Biochemical recurrence (BCR) following radiotherapy for prostate cancer is accepted as treatment failure and is used to guide clinical management. PSA nadir + 2 ng/mL (Phoenix definition) is the formula most commonly used to establish BCR, however, not all patients that meet the definition progress to clinical recurrence. The purpose of this study is to analyze the performance of the Phoenix definition in a cohort of patients with intermediate-risk prostate cancer, treated with external beam radiotherapy (EBRT) with or without hormones. We conducted a retrospective review of all intermediate risk prostate cancer patients treated curatively at our cancer center, which is the sole provider of radiotherapy within our provincial local health region, serving 1.3 million people. Patient demographics, cancer, treatment, and subsequent clinical course details were obtained from the electronic medical record. Descriptive statistics, Kaplan-Meier (KM) survival estimates, and Cox proportional hazards were used to analyze risk factors for clinical recurrence in patients with BCR. Between 2002 and 2007, 542 men were treated with EBRT to a median dose of 76 Gy (70 Gy - 85 Gy). Median age was 70 years (40 - 83 years), median PSA was 9 ng/mL (1.3 – 20 ng/mL). Seventy-three percent of patients had Gleason 7, 54.3% had stage T1 and 45.7% stage T2. Median follow up for all patients was 9 years (3 months - 16 years). Ninety-three patients (17.15%) had BCR (median follow up of 10.5 years, range 2– 16 years). Demographics and median PSA for these patients were similar to those in the main cohort. Eighty-five percent had Gleason 7, 48% had stage T1, and 52% had T2 disease. Treatment at BCR included: hormonal treatment for 74%, local treatment for 7.5%, while 18.5% were observed. Median time to BCR was 4.4 years (7 months – 14.3 years) for an actuarial probability of having BCR of 24.9% at 10 years. PSA at diagnosis (HR = 1.4, p = 0.02) and Gleason 7 (HR = 2.07, p = 0.01), were statistically significant risk factors for BCR, while age and stage were not. Forty-nine (52.7%) patients with BCR developed clinical recurrence at a median of 13.5 months (0 – 132 months), for an actuarial probability of clinical recurrence of 40% at 5 years and 71% at 10 years. One patient developed clinical recurrence without having BCR (local recurrence, small cell differentiation with undetectable PSA). There were no statistically significant risk factors for clinical recurrence identified. Patients with stage T2 (HR = 1.7, p = 0.07) and with first PSA at time of BCR >5 showed trends towards increased clinical recurrence risk (HR = 1.7, p = 0.08). In a large cohort of intermediate risk prostate cancer patients, treated with high dose radiation with or without hormones, the risk of biochemical recurrence is modest at 10 years. Of those patients who fail, 70% have developed clinical recurrence ten years after biochemical recurrence. The Phoenix definition of BCR does a reasonable job of predicting long term outcomes.

Selecting the right treatment for locally advanced laryngeal cancer is challenging. It can be treated with total laryngectomy (TL) or larynx-preservation (LP). TL is recommended for more advanced (T4) disease, whereas LP is usually reserved for T3 disease. We hypothesize that patients with T3 disease, despite having larynx preservation (T3-LP), have a better clinical outcome compared to those with T4 disease treated with TL (T4-TL). A retrospective analysis was conducted on patients with T3 and T4 laryngeal cancer, treated at our institution between January 2007 and July 2015. Patients with history of other malignancies within 3 years of laryngeal cancer diagnosis, metastatic disease at diagnosis and/or intent of palliative treatment were excluded. All patients who received radiotherapy were treated with intensity modulated radiotherapy (IMRT); Tomotherapy is used at our centre. Demographics, tumor and treatment factors were collected and clinical outcomes, including overall survival (OS), salvage laryngectomy-free survival (LFS), and failure free survival (FFS), were analyzed. A total of 103 patients were eligible for analysis. Median age at diagnosis was 64 years (range: 37-93 years). Median follow-up was 36 months (range: 1-123 months) and 53 months for the patients alive at last follow up. Among all patients, 68% had clinical T3 disease, among which 83% underwent LP, while 32% of patients had T4 disease, among which 70% underwent TL. N0 disease was found in 59% of patients, while 41% had N+ disease. Out of 58 T3-LP patients, 31% had salvage laryngectomy at median 11 months after diagnosis. No statistically significant difference was observed between T3-LP and T4-TL groups in 3-year OS (66% versus 64%, respectively, p = 0.5) or 5-year OS (57% versus 47%, respectively, p = 0.5). Three-year FFS was 52% in T3-LP group versus 75% in T4-TL group (p = 0.07). The findings were as a result of higher loco-regional failure rate in T3-LP group compared to T4-TL group (RR = 5.53, 95% CI: 1-15.6, p = 0.025). Three-year LFS was 68% in T3-LP group. In the era of IMRT, about two thirds of patients with T3 disease treated with larynx preservation at our centre continue to have an intact larynx 3 years after their diagnosis. Although these patients have higher loco-regional failure rate, they can be salvaged and have similar survival outcomes compared to patients with T4 disease treated with total laryngectomy. Therefore, larynx preservation remains a suitable option for patients with T3 laryngeal cancer.

