Mark Ritter, MD, PhD

PURPOSE: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach.

METHODS AND MATERIALS: Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT.

RESULTS: A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume.

CONCLUSIONS: SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

PMID:32942002 | DOI:10.1016/j.ijrobp.2020.09.010

PURPOSE: This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer.

METHODS AND MATERIALS: Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity.

RESULTS: A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively.

CONCLUSIONS: HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

PMID:32169590 | PMC:PMC7483248 | DOI:10.1016/j.prro.2020.02.013

PURPOSE: The purpose of this study was to evaluate predictors of cardiac events in esophageal cancer patients treated with neoadjuvant chemoradiotherapy (NA CRT) followed by surgery compared with surgery alone.

MATERIALS AND METHODS: We retrospectively identified patients treated for esophageal cancer between 2006 and 2016. A total of 123 patients were identified; 70 were treated with surgery alone, and 53 were treated with NA CRT. Cardiac events were scored based on Common Terminology Criteria for Adverse Events (version 4.03), and dosimetric data was compiled for all patients who received radiation. Univariate analysis and multivariable analysis (MVA) were performed to identify predictors of cardiac events. Competing risk of death regression was performed to a model the cumulative incidence of cardiac events.

RESULTS: The overall rates of grade ≥3 cardiac events were 24.5% in the NA CRT group versus 10% in the surgery group (P=0.04). On MVA, use of NA CRT (P<0.01, hazard ratio [HR]: 3.45, 95% confidence interval [CI]: 1.35-9.09) predicted for grade ≥3 cardiac events, though no dosimetric variable predicted for grade ≥3 cardiac events or overall survival. On MVA, NA CRT predicted for pericardial effusions of any grade (P<0.01, HR: 3.70, 95% CI: 1.67-8.33). The V45 Gy was the most significant predictor of pericardial effusions (P=0.012, HR: 1.03, 95% CI: 1.01-1.06) CONCLUSIONS:: NA CRT significantly increased the rate of grade ≥3 cardiac events compared with patients treated with surgery alone. Although no dosimetric parameter predicted for grade ≥3 cardiac events or survival, the V45 Gy predicted for pericardial effusions.

PMID:31313677 | PMC:PMC6828548 | DOI:10.1097/COC.0000000000000573

BACKGROUND: Alpha methylacyl A coenzyme racemase (AMACR) has shown to be an excellent immunohistological biomarker for prostate cancer (CaP). Given the connection between prostate and urethra, we hypothesized that semen ejaculate would be an ideal specimen for detection of CaP specific biomarkers, such as AMACR. This study explores the detection of semen AMACR protein in men with and without CaP.

METHODS: Semen ejaculates from 28 biopsy proven CaP patients prior to radical prostatectomy and 15 age-comparable controls were analyzed. An indirect sandwich ELISA chemiluminescence assay was used to detect semen AMACR, PSA, and Matriptase proteins. Tissue AMACR protein was quantified in 12 corresponding prostatectomy specimens using automated quantitative analysis (AQUA).

RESULTS: Semen AMACR protein was detected in 23 of 28 (82%) CaP patients and 23 of 24 (96%) CaP patients with significant tumor volume (>0.5 cc or 0.3 g). Among the 5 cancer patients with undetectable semen AMACR, 4 patients had small tumor volumes (<1% or 0.3 g). Semen AMACR protein was also detected in 7 of 15 (47%) control noncancer patients. Using 76 ng/ml as a cutoff value, 20 of 28 (71%) patients and 20 of 24 (83%) patients with significant tumor volume were positive for semen AMACR protein, whereas only 5 of 15 (33%) age-comparable controls were positive. AMACR levels degrade with time.

CONCLUSIONS: This is the first study to demonstrate that AMACR protein is detectable in semen ejaculate. The higher AMACR levels detected in cancer patients suggests that semen AMACR protein may be useful as a noninvasive test for prostate cancer. Further validation is warranted.

PMID:30337219 | DOI:10.1016/j.urolonc.2018.09.010

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/β ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.

PMID:29353654 | DOI:10.1016/j.ijrobp.2017.10.020

BACKGROUND AND PURPOSE: Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer.

MATERIALS AND METHODS: In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression.

RESULTS: 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]).

CONCLUSIONS: Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.

PMID:27890426 | DOI:10.1016/j.radonc.2016.10.013

PURPOSE: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy.

METHODS AND MATERIALS: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching.

RESULTS: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses).

CONCLUSIONS: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.

PMID:27869098 | DOI:10.1016/j.ijrobp.2016.08.016

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer.

METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data.

RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001).

CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

PMID:27203227 | PMC:PMC4998053 | DOI:10.1002/cncr.30079

OBJECTIVE: This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer.

METHODS: 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years.

RESULTS: Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment.

CONCLUSIONS: Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer.

PMID:26755165 | PMC:PMC4764419 | DOI:10.1016/j.radonc.2015.12.018

PMID:25332250 | DOI:10.1200/JCO.2014.57.8302

PURPOSE: To identify sequence variants of the ataxia telangiectasia mutated (ATM) gene and establish their prevalence rate among American Indian (AI) as compared with non-AI cancer patients.

