Background and Purpose: Larynx cancer represents one of the most frequently diagnosed head and neck malignancies, which is most often confined to the glottic area. The aim of this study was to report the oncological outcome and identify prognostic factors in early-stage glottic squamous cell carcinoma treated with radiotherapy. Material and Methods: Patients (n = 761) diagnosed and treated in 10 centers between 1990 and 2015 were retrospectively analyzed. Probabilities of loco-regional control (LRC) and overall survival (OS) were calculated and possible prognostic factors were analyzed using Cox proportional hazards models. Results: The median follow-up was 63 months (range: 2-243). Three hundred and sixty-four, 148 and 249 patients had cT1a, cT1b, and cT2 stage I-II disease, respectively. Five and 10-years LRC/OS rates in the whole cohort were 83/82% and 80/68%, respectively. Three patients developed distant recurrences. In univariate analysis, male sex (HR: 3.49; 95% CI: 1.47-11.37; p < 0.01), T2 vs. T1a (HR: 1.62; 95% CI: 1.08-2.43; p = 0.02) and anterior commissure involvement (ACI) (HR: 1.66; 95% CI: 1.38-2.45; p < 0.01) were associated with impaired LRC. In multivariate analysis, male sex (HR: 3.42; 95% CI: 1.44-11.17; p < 0.01) and ACI (HR: 1.51; 95% CI: 1.01-2.28; p = 0.047) remained poor prognostic factors. No relation of treatment technique and biologically equivalent dose (BED) to oncological outcome was identified except for higher BED10(L = 25; T = 1) yielding better LRC in T1a tumors (p = 0.04) in univariate analyses. Conclusion: Our results highlight the negative impact of ACI on tumor control. A less-expected finding was the impact of sex on tumor control. Further research is needed to validate its prognostic value and investigate any related biologic or behavioral factors, which may be modified to improve oncologic outcome.

Abstract Background: The aim of this study was to identify factors that influence the delivery of post-mastectomy radiotherapy (PMRT) in Switzerland, and to analyze the adherence to consensus guidelines. Methods: Based on 7 regional cancer registries covering 45% of the Swiss population, we identified 1408 women which underwent mastectomy for stage I-III breast cancer between January 1, 2003 and December 31, 2005. We categorized patients according to ASCO grouping in similar fashion to other comparable studies: low-risk group (T1/T2 N0): PMRT not routinely recommended; intermediate-risk group (T1/T2 N1): PMRT controversial; high risk group (T3-T4 and/or N2-N3): PMRT recommended. We further investigated factors leading to potential overtreatment (PMRT in low-risk group) or undertreatment (absence of PMRT in high-risk group). Data analysis was performed for the entire cohort, and separately for patients <70 years and ≥ 70 years of age. Probability of receiving PMRT was assessed using multivariable logistic regression. Results: A total of 421 patients (29.9%) received adjuvant RT after mastectomy. The rate of PMRT delivery was 67% in the high-risk group, compared to 6% and 18% in the low-risk and intermediate-risk groups, respectively. For patients at high-risk of chest wall recurrence after mastectomy (T3-T4 or N2-N3 disease), the risk of PMRT omission wassignificantly associated to older age (OR 4.25 [95% CI: 2.27-7.95] for patients ≥ 70 years) and to the absence of chemotherapy (OR 4.30 [95% CI: 1.97-9.36]). In patients with T3-T4 disease, PMRT was delivered in 77% of patients < 70 years and in 42% of patients ≥ 70 years (p<0.001). In patients with N2-N3 disease, PMRT was delivered in 82% of patients < 70 years and in 51% of patients ≥70 years (p<0.001). PMRT was delivered to 28 patients (7%) at low-risk of recurrence after mastectomy (T1-T2 N0, negative margins). It was more frequently offered to patients <40 years of age (OR 3.86 [95% CI: 1.01-14.76]), with T2 tumors (OR 3.43 [95% CI: 1.45-8.11]) and negative hormone receptor status (OR 2.60 [95% CI: 1.04-6.50]). Positive or close surgical margins (< 1mm) were a strong indicator for PMRT (p=0.001) and chest wall boost (p<0.03). Conclusions: After mastectomy, one third of patients (33.26%) with high-risk disease did not receive PMRT. Even if we consider only patients < 70 years, a non-trivial proportion of patients with clear indication for treatment delivery did not receive PMRT (T3-T4 disease: 23%; N2-N3 disease: 18%). Further analyses are planned to explain the apparent failure of evidence-based guidelines to impact the adoption of PMRT in women with high-risk breast cancer. Citation Format: Zwahlen DR, Ess S, Zimmermann M, Bordoni A, Bouchardy C, Frick H, Konzelmann I, Mousavi M, Rohrmann S, Oehler C. Disparities in the application of post-mastectomy radiotherapy in Switzerland: A pooled analysis of 7 cancer registries over the 2003-2005 period [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-24.