Patients receiving definitive chemoradiation for head and neck cancers remain at risk for hospital admission often owing to poor oral intake and frequent underlying dehydration. The objective of this study was to determine potential differences between those receiving prophylactic versus emergent enteral nutrition in regards to hospitalization rates and survival outcomes. A retrospective chart review of adult head and neck cancer patients receiving radical radiation therapy +/- chemotherapy (CRT) at our tertiary care cancer centre was completed. Patients were grouped into 2 categories; group 1 receiving either no tube feeding or emergent nasogastric (e-NG) or percutaneous gastrostomy (e-PEG) tube and group 2 which received prophylactic PEG (p-PEG) tube. Hospitalisation rates while on treatment and the 3 months after treatment were compared via Chi-Square test. Baseline characteristics were compared between groups by either t-tests or chi-square tests. Survival was determined by Kaplan-Meier Method and Log-Rank tests. Overall, 203 patients treated between 2006 and 2016 were included with median follow-up of 22 months. Incidence was predominantly male at 82%. Median age at diagnosis was 62 years with most common sites treated being oropharynx (72%; 31% of these being base of tongue) followed by larynx (15%) and nasopharynx (8%). Seventy-two percent of all patients received primary chemoradiation therapy with most common fractionation regimen being 70 Gy in 35 daily fractions. Details regarding the two groups are presented in the table below: Abstract MO_14_2585; Table 1Group 1 (n=182)Group 2 (n=21)Age (years)6262Male (%)8286Disease Site (%) (p=0.08)Oropharynx LarynxHypopharynxNasopharynx75143743 29 14 14Histology (%) (p=0.73)Squamous Cell Carcinoma Adenocarcinoma99.5 (n=181)0.5 (n=1)1000P16 positivity (%)4929Social History (%)Tobacco use (p=0.43)Current smokersFormer smokersPack history (years)304425245731Alcohol Use (p=0.16)>10 Drinks/ week3024AJCC 7 Stage (%) (p=0.76)I20II65III2514IVA6376IVB51Enteral Nutrition Rates (%)None510e-NG280e-PEG210p-PEG0100Hospitalization during/3 months post treatment (%) (p=0.62)37 (n=68)43 (n=9) Open table in a new tab Of the 60 patients in either group who had a PEG tube placed, 53% went on to have a tube dependent lifestyle. Median survival was 63 months for group 1 and 35 months for Group 2 (p<0.001). In definitive CRT treated head and neck cancer, patients with prophylactic PEG enteral nutrition possessed several negative prognostic factors such as higher smoking rates, lower HPV association and more advanced stage disease at time of presentation. These patients also required hospitalization at a higher rate and had poorer median survival. This likely demonstrates current practice patterns for prophylactic enteral feeding but does not provide convincing evidence in favor of prophylactic PEG tube placement.

Background: Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9.Methods: We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels.Results: In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (I) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9.Conclusions: We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. (C) 2015 Elsevier B.V. All rights reserved.

