Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK.

OBJECTIVE: To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. PATIENTS AND METHODS: A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] ≤10 ng/mL, Gleason score 6, ≤T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. RESULTS: The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (bRFS) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). CONCLUSIONS: Our prospective multicentre series showed excellent bRFS with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy.

Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer.

BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome. STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009. RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with ≥grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with ≥grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed ≥grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with ≥grade 2 PTN (P=0.028). CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively.

The case for including bowel urgency in toxicity reporting after pelvic cancer treatment.

Bowel toxicity is a major complication of cancer treatment, and its accurate reporting is important for assessing outcomes. The NCI's Common Terminology Criteria for Adverse Events (CTCAE) is the preferred method for capturing adverse events after all cancer treatments, particularly within clinical trials. However, the CTCAE version 4 does not include urgency of defecation as an item, despite this being one of the most common and persistent adverse consequences of treatment of pelvic cancers. The importance of bowel urgency to patients is well documented, and this treatment effect has a negative impact on social function and quality of life. Bowel urgency is also important clinically because it may represent significant underlying problems. This article presents the case for including patient reported assessment of bowel urgency as an independent item in cancer treatment adverse event reporting.

Structured gastroenterological intervention and improved outcome for patients with chronic gastrointestinal symptoms following pelvic radiotherapy.

PURPOSE: Fifty percent of patients develop chronic gastrointestinal (GI) symptoms following pelvic radiotherapy that adversely affect quality of life. Fewer than 20 % are referred to a gastroenterologist. We aimed to determine if structured gastroenterological evaluation is of benefit to this patient group. METHODS: Sixty patients with GI symptoms at ≥ 6 months after radical pelvic radiotherapy were identified prospectively from oncology clinics in this service evaluation. Those requiring urgent investigation were excluded. Patients were assessed at baseline using patient-reported questionnaires: inflammatory bowel disease questionnaire (IBDQ), Vaizey incontinence questionnaire, and the Common Terminology Criteria for Adverse Events (CTCAE) pelvis questionnaire. Participants were referred for gastroenterological evaluation using an algorithmic approach. Further assessments were made at 3 and 6 months. RESULTS: Twenty men and 36 women with primary gynecological (31), urological (17), or lower GI (8) tumors were included (mean age, 58.5 years). Median time from radiotherapy to baseline assessment was 3.0 years. Multiple GI symptoms were reported (median, 8; range, 4-16) including frequency, urgency, loose stool, fecal incontinence, flatulence, bloating/distension, and rectal bleeding. Common diagnoses included radiation proctopathy, bile acid malabsorption, diverticulosis, and colonic polyps. Statistically significant improvements in all questionnaire scores between baseline and 6 months were found: IBDQ (p = 0.014), Vaizey (p < 0.0005), and CTCAE rectum-bowel subset (p = 0.001). CONCLUSIONS: Gastroenterological evaluation identifies significant, potentially treatable diagnoses in patients who develop chronic GI symptoms following pelvic radiotherapy. Some findings are incidental and unrelated to previous cancer treatment. Radiation-induced GI symptoms have historically been considered "untreatable." We report the first data to show that structured gastroenterological assessment has the potential to improve outcome by identifying diagnoses and facilitating focused treatment.

Early prostate cancer--which treatment do men prefer and why?