Background: To evaluate local control (LC), survival and toxicity in anal cancer patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy at a single institution.Material and methods: From August 2010 to May 2015, 26 patients were treated at our institution with IMRT and concurrent 5-fluorouracil/mitomycin-C (5-FU/MMC) for localized squamous cell carcinoma of the anal canal (SCCAC). Radiotherapy (RT) with 50.4-60Gy was delivered with a sequential boost in 31%, and a simultaneous-integrated boost (SIB-IMRT) in 69% of cases. Initial staging was based on PET-CT and MRI. Clinical measures of interest were the influence of PET-CT on staging and treatment planning, LC, disease free survival (DFS), overall survival (OS), colostomy free survival (CFS) and toxicities.Results: Median age was 61 years, 22 patients (85%) were female, and no patient was HIV-positive. The proportion of patients with stage I, II, IIIA and IIIB disease was 15%, 35%, 23% and 27%, respectively. PET-CT modified the extent of nodal disease in 9/23 cases (39%) and lead to major changes in treatment planning in 4/23 patients (17%). MRI was more accurate at identifying T4 disease. RT was delivered at full dose in 26 patients (100%) and chemotherapy in 22/26 patients (85%). Two patients (7.7%) required RT breaks. Median follow-up was 35 months [IQR: 19-52]. The 2-year LC, DFS, OS and CFS were 100%, 100%, 100% and 92%. Acute grade 3 dermatitis and diarrhea occurred in 73% and 8% of cases, respectively. Grade 3-4 neutropenia was seen in 10/23 patients (43%). Four patients (15%) developed chronic grade 2 GI toxicity.Conclusions: PET-CT provided additional information leading to major changes in treatment planning for 17% of patients. Considering our excellent outcomes, routine use of PET-CT as standard staging modality and IMRT planning procedure appears justified for patients with SCCAC.

Stereotactic body radiotherapy (SBRT) for oligometastatic prostate cancer has been associated with prolonged progression-free survival (PFS) and clinically meaningful time without androgen-deprivation therapy (ADT). However, benefit may vary greatly in magnitude among patients, and there is no consensus how to best select them. The goal of this study was to identify prognostic factors associated with improved outcome after SBRT for oligometastatic prostate cancer. We performed a retrospective analysis of 25 consecutive prostate cancer patients presenting with isolated or limited lymph node (LN) recurrence (1-3 lesions) on choline PET-CT between January 2010 and July 2015. Prior therapy was radical prostatectomy (RP) alone (40%), or RP followed by salvage radiotherapy (60%), in absence of any systemic therapy. SBRT to LN was delivered via Cyberknife with 30 – 45 Gy in 3 fractions (median: 36 Gy). Endpoints of interest were biochemical response rate (defined as a reduction by at least 10% of the initial PSA value), time to biochemical recurrence (TBR) (defined as the time interval from SBRT until second PSA rise), and time interval between SBRT and ADT start. Univariate analysis was used to identify prognostic factors; the optimal cut-off point for LN size was calculated using the Contal and O'Quigley method. Median follow-up after SBRT was 18 months (interquartile range 15.0-22.3). Median age was 68 years (range 52-81). The number of positive LN treated was 1 (64%), 2 (28%) and 3 (8%), respectively, with a median LN diameter of 10.5 mm (range 5 – 28 mm). Biochemical response rate was 68% (17/25 patients). We found a trend towards a worse biochemical response for patients with positive surgical margins at RP (odds ratio [OR] 0.18, P=0.076) or previous salvage-radiotherapy (OR 0.13, P=0.079). Median TBR was 11.99 months (95% confidence interval [CI]: 10.5-21.2) and significantly longer in patients with larger LN (P=0.03). Using 14 mm as cut off for LN size, median TBR was 10.8 months for patients with small LN, and 21.2 months for patients with large LN (Punadjusted=0.009; Padjusted=0.099). There was a trend showing that the larger the LN size the lower the probability of receiving a second SBRT (hazard ratio [HR] 0.74, P=0.09). Until last follow-up, 32% of patients started ADT. The HR of starting ADT was 9.34 for pT3 versus pT2 (P=0.039) and 10.29 for extra-capsular extension (ECE) versus no ECE (P=0.030). For prostate cancer patients with oligometastatic LN recurrence after RP (± salvage RT), SBRT results in a better biochemical control when the treatment is delivered to larger size (≥ 14 mm) LN metastases. SBRT might also delay ADT introduction in those cases where prostate cancer was initially confined to the gland (pT2, no ECE).

