. All seven experienced grade 2 nausea, three had grade 2 diarrhoea and two had grade 2 oesophagitis. Weight loss ranged from 0-12% (mean 6.1% and median 5.8%). IMRT in the treatment of gastric malignancies reduces the mean and above threshold doses to critical normal tissues. In an initial cohort of seven patients, 50.4 Gy delivered by IMRT is well tolerated and safe.

Impact of hormone therapy on acute radiotherapy toxicity in the treatment of prostate cancer.

PURPOSE: To analyze the impact of neoadjuvant hormone therapy (HT) on acute gastrointestinal (GI) and genitourinary (GU) toxicity from radiotherapy (RT). SCOPE: The toxicity rates of 480 consecutive prostate cancer patients were reviewed and compared using the chi2 test. Ordered logit regression analyses were performed including the major demographic, disease, and treatment factors. Although no reduction in acute GI toxicity from HT use was observed (P=0.067), a lower rate of acute GU toxicity was observed (P=0.002). No factor reached statistical significance on regression analysis. CONCLUSIONS: Observed toxicity rates were similar or lower in patients receiving HT. Thus, increased RT toxicity should not be a concern when deciding to add neoadjuvant HT to RT for prostate cancer.

The impact of age and comorbidity on survival outcomes and treatment patterns in prostate cancer.

The management of localized prostate cancer is based on stage, grade, PSA, and subjective assessment of comorbidity and life expectancy. Over the last 15 y, stage migration and the improved use of Gleason sum, PSA and TNM staging have led to many treatment options for patients with newly diagnosed localized prostate cancer. At the same time, advances in treatment techniques have helped decrease the long-term complications of surgery and radiotherapy. However, the importance of age and comorbidity, in survival outcomes and treatment decision-making has been largely overlooked. Currently, stage, grade, and PSA are the only quantifiable variables consistently used in research and treatment decision-making. Comorbidity and life expectancy have remained largely subjective variables. Increasing longevity and a rapidly aging population have made age and comorbidity increasingly important factors in clinical research and treatment decision-making. This article reviews the importance of age and comorbidity on treatment decisions and survival outcomes in prostate cancer, as well as their use as objectively quantifiable variables. Examples from the general oncology literature are given. The overview also examines validated comorbidity indices and advocates the use of the Charlson Comorbidity Index (CCI) in research outcomes and treatment decision-making in prostate cancer. Several clinical vignettes are provided to demonstrate the potential clinical utility of the CCI as applied to prostate cancer.

Treatment of radiation-relapsing primary cutaneous B-cell lymphoma with an anti-CD20 monoclonal antibody.

Primary cutaneous B cell lymphomas have a high recurrence rate after treatment with surgery and/or local radiation therapy. Two men are described in whom radiotherapy-relapsing cutaneous B-cell lymphomas were successfully treated with the monoclonal anti-CD20 antibody rituximab. Both patients had a complete response with no recurrence at follow-up at 17 and 24 months for the large B-cell lymphoma of the leg and the follicle centre cell lymphoma, respectively. These are two of the few cases in the literature showing that rituximab is an effective and well-tolerated treatment for radiotherapy-relapsing primary cutaneous B cell lymphoma.

Sparing of the penile bulb and proximal penile structures with intensity-modulated radiation therapy for prostate cancer.