Intermediate risk prostate cancer (Pca) is a heterogeneous group with relapse rates ranging from 10-40%. Improved risk stratification using biomarkers would allow clinicians to tailor therapy. The purpose of our research is to determine whether a protein signature exists in patient blood that can differentiate between recurrent and non-recurrent intermediate risk prostate cancer patients. Four hundred thirty-eight Intermediate risk PCa pts were entered on a Phase 3 Trial evaluating optimal sequencing of 6 months ADT in combination with dose escalated XRT (76 Gy). Two cohorts were identified: recurrence < 3 years and those tumor free > 7 yrs. We performed in depth proteomic analysis of pretreatment blood samples to identify biomarkers of recurrence using 2 recurrent and 3 non-recurrent patients. In the discovery work we performed 2D gel electrophoresis on depleted plasma, followed by protein sequencing of tryptic fragments of differentially present proteins by mass spectrometry to identify 57 proteins that were differentially present between the 2 cohorts. A test cohort of 20 patients per group was subsequently analyzed for the levels of these 57 proteins along with an additional 14 candidates selected by literature evidence using selection reaction monitoring tandem mass spectrometry (SRM-MS). An optimization phase was included to ensure detection of 2 peptides per protein with 2 transitions for each peptide. Relative protein expression was determined using SRM transition peak areas derived from MultiQuant software. Logistic regression models were used to develop models that identified potential biomarkers of recurrence, and the area under the receiving operating characteristic (ROC) curve was used to assess the ability of each model to differentiate between recurrent and non-recurrent patients. Of the 71 total proteins interrogated, sufficient signal was obtained for 64 of them. A series of 3 models using different combinations of 6 proteins were found to be predictive of recurrence with good sensitivity and negative predictive value (NPV). Inclusion of diagnostic PSA levels did not enhance the predictive ability of the identified models. Using SRM-MS a series of 3 models using different combinations of 6 proteins were found to be predictive of recurrence. We are currently evaluating whether ELISA techniques are sufficiently sensitive to detect the differences between these protein levels in blood samples from our two cohorts.Oral Scientific Abstract 346; Table 1Receiver Operating Characteristics for the Identified Proteomic Prediction Models.Model (after cross-validation)AUC (95% CI)SensitivityNegative Predictive Value3-feature model 10.778 (0.616-0.895)90.5%85.7%3-feature model 20.804 (0.646-0.914)90.5%80.0%4-feature model 10.772 (0.610-0.891)90.5%80.0% Open table in a new tab

The purpose of this study was to examine whether or not underdosing occurs in the mucosal layer during treatment of glottis cancer. A larynx phantom was produced and regions at risk of recurrence due to suspected underdosing were identified and wells drilled into the phantom for flush placement of TLDs. Seven interest points were chosen. CT simulation was completed prior to the wells being drilled, and again afterwards with the TLD locations indicated using BBs. Treatment plans created for this investigation included: 3DCRT using Elekta-XiO (n=9) and VMAT created using Elekta-Monaco (n=9), both delivered on an Elekta linac; standard TomoTherapy plan (n=11) and a directionally blocked TomoTherapy plan to approximate a 3D-conformal approach (n=5). Imaging dose during TomoTherapy deliveries was accounted for. The average TLD result at each interest point was compared to the planned value using a paired t-test. There was no significant difference between the planned and measured 3DCRT dose (268.9 vs. 267.0 cGy, respectively; p>0.05). Similarly, the planned and measured TomoTherapy treatment did not show any significant differences (271.7 vs 269.7 cGy; p>0.05). In the blocked TomoTherapy plan, significant overdosing was seen (274.5 vs 294.9 cGy; p<0.05) and underdosing was not seen in the VMAT treatment (303.5 vs 321.8 cGy; p>0.05). Further investigation is ongoing to ensure appropriate normalization of results and to investigate the overdosing noted with the blocked TomoTherapy plan. Results from this study suggest that significant underdosing does not occur in the conventional treatment of early glottic cancer using 6MV photons.