Purpose/Objective(s)Image-guided radiation therapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method in delivering RT for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. We applied the Van Herk formula to calculate the margin for PTV of prostate using CBCT or FM.Materials/MethodsTwenty patients with low, intermediate or high risk PC received IGRT (VMAT) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted prior to treatment. Patients were planned and treated with rectal balloon (RB). CBCT was performed on day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. For 10 patients CBCT was performed after each fraction to assess intra-fractional motion. Contouring of the prostate (P) for low risk and of the prostate/seminal vesicles (PSV) for intermediate/high risk PC was performed independently by 3 clinicians and mean differences in vertical, lateral and longitudinal directions between the intersections and the unions of the three contours were assessed. The Van Herk formula M = 2.5Σ + 0.7σ3 was used for PTV margin calculation, where Σ represents the systematic and σ the random error. We calculated the systematic errors for intra-fractional motion, contouring as well as setup using CBCT, kV/kV and FM referring to prostate position in the CBCT and random errors for intra-fractional motion and patient setup.ResultsCalculated PTV margins were 6.1 mm vertically, 7.1 mm longitudinally and 4.4 mm laterally for contouring and intra-fractional but not setup errors. Systematic error for contouring was more influential than intra-fractional motion (0.9-1.4mm) and more pronounced in intermediate/high risk (2.5-3.2mm) than in low risk PC (1.3-2.1mm). Including setup errors, enlargement was least for CBCT and kV/kV-imaging using FM: +0.4-0.6mm (P) / +2.0-2.3mm (PSV) vertically, +0.1-0.7mm (P) / +2.5-2.9mm (PSV) longitudinally and +0.3mm (P) / +3.0-3.1mm (PSV) laterally. Higher increases were noticed for bone matching: +1.8-2.0mm (P) / +2.2-2.4mm (PSV) vertically, +1.4-1.5mm (P) / +3.6mm (PSV) longitudinally and +0.4-0.7mm (P) / +3.0-3.3mm (PSV) laterally. Largest increases were found for rectal balloon matching: +1.3-1.6mm (P) / +2.8-3.0mm (PSV) vertically, +0.9-4.5mm (P) / +3.1-6.2mm (PSV) longitudinally and +0.5-2.0mm (P) / +3.1-4.1mm (PSV) laterally.ConclusionCalculated PTV margins are comparable using either CBCT or kV/kV-imaging FM matching. The systematic error for contouring was more influential than intra-fractional motion. Margins for intermediate/high risk PC are notably larger than those for low risk PC due to seminal vesicles. Purpose/Objective(s)Image-guided radiation therapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method in delivering RT for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. We applied the Van Herk formula to calculate the margin for PTV of prostate using CBCT or FM. Image-guided radiation therapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method in delivering RT for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. We applied the Van Herk formula to calculate the margin for PTV of prostate using CBCT or FM. Materials/MethodsTwenty patients with low, intermediate or high risk PC received IGRT (VMAT) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted prior to treatment. Patients were planned and treated with rectal balloon (RB). CBCT was performed on day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. For 10 patients CBCT was performed after each fraction to assess intra-fractional motion. Contouring of the prostate (P) for low risk and of the prostate/seminal vesicles (PSV) for intermediate/high risk PC was performed independently by 3 clinicians and mean differences in vertical, lateral and longitudinal directions between the intersections and the unions of the three contours were assessed. The Van Herk formula M = 