STUDY TYPE: Preference (prospective cohort). LEVEL OF EVIDENCE: 1b. What's known on the subject? and What does the study add? In general the literature suggests that there is a need for improvement in aiding men diagnosed with early prostate cancer in their decision making about treatment options and that our understanding of this process is inadequate. There is limited data analyzing the reasons why these men decide between potentially curative or observational treatments and data evaluating patients' views before and after definitive therapy are scarce. This study begins the process of understanding the reasons underlying a patient's final treatment decision. Being a prospective study, it looks at the thought processes of these men before treatment during the time the decision is made. It also documents how satisfied patients are with their choice after their treatment and whether they would choose the same treatment again. OBJECTIVE: To identify the reasons for patients with localised prostate cancer choosing between treatments and the relationship of procedure type to patient satisfaction post-treatment. PATIENTS AND METHODS: 768 men with prostate cancer (stage T1/2, Gleason≤7, PSA<20 ug/L) chose between four treatments: radical prostatectomy, brachytherapy, conformal radiotherapy and active surveillance. Prior to choosing, patients were counselled by a urological surgeon, clinical (radiation) oncologist and uro-oncology specialist nurse. Pre-treatment reasons for choice were recorded. Post-treatment satisfaction was examined via postal questionnaire. RESULTS: Of the 768 patients, 305 (40%) chose surgery, 237 (31%) conformal beam radiotherapy, 165 (21%) brachytherapy and 61 (8%) active surveillance. Sixty percent of men who opted for radical prostatectomy were motivated by the need for physical removal of the cancer. Conformal radiotherapy was mainly chosen by patients who feared other treatments (n=63, 27%). Most men chose brachytherapy because it was more convenient for their lifestyle (n=64, 39%). Active surveillance was chosen by patients for more varied reasons. Post-treatment satisfaction was assessed in a subgroup who took part in the QOL aspect of this study. Of the respondents to the questionnaire, 212(87.6%) stated that they were satisfied/extremely satisfied with their choice and 171(92.9%) indicated they would choose the same treatment again. CONCLUSION: Men with early prostate cancer have clear reasons for making decisions about treatment. Overall, patients were satisfied with the treatment and indicated that despite different reasons for choosing treatment, they would make the same choice again.

Tumour budding and a low host inflammatory response are associated with a poor prognosis in oesophageal and gastro-oesophageal junction cancers.

AIMS: Tumour budding and host inflammatory response are parameters easily assessed histologically that have prognostic significance in many cancers. There have been few studies examining these parameters in oesophageal or gastro-oesophageal cancers. This study aims to address that deficiency. METHODS AND RESULTS: A two-centre, retrospective study was carried out on 356 patients. Tumour budding and host inflammatory response at the invasive front were assessed histologically. Statistical analysis was performed to determine the prognostic significance of these factors. The median number of tumour buds was four (range 0-50) with 172 of 356 cases having five or more buds at the invasive front. The presence of five or more buds was associated with a poor prognosis on univariate analysis (P = 0.0001), as was a sparse or moderate host inflammatory response (P = 0.001). Tumour budding retained prognostic significance when tumours were separated into adenocarcinomas (n = 287) and squamous cell carcinomas (n = 69), but host inflammatory response was a significant prognostic factor only for adenocarcinomas. On multivariate analysis the presence of five or more buds retained significance (P = 0.002). CONCLUSIONS: Tumour budding and host inflammatory response are important prognostic factors in patients with oesophageal/gastro-oesophageal cancer and can be used to identify high-risk patients who would benefit from closer follow-up and adjuvant therapies.

External beam boost for cancer of the cervix uteri when intracavitary therapy cannot be performed.

PURPOSE: To assess the outcome of patients treated with radical radiotherapy for cervical cancer who received an external beam boost, in place of intracavitary brachytherapy (ICT), after irradiation to the whole pelvis. METHODS AND MATERIALS: Case notes were reviewed for all patients treated in this way in a single center between 1996 and 2004. Patient and tumor details, the reasons why ICT was not possible, and treatment outcome were documented. RESULTS: Forty-four patients were identified. The mean age was 56.4 years (range, 26-88 years). Clinical International Federation of Gynecology and Obstetrics or radiologic stage for Stages I, II, III, and IV, respectively, was 16%, 48%, 27%, and 7%. A total radiation dose of 54-70 Gy was given (75% received > or =60 Gy). Reasons for ICT not being performed were technical limitations in 73%, comorbidity or isolation limitations in 23%, and patient choice in 4%. The median follow-up was 2.3 years. Recurrent disease was seen in 48%, with a median time to recurrence of 2.3 years. Central recurrence was seen in 16 of the 21 patients with recurrent disease. The 5-year overall survival rate was 49.3%. The 3-year cancer-specific survival rate by stage was 100%, 70%, and 42% for Stages I, II, and III, respectively. Late Grades 1 and 2 bowel, bladder, and vaginal toxicity were seen in 41%. Late Grade 3 toxicity was seen in 2%. CONCLUSION: An external beam boost is a reasonable option after external beam radiotherapy to the pelvis when it is not possible to perform ICT.

Patterns of relapse following radiotherapy for differentiated thyroid cancer: implication for target volume delineation.