OBJECTIVE:The objective of the present study was to evaluate the incidence, time of onset, and extent of hemoglobin, testosterone, and erythropoietin changes in patients with localized prostate cancer receiving either radiation alone or radiation combined with total androgen blockade (tab).METHODS:The study enrolled 35 patients (median age: 69 years) with clinically localized prostate cancer who received 3-dimensional conformal radiation with or without tab. Patients were generally treated with radiation alone (group 1), radiation plus short-term (≤6 months) tab (group 2), or radiation plus long-term (≥2 years) tab (group 3). Serum hemoglobin, testosterone, and erythropoietin in these patients were prospectively evaluated.RESULTS:The mean baseline serum hemoglobin for group 1 (n = 20), group 2 (n = 6), and group 3 (n = 9) was 149 g/L, 153 g/L, and 143 g/L respectively. We observed no significant decline in serum hemoglobin, testosterone, or erythropoietin among patients treated with radiotherapy alone. A significant drop in serum testosterone was noted in the group 2 and 3 patients within 1 month (p < 0.001), reaching a plateau at approximately 6 months. That change was followed by a significant decline (p < 0.001) in serum hemoglobin at 3-6 months (137 g/L in group 2 and 129 g/L in group 3). We observed a small but statistically significant increase in serum erythropoietin (p < 0.001) of 8 U/L in group 2 and 4 U/L in group 3 after 6 months of tab. No immediate recovery in serum hemoglobin, testosterone, or erythropoietin was observed upon completion of tab.CONCLUSIONS:Although conformal radiotherapy alone for localized prostate cancer had no effect on serum hemoglobin, testosterone, or erythropoietin, tab led to a significant decline in testosterone, which was followed by decline in hemoglobin that was not a result of a deficiency of erythropoietin.

To evaluate whether involvement of various Nodal Levels are associated with a different risk of Distant Metastasis (DM) in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC). A prospective study have accrued 92 HNSCC patients (Stage II-IVa) that were treated using Intensity Modulated Radiation Therapy on a Helical Tomotherapy unit to a total dose of 70 Gy with/without Concurrent Platinum Based Chemotherapy where 88 patients have completed the treatment as per the protocol who were included in this report. The majority of patients were males (69 patients) with a median age of 60 years (39-87). Primary involved sites were Oropharynx (59 patients), Larynx (10), Nasopharynx (7), Hypopharynx (6), Oral Cavity (3) and Unknown Primary (3). Lymph Nodal (LN) levels of each patient were identified using their diagnostic/planning CT scans, MRI or FDG-PET scans based on size and morphology criteria as well as their contrast enhancement or FDG avidity (for patients who had FDG-PET scans). Different LN levels were defined based on the DAHANCA/EORTC/GORTEC/NCIC/RTOG Nodal Delineation Consensus Guidelines. Detailed Database was generated that included the patients and their tumors characteristics including the LN levels involved for each patient and correlated to whether the patients eventually developed DM or not. For each LN level, the percentage risk of DM was identified by calculating "the number of patients with the involved LN Level who developed DM" by "the total number of patients who had that LN level involved". The patients (pts) were followed-up for a median period of 31 months (3-65 months). Thirteen patients (15%) developed Distant Metastasis with a median time to DM of 20 months (1-44 months). Lymph Node levels Involvement among the 88 patients were distributed as follows: Level I (9 pts), Level II (61 pts), Level III (40 pts), Level IV (18 pts), Level V (13 pts) and Retro-Pharyngeal (RP) LN group was involved in (6 pts). Out of the 13 patients who developed DM, the LN levels involved were: Level I (3 pts), Level II (12 pts), Level III (8 pts), Level IV (7 pts), Level V (6 pts) and RP group (2 pts). Hence, the risk of DM stratified based on each LN level was calculated as follows: Level I (33%), Level II (20%), Level III (20%), Level IV (39%), Level V (46%) and RP group (33%). The 3 patients with DM who had Level I LN involved had extra-oral cavity primaries with multi-level involvement (Supraglottic Larynx "level I-V", Base of Tongue "Levels I,III,IV" and Tonsil "Level I-II"). The most common site for DM was lung (8 pts), followed by bones (5), liver (2) and brain (1). Patients with HNSCC who have involved Lymph Node levels IV, V or RP group are associated with 33-46% risk of DM on this cohort and should be considered to be further assessed for the role of adjuvant systemic therapy.