Quality of life is an important consideration in the treatment of early prostate cancer. Laboratory and clinical data suggest that higher radiation doses delivered to the bulb of penis and proximal penile structures correlates with higher rates of post-radiation impotence. The goal of this investigation was to determine if intensity-modulated radiation therapy (IMRT) spares dose to the penile bulb while maintaining coverage of the prostate. 10 consecutive patients with clinically organ confined prostate cancer were planned with 3D conformal radiation therapy (3D-CRT) or IMRT to give a dose of 74 Gy without specifically constraining the plans to spare the penile bulb. All 10 patients were ultimately treated with IMRT. Dose-volume histograms were evaluated and the doses to prostate, rectum, bladder and penile bulb were compared. IMRT reduced the mean penile bulb doses compared with 3D-CRT (33.2 Gy vs 48.9 Gy, p<0.001), the percentage of penile bulb receiving over 40 Gy (37.7% vs 67.2%, p<0.001) and the dose received by >95% of penile bulb (5.3 Gy vs 11.7 Gy, p=0.003). Maximum penile bulb doses were higher with IMRT (81.2 Gy vs 73.1 Gy, p<0.001) although the volume of this high dose region was small. Both methods resulted in similar coverage of the prostate. The volume of rectum receiving 70 Gy was significantly reduced with IMRT (18.4% vs 21.9%, p=0.003) but the volumes of bladder receiving 70 Gy were similar (p=0.3). IMRT may potentially reduce long term sexual morbidity by reducing the dose to the majority of the penile bulb.

Changing face and different countenances of prostate cancer: racial and geographic differences in prostate-specific antigen (PSA), stage, and grade trends in the PSA era.

The purpose of this investigation was to examine changes in pretreatment prostate-specific antigen (PSA), stage, and grade over the past decade as a function of race and geographic region. A multiinstitutional database representing 6,790 patients (1,417 African-American, 5,373 white) diagnosed with nonmetastatic prostate cancer between 1988 and 1997 was constructed. PSA, stage, and grade data were tabulated by calendar year and region, and time trend analyses based on race and region were performed. There was an overall decline of PSA of 0.8%/year, which was significant (P = 0.0001), with a faster rate of decline in African-Americans (1.9%/year) than for whites (0.6%/year). The odds ratio (OR) for a stage shift was 1.09, which was significant (P < 0.0001), and this shift was greater in whites. The OR for an overall grade shift was 1.15, which was significant (P < 0.0001). Although grade and PSA trends were similar for the different regions, there were significant regional differences in stage trends. The implications are that the face of prostate cancer has changed over the past decade; i.e., the distributions of stage, grade, and PSA (the most important prognosticators) have changed. In addition, the countenances of that face are different for whites and African-Americans. For African-Americans, this is good news: the stage, grade, and PSA distributions are more favorable now than before. For whites, the trends are more complex and more dependent on region. These findings should be used for future clinical and health-policy decisions in the screening and treatment of prostate cancer.

Equivalent racial outcome after conformal radiotherapy for prostate cancer: a single departmental experience.

PURPOSE: African-American (AA) men with prostate cancer present with advanced disease, relative to white (W) men. This report summarizes our clinical and biochemical control (bNED) rates after conformal radiotherapy (RT). In particular, we aim to characterize any race-based outcome differences seen after comparable treatment. PATIENTS AND METHODS: We reviewed 893 patients (418 AA and 475 W) with clinically localized prostate cancer treated between 1988 and 1997. Neoadjuvant hormonal blockade was used in 22.5% of cases, and all patients received conformal RT to a median dose of 68 Gy (range, 60 to 74.8 Gy). Biochemical failure was defined according to the American Society of Therapeutic Radiology and Oncology consensus definition. Median follow-up was 24 months (range, 1 to 114 months). RESULTS: The 5-year actuarial survival, disease-free survival, and bNED rates for the entire population were 80.5%, 70.0%, and 57.6%, respectively. When classified by prognostic risk category, the 5-year actuarial bNED rates were 78.7% for favorable, 57.7% for intermediate, and 39.8% for unfavorable category patients. AA men presented at younger ages and with more advanced disease. Controlled for prognostic risk category, AA and W men had similar 5-year actuarial bNED rates in favorable (78% v 79%, P: = .91), intermediate (52% v 62%, P: =.44), and unfavorable categories (36% v 45%, P: = .09). Race was not an independent prognostic factor (P: = .36). CONCLUSION: Conformal RT is equally effective for AA and W patients. More research is needed in order to understand and correct the advanced presentations in AA men. These data suggest a need for early screening in AA populations.