2.5Σ + 0.7σ3 was used for PTV margin calculation, where Σ represents the systematic and σ the random error. We calculated the systematic errors for intra-fractional motion, contouring as well as setup using CBCT, kV/kV and FM referring to prostate position in the CBCT and random errors for intra-fractional motion and patient setup. Twenty patients with low, intermediate or high risk PC received IGRT (VMAT) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted prior to treatment. Patients were planned and treated with rectal balloon (RB). CBCT was performed on day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. For 10 patients CBCT was performed after each fraction to assess intra-fractional motion. Contouring of the prostate (P) for low risk and of the prostate/seminal vesicles (PSV) for intermediate/high risk PC was performed independently by 3 clinicians and mean differences in vertical, lateral and longitudinal directions between the intersections and the unions of the three contours were assessed. The Van Herk formula M = 2.5Σ + 0.7σ3 was used for PTV margin calculation, where Σ represents the systematic and σ the random error. We calculated the systematic errors for intra-fractional motion, contouring as well as setup using CBCT, kV/kV and FM referring to prostate position in the CBCT and random errors for intra-fractional motion and patient setup. ResultsCalculated PTV margins were 6.1 mm vertically, 7.1 mm longitudinally and 4.4 mm laterally for contouring and intra-fractional but not setup errors. Systematic error for contouring was more influential than intra-fractional motion (0.9-1.4mm) and more pronounced in intermediate/high risk (2.5-3.2mm) than in low risk PC (1.3-2.1mm). Including setup errors, enlargement was least for CBCT and kV/kV-imaging using FM: +0.4-0.6mm (P) / +2.0-2.3mm (PSV) vertically, +0.1-0.7mm (P) / +2.5-2.9mm (PSV) longitudinally and +0.3mm (P) / +3.0-3.1mm (PSV) laterally. Higher increases were noticed for bone matching: +1.8-2.0mm (P) / +2.2-2.4mm (PSV) vertically, +1.4-1.5mm (P) / +3.6mm (PSV) longitudinally and +0.4-0.7mm (P) / +3.0-3.3mm (PSV) laterally. Largest increases were found for rectal balloon matching: +1.3-1.6mm (P) / +2.8-3.0mm (PSV) vertically, +0.9-4.5mm (P) / +3.1-6.2mm (PSV) longitudinally and +0.5-2.0mm (P) / +3.1-4.1mm (PSV) laterally. Calculated PTV margins were 6.1 mm vertically, 7.1 mm longitudinally and 4.4 mm laterally for contouring and intra-fractional but not setup errors. Systematic error for contouring was more influential than intra-fractional motion (0.9-1.4mm) and more pronounced in intermediate/high risk (2.5-3.2mm) than in low risk PC (1.3-2.1mm). Including setup errors, enlargement was least for CBCT and kV/kV-imaging using FM: +0.4-0.6mm (P) / +2.0-2.3mm (PSV) vertically, +0.1-0.7mm (P) / +2.5-2.9mm (PSV) longitudinally and +0.3mm (P) / +3.0-3.1mm (PSV) laterally. Higher increases were noticed for bone matching: +1.8-2.0mm (P) / +2.2-2.4mm (PSV) vertically, +1.4-1.5mm (P) / +3.6mm (PSV) longitudinally and +0.4-0.7mm (P) / +3.0-3.3mm (PSV) laterally. Largest increases were found for rectal balloon matching: +1.3-1.6mm (P) / +2.8-3.0mm (PSV) vertically, +0.9-4.5mm (P) / +3.1-6.2mm (PSV) longitudinally and +0.5-2.0mm (P) / +3.1-4.1mm (PSV) laterally. ConclusionCalculated PTV margins are comparable using either CBCT or kV/kV-imaging FM matching. The systematic error for contouring was more influential than intra-fractional motion. Margins for intermediate/high risk PC are notably larger than those for low risk PC due to seminal vesicles. Calculated PTV margins are comparable using either CBCT or kV/kV-imaging FM matching. The systematic error for contouring was more influential than intra-fractional motion. Margins for intermediate/high risk PC are notably larger than those for low risk PC due to seminal vesicles.