Treatment options for low risk prostate cancer (PCA) include radical prostatectomy (RP), external beam radiation (EBRT), and brachytherapy (BT). The purpose of this study was to review published quality of life data stratified by treatment modality. Using a systematic literature search, 110 articles with EPIC data were gathered. Articles containing post treatment time-point data with means and standard deviations were included. Each article was reviewed by an urologist or a radiation oncologist to assess quality of treatment. Articles with potential overlapping patient populations were excluded. Pooled analysis of means for each quality of life domain at each time point was determined. The following pre-specified time points were abstracted: 0 (baseline), 0.5-2 months, 3-5 months, 6-8 months, 9-11 months, 12 months, 13-24 months, and 25 months or more post-treatment. Main comparisons included RP VS EBRT, RP VS BT, as well as RP VS EBRT or BT. Twenty-five articles met inclusion criteria. Urinary summary domain for RP was 89.8+/-11.2 at baseline, dropped to 53.9+/-19.4 (p<0.005) at 2 months but approached baseline at 24 months (87.6+/-14.3, p=0.025). EBRT baseline was 96.4+/-7.16, dropped to 92.2+/-12.9 at 5 months (p<0.005), and remained worse at 24 months (92.7+/-12.2, p<0.005). In contrast, BT score dropped from 90.2+/-12.5 to 72+/-19.7 at 2 months (p<0.005) but recovered by 8 months, and was better by 24 months (92.4+/-13.3, p =0.02). The bowel summary domain for RP dropped from 94.6+/-7.29 at baseline to 84.3+/-14.0 at 2 months (p <0.005) but recovered by 5 months and became better by 24 months (96.2+/-8.87, p = 0.02). BT shared the same pattern as RP with initial drop from 95.9+/-8.21 to 70+/-21.7 (p <0.005) but recovered by 12 months and became better by 24 months (97.9+/-4.97, p<0.005). Only EBRT score decreased from 96.9+/-5.59 to 93.8+/-12.8 at 5 months (p <0.005) and never recovered by 24 months (92.2+/-13.6, p <0.005). Overall, BT has worse acute bowel score compared to RP but same long term score. For sexual summary domain, RP baseline score dropped sharply from 67.12+/-24.7 to 25.1+/-20.5 (p<0.005) and never recovered by 24 months (30.9+-/-23.4, p<0.005). EBRT dropped from 50.3+/-28.3 to 42.9+/-27.2 at 5 months (p=0.005), recovered by 8 months (45.5+/-28.6, p = 0.08), then dropped again and remained worse at 24 months (40.3+/-27.3, p<0.005). BT baseline scores was 48.6+/-28.2 and remained similar by 24 months (49.8+/-29.8, p = 0.63). Treatment modalities may have differential impact on quality of life domains. Review of published literature suggests that RP has the least impact on early post-treatment bowel function. Both RP and EBRT have adverse long term side effects on urinary and sexual functions. BT seems to have the most favorable long term side effect profile in urinary, sexual, and bowel domains.