INTRODUCTION: Post-operative residual disease in differentiated thyroid cancer is an indication for external beam radiotherapy (EBRT) especially if there is poor radioiodine uptake by the residual disease. There are no standardized guidelines or consensus in target delineation for radiotherapy in thyroid cancer. AIMS: To determine the pattern of recurrence in patients with well differentiated thyroid cancer who received adjuvant or definitive radiotherapy as well as radioiodine ablation following surgery or biopsy with a view to better defining future target volume delineation for radiotherapy. MATERIALS AND METHODS: Forty-nine patients with differentiated thyroid cancer received radical external beam radiotherapy and radioiodine ablation (3.5GBq) following thyroidectomy or biopsy between 1990 and 2000. Nineteen patients had macroscopic residual (11) or inoperable disease (8), whilst 30 patients had clear (5) or microscopic positive resection margin (24), and 1 patient the resection margin status was unknown. All the patients were deemed high risk for local recurrence or progressive disease. The thyroid bed and regional nodes were irradiated using two radiotherapy techniques: (1) non co-planar lateral fields (NCLF) in coronal plane using 6MV photons to a dose of 45-50Gy in 16 fractions over 22 days and (2) anterior-posterior parallel pair of 6MV photons to a dose of 40-42.5Gy in 16 fractions over 22 days. There was no attempt to irradiate the lymph nodes in that part of the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina. RESULTS: The median follow-up was 5.4 years (range 0.9-12.4 years). The actuarial 5-year cause-specific survival and local control for the whole group was 75.7% and 81.4%, respectively. Of the 4 patients with mediastinal recurrence, all had neck recurrences and two had distant metastases. All the medisastinal recurrences occurred in superior mediastinum (level VII) and all were treated with NCLF in coronal plane radiotherapy technique. Furthermore, mediastinal recurrences did not occur in isolation. The 5-years loco-regional control rate was 89.1% for those with clear or microscopic positive margins and 69.2% for those with macroscopic residual or inoperable disease. Five-year cause specific survival was 58.3% for patients with macroscopic residual or inoperable disease and 91.4% for those with clear or microscopic positive margins. CONCLUSION: The status of postoperative margin relating to bulk of disease influences local control and cause specific survival. Surgical resection in locally advanced thyroid cancer should be performed by an experienced surgeon to achieve macroscopic clearance where possible. The majority of recurrences were loco-regional. The few superior mediastinal recurrences did not occur in isolation. All the mediastinal recurrences occurred in the superior mediastinum (level VII). We recommend the target volume should encompass the thyroid bed and regional neck nodes and the superior mediastinum level VII excluding the lymph nodes on both sides of the trachea within the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina (compartment 4). Thus, this should facilitate dose escalation to improve loco-regional control and avoiding radiation induced mediastinal toxicity.

Analysis of prostate-specific antigen bounce after I(125) permanent seed implant for localised prostate cancer.

BACKGROUND AND PURPOSE: To report on the incidence of benign prostate-specific antigen bounce following permanent I(125) prostate brachytherapy, to describe the associations in our population and review the relationship of bounce to subsequent biochemical failure. MATERIALS AND METHODS: From February 2000 to May 2005, 374 patients with localised prostate cancer were treated with I(125) permanent prostate brachytherapy at a single institution. A prospectively collected database was used to identify cases of prostate-specific antigen (PSA) bounce, defined as a rise of 0.2 ng/ml above an initial PSA nadir with subsequent decline to or below that nadir without treatment. The patients who received neo-adjuvant or adjuvant hormone manipulation were excluded. Biochemical failure was determined using the both the ASTRO consensus definition and Phoenix (nadir +2 ng/mL) definition. RESULTS: Two hundred and five patients were identified with a median follow-up of 45 months (24-85). PSA bounce was noted in 79 (37%) men, occurring at a median of 14.8 months (1.7-40.6) following implant. The median peak PSA was 1.8 ng/ml (0.4-7.4) with a bounce magnitude of 0.91 ng/ml (0.2-5.8). When pre- and post-implant factors were assessed for association to bounce, only younger age was statistically significant (p=0.002). The threshold for biochemical failure as defined by the ASTRO consensus definition (1997) was met in 4 (5%) patients after experiencing bounce as opposed to 19 (15%) non-bounce patients (p=0.01). The threshold for Phoenix (nadir +2 ng/mL) was met in 6 (7.5%) patients following bounce versus 22 (17%) of non-bounce patients (p=0.003). Both definitions are prone to false positive calls during bounce. Median PSA velocity during the bounce was 0.08 ng/mL/month (0.02-0.98) and was statistically significantly lower than the median velocity prior to the Phoenix biochemical failure at 0.28 ng/mL/month (0.07-2.04) (p=0.0005). CONCLUSION: PSA bounce is a common finding in our population and is associated with a lower rate of subsequent biochemical failure. The noted differences in PSA velocity will require verification in a future analysis to reduce the influence of median follow-up on this finding. Patients should be advised of the potential of bounce in PSA follow-up after permanent I(125) prostate brachytherapy and physicians involved in follow-up of prostate brachytherapy patients should be aware of this phenomenon, allowing them to commit to appropriate PSA surveillance, avoiding the premature and inappropriate initiation of salvage therapy during PSA bounce.