Volume rendering quantification algorithm for reconstruction of CT volume-rendered structures: Part I. Cerebral arteriovenous malformations.

Volume rendering is a visualization technique that has important applications in diagnostic radiology and in radiotherapy but has not achieved widespread use due, in part, to the lack of volumetric analysis tools for comparison of volume rendering to conventional visualization techniques. The volume rendering quantification algorithm (VRQA), a technique for three-dimensional (3-D) reconstruction of a structure identified on six principal volume-rendered views, is introduced and described. VRQA involves three major steps: 1) preprocessing of the partial surfaces constructed from each of six volume-rendered images; 2) merging these processed partial surfaces to define the boundaries of a volume; and 3) computation of the volume of the structure from this boundary information. After testing on phantoms, VRQA was applied to CT data of patients with cerebral arteriovenous malformations (AVM's). Because volumetric visualization of the cerebral AVM is relatively insensitive to operator dependencies, such as the choice of opacity transfer function, and because precise volumetric definition of the AVM is necessary for radiosurgical treatment planning, it is representative of a class of structures that is ideal for testing and calibration of VRQA. AVM volumes obtained using VRQA are intermediate to those obtained using axial contouring and those obtained using CT-correlated biplanar angiography (two routinely used visualization techniques for treatment planning for AVM's). Applications and potential expansions of VRQA are discussed.

Analysis of the role of adjuvant chemotherapy for invasive carcinoma of the esophagus.

The purpose of this report is to analyze the role and optimum integration of chemotherapy for invasive carcinoma of the esophagus in the combined modality setting. The charts of 157 patients with primary invasive nonmetastatic carcinoma of the esophagus treated with curative intent between 1984 and 1998 were reviewed. Various combinations of chemotherapy (C), radiotherapy (R), and surgery (S) were used. Chemotherapy was multiagent (typically 5-fluorouracil [5-FU]/cisplatin/hydroxyurea, 5-FU/cisplatin/leucovorin, or docetaxel/cisplatin) for all but seven patients treated with single agents. The clinical endpoints examined were overall survival (OS) and cause-specific survival (CSS). Multivariate analyses and pairwise comparisons were made for determination of the benefit of chemotherapy. On the multivariate analyses, only American Joint Committee on Cancer stage and chemotherapy were statistically significant determinants of both OS and CSS. Following are the results of the pairwise analyses: 3-year OS: (no C) versus (any C): 16% versus 27% (p = 0.02); (S) versus (C+S): 19% versus 34% (p = 0.35); (R) versus (C+R): 0% versus 13% (p = 0.05); (R + S) versus (C + R + S): 18% versus 33% (p = 0.03). The administration of adjuvant chemotherapy can improve survival in patients with invasive nonmetastatic esophageal carcinoma. This benefit appears to be greater when chemotherapy is given with radiotherapy (with or without surgery) than in the absence of radiotherapy, perhaps because of a radiosensitizing effect not possible when using surgery is the only local control modality.

PSA-based outcome analysis after radiation therapy for prostate cancer: a new definition of biochemical failure after intervention.

OBJECTIVES: To examine pretreatment variables that influence biochemical failure, and to describe and test a new definition of prostate-specific antigen (PSA)-based biochemical failure. METHODS: We introduce and describe a new definition of biochemical failure, which is based on quadratic fitting of the logarithm of the follow-up PSA profile curve. From a data base of 449 patients with prostate cancer treated with definitive radiation therapy, 230 patients who had at least five follow-up PSA observations were chosen for analysis. The new definition of failure was applied to this cohort, as was the conventional definition of two consecutive PSA rises. Univariate and multivariate analyses were performed using established pretreatment prognostic factors as covariates. Also, the association of both definitions of failure with clinical outcome (local recurrence and any recurrence) was examined. RESULTS: Application of the new definition of biochemical failure resulted in smoothing of the "noise" that is inherent in using definitions based on successive PSA rises. This smoothing was verified by smaller P values for the statistically significant covariates in the univariate analysis. Furthermore, the new definition correlated better with clinical outcome, as demonstrated by the statistically significant P values on regression analysis when using the quadratic fitted nadir compared with using the observed nadir. CONCLUSIONS: We devised a new criterion based on quadratic curve fitting for PSA-based biochemical failure. This definition is based on all available PSA information, correlates with both pretreatment factors and post-treatment clinical outcome, is relatively insensitive to noise, and allows for prediction of time of failure.

