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This pilot study (ClinicalTrials.gov NCT04543851) investigates a novel breast positioning device using a low density, high tensile carbon-fiber cradle to support the breast, remove the inframammary fold, and reduce dose to organs at risk for whole breast radiation therapy in the supine position. Thirty patients with inframammary folds ≥1 cm or lateral ptosis in supine treatment position were planned with standard positioning and with a carbon-fiber Adjustable Reusable Accessory (CARA) breast support. Twenty patients received whole breast with or without regional nodal irradiation with 42.5 Gy in 16 fractions or 50 Gy in 25 fractions using CARA. Median body mass index was 32 in this study. CARA removed all inframammary folds and reduced V20Gy ipsilateral lung, V105% breast , and V50% body , without compromising target coverage. Median (range) V20Gy ipsilateral lung for whole breast radiation therapy was 12.3% (1.4%-28.7%) with standard of care versus 10.9% (1.2%-17.3%) with CARA (Wilcoxon P =.005). Median V105% breast was 8.0% (0.0%-29%) with standard of care versus 4.0% (0.0%-23%) with CARA (P =.006) and median V50% body was 3056 mL (1476-5285 mL) versus 2780 mL (1415-5123 mL) with CARA (P =.001). CARA was compatible with deep inspiration breath hold and achieved median V25Gy heart = 0.1% (range 0%-1.9%) for all patients with left breast cancer. Skin reactions with CARA were consistent with historical data and daily variation in treatment setup was consistent with standard supine positioning. CARA can reduce V105% breast , lung and normal tissue dose, and remove the inframammary fold for breast patients with large or pendulous breasts and high body mass index treated in the supine position, without compromising target coverage. CARA will undergo further study in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

The study objective was to investigate the effectiveness of palliative radiation therapy (RT) for patients with diffuse large B-cell lymphoma (DLBCL) and to identify factors, such as chemotherapy relapsed/refractory (R/R) disease, that may influence RT outcomes. Patients with DLBCL who received palliative RT from 2001 to 2015 in British Columbia were reviewed for patient characteristics, treatment details, and outcomes. Univariable and multivariable analyses for response and local progression were performed. Three-hundred and seventy courses of palliative RT in 217 patients were identified. Median equivalent dose in 2 Gy fractions was 19 Gy (range, 2-42 Gy). Clinical and/or radiologic response occurred in 230 (83%) of the 276 courses with response data available. Local control following palliative RT at 6 months was 66.7%. On univariable analysis, R/R disease was not associated with lower clinical response rates but had higher risk of progression (hazard ratio [HR], 0.5; P =.040). On multivariable analyses, patients with R/R disease who did not require concurrent steroids had greater response compared with those who received upfront palliative RT (odds ratio, 3.5; P =.011). Response to first-line chemotherapy and smaller lesion size were associated with improved local progression rates (HR, 0.2; P <.001 and HR, 0.5; P =.020, respectively). RT dose fractionation factors were not significant on any analyses. Palliative RT for DLBCL is effective for symptom improvement, including in the chemotherapy R/R setting. Not requiring concurrent steroids, response to first-line chemotherapy, and smaller lesion size predicted better RT outcomes. There was no association between dose fractionation and response rates or local control to suggest that higher RT doses are more effective for palliation. [ABSTRACT FROM AUTHOR]

Purpose To determine Canadian radiation oncologists’ (ROs) views regarding the benefits, workload implications, and legal liability of the peer review quality assurance (QA) process. Methods and materials A 26-item anonymous survey was electronically distributed to all current practicing ROs in Canada through the Canadian Association of Radiation Oncologists membership to obtain their opinions regarding peer review. Results The survey was completed by 145 (36%) of 404 ROs. Most (82%) reported their practice is moderately or very busy and more than two-thirds (69%) felt stressed by their workload. A peer review process is standard at 92% of respondents’ institutions. The majority reported this consists of weekly meetings where ROs and other health care providers convene to review radiation treatment plans; some have tumor site-specific rounds while others have 1 meeting for all sites. Nearly all (97%) found this type of QA is beneficial for review of radical plans and 71% found it is beneficial for palliative plans. Incorporating peer review into their current work schedule for all sites was deemed by 37% of respondents to be not or slightly difficult, while 40% found it moderately difficult and 22% very or extremely difficult. The majority (91%) reported that creating a work code to document QA meetings would be helpful and 69% stated that extra resources such as scheduling protected time, designating other health care providers QA coordinators, and increasing overall RO manpower are needed to implement effective peer review. Over half (52%) felt documenting QA meeting minutes would increase legal liability. Conclusions The majority of ROs who responded found that peer review is beneficial and participate in peer review for at least some of the tumor sites they treat. However, most stated that extra resources are required to effectively implement QA for all tumor sites in their current schedule. [ABSTRACT FROM AUTHOR]