MATERIALS AND METHODS: DNA was isolated from blood samples collected from 100 AI and 100 non-AI cancer patients undergoing radiation therapy, and a blinded assessment of the ATM sequence was conducted. Quantitative PCR assessment of copy number for each exon was also performed. The main outcome measure was the prevalence of ATM variants in the two patient populations.

RESULTS: No statistically significant differences for total prevalence of ATM variants among AI and non-AI patients were found. Of the 25 variants identified, 5 variants had a prevalence of >2%, of which 4 occurred at a rate of >5% in one or both groups. The prevalence of these four variants could meaningfully be compared between the two groups. The only statistically significant difference among the groups was the c.4138C > T variant which is predicted not to affect protein function, seen in 8% of AI versus 0% of non-AI patients (P = 0.007). No exonic copy number changes were found in these patients.

CONCLUSION: This study is the first to determine the prevalence of ATM variants in AIs.

PMID:24416720 | PMC:PMC3874556 | DOI:10.3389/fonc.2013.00318

Since delivered dose is rarely the same with planned, we calculated the delivered total dose to ten prostate radiotherapy patients treated with rectal balloons using deformable dose accumulation (DDA) and compared it with the planned dose. The patients were treated with TomoTherapy using two rectal balloon designs: five patients had the Radiadyne balloon (balloon A), and five patients had the EZ-EM balloon (balloon B). Prostate and rectal wall contours were outlined on each pre-treatment MVCT for all patients. Delivered fractional doses were calculated using the MVCT taken immediately prior to delivery. Dose grids were accumulated to the last MVCT using DDA tools in Pinnacle3 TM (v9.100, Philips Radiation Oncology Systems, Fitchburg, USA). Delivered total doses were compared with planned doses using prostate and rectal wall DVHs. The rectal NTCP was calculated based on total delivered and planned doses for all patients using the Lyman model. For 8/10 patients, the rectal wall NTCP calculated using the delivered total dose was less than planned, with seven patients showing a decrease of more than 5% in NTCP. For 2/10 patients studied, the rectal wall NTCP calculated using total delivered dose was 2% higher than planned. This study indicates that for patients receiving hypofractionated radiotherapy for prostate cancer with a rectal balloon, total delivered doses to prostate is similar with planned while delivered dose to rectal walls may be significantly different from planned doses. 8/10 patients show significant correlation between rectal balloon anterior-posterior positions and some VD values.

PMID:24354754 | PMC:PMC4554757 | DOI:10.7785/tcrt.2012.500397

PURPOSE: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08.

METHODS AND MATERIALS: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria.

RESULTS: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation.

CONCLUSIONS: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

PMID:23474109 | PMC:PMC3646974 | DOI:10.1016/j.ijrobp.2013.01.016

Adenocarcinoma of the cervical esophagus is a rare tumor, in comparison to adenocarcinoma of the distal esophagus which is on the rise and is often associated with Barrett's esophagus. We present a case of aggressive cervical esophageal adenocarcinoma in a 46-year-old female with no endoscopic or histopathologic evidence of Barrett's esophagus. We discuss the possible etiology of this tumor and review the treatment options, highlighting the importance of a multidisciplinary approach to the management of this rare disease.

PMID:23304576 | PMC:PMC3529900 | DOI:10.1155/2012/826246

What's known on the subject? and What does the study add? Very few studies have examined end-of-life urological studies in men with prostate cancer. These studies reported fewer procedures in men who received primary therapy for prostate cancer. However, these studies were typically single institution or had a short follow-up period. The present study is the first population-based study examining end-of-life urological procedures and uses a geographic region encompassing 385 000 patients. Furthermore, this study incorporates both hospital- and office-based procedures. This approach has not been previously undertaken.

OBJECTIVE: To determine using a population-based approach whether men with end-stage prostate cancer who had definitive primary therapy might require fewer urological interventions. Repeated urological procedures can impact health-related quality of life in patients dying from prostate cancer.

PATIENTS AND METHODS: Using the Marshfield Epidemiological Study Area (MESA) database and tumour registry, we compared end-of-life interventions in men who died from prostate cancer between 1991 and 2009. Patient charts were queried for urological procedures using International Classification of Disease Modification, 9th edition (ICD9) codes for 3 years before death. Clinicopathological information was examined including whether the patient had a history of primary therapy (radiation or radical prostatectomy).

RESULTS: Among 280 patients dying from prostate cancer, 52 (19%) required 153 urological procedures during the last 3 years of life. The frequency of procedures increased closer to death. The most common procedures involved nephrostomy tube (56%), Foley catheter (24%) and transurethral resection of the prostate (10%). Clinicopathological features did not predict the need for an end-of-life urological procedure. There was no difference in the frequency of upper or lower tract procedures in surgery or radiation patients compared with patients without primary therapy (P = 0.556 and P = 0.508). Using a Kaplan-Meier analysis, there were no differences between groups in the proportion of patients not requiring a procedure (n = 280; P = 0.179).

CONCLUSIONS: This is the first population-based study to examine the frequency of urological procedures in patients with end-stage prostate cancer. A minority of patients (19%) required urological procedures during the final 3 years of life. A history of surgery or radiation did not influence the overall risk for urological intervention.