Purpose/Objective(s)Image-guided radiotherapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method to deliver curative treatment for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. There is little consensus defining which of these techniques should be applied.Materials/MethodsTwenty patients received IGRT (RapidArc) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted two weeks prior to treatment and all patients were planned and treated with rectal balloon (RB). CBCT was performed on treatment day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. Additionally kV-image pairs and CBCT were performed on the same day in some patients. Online positioning of the isocenter was performed according to FM using CBCT or kV image pairs. Absolute isocenter shifts between tattoos and either FM, bony landmarks, RB or prostate tissue were measured using manual matching in offline review. In addition, relative shifts between matching techniques including FM - RB, FM - bony landmarks and bony landmarks - RB were measured.ResultsMean absolute isocenter shifts were 6.9mm ± 3.7 (kV/kV) and 6.1mm ± 3.4 (CBCT) for tattoos to FM and 6.2mm ± 3.4 (CBCT) for tattoos to prostate tissue. KV/kV matching for FM correlated well with CBCT matching for FM (R2 = 0.92). Mean relative shift for FM (kV/kV) - FM (CBCT) was 1.7mm ± 0.9. As expected, CBCT matching for FM correlated well with matching for prostate tissue (R2 = 0.922) with a mean relative shift of 1.3mm ± 1.1. However, CBCT matching for FM poorly correlated with matching for RB (R2 = 0.608) or bony landmarks (R2 = 0.617).Mean relative shifts for FM - RB, FM - bony landmarks and bony landmarks - RB were, 2.6mm ± 2.2, 2.6mm ± 2.3and 2.0mm ± 2.5 using CBCT compared to 4.9mm ± 2.8, 3.5mm ± 2.3 and 5.9mm ± 3.4 using kV/kV.ConclusionsIGRT in combination with either FM or CBRT has an equally high accuracy in the matching process of prostate tissue. FM in combination with kV-image pairs combines the advantages of a low imaging dose to the patient with a high precision setup equivalent to a soft tissue match. A reduction of daily setup errors can be achieved allowing reduction of CTV to PTV margins. RB is an unreliable substitute for prostate tissue localization. Purpose/Objective(s)Image-guided radiotherapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method to deliver curative treatment for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. There is little consensus defining which of these techniques should be applied. Image-guided radiotherapy (IGRT) using fiducial markers (FM) or cone beam CT (CBCT) is the preferred method to deliver curative treatment for prostate cancer (PC) enabling precise targeting and dose escalation. These techniques should enable reduced CTV to PTV margins resulting in lower toxicity. There is little consensus defining which of these techniques should be applied. Materials/MethodsTwenty patients received IGRT (RapidArc) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted two weeks prior to treatment and all patients were planned and treated with rectal balloon (RB). CBCT was performed on treatment day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. Additionally kV-image pairs and CBCT were performed on the same day in some patients. Online positioning of the isocenter was performed according to FM using CBCT or kV image pairs. Absolute isocenter shifts between tattoos and either FM, bony landmarks, RB or prostate tissue were measured using manual matching in offline review. In addition, relative shifts between matching techniques including FM - RB, FM - bony landmarks and bony landmarks - RB were measured. Twenty patients received IGRT (RapidArc) to a dose of 74Gy/37f, 60Gy/20f or 57Gy/19f. Three gold FM were implanted two weeks prior to treatment and all patients were planned and treated with rectal balloon (RB). CBCT was performed on treatment day 1 to 3, then once every week. KV-image pairs (kV/kV) were used on all other days. Additionally kV-image pairs and CBCT were performed on the same day in some patients. Online positioning of the isocenter was performed according to FM using CBCT or kV image pairs. Absolute isocenter shifts between tattoos and either FM, bony landmarks, RB or prostate tissue were measured using manual matching in offline review. In addition, relative shifts between matching techniques including FM - RB, FM - bony landmarks and bony landmarks - RB were measured. ResultsMean absolute isocenter shifts were 6.9mm ± 3.7 (kV/kV) and 6.1mm ± 3.4 (CBCT) for