Massage in patients undergoing intensive chemotherapy reduces serum cortisol and prolactin.

OBJECTIVE: The objective is to identify whether single 20 min massage sessions were safe and effective in reducing stress levels of isolated haematological oncology patients. DESIGN: Based on a randomised controlled trial, 39 patients were randomised to aromatherapy, massage or rest (control) arm. MEASURES: The measures were serum cortisol and prolactin levels, quality of life (EORTC QLQ-C30) and semi-structured interviews. Primary outcome measure was the fall in serum cortisol levels. RESULTS: A significant difference was seen between arms in cortisol (P=0.002) and prolactin (p=0.031) levels from baseline to 30 min post-session. Aromatherapy and massage arms showed a significantly greater drop in cortisol than the rest arm. Only the massage arm had a significantly greater reduction in prolactin then the rest arm. The EORTC QLQ-C30 showed a significant reduction in 'need for rest' for patients in both experimental arms compared with the control arm, whereas the semi-structured interviews identified a universal feeling of relaxation in patients in the experimental arms. CONCLUSION: This pilot study demonstrated that in isolated haematological oncology patients, a significant reduction in cortisol could be safely achieved through massage, with associated improvement in psychological well-being. The implications are discussed.

Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.

AIMS: In this retrospective comparison, we describe the differences in dose intensity, delays and toxicity between weekly Cisplatin and 3-weekly Cisplatin given concurrently to patients with locally advanced squamous head and neck cancer (SCCHN) at New Cross Hospital, Wolverhampton. MATERIALS AND METHODS: Fifty-one patients received radical Cisplatin based chemoradiotherapy for stage 4a SCCHN of the head and neck between September 2000 and December 2004. Twenty-seven patients were treated with 3-weekly inpatient Cisplatin for 3 cycles (20 patients-80 mg/m(2); 7 patients-100 mg/m(2)) concomitantly with radiotherapy (66-70 Gy/33-35 fractions). Twenty-four patients received a similar radiotherapy schedule but received weekly Cisplatin 33-40 mg/m(2). RESULTS: More patients received a higher cumulative dose of at least 240 mg/m(2) if given weekly Cisplatin 40 mg/m(2) or 3-weekly Cisplatin 80 mg/m(2) compared with those receiving Cisplatin 3-weekly 100 mg/m(2) (p=0.04). Maximum cumulative dose achievable in the latter group was only 200 mg/m(2) and none achieved the full 3 cycles. Mean Cisplatin dose in the weekly Cisplatin 40 mg/m(2) regime (mean 202 mg/m(2)) and 3-weekly arm of 80 mg/m(2) (mean 203 mg/m(2)) was higher than that reached if given 3-weekly Cisplatin 100 mg/m(2) (mean 180 mg/m(2)) although statistically insignificant (p=0.39) due to the small number of patients. More delays (29% vs. 41%) and omission of chemotherapy (5.6% vs. 17.4%) occurred in the 3-weekly compared with the weekly regime. Toxicity, radiotherapy overall treatment time and delays were similar between the two groups. CONCLUSION: Delivery of 100 mg/m(2) Cisplatin 3-weekly with radiotherapy was less tolerated than 40 mg/m(2) weekly and resulted in less patients achieving cumulative dose beyond 200 mg/m(2), potentially lowering chemotherapy dose intensity.

Enhancing fraction predicts clinical outcome following first-line chemotherapy in patients with epithelial ovarian carcinoma.