PMID:23130676 | PMC:PMC4209594 | DOI:10.1111/j.1464-410X.2012.11517.x

OBJECTIVE: To quantify outcomes of individuals diagnosed and treated for prostate cancer in a single institution.

DESIGN: Retrospective electronic chart abstraction.

SETTING: Marshfield Clinic, the largest private multispecialty group practice in Wisconsin, and one of the largest in the United States, provides health care services annually to approximately 385,000 unique patients through 1.8 million annual patient encounters.

PARTICIPANTS: Individuals within the Marshfield Clinic cancer registry who had been diagnosed with prostate cancer between 1960 and 2009.

METHODS: Electronic chart abstraction from the cancer registry and the electronic medical record was conducted (N=6,181). Data abstracted included age at diagnosis; stage and grade of tumor; prostate specific antigen (PSA) values before, at, and after diagnosis; initial cancer treatment; follow-up time; subsequent cancer treatments; evidence of metastasis; age of death; and cause of death, if known.

RESULTS: The average age of prostate cancer diagnosis has decreased from 70-71 years in the 1960's and 1970's to an average age at diagnosis of 67 years in the 2000's (P<0.001). This decrease in age occurred within the decades of implementation of PSA screening. Approximately 74% of men diagnosed with prostate cancer within the PSA screening era had at least one PSA test, and the presence of a PSA test did not appear to change treatment outcome. Age, grade, and stage were the biggest predictors of prostate cancer outcome. There was no difference in event-free survival between current treatment types (radical prostatectomy, brachytherapy, photon treatment, or intensity-modulated radiation therapy) (2003 or later) when stratified by age (greater than 85%, 5-year event-free survival P=0.85); however, more events occurred with older external beam radiation treatment regimens (1993-2003) (70% to 75%, 5-year event-free survival P=0.001).

CONCLUSION: Individuals diagnosed and treated for prostate cancer within the Marshfield Clinic comprehensive care setting follow national trends with a decreased age of diagnosis since the advent of PSA screening. Outcomes for individuals treated within the Clinic system are also comparable to national trends.

PMID:22537761 | PMC:PMC3421330 | DOI:10.3121/cmr.2011.1042

BACKGROUND: Postprostatectomy adjuvant or salvage radiotherapy, when using standard fractionation, requires 6.5 to 8 weeks of treatment. The authors report on the safety and efficacy of an expedited radiotherapy course for salvage prostate radiotherapy.

METHODS: A total of 108 consecutive patients were treated with salvage radiation therapy to 65 grays (Gy) in 26 fractions of 2.5 Gy. Median follow-up was 32.4 months. Median presalvage prostate-specific antigen (PSA) was 0.44 (range, 0.05-9.50). Eighteen (17%) patients received androgen deprivation after surgery or concurrently with radiation.

RESULTS: The actuarial freedom from biochemical failure for the entire group at 4 years was 67% ± 5.3%. An identical 67% control rate was seen at 5 years for the first 50 enrolled patients, whose median follow-up was longer at 43 months. One acute grade 3 genitourinary toxicity occurred, with no acute grade 3 gastrointestinal and no late grade 3 toxicities observed. On univariate analysis, higher Gleason score (P = .006), PSA doubling time ≤12 months (P = .03), perineural invasion (P = .06), and negative margins (P = .06) showed association with unsuccessful salvage. On multivariate analysis, higher Gleason score (P = .057) and negative margins (P = .088) retained an association with biochemical failure.

CONCLUSIONS: Hypofractionated radiotherapy (65 Gy in 2.5 Gy fractions in about 5 weeks) reduces the length of treatment by from 1-½ to 3 weeks relative to other treatment schedules commonly used, produces low rates of toxicity, and demonstrates encouraging efficacy at 4 to 5 years. Hypofractionation may provide a convenient, resource-efficient, and well-tolerated salvage approach for the estimated 20,000 to 35,000 US men per year experiencing biochemical recurrence after prostatectomy.

PMID:21656740 | PMC:PMC3064951 | DOI:10.1002/cncr.25824

PURPOSE: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks.

METHODS AND MATERIALS: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months.

RESULTS: The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only.

CONCLUSIONS: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.

PMID:21163590 | PMC:PMC3347884 | DOI:10.1016/j.ijrobp.2010.09.018

PURPOSE: To assess patient setup corrections based on daily megavoltage CT (MVCT) imaging for four anatomic treatment sites treated on tomotherapy.

METHOD AND MATERIALS: Translational and rotational setup corrections, based on registration of daily MVCT to planning CT images, were analyzed for 1,179 brain and head and neck (H&N), 1,414 lung, and 1,274 prostate treatment fractions. Frequencies of three-dimensional vector lengths, overall distributions of setup corrections, and patient-specific distributions of random and systematic setup errors were analyzed.

RESULTS: Brain and H&N had lower magnitude positioning corrections and smaller variations in translational setup errors but were comparable in roll rotations. Three-dimensional vector translational shifts of larger magnitudes occurred more frequently for lung and prostate than for brain and H&N treatments, yet this was not observed for roll rotations. The global systematic error for prostate was 4.7 mm in the vertical direction, most likely due to couch sag caused by large couch extension distances. Variations in systematic errors and magnitudes of random translational errors ranged from 1.6 to 2.6 mm for brain and H&N and 3.2 to 7.2 mm for lung and prostate, whereas roll rotational errors ranged from 0.8 degrees to 1.2 degrees for brain and H&N and 0.5 degrees to 1.0 degrees for lung and prostate.