tattoos to FM and 6.2mm ± 3.4 (CBCT) for tattoos to prostate tissue. KV/kV matching for FM correlated well with CBCT matching for FM (R2 = 0.92). Mean relative shift for FM (kV/kV) - FM (CBCT) was 1.7mm ± 0.9. As expected, CBCT matching for FM correlated well with matching for prostate tissue (R2 = 0.922) with a mean relative shift of 1.3mm ± 1.1. However, CBCT matching for FM poorly correlated with matching for RB (R2 = 0.608) or bony landmarks (R2 = 0.617).Mean relative shifts for FM - RB, FM - bony landmarks and bony landmarks - RB were, 2.6mm ± 2.2, 2.6mm ± 2.3and 2.0mm ± 2.5 using CBCT compared to 4.9mm ± 2.8, 3.5mm ± 2.3 and 5.9mm ± 3.4 using kV/kV. Mean absolute isocenter shifts were 6.9mm ± 3.7 (kV/kV) and 6.1mm ± 3.4 (CBCT) for tattoos to FM and 6.2mm ± 3.4 (CBCT) for tattoos to prostate tissue. KV/kV matching for FM correlated well with CBCT matching for FM (R2 = 0.92). Mean relative shift for FM (kV/kV) - FM (CBCT) was 1.7mm ± 0.9. As expected, CBCT matching for FM correlated well with matching for prostate tissue (R2 = 0.922) with a mean relative shift of 1.3mm ± 1.1. However, CBCT matching for FM poorly correlated with matching for RB (R2 = 0.608) or bony landmarks (R2 = 0.617).Mean relative shifts for FM - RB, FM - bony landmarks and bony landmarks - RB were, 2.6mm ± 2.2, 2.6mm ± 2.3and 2.0mm ± 2.5 using CBCT compared to 4.9mm ± 2.8, 3.5mm ± 2.3 and 5.9mm ± 3.4 using kV/kV. ConclusionsIGRT in combination with either FM or CBRT has an equally high accuracy in the matching process of prostate tissue. FM in combination with kV-image pairs combines the advantages of a low imaging dose to the patient with a high precision setup equivalent to a soft tissue match. A reduction of daily setup errors can be achieved allowing reduction of CTV to PTV margins. RB is an unreliable substitute for prostate tissue localization. IGRT in combination with either FM or CBRT has an equally high accuracy in the matching process of prostate tissue. FM in combination with kV-image pairs combines the advantages of a low imaging dose to the patient with a high precision setup equivalent to a soft tissue match. A reduction of daily setup errors can be achieved allowing reduction of CTV to PTV margins. RB is an unreliable substitute for prostate tissue localization.

Purpose/Objective(s)To evaluate 18F-FMISO PET in monitoring tumor response to the clinical antivascular compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA).Materials/MethodsSerial 18F-FMISO microPET (R4 or Focus 120) imaging was performed prior to and 24 hours after treatment with DMXAA (20mg/kg) or sham treatment in mice bearing HT29 xenografts. Pimonidazole was co-administered with the first 18F-FMISO injection and EF5 with the second. Hoechst 33342 was administered 5 min before sacrifice. Digital autoradiograms of cryo-cut tumor sections were acquired, followed by (immuno-) fluorescence microscopy visualization of pimonidazole, EF5, Hoechst 33342, CD31 and α-SMA.ResultsOf 12 DMXAA-treated tumors, 5 showed marked reductions in 18F-FMISO SUV and 7 did not. 18F-FMISO SUV reduction correlated with the difference between pimonidazole- and EF5-positive tumor fractions (r2∼0.5), as well as with diminished blood perfusion (r2∼0.58). Compared with controls, tumors with decreased SUV had less CD31+/SMA+ microvessels (p = 0.02) and more CD31-/SMA+ microvessels (p = 0.07).ConclusionsSerial 18FMISO micro-PET imaging prior to and after DMXAA can distinguish between different tumor responses in a specific xenograft model. A reduction in 18F-FMISO SUV following DMXAA most likely indicates reduced blood perfusion, and thus hypoxia tracer supply, rather than a real reduction in tumor hypoxia. Purpose/Objective(s)To evaluate 18F-FMISO PET in monitoring tumor response to the clinical antivascular compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA). To evaluate 18F-FMISO PET in monitoring tumor response to the clinical antivascular compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Materials/MethodsSerial 18F-FMISO microPET (R4 or Focus 120) imaging was performed prior to and 24 hours after treatment with DMXAA (20mg/kg) or sham treatment in mice bearing HT29 xenografts. Pimonidazole was co-administered with the first 18F-FMISO injection and EF5 with the second. Hoechst 33342 was administered 5 min before sacrifice. Digital autoradiograms of cryo-cut tumor sections were acquired, followed by (immuno-) fluorescence microscopy visualization of pimonidazole, EF5, Hoechst 33342, CD31 and α-SMA. Serial 18F-FMISO