Purpose: ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters. Methods and Materials: A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years. Results: The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067). Conclusions: In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on multivariate analysis. [Copyright &y& Elsevier]

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Abstract: Background and purpose: A subset of patients in a clinical study where sequential biopsies were to be obtained during multifraction radiotherapy received pimonidazole prior to initiating treatment, allowing a unique opportunity of following hypoxic cells in situ during therapy. Material and methods: After institutional ethics review and with informed consent, women expecting to undergo radical treatment for cancer of the cervix received pimonidazole hydrochloride, with a biopsy approximately 24h later. Therapy was then started, and weekly biopsies were obtained. In the laboratory, the biopsies were reduced to single cell suspensions for flow cytometry analysis of DNA content, pimonidazole, and proliferation markers. Results: Pre-treatment pimonidazole-positive cells were largely in G0/G1. Pimonidazole-labelled cells, though expected to be radioresistant, were markedly decreased even early into treatment, and continued to disappear with a half-time of about 3 days. Concurrently, the cell cycle distribution of the previously hypoxic cells changed from predominantly quiescent to mostly proliferating. Conclusions: While a part of the rapid apparent loss of hypoxic cells was certainly due to loss of pimonidazole adducts through repair and dilution by cell division, the speed with which this occurred suggests that many labelled cells could rapidly re-enter the proliferative pool, a result consistent with many of those pimonidazole-labelled human cervix tumour cells being cyclically, rather than continuously, hypoxic. [Copyright &y& Elsevier]

: PurposeTo quantify cervix tumor response via weekly biopsies during therapy.: Methods and materialsPretreatment and subsequent weekly biopsies (when feasible) were obtained during radical external beam radiotherapy, reduced to single-cell suspensions, and assessed for DNA content by flow cytometry.: ResultsData for 41 patients ranging from FIGO Stage Ib to IIIb and with follow-up >100 days are presented. No clinically significant complications due to the weekly biopsies were noted. The actuarial progression-free survival at 2 years was 68%, with initial pelvic progression observed in 3 patients. The biopsies showed (1) Increased tumor cell proliferation was evident even for the earliest on-treatment samples; (2) Sustained cell yields, coupled with high proliferation 2 or more weeks into treatment, were associated with early failure; and (3) Therapy often “selected” for cell subpopulations that were only minor components of the pretreatment biopsy.: Conclusions“Accelerated repopulation” began surprisingly rapidly in cervix tumors after the initiation of chemoradiotherapy, and patients with a sustained cell yield and S-phase fraction 2 or more weeks into therapy were at increased risk for tumor progression. Although clearly implicating tumor (re)growth kinetics as a factor in outcome, the sequential biopsy data also suggested interplay between growth potential and in situ sensitivity to treatment. [Copyright &y& Elsevier]

Abstract: Purpose: To investigate in-field and peripheral kilovoltage cone beam CT (CBCT) doses in gynecological patients in comparison with IMRT or RapidArc scatter and linac leakage doses. Materials and methods: Monte Carlo codes BEAMnrc/DOSXYZnrc were used to simulate dose for daily use of kV CBCT in patients undergoing adjuvant pelvic radiotherapy for uterine or ovarian malignancies. Biological effectiveness was accounted for using a lineal energy based quality factor. Organ equivalent doses (OED) within the treatment field were modeled with linear-exponential, plateau and linear dose response curves. CBCT doses in peripheral regions were compared with IMRT and RapidArc scatter doses as well as linac leakage doses. Results: CBCT doses in peripheral regions were on the order of linac leakage doses and one order of magnitude lower than IMRT or RapidArc scatter doses. OEDs increased slightly, leveled off or even decreased within the treatment field with the addition of CBCT doses according to different dose response models. Conclusion: The results of this study indicate that patients undergoing IMRT or RapidArc treatments with daily use of kV CBCT imaging are not subjected to additional risk due to CBCT imaging doses. [Copyright &y& Elsevier]