CONCLUSIONS: Differences in setup were observed between brain, H&N, lung, and prostate treatments. Patient setup can be improved if daily imaging is performed. This analysis can assess the utilization of daily image guidance and allows for further investigation into improved anatomic site-specific and patient-specific treatments.

PMID:19251098 | PMC:PMC2749998 | DOI:10.1016/j.ijrobp.2008.11.054

PMID:18574097 | DOI:10.1001/archinte.168.12.1352-a

PMID:18236713

BACKGROUND: Helical tomotherapy is a unique approach to image-guided IMRT that combines features of a linear accelerator and a CT scanner. This design allows generation of megavoltage CT (MVCT) images, which among other uses, are used to verify daily setup. In this study, we assessed the image-quality, absorbed radiation doses, and clinical practicality of MVCT from our helical tomotherapy prototype unit.

MATERIALS AND METHODS: Phantom studies were first performed to assess the capabilities of MVCT. Next, MVCT images from human patients prospectively enrolled on institutional review board-approved imaging and treatment protocols were analyzed. MVCT was obtained using a 4-MV beam from the University of Wisconsin helical tomotherapy prototype device. These scans were compared with conventional kilovoltage (kVCT) images from a diagnostic CT scanner.

RESULTS: MVCT images in phantoms demonstrate an ability to detect contrast differences as small as 3%. Small objects, 1.2 to 1.6 mm, were seen with good resolution. In human subjects, MVCT imaging of tumor targets and normal anatomy revealed sufficient detail for patient repositioning. MVCT imaging of metallic objects showed minimal artifact in comparison with kVCT. Patient scans were obtained in about 1 to 5 minutes and resulted in absorbed radiation doses of 1.5 to 3 cGy.

CONCLUSIONS: MVCT is an elegant pretreatment position and setup verification tool. MVCT images of human subjects obtained from the helical tomotherapy unit showed good resolution and contrast. The high-quality three-dimensional information permits its use in day-to-day setup verification. The unique properties of MVCT also provide the potential for primary imaging of anatomic regions near metal prostheses as well as nonmedical applications. Additional investigations are underway to improve image quality, further reduce patient dose, and aid adaptive radiotherapy and dose reconstruction.

PMID:18091057 | DOI:10.1097/COC.0b013e3180546770

BACKGROUND: COX-2 is overexpressed in some cancers, including prostate cancer; however, little is known about the effect of COX-2 overexpression on outcome in radiation-treated patients with prostate cancer. We aimed to study COX-2 overexpression and outcome in a well-defined cohort of men who received treatment with short-term androgen deprivation (STAD) plus radiotherapy or long-term androgen deprivation (LTAD) plus radiotherapy.

METHODS: Men with prostate cancer who had participated in the Radiation Therapy Oncology Group (RTOG) 92-02 trial and for whom sufficient diagnostic tissue was available for immunohistochemical staining and image analysis of COX-2 expression were enrolled in this study. Patients in the 92-02 trial had been randomly assigned to treatment with STAD plus radiotherapy or LTAD plus radiotherapy. Multivariate analyses by Cox proportional hazards models were done to assess whether associations existed between COX-2 staining intensity and the RTOG 92-02 primary endpoints of biochemical failure (assessed by the American Society for Therapeutic Radiology and Oncology [ASTRO] and Phoenix criteria), local failure, distant metastasis, cause-specific mortality, overall mortality, and any failure.

FINDINGS: 586 patients with sufficient diagnostic tissue for immunohistochemical staining and image analysis of COX-2 expression were included in this study. In the multivariate analyses, the intensity of COX-2 staining as a continuous covariate was an independent predictor of distant metastasis (hazard ratio [HR] 1.181 [95% CI 1.077-1.295], p=0.0004); biochemical failure by two definitions (ASTRO HR 1.073 [1.018-1.131], p=0.008; Phoenix HR 1.073 [1.014-1.134], p=0.014); and any failure (HR 1.068 [1.015-1.124], p=0.011). The higher the expression of COX-2, the greater the chance of failure. As a dichotomous covariate, COX-2 overexpression seemed to be most discriminating of outcome for those who received STAD compared with those who received LTAD.

INTERPRETATION: To our knowledge, this is the first study to establish an association of COX-2 expression with outcome in patients with prostate cancer who have had radiotherapy. Increasing COX-2 expression was significantly associated with biochemical failure, distant metastasis, and any failure. COX-2 inhibitors might improve patient response to radiotherapy in those treated with or without androgen deprivation. Our findings suggest that LTAD might overcome the effects of COX-2 overexpression. Therefore, COX-2 expression might be useful in selecting patients who need LTAD.

PMID:17881290 | PMC:PMC2080621 | DOI:10.1016/S1470-2045(07)70280-2

PURPOSE: To evaluate whether hypofractionation is well tolerated and to preliminarily assess biochemical control of this regimen in a postprostatectomy, salvage setting.