microPET (R4 or Focus 120) imaging was performed prior to and 24 hours after treatment with DMXAA (20mg/kg) or sham treatment in mice bearing HT29 xenografts. Pimonidazole was co-administered with the first 18F-FMISO injection and EF5 with the second. Hoechst 33342 was administered 5 min before sacrifice. Digital autoradiograms of cryo-cut tumor sections were acquired, followed by (immuno-) fluorescence microscopy visualization of pimonidazole, EF5, Hoechst 33342, CD31 and α-SMA. ResultsOf 12 DMXAA-treated tumors, 5 showed marked reductions in 18F-FMISO SUV and 7 did not. 18F-FMISO SUV reduction correlated with the difference between pimonidazole- and EF5-positive tumor fractions (r2∼0.5), as well as with diminished blood perfusion (r2∼0.58). Compared with controls, tumors with decreased SUV had less CD31+/SMA+ microvessels (p = 0.02) and more CD31-/SMA+ microvessels (p = 0.07). Of 12 DMXAA-treated tumors, 5 showed marked reductions in 18F-FMISO SUV and 7 did not. 18F-FMISO SUV reduction correlated with the difference between pimonidazole- and EF5-positive tumor fractions (r2∼0.5), as well as with diminished blood perfusion (r2∼0.58). Compared with controls, tumors with decreased SUV had less CD31+/SMA+ microvessels (p = 0.02) and more CD31-/SMA+ microvessels (p = 0.07). ConclusionsSerial 18FMISO micro-PET imaging prior to and after DMXAA can distinguish between different tumor responses in a specific xenograft model. A reduction in 18F-FMISO SUV following DMXAA most likely indicates reduced blood perfusion, and thus hypoxia tracer supply, rather than a real reduction in tumor hypoxia. Serial 18FMISO micro-PET imaging prior to and after DMXAA can distinguish between different tumor responses in a specific xenograft model. A reduction in 18F-FMISO SUV following DMXAA most likely indicates reduced blood perfusion, and thus hypoxia tracer supply, rather than a real reduction in tumor hypoxia.

Loss of caspase-8 expression - which has been demonstrated in a subset of Medulloblastoma (MB) - might block important apoptotic signalling pathways and therefore contribute to treatment resistance. In this study, IFN-gamma mediated up-regulation of caspase-8 in human MB cells was found to result in chemosensitization to cisplatin, doxorubicin and etoposide, and sensitisation to radiation. These effects were more prominent in D425 and D341 MB cells (low basal caspase-8 expression) when compared to DAOY MB cells (high basal caspase-8 expression). IFN-gamma mediated chemosensitization and radiosensitization effects were reduced by treatment with the caspase-8 specific inhibitor z-IETD-fmk. Treatment of IFN-gamma resulted in activation of STAT1 in DAOY MB cells and to a lesser extent in D425, but not in D341, indicating that IFN-gamma acts in MB cells through STAT1-dependent and -independent signalling pathways. Taken together, our results demonstrate that IFN-gamma mediated restoration of caspase-8 in MB cells might enhance apoptotic pathways relevant to the response to chemo- and radiotherapy.

Most of methylxanthine derivatives including caffeine have been known to radiosensitize cancer cells, but the obstacles such as toxicity, request of high dose and poor solubility hinder their preclinical evaluations and clinical applications. In this study, we evaluated the efficacy of 1-methylxanthine (1-MTX), a caffeine metabolite as a radiosensitizer and the in vivo effectiveness of the temperature-sensitive liposomal 1-methylxanthine (tsl-MTX) in combination with ionizing radiation and regional hyperthermia. In human colorectal and lung cancer cells, treatment of 1-MTX sensitized cells to ionizing radiation. To evaluate the in vivo capability of 1-MTX to radiosensitize tumors, we developed temperature-sensitive liposomal 1-MTX using DPPC:DMPC:DSPC (4:1:1 molar ratio) with intention of overcoming lethal toxicity of 1-MTX and controlling drug-release. The particle size of the liposomes was approximately 200 nm in diameter. The release of 1-MTX from the liposomes was responding to increase of temperature. In xenograft tumor-bearing mice, the tsl-MTX administered using the i.p. route showed delay of tumor growth. Importantly, tsl-MTX in combination with radiation and regional hyperthermia exhibited marked delay of tumor growth, suggesting that 1-MTX effectively enhanced radiation-induced suppression of tumor growth. In conclusion, tsl-MTX has highly efficacious anticancer competence in vivo, enhancing radiotherapeutic effectiveness, and feasibility for further clinical applications.