PURPOSE: To define a simple radiologic biomarker of prognosis in patients with advanced epithelial ovarian carcinoma on first-line chemotherapy. EXPERIMENTAL DESIGN: Twenty-seven patients receiving platinum-based chemotherapy with >2 cm residual disease [International Federation of Gynecology and Obstetrics (FIGO) stages IIIC or IV] after surgery were identified. The proportion of enhancing tumor tissue--the enhancing fraction--was calculated on pre-chemotherapy computed tomography scans at four Hounsfield unit (HU) thresholds and assessed for correlation with CA125 response, Response Evaluation Criteria in Solid Tumors (RECIST) radiologic response, and time to progression. Discriminative power was assessed by leave-one-out discriminant analysis. RESULTS: Pre-chemotherapy residual tumor volume did not correlate with clinical outcome. Pre-chemotherapy enhancing fraction at all thresholds significantly correlated with CA125 response (P < 0.001, rho = 0.553 for 50 HU; P < 0.001, rho = 0.565 for 60 HU; P < 0.001, rho = 0.553 for 70 HU; P = 0.001, rho = 0.516 for 80 HU). Significant correlations were also shown for radiologic response at all thresholds. Enhancing fraction predicted CA125 response with 81.9% to 86.4% specificity and Response Evaluation Criteria in Solid Tumors response with 74.9% to 76.8% specificity at 95% sensitivity (dependent on threshold). Enhancing fraction correlated with time to progression at the 60 HU (P = 0.045, rho = 0.336) and 70 HU (P = 0.042; rho = 0.340) thresholds. CONCLUSION: Pre-chemotherapy enhancing fraction is a simple quantitative radiologic measure. Further evaluation in larger trials is required to confirm the potential of enhancing fraction as a predictive factor, particularly for patients who may benefit from the addition of antiangiogenic therapy.

Comparison of doxycycline delivery methods for Tet-inducible gene expression in a subcutaneous xenograft model.

Doxycycline (Dox) controlled Tet systems provide a powerful and commonly used method for functional studies on the consequences of gene overexpression/downregulation. However, whereas Dox delivery in tissue culture in vitro is relatively simple, the situation in vivo is more complex. Several methods of Dox delivery in vivo have been described-e.g., in drinking water containing alcohol, in drinking water containing various concentrations of sucrose, and in feed. Unfortunately there are no reports directly comparing the advantages and disadvantages of these diverse methods, and there is no generally accepted standard. We therefore compared four non-invasive methods of Dox delivery in vivo-in drinking water, by gavage, as a jelly, and in standard feed. To assess the delivery of Dox by these methods, we used a subcutaneous xenograft model based on colorectal carcinoma cells engineered for Dox-inducible expression of an activated mutant of c-Src and the luciferase reporter gene. Our results indicate that feed represents the most favorable method of Dox administration.

Adult weight gain and central obesity in women with and without a family history of breast cancer: a case control study.

Adult weight gain and central obesity can increase breast cancer risk. We determined the prevalence of adult weight gain and central obesity amongst women with a family history (FH) as compared to women with a population risk to determine whether adiposity could contribute to their increased risk. Adult weight gain, waist and waist:hip ratio (WHR) were determined amongst 475 women (aged 20-60 years) attending a regional FH breast cancer risk clinic, compared to 312 age matched women at population risk. Patterns of adult weight gain did not differ between women with and without a FH of breast cancer. The majority of weight gain occurred between the ages of 20 and 40 in both groups. Mean (sd) weight gain for women aged >40 years with a FH was 8.9 (10.3) kg compared to 9.1 (10.6) kg for controls (p = 0.85). Women with a FH had a significantly greater waist and WHR than controls. Mean (sd) waist was 83.7 (13) cm compared to 81.6 (11.3) cm for controls (p < 0.01). Mean (sd) WHR was 0.82 (0.1) compared to 0.80 (0.1) for controls (p < 0.01). FH of breast cancer was an independent predictor of having a WHR of >0.85; odds ratio (95% CI) = 1.42 (1.01-2.01) (p = 0.044). Significant weight gain between the ages of 20 and 40 and the prevalence of central obesity amongst FH women suggest the need for weight management within FH clinics.

Early change in glucose metabolic rate measured using FDG-PET in patients with high-grade glioma predicts response to temozolomide but not temozolomide plus radiotherapy.