Background: A pooled analysis of trials using conventional dose radiation (XRT) indicates 6 months androgen deprivation therapy (ADT) improves prostate cancer survival in Gleason 7 disease (D'Amico, JCO 2011). The benefit of ADT when used in combination with dose escalated XRT remains controversial. In EORTC 22991 trial 6 months ADT improved disease free survival at all XRT dose levels (Bolla, JCO 2016). We present long-term results of dose escalated XRT (76 Gy) in combination with 6 months ADT in the context of a Phase 3 Trial evaluating the optimal timing of ADT in combination with XRT. Methods: 438 pts were entered on the trial. Inclusion criteria were cT1-T3, Gleason < 8, PSA < 30. Low risk pts were excluded. ADT consisted of 6 mo Total Androgen Blockade (TAB) with Goserelin and Biclutamide. Pts were randomized to upfront XRT (day 1 of ADT) or XRT after 4 months ADT. Median follow-up is 12 yrs. 10 yr overall Survival (OS), Cause Specific Survival (CSS) PSA Disease Free Survival (DFS) and Local DFS were estimated using Kaplan-Meier (KM) method. Results: Clinical characteristics are as follows: mean age 69; 69% cT1-T2A, 31% cT2B-T3; 75% Gleason 7; mean PSA = 10. Protocol compliance: 96% of pts completed 6 mo TAB and 99% completed 6 mo Goserelin. 4% of patients stopped Biclutamide early (3% due to Grade 1-3 reversible liver toxicity). 4% of patients developed late Gr 3 proctitis. 10 yr results: PSA DFS 83%, CSS 98%, OS 76%, and local DFS 95%. The results by treatment arm will be presented in the near future. Conclusions: The durable DFS, local control and CSS support the benefit of 6 mo ADT in combination with Dose Escalated (76 Gy) XRT. The favourable compliance, tolerance and toxicity data support this treatment approach. Potential survival benefits of ADT in intermediate risk prostate cancer will be evaluated by mature results from EORTC 22991 and RTOG 0815 trials. Clinical trial identification: OTT 01-01 Legal entity responsible for the study: Ottawa Hospital Research Institute Funding: None Disclosure: All authors have declared no conflicts of interest.

Dicentric Chromosome Assay (DCA) is a validated biodosimetry technique. It has been used to determine previous exposure to radiation by measuring chromosome damage in Tcells that have lifespan of about 3 years. Association of increased background dicentric chromosomes (DC) and risk of cancer development has been reported before. Previously, we reported results supporting radiation induced DC and excess fragments (EF) as potential biomarkers of increased radiosensitivity. In this study we studied number of DCs and EFs in a cohort of cancer patients cancer to assess that as a marker of cancer susceptibility. Radiation induces temporary cell cycle delay to provide cells with more time to repair DNA. So cells with more DNA damages may have slower cycles. We also studied the percentage of cells that had progressed into the 2nd metaphase after a certain time as a potential radiosensitivity marker. This study is part of a randomized trial evaluating the timing of Radiation and Hormonal Therapy for intermediate prostate cancer patients. 438 patients have been accrued. Three percent of patients (Radiosensitive Cohort (RS)) in long-term follow-up have developed grade 3 proctitis. RS cohort was compared to patients with no proctitis (Control Cohort). Using DCA, unirradiated blood samples of 30 patients were analyzed for the DC and EF frequency per cell. Slides were stained with fluorescence plus Giemsa to allow discrimination between cells in 1st and 2nd metaphase (M1 and M2 respectively). The percentage of cells in M2 (M2%) at 0Gy and 6Gy in both RS and Control group were compared. With no in vitro radiation, the mean number of DA was higher in the total group of patients compared with our baseline laboratory data from a normal, noncancerous population (1 per 100 cells in cancer patient cohort versus 1-2 per 1000cells). Mean EF was higher in RS group(1/100 vs 5/1000 in RS and control group respectively). The difference was not significant. Mean DA was same in both groups (1 dicentric per 100 cell). Comparing M2% between RS and control samples at 0Gy, there was no discernable difference (mean values 0.068 and 0.044 respectively with p = 0.082). After an in vitro exposure of 6Gy, the difference in the mean values between the 2 groups (0.28 vs 0.03 and 0.46 vs 0.02 respectively) was 0.18 with 95% confidence interval of 0.11 to 0.25 (p < 0.001). Results of this study suggest that chromosomal aberration frequency might be associated with cancer development and impairment in repair. This also suggests an association between chromosomal aberration and excess fragments and further chance of toxicity from radiation treatment. Difference in M2% between two groups further validates the association of more in vitro radiation induced DNA damage and clinical radiosensitivity. This can be considered as an in vitro radiosensitivity biomarker.