Volumetric visualization of head and neck CT data for treatment planning.

PURPOSE: To demonstrate the utility of volume rendering, an alternative visualization technique to surface rendering, in the practice of CT based radiotherapy planning for the head and neck. METHODS AND MATERIALS: Rendo-avs, a volume visualization tool developed at the University of Chicago, was used to volume render head and neck CT scans from two cases. Rendo-avs is a volume rendering tool operating within the graphical user interface environment of AVS (Application Visualization System). Users adjust the opacity of various tissues by defining the opacity transfer function (OTF), a function which preclassifies voxels by opacity prior to rendering. By defining the opacity map (OTF), the user selectively enhances and suppresses structures of various intensity. Additional graphics tools are available within the AVS network, allowing for the manipulation of perspective, field of view, data orientation. Users may draw directly on volume rendered images, create a partial surface, and thereby correlate objects in the 3D scene to points on original axial slices. Information in volume rendered images is mapped into the original CT slices via a Z buffer, which contains the depth information (Z coordinate) for each pixel in the rendered view. Locally developed software was used to project conventionally designed GTV contours onto volume rendered images. RESULTS: The lymph nodes, salivary glands, vessels, and airway are visualized in detail without prior manual segmentation. Volume rendering can be used to explore the finer anatomic structures that appear on consecutive axial slices as "points." Rendo-avs allowed for acceptable interactivity, with a processing time of approximately 5 seconds per 256 x 256 pixel output image. CONCLUSIONS: Volume rendering is a useful alternative to surface rendering, offering high-quality visualization, 3D anatomic delineation, and time savings to the user, due to the elimination of manual segmentation as a preprocessing step. Volume rendered images can be merged with conventional treatment planning images to add anatomic information to the treatment planning process.

Accuracy of object depiction and opacity transfer function optimization in CT volume-rendered images.

Volume rendering is a visualization technique that has important applications in diagnostic radiology and radiotherapy. A methodology is presented for (a) evaluation of the quantitative accuracy of representation of known objects in volume-rendered scenes and for (b) optimization of the opacity transfer function to achieve the most accurate representation of a particular structure. Results using this methodology are shown for structures representing each of the major tissue interfaces and are discussed.

MR image classification algorithms for neurosurgical and stereotactic radiosurgical trajectory planning and volumetric analysis.

Neurosurgical and stereotactic radiosurgical trajectory planning involves a phase of image data acquisition followed by localization of tissues to be avoided or crossed during the procedure. Success of the procedure is often assessed during follow-up by performing volumetric analysis of tissues of interest. Both localization and volumetric analysis can be facilitated by classifying the input data into different tissue types. This study compares classification results based on four different input image data: (1) MR data obtained with one TR and TE parameter combination, (2) MR data acquired with eight combinations of TR and TE parameters, (3) input data compressed into four principal components, and (4) the input data (3) together with first- and second-order texture features. The algorithms (a) to reduce the dimensionality using principal components, (b) to generate texture features, (c) to determine feature usefulness in classification using the Wilk's lambda criterion, and (d) to classify the input set are described. Classification results are found to be poor for input data 1 and much improved (qualitatively and quantatively) for input data 2. Input data 3 produces classification results (quantitatively and qualitatively) similar to that of 2. Input data 4 is found to produce quantitative results similar to those of 2 and 3, but the qualitative results show enhanced classification of some tissues and distortion of others.