Abstract: Background and purpose: Hypoxia adversely affects treatment outcome in human uterine cervical cancer. Here, we present the results of a prospective international multi-centre study evaluating the prognostic value of pre-treatment tumour oxygen partial pressure (pO2) and the hypoxia marker pimonidazole (pimo). Materials and methods: One hundred and twenty-seven patients with primary cervix cancer were entered. Pre-treatment tumour pO2 measurements were obtained, and reported by the median tumour pO2, the fraction of pO2 values ⩽10mmHg (HP10), ⩽5mmHg (HP5) and ⩽2.5mmHg (HP2.5). Following intravenous pimonidazole administration, biopsies were taken, stained for pimonidazole adducts, and scored for the area of labelled tumour cells on a scale from 0 to 4. Treatment modalities were surgery (11%), radiotherapy (98%), chemotherapy (33%) and carbogen (14%). Results: None of the hypoxia descriptors were statistically significant prognostic factors for loco-regional tumour control or overall survival when analyzed as continuous variables or divided by the sample median. By univariate analysis only tumour size and nodal status were significant prognostic factors for local control. Tumour size and FIGO stage were significant for overall survival. In a multivariate analysis stratified by centre, only tumour size above 5cm and lower pre-treatment haemoglobin predicted poorer overall survival among FIGO stage, nodal involvement, tumour size, pre-treatment haemoglobin dichotomized at 12g/dl and pimo 1, pimo 4 and HP5 as continuous variables. Conclusion: Neither Eppendorf nor pimonidazole should be dismissed based on the current results. However, further investigations are needed to readdress the hypotheses of the current study having optimized statistical designs, and a population of sufficient size treated more homogenously following rigorous protocols. [Copyright &y& Elsevier]

Background and purpose: The measurement of tumour oxygenation using Eppendorf oxygen-sensitive needle electrodes can provide prognostic information but the method is limited to accessible tumours that are suitable for electrode insertion. In this paper the aim was to study the relationship between such physiological measurements of tumour hypoxia and the labelling of tumours with the hypoxia-specific marker pimonidazole.Materials and methods: Assessment of tumour oxygen partial pressure (pO2) using an Eppendorf pO2 histograph and immunohistochemical pimonidazole labelling was carried out in 86 patients with primary cervix carcinomas. Pimonidazole was given as a single injection (0.5 g/m2 i.v.) and 10–24 h later pO2 measurements were made and biopsies taken. Tumour oxygenation status was evaluated as the median tumour pO2 and the fraction of pO2 values ≤10 mmHg (HP10), ≤5 mmHg (HP5) and ≤2.5 mmHg (HP2.5). Hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was scored using a light microscope. Each tumour was evaluated by the relative area pimonidazole at highest score and the accumulated area of pimonidazole labelling from score 1 to 4. Necrosis was measured in HE stained sections.Results and conclusions: The degree of hypoxia assessed by either pimonidazole binding or invasive electrode measurements varied significantly between tumours. There was a trend that the most hypoxic tumours measured by oxygen electrodes had the highest score of necrosis, and no or little pimonidazole binding. However, this observation was not consistent and there was no correlation between pimonidazole staining expressed in this way and oxygen electrode measurements of hypoxia. [Copyright &y& Elsevier]

Purpose The purpose of this work was to study the association between specific urinary sequelae and locally accumulated dose to the bladder wall and bladder neck in the treatment of cervical cancer with multifraction high-dose-rate (HDR) brachytherapy. Methods and Materials A cohort of 60 cervical cancer patients, treated with both external beam and five HDR brachytherapy insertions between 2008 and 2014 at the BC Cancer Agency, was identified. The accumulated dose received over five brachytherapy sessions was evaluated for the bladder wall and bladder neck of each patient using dosimetric parameters calculated from deformably registered image data sets. These parameters were examined as potential predictors of urinary sequelae including hematuria, frequency, urgency, incontinence, stream, nocturia, and dysuria. Two different dichotomization schemes were evaluated for grouping patients into Case and Control groups. The two-sample Student's t test was used for normally distributed samples and the Mann–Whitney nonparametric U test for non-normal distributions. Results A strong association between dose to the bladder neck and incontinence was found ( p = 0.001). A statistically significant association ( p < 0.05) was also observed between urgency and certain bladder-wall parameters. Conclusions Localized dose to the bladder neck is a potential predictor of urinary incontinence, whereas weaker associations were observed between urgency and some bladder-wall parameters. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The objective of this study was to determine if use of a rectal retractor (RR) in high-dose-rate intracavitary brachytherapy for cervical cancer reduces rectal dose parameters. Methods and Materials: We reviewed data obtained from patients treated with intracavitary brachytherapy for cervical cancer with and without an RR. Treatment plans for each brachytherapy fraction were separated into two groups; R group with use of an RR and P group with use of vaginal packing. Dose–volume parameters for high-risk clinical target volume (HR-CTV), rectum, sigmoid, small bowel, and vaginal surface were collected for each fraction. Rectal D 2cc and International Commission on Radiation Units & Measurements (ICRU) rectal point doses were compared between groups using Student's t tests. Predictors of higher rectal D 2cc were determined by univariate and multivariate regression analyses. Results: Four hundred sixty-three brachytherapy fractions from 114 patients were used for analysis, 377 fractions with a RR (R group) and 86 with vaginal packing only (P group). Both groups were similar except for slightly higher mean HR-CTV and mean bladder volume in P group. Both mean ICRU rectal point dose (241.1 vs. 269.9 cGy, p = 0.006) and rectal D 2cc (240.6 vs. 283.6 cGy