6 months androgen deprivation therapy (ADT) improves prostate cancer survival in Gleason 7 Prostate Cancer when added to conventional dose radiation (XRT) (D’Amico, JCO) 1 . The benefits of ADT when used in combination with dose escalated XRT remains to be determined. The purpose of the report is to evaluate the compliance, toxicity and efficacy of Dose Escalated XRT in combination with 6 months ADT (Zoladex + Casodex) in a Phase 3 Trial. The primary endpoint in the trial is to determine the optimal timing of XRT in relation to ADT.

Simultaneous integrated boost techniques deliver different total doses with differing fraction size but identical fraction number to more than one CTV. Radiobiological gain from increased total dose and/or accelerated delivery is limited by toxicity resulting from the dose density in the normal tissues within the PTV. The premise of ISIB is that further clinical gain can be obtained by boosting subvolumes of the GTV to still higher doses provided that these subvolumes exclude embedded normal tissue and are sufficiently distant from the GTV-normal tissue interphase. We evaluate the metrics of our initial ISIB clinical experience employing Niemierko EUD (equivalent uniform dose) and EUBED(equivalent biologically uniform dose) calculations. Two patients were treated conventionally (#1 palliative intra-abdominal sarcoma, #2 curative ENT) but had ISIB plans generated. Three other patients were treated with ISIB plans (#3 palliative oropharynx , #4 palliative melanoma and #5 curative head and neck) #1 3 and 5 were tomotherapy plans #4 3DCRT and #2 VMAT. The high dose subvolume PTV was contoured by shrinking 0.5 - 1.0cm within the GTV. The ISIB planning ensured the GTV-normal tissue interphase received standard dose whilst the GTV subvolume received a significantly higher dose. For each case a uniform PTV dose plan and an ISIB plan were compared by calculating EUD and EUBED. In each of the 5 cases the table details the GTV volumes, EUD and EUBED calculations (for both a conventional homogeneous plan and the ISIB plan) using a value of 10 both for the 'a' value and the alpha/beta ratio in the EUD and EUBED calculations respectively. The relative gain in these two parameters between the homogeneous and ISIB plans are calculated. In each case a net gain is seen for EUD (range 10.3 - 32%) and EUBED (range 12.3 - 41%) The preliminary clinical experience and evaluated radiobiological/dosimetric parameters suggest the potential for therapeutic gain without additional toxicity with ISIB.

Approximately 5% of prostate cancer patients treated with radiation develops severe proctitis. The development of an in vitro assay for radiation response would allow radiosensitive patients to be identified and considered for alternative therapy. The translational research study is part of a randomized trial evaluating the optimal timing of Dose Escalated Radiation and short course Androgen Deprivation Therapy. 430 patients have entered the phase III clinical trial. 3% of patients (Radiosensitive Cohort (RS)) in long-term follow-up have developed grade 3 proctitis. The RS cohort was compared to patients with no proctitis (Control Cohort). Dose Volume Histograms (DVHs) were reviewed in both cohorts. We examined the in vitro γH2AX response in lymphocytes and lymphocyte subsets. Cytogenetic endpoints were examined to provide information about the mechanisms of radio-sensitivity. Peripheral blood samples were irradiated and examined for γH2AX response. A dose course experiment was conducted with 6 dose points (range 0 - 10 Gy), processed 1 hour after irradiation. The time response of γH2AX was also monitored, with 2 Gy irradiated samples being incubated for 0 to 24 hours before processing. Samples were fixed stained with γH2AX-FITC, CD4-PE, CD8-APC and CD19-PC7 for analysis with flow cytometry. Zero and 6 Gy irradiated blood samples were analyzed for chromosome aberrations and excess fragments per cell. Rectal DVHs were comparable between the two groups. At 6 Gy, the mean number of excess fragments per cell in the RS cohort was significantly higher than in the control cohort with mean values of 2.1 ± 0.4 and 1.7 ± 0.3 respectively (p = 0.005). At 6 Gy, there was a trend toward higher number of aberrations per cell in the RS cohort than in controls with mean values of 3.2 ± 0.3 and 3.0 ± 0.3 respectively (NSS ; p = 0.168). In a subset of the data for the RS population, the γH2AX response was higher in the time course experiment. These preliminary results suggest the existence of potential markers for radio-sensitivity. These biomarkers may be useful in the future for tailoring radiotherapy treatments. Further work is being done to validate the results.