METHODS AND MATERIALS: A retrospective analysis was performed in 50 patients treated between May 2003 and December 2005 with hypofractionated radiotherapy for biochemical recurrence after radical prostatectomy. Radiotherapy was prescribed to the prostatic fossa to 65-70 Gy in 26-28 fractions of 2.5 Gy each, using intensity-modulated radiotherapy with daily image localization. Toxicities were scored using a modified Radiation Therapy Oncology Group scale and the Fox Chase modification of Late Effects Normal Tissue scale. The median follow-up was 18.9 months (range, 5.3-35.9).

RESULTS: No Grade 3 or greater acute or late toxicities were observed. Grade 2 toxicities included four acute genitourinary, one acute gastrointestinal, two late genitourinary, and two late gastrointestinal toxicities. Of the 50 patients, 39 demonstrated a continuous biochemical response after salvage therapy, 3 had an initial response before prostate-specific antigen failure, and 7 had prostate-specific antigen progression, 1 of whom died of progressive metastatic disease. Finally, 1 patient discontinued therapy because of the diagnosis of a metachronous pancreatic cancer and died without additional prostate cancer follow-up. All remaining patients were alive at the last follow-up visit. A lower presalvage prostate-specific antigen level was the only significant prognostic factor for improved biochemical control. The estimated actuarial biochemical control rate at 2 years was 72.9%.

CONCLUSIONS: The toxicity and early biochemical response rates were consistent with expectations from conventional fractionation. Additional follow-up is required to better document the biochemical control, but these results suggest that hypofractionation is a well-tolerated approach for salvage radiotherapy.

PMID:17869014 | DOI:10.1016/j.ijrobp.2007.06.042

Depending on initial prognostic factors, an estimated 10%-60% of men who undergo definitive radiation therapy for prostate cancer may experience a biochemical recurrence. Even though hormonal therapy is standard for metastatic recurrences, no consensus exists on optimal salvage therapy for those recurrences thought confined to the prostate. Salvage treatment options for these local recurrences have historically been limited to salvage prostatectomy, hormonal therapy, or cryotherapy. Salvage prostate brachytherapy, however, uses a widely available technique and may provide another option for attaining disease control in patients with localized failures, although only about 110 cases have been reported in the literature. In this report, the authors have described their own series of salvage brachytherapy cases as well as presented a review of other such series reported in the literature. In addition, the authors included a comprehensive review of published experiences with surgery and cryotherapy as salvage options. It appears that salvage brachytherapy, when combined with careful patient selection, is at least as effective as other salvage options with comparable or potentially fewer treatment-related side effects.

PMID:17685384 | DOI:10.1002/cncr.22940

Helical tomotherapy is a volumetric image-guided, fully dynamic, intensity-modulated radiation therapy (IMRT) delivery system. The daily use of its pretreatment megavoltage (MV) CT imaging for patient setup verification allows one to correct for interfraction setup error. This is a primary requirement for the accurate delivery of complex IMRT treatment plans, which give differential radiation doses to various target volumes while conformally avoiding normal critical structures. In particular, image guidance using MV CT allows for direct target position verification with the patient in the actual treatment position just prior to therapy delivery. Moreover, since helical MV CT imaging is a slow CT imaging technique, it allows for the encoding of target motion in the resulting MV CT data set, and therefore the pretreatment verification of a motion envelope defined from four-dimensional CT.

PMID:17641508 | DOI:10.1159/000106034

PURPOSE: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT).

EXPERIMENTAL DESIGN: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure.

RESULTS: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT.

CONCLUSIONS: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.

PMID:17575222 | PMC:PMC2763095 | DOI:10.1158/1078-0432.CCR-06-2972

The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45-50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving >or=45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95% of both the PTV 70 (prostate) and PTV 56 (nodes). The EUDs for PTV 70 and PTV 56 were greater than prescription dose for all eight plans. Analysis of bio-effective DVHs demonstrated similar amounts of small bowel receiving >or=45 Gy for H-CAD and sequential plans, in spite of the significantly higher dose to which H-CAD treated the pelvic nodes. The treatment was well tolerated in the eight treated patients in that no grade 2 or higher acute gastrointestinal toxicities were seen. Prostate hypofractionation with concurrent conformal avoidance-based pelvic IMRT for high risk prostate cancer represents an efficient and promising method for achieving dose escalation both of pelvic lymph nodes and the prostate with modest acute toxicity. Unlike a vascular-guided targeting approach, conformal avoidance has the potential advantage of also encompassing at-risk nodes that are not contained within major nodal chains. A phase II trial to more thoroughly examine this treatment approach is currently underway.

PMID:16938815 | DOI:10.1080/02841860600781781

BACKGROUND: This study was designed to evaluate the integral dose (ID) received by normal tissue from intensity-modulated radiotherapy (IMRT) for prostate cancer.

METHODS AND MATERIALS: Twenty-five radiation treatment plans including IMRT using a conventional linac with both 6 MV (6MV-IMRT) and 20 MV (20MV-IMRT), as well as three-dimensional conformal radiotherapy (3DCRT) using 6 MV (6MV-3DCRT) and 20 MV (20MV-3DCRT) and IMRT using tomotherapy (6MV) (Tomo-IMRT), were created for 5 patients with localized prostate cancer. The ID (mean dose x tissue volume) received by normal tissue (NTID) was calculated from dose-volume histograms.