PURPOSE: To compare the ability of positron emission tomography (PET) to predict response to temozolomide vs. temozolomide plus radiotherapy. METHODS AND MATERIALS: Nineteen patients with high-grade glioma (HGG) were studied. Patients with recurrent glioma received temozolomide 75 mg/m2 daily for 7 weeks (n=8). Newly diagnosed patients received temozolomide 75 mg/m2 daily plus radiotherapy 60 Gy/30 fractions over 6 weeks, followed by six cycles of adjuvant temozolomide 200 mg/m2/day (Days 1-5 q28) starting 1 month after radiotherapy (n=11). [18F]Fluorodeoxyglucose ([18F]FDG) PET scan and magnetic resonance imaging (MRI) were performed at baseline, and 7 and 19 weeks after initiation of temozolomide administration. Changes in glucose metabolic rate (MRGlu) and MRI response were correlated with patient survival. RESULTS: In the temozolomide-alone group, patients who survived>26 vs. or=25%, survived longer than nonresponders with mean survival times of 75 weeks (95% CI, 34-115 vs. 20 weeks (95% CI, 14-26) (p=0.0067). In the small group of patients studied, there was no relationship between MRI response and survival (p=0.52). For patients receiving temozolomide plus radiotherapy, there was no difference in survival between PET responders and nonresponders (p=0.32). CONCLUSIONS: Early changes in MRGlu predict response to temozolomide, but not temozolomide plus radiotherapy.

Radical radiotherapy alone for glomus jugulare and tympanicum tumours.

The management of glomus jugulare and tympanicum tumours is controversial due the long natural history and morbidity associated with intervention. We report the experience of radical radiotherapy (RT) alone for these tumours. Between 1965 and 1987, 49 patients received RT. Median age at presentation was 55 years (range, 23-82). Common presentations were deafness in 27 patients, tinnitus in 25 and cranial nerve palsies in 18. RT was given as a 2D simulator-planned wedge pair in the majority with a median dose of 45 Gy (range, 37.5-50.0) in 15 or 16 fractions over 21 days (range, 20-26). Median follow-up was 7.4 years (range, 2.0-23.4). At 6 months post-RT, complete clinical response was seen in 38 patients, partial response in 4, no response in 1 and no data were available for 6. At both 5 and 10 years, 92% of patients were recurrence-free and cancer-specific survival was 96%. There were no reports of radionecrosis. Although tumour eradication is not the aim, RT can achieve good local control, survival and symptom relief without the significant morbidity that can be associated with radical surgery. Therefore, RT alone has a significant role in the management of these tumours.

Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.

PURPOSE: Heparan sulfate proteoglycans have been implicated in cancer cell growth, invasion, metastasis, and angiogenesis. This study was designed to compare their expression in normal ovary and ovarian tumors and then to examine their prognostic significance in ovarian cancer. EXPERIMENTAL DESIGN: The expression of syndecan-1, -2, -3, and -4, glypican-1, and perlecan was assessed by immunohistochemistry in 147 biopsies that included normal ovary and benign, borderline, and malignant ovarian tumors. Clinical data, including tumor stage, performance status, treatment, and survival, were collected. Univariate and multivariate analyses were performed to evaluate prognostic significance. RESULTS: The expression patterns of syndecan-1 and perlecan were altered in ovarian tumors compared with normal ovary. Syndecan-1 was not detected in normal ovary but was present in the epithelial and stromal cells of benign and borderline tumors and in ovarian adenocarcinomas. Perlecan expression was decreased in basement membranes that were disrupted by cancer cells but maintained in the basement membranes of blood vessels. Syndecan-2, -3, and -4, and glypican-1 were expressed in normal ovary and benign and malignant ovarian tumors. Stromal expression of syndecan-1 and glypican-1 were poor prognostic factors for survival in univariate analysis. CONCLUSION: We report for the first time distinct patterns of expression of cell surface and extracellular matrix heparan sulfate proteoglycans in normal ovary compared with ovarian tumors. These data reinforce the role of the tumor stroma in ovarian adenocarcinoma and suggest that stromal induction of syndecan-1 contributes to the pathogenesis of this malignancy.

Parametrized rectal dose and associations with late toxicity in prostate cancer radiotherapy.