5504 Background: A significant proportion of node-positive HNC patients will have residual nodes visible on CT following curative radiation therapy +/- concurrent chemotherapy (RT+/-Chemo). A third of these will harbor residual cancer and can be cured by neck dissection (ND). This study examines the ability of PET/CT to detect residual nodal cancer following RT+/-Chemo in HNC patients. METHODS This prospective multi-center study was conducted at 4 regional cancer centers in Ontario. Eligible patients had squamous cell carcinomas with N2 or N3 neck disease. They were treated curatively with RT+/-Chemo to include full radiation dose to nodes deemed involved by tumor. Contrast enhanced CT scans and PET/CT were performed prior to and 8-10 weeks following RT+/-Chemo. Patients with residual nodes >1cm axial dimension on CT were mandated to undergo ND within 4 weeks of imaging. The pathologic results of ND were correlated with post treatment imaging. Patients were followed for neck recurrence for 2 years. RESULTS 399 patients were enrolled: 335 (84%) male and 64 (16%) female, with a mean age of 57 years (range: 27-84). Primary sites included: oropharynx 301 (75%), oral cavity 35 (9%), hypopharynx 31 (8%), larynx 31 (8%) and unknown primary site 56 (14%). T and N categories were T0 58 (15%), T1-T2 191 (48%), T3-T4 146 (37%), N2a 58 (15%), N2b 173 (43%), N2c 130 (33%) and N3 38 (10%). 325 patients have been followed for at least 18 months. 350 patients completed post-treatment PET/CT at a mean of 9.2 weeks (range: 4-19). Results for 152 patients having ND are shown in the table. PET/CT sensitivity was significantly lower than that for CT (53% vs 94%; p<0.001). Of the 201 patients who did not have ND, 8/201 (4%) had neck recurrence on follow-up. Post-treatment PET/CT was positive in 4/8 (50%) of these, and it was also positive in 24/193 (12%) who had no neck recurrence on follow-up. CONCLUSIONS PET/CT performed 8-10 weeks following RT+/-Chemo is not a reliable indicator of residual nodal disease and should not be used to determine the need for ND. [Table: see text].

The objective of this study was to evaluate the incidence, time of onset and extent of hemoglobin changes in patients with localized prostate cancer receiving either radiation alone or combined with androgen deprivation therapy (ADT). Patients with clinically localized prostate cancer receiving 3D-conformal radiation with or without ADT were enrolled. Patients were generally treated with radiation alone (Group l), radiation plus short-term (≤ 6 months) ADT (Group 2), or radiation plus long-term (≥2 years) ADT (Group 3). A prospective evaluation of serum hemoglobin, testosterone and erythropoietin levels was carried out for these patients. The linear regression analysis model used to evaluate the data. Thirty-five patients were evaluated with a median age of 69 years. The number of patients in Groups 1, 2 and 3 were 20, 6, and 9 respectively. The mean baseline hemoglobin for group 1,2 and 3 were 149, 143 and 153 in the order given. There was no significant decrease in hemoglobin, testosterone or erythropoietin levels among patients treated with radiotherapy alone. There was a significant drop in testosterone levels noted in the Groups 2 and 3 patients within one month (p value <0.001) and it reached a plateau at approximately six months. This was followed by a significant decrease in hemoglobin levels of 16 and 14 g/L among patients in Groups 2 and 3 respectively (p value <001) at three to six months. There was a small but statistically significant increase in erythropoietin levels noted after six months in the patients receiving ADT (p value <0.001). There was no immediate recovery in hemoglobin, testosterone or erythropoietin levels upon completion of ADT. Although conformal radiotherapy alone for localized prostate cancer has no effect on hemoglobin, testosterone or erythropoietin levels, ADT leads to a significant decrease in testosterone levels, which is followed by decrease in hemoglobin levels, and this is not due to a deficiency in erythropoietin.