RESULTS: The 6MV-IMRT resulted in 5.0% lower NTID than 6MV-3DCRT; 20 MV beam plans resulted in 7.7%-11.2% lower NTID than 6MV-3DCRT. Tomo-IMRT NTID was comparable to 6MV-IMRT. Compared with 6MV-3DCRT, 6MV-IMRT reduced IDs to the rectal wall and penile bulb by 6.1% and 2.7%, respectively. Tomo-IMRT further reduced these IDs by 11.9% and 16.5%, respectively. The 20 MV did not reduce IDs to those structures.

CONCLUSIONS: The difference in NTID between 3DCRT and IMRT is small. The 20 MV plans somewhat reduced NTID compared with 6 MV plans. The advantage of tomotherapy over conventional IMRT and 3DCRT for localized prostate cancer was demonstrated in regard to dose sparing of rectal wall and penile bulb while slightly decreasing NTID as compared with 6MV-3DCRT.

PMID:16458781 | DOI:10.1016/j.ijrobp.2005.11.005

The addition of concurrent chemotherapy (CT) to standard radiotherapy (RT) for locoregional treatment has been established to improve overall survival in a variety of solid tumors. Among the many CT regimens evaluated in combination with RT in randomized controlled clinical trials and summarized in meta-analyses, platinum-containing regimens have consistently shown a survival benefit across tumor types. Cisplatin and carboplatin have been studied both as single agents and in combination with other cytotoxic drugs, concurrently with RT, but the optimal platinum-based regimen to be combined with RT continues to be explored with further investigation. In this article, the role of platinum-based CT as part of concurrent CT/RT will be discussed using 2 tumor sites in the aerodigestive tract as a paradigm: squamous-cell carcinomas of the head and neck and esophageal carcinomas. For each tumor type, we will review the state of the evidence and comment on the current state of practice and on future directions for clinical research in combined modality CT/RT.

PMID:16378902 | DOI:10.1016/j.semradonc.2005.08.002

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated.

METHODS: Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography.

RESULTS: Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion.

CONCLUSION: Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

PMID:16133531 | DOI:10.1007/s00280-005-0071-y

Two recent studies of fractionated external beam radiotherapy in early prostate cancer provide outcome data that allow a statistical estimation of the alpha/beta-ratio of the linear-quadratic model when combined with clinical data on the steepness of the dose-response curve. Results of the large randomized PR5 trial by the Ontario Clinical Oncology Group/National Cancer Institute of Canada yield an estimate of alpha/beta at 1.12 Gy with 95% confidence interval (-3.3, 5.6) Gy. A non-randomized study by Valdagni and colleagues of hyper-fractionation delivered BID versus conventional fractionation yields an alpha/beta-estimate of 8.3 Gy with 95% confidence interval (0.7, 16) Gy. Thus, the confidence interval of this latter study cannot exclude even very low values of alpha/beta. Furthermore, this point estimate may be an over-estimate if incomplete repair plays a role in the BID group of the Italian study. Taken together, the outcomes of these two studies still favor a high fractionation sensitivity of prostate cancer.

PMID:15990189 | DOI:10.1016/j.radonc.2005.06.009

PMID:14688789 | DOI:10.1016/j.currproblcancer.2003.10.002

PMID:12957275 | DOI:10.1016/s0360-3016(03)00364-x

BACKGROUND AND PURPOSE: To compare the rectal wall and bladder volume in the high dose region with or without the use of a balloon catheter with both three-dimensional (3D)-conformal and intensity modulated radiation therapy (CRT, IMRT) approaches in the treatment of prostate cancer.

MATERIAL AND METHODS: Five patients with a wide range of prostate volumes and treated with primary external beam radiation therapy for localized prostate cancer were selected for analysis. Pinnacle treatment plans were generated utilizing a 3D conformal six-field design and an IMRT seven coplanar-field plan with a novel, three-step optimization and with ultrasound localization. Separate plans were devised with a rectal balloon deflated or air inflated with and without inclusion of the seminal vesicles (SV) in the target volume. The prescription dose was 76Gy in 38 fractions of 2Gy each. Cumulative dose-volume histograms (DVHs) were analyzed for the planning target volume (PTV), rectal wall, and bladder with an inflated (60cc air) or deflated balloon with and without SV included. The volumes of rectal wall and bladder above 60, 65, and 70Gy with each treatment approach were evaluated.

RESULTS: Daily balloon placement was well-tolerated with good patient positional reproducibility. Inflation of the rectal balloon in all cases resulted in a significant decrease in the absolute volume of rectal wall receiving greater than 60, 65, or 70Gy. The rectal sparing ratio (RSR), consisting of a structure's high dose volume with the catheter inflated, divided by the volume with the catheter deflated, was calculated for each patient with and without seminal vesicle inclusion for 3D-CRT and IMRT. For 3D-CRT, RSRs with SV included were 0.59, 0.59, and 0.56 and with SV excluded were 0.60, 0.58, and 0.54 at doses of greater than 60, 65, and 70Gy, respectively. Similarly, for IMRT, the mean RSRs were 0.59, 0.59, and 0.63 including SV and 0.71, 0.66, and 0.67 excluding SV at these same dose levels, respectively. Averaged over all conditions, inflation of the rectal balloon resulted in a significant reduction in rectal volume receiving > or =65Gy to a mean ratio of 0.61 (P=0.01) or, in other words, a mean fractional high dose rectal sparing of 39%. There was a slight overall increase to 1.13 in the relative volume of bladder receiving at least 65Gy; however, this was not significant (P=0.6). Use of an endorectal balloon with a non-image-guided 3D-CRT plan produced about as much rectal dose sparing as a highly conformal, image-guided IMRT approach without a balloon. However, inclusion of a balloon with IMRT produced further rectal sparing still.