OBJECTIVE: We investigated possible associations between planned dose-volume parameters and rectal late toxicity in 170 patients having radical prostate cancer radiotherapy. METHODS: For each patient, the rectum was outlined from anorectal junction to sigmoid colon, and rectal dose was parametrized using dose-volume (DVH), dose-surface (DSH) and dose-line (DLH) histograms. Generation of DLHs differed from previous studies in that the rectal dose was parametrized without first unwrapping onto 2-dimensional dose-surface maps. Patient-reported outcomes were collected using a validated Later Effects in Normal Tissues Subjective, Objective, Management and Analytic questionnaire. Associations between dose and toxicity were assessed using a one-sided Mann-Whitney U test. RESULTS: Associations (p < 0.05) were found between equieffective dose (EQD23) and late toxicity as follows: overall toxicity with DVH and DSH at 13-24 Gy; proctitis with DVH and DSH at 25-36 Gy and with DVH, DSH and DLH at 61-67 Gy; bowel urgency with DVH and DSH at 10-20 Gy. None of these associations met statistical significance following the application of a Bonferroni correction. CONCLUSION: Independently confirmed associations between rectal dose and late toxicity remain elusive. Future work to increase the accuracy of the knowledge of the rectal dose, either by accounting for interfraction and intrafraction rectal motion or via stabilization of the rectum during treatment, may be necessary to allow for improved dose-toxicity comparisons. ADVANCES IN KNOWLEDGE: This study is the first to use parametrized DLHs to study associations with patient-reported toxicity for prostate radiotherapy showing that it is feasible to model rectal dose mapping in three dimensions.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Do differences in target volume definition in prostate cancer lead to clinically relevant differences in normal tissue toxicity?

PURPOSE: Many studies have described the quantitated differences between clinicians in target volume definition in prostate cancer. However, few studies have looked at the clinical effects of this. We aimed to assess the relevance and sequelae of such differences. METHODS AND MATERIALS: Five experienced radiation oncologists were given the clinical details of 5 patients with early-stage prostate cancer and asked to define the clinical target volume, consisting of the prostate and seminal vesicles (CTV1) and the prostate alone (CTV2), on specified planning CT scans of the pelvis. Planning target volumes (PTV1) were generated by automatic expansion of the CTV1 by a 1-cm margin. The PTV2 was defined as the CTV2. The rectum and bladder were defined by a single experienced clinician for each plan without knowledge of the involved clinician marking the CTVs. The Pinnacle planning system was used to generate the plans, using four-field conformal radiotherapy, to deliver 64 Gy in 32 fractions to the PTV1 followed by a boost of 10 Gy to the PTV2 (Medical Research Council RT01 trial protocol). Dose-volume histograms were generated for the whole bladder and rectum for each plan and the volume receiving a specific percentage of the dose (e.g., V(90)) calculated for 74 Gy, followed by estimates of normal tissue complication probabilities (NTCPs) for the bladder and rectum. RESULTS: Statistically significant differences were found in the CTV1 and CTV2 and, consequently, the PTV1 among the 5 clinicians (p < 0.0005). Most of the discrepancies occurred at the delineation of the prostatic apex and seminal vesicles, with the smallest variance noted at the rectum-prostate and bladder-prostate interfaces. No statistically significant differences were found among clinicians for the rectal V(90), V(85), V(80), V(70), or V(50) or for the bladder V(85), V(80), V(70), or V(50). A difference was noted among consultants for the bladder V(90) (p = 0.015), although no correlation was found between the bladder V(90) and the size of the outlined volumes. No statistically significant differences were found between the estimates of bladder (p = 0.1) and rectal (p = 0.09) NTCPs. CONCLUSION: The statistically significant difference in outlined volumes of the CTV1, CTV2, and PTV1 among the 5 clinicians is in keeping with the findings of previous studies. However, the interclinician variability did not result in clinically relevant outcomes with respect to the irradiated volume of rectum and bladder or NTCP. This may have been because the outlined areas in which interclinician differences were smallest (the rectal-prostate and prostate-bladder interfaces) are the areas that have the greatest effect on normal tissue toxicity. For the areas in which the interclinician correlation was lowest (the prostatic apex and distal seminal vesicles), the effects on normal tissue toxicity are smallest. The results of this study suggest that interclinician outlining differences in prostate cancer may have less clinical relevance than was previously thought.