CONCLUSION: These results indicate that use of a rectal balloon with a 3D-CRT plan incorporating typical treatment margins will produce significant high dose rectal sparing that is comparable to that achieved by a highly conformal IMRT with ultrasound localization. Further sparing is achieved with the inclusion of a balloon catheter in an IMRT plan. Thus, in addition to a previously reported advantage of prostate immobilization, the use of a rectal displacement balloon during daily treatment results in high dose rectal wall sparing during both modestly and highly conformal radiotherapy. Such sparing could assist in controlling and limiting rectal toxicity during increasingly aggressive dose escalation.

PMID:12865176 | DOI:10.1016/s0167-8140(03)00056-2

PURPOSE: Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the alpha/beta ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low alpha/beta value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (alpha/beta nominally 3 Gy, but also likely to be in the 4-5 Gy range). This lower alpha/beta ratio for prostate cancer than for the surrounding late-responding normal tissue creates the potential for therapeutic gain. We analyze here possible high-gain/low-risk hypofractionated protocols for prostate cancer to test this suggestion.

METHODS AND MATERIALS: Using standard linear-quadratic (LQ) modeling, a set of hypofractionated protocols can be designed in which a series of dose steps is given, each step of which keeps the late complications constant in rectal tissues. This is done by adjusting the dose per fraction and total dose to maintain a constant level of late effects. The effect on tumor control is then investigated. The resulting estimates are theoretical, although based on the best current modeling with alpha/beta parameters, which are discussed thoroughly.

RESULTS: If the alpha/beta value for prostate is less than that for the surrounding late-responding normal tissue, the clinical gains can be rather large. Appropriately designed schedules using around ten large fractions can result in absolute increases of 15% to 20% in biochemical control with no evidence of disease (bNED), with no increase in late sequelae. Early sequelae are predicted to be decreased, provided that overall times are not shortened drastically because of a possible risk of acute or consequential late reactions in the rectum. An overall time not shorter than 5 weeks appears advisable for the hypofractionation schedules considered, pending further clinical trial results. Even if the prostate tumor alpha/beta ratio turns out to be the same (or even slightly larger than) the surrounding late-responding normal tissue, these hypofractionated regimens are estimated to be very unlikely to result in significantly increased late effects.

CONCLUSIONS: The hypofractionated regimens that we suggest be tested for prostate-cancer radiotherapy show high potential therapeutic gain as well as economic and logistic advantages. They appear to have little potential risk as long as excessively short overall times (<5 weeks) and very small fraction numbers (<5) are avoided. The values of bNED and rectal complications presented are entirely theoretical, being related by LQ modeling to existing clinical data for approximately intermediate-risk prostate cancer patients as discussed in detail.

PMID:12829147 | DOI:10.1016/s0360-3016(03)00132-9

Helical tomotherapy represents both a novel radiation treatment device and an innovative means of delivering radiotherapy. The helical tomotherapy unit itself is essentially a hybrid between a linear accelerator and a helical CT scanner for the purpose of delivering intensity-modulated radiation therapy (IMRT). The imaging capacity conferred by the CT component allows targeted regions to be visualized prior to, during, and immediately after each treatment. The megavoltage CT (MVCT) images supplant the port-films used in conventional radiotherapy, providing unprecedented anatomical detail. Image-guidance through MVCT will allow the development and refinement of the concept of "adaptive radiotherapy", the reconstruction of the actual daily delivered dose (as opposed to planned dose) accompanied by prescription and delivery adjustments when appropriate. In addition to this unique feature, helical tomotherapy appears capable of further improvements over 3-dimensional conformal radiation therapy and non-helical IMRT in the specific avoidance of critical normal structures, i.e "conformal avoidance", the counterpart of conformal radiation therapy. Based on radiobiological principles that exploit the physical advantages of helical tomotherapy, several dosimetric and clinical investigations are underway.

PMID:12625791 | DOI:10.1177/153303460200100413

Until quite recently, there was no firmly established role for cytotoxic chemotherapy in the curative management approach for many of our most common malignancies. Systemic therapy was often reserved for recurrent or metastatic disease after initial surgery and/or radiotherapy. Today, the treatment of many advanced cancer patients involves integration of chemotherapy into the definitive treatment strategy. This evolution in therapy is largely a reflection of the clinical trials process that has defined clinical benefit for the addition of chemotherapy in several settings. This is good news overall. It validates years of preclinical experimentation that predicted advantage in combining chemotherapy with radiation. Moreover, with a primary objective to increase cancer cure rates, we now see confirmatory evidence across a spectrum of recent clinical trials. Tempering this good news is the fact that these gains are often quite small. They are commonly accompanied by increased toxicity and are generally achieved in good performance status patients who may not accurately reflect the broad cancer population. In addition, the first generation of positive trials for a particular disease site are often accomplished with vastly differing treatment regimens. This frequently leaves the general oncologist to query "which specific approach is best?" In this article, we briefly trace the evolution of current therapy approaches in 2 common human solid tumors, namely cancer of the head and neck and non-small-cell cancer of the lung. The focus involves the development of chemoradiation strategies in the definitive treatment setting. Clearly, surgery plays a critical role in treatment for many patients in these anatomic categories. However, we lack randomized trials that directly compare operative versus nonoperative treatment approaches and thus have consciously neglected review of the surgical series for purposes of this article.

PMID:12520459 | DOI:10.1053/srao.2003.50001

PURPOSE: To derive optimal correction strategies for setup errors, including the uncertainty in their measurement, and to analyze their impact on treatment margins.

METHODS AND MATERIALS: New concepts like image-guided radiotherapy aim to provide an increasing amount of targeting information during treatment. Future treatment devices incorporating imaging capabilities will facilitate frequent correction of treatment setup errors. It is, therefore, possible to design new correction protocols that reduce not only systematic but also random setup errors. A novel, very general approach to developing optimal correction strategies in the presence of measurement uncertainties is derived from linear systems theory. In the simplest approach, the state variable of the system, which represents the patient, is the spatial displacement of the center-of-mass of the clinical target volume with respect to the planning CT. This displacement is the sum of a systematic and a random component. Uncertainties in the measured value of the state variable due to the measurement process, image processing technique, or organ deformation are naturally incorporated into a linear system. The true value of the displacement can be estimated from the noisy measurements with a stochastic filter (Kalman filter). These estimates provide an optimal control law for the system and therefore optimal values for the setup corrections. In the case of unknown systematic and random error variances, an adaptive version of the filter was implemented. The statistical properties of the filter were investigated by performing simulations of the state space model and assessed for individual patients and a large patient population subject to different action criteria.

RESULTS: Over a patient population, the corrections by the Kalman filter estimates are always advantageous compared with the corrections by the measured values themselves. For a small percentage of individual patients, however, the Kalman corrections worsen the results. For large measurement error, the residual standard deviation of the random setup errors can be reduced by approximately 28% for over 90% of the patients. The uncertainty in the measured value impairs the ability to completely account for uncertainties.

CONCLUSIONS: The Kalman estimates provide an effective means to perform daily setup corrections in the presence of measurement errors. The linear system approach is very versatile and can be extended to more general state variables.

PMID:12504060 | DOI:10.1016/s0360-3016(02)03867-1

PURPOSE: Some prostate cancers may have molecular alterations that render them less responsive to radiation therapy; identification of these alterations before treatment might allow improved treatment optimization. This study investigated whether p53, a potential molecular determinant, could predict long-term radiation therapy outcome in a restricted group of relatively favorable-risk prostate cancer patients treated uniformly with irradiation alone.

METHODS AND MATERIALS: This study included 53 patients previously treated with radiotherapy for favorable-to-intermediate-risk prostate cancer. These patients were selected for relatively low pretreatment PSAs (< or =21 ng/mL) and Gleason scores (< or =7) to decrease the likelihood of nonlocalized disease, because disease localization was necessary to examine the efficacy of localized radiation therapy. The status of p53 was immunohistochemically assessed in paraffin-embedded pretreatment biopsy specimens, along with appropriate controls. This marker was selected based upon a usable mutation prevalence in early-stage prostate cancer and its potential linkage with radiation response via cell cycle, DNA repair, and cell death pathways. Correlation between p53 mutation and clinical outcome was analyzed in univariate and multivariate fashion and included conventional prognosticators, such as stage, grade, and PSA. Freedom from biochemical failure was determined using American Society for Therapeutic Radiology and Oncology criteria. Limitations of prior studies were potentially avoided by requiring adequate posttreatment follow-up (median follow-up in nonfailing patients of 5.1 years), as well as pretreatment PSA and Gleason scores that suggested localized disease, and uniformity of treatment.

RESULTS: The total group of 53 favorable-to-intermediate-risk patients demonstrated an actuarial biochemical failure rate of 35% at 5 years. Forty percent of all specimens had a greater than 10% labeling index for p53 mutation, and actuarial biochemical control was found to strongly and independently correlate with p53 status. Patients with higher p53 labeling indices demonstrated significantly higher PSA failure rates (p < 0.001). In contrast, p53 status did not correlate with pretreatment PSA, grade, or tumor stage. Similarly, pretreatment PSA (log-rank 0.22), Gleason score (log-rank 0.93), and T stage (log-rank 0.15) were not prognostic for outcome in this group of patients selected for their relatively favorable clinical characteristics.

CONCLUSIONS: (1) p53 status in pretreatment biopsies strongly predicted for long-term biochemical control after radiation therapy in favorable-to-intermediate-risk prostate cancer patients. (2) If validated in other independent clinical data sets, p53 status should be considered as a stratification factor in future clinical trials and could be useful in guiding treatment. Abnormal p53 status might favor surgical management, aggressive dose escalation, or p53-targeted therapy.

PMID:12062599 | DOI:10.1016/s0360-3016(02)02781-5

PMID:11777616 | DOI:10.1016/s0360-3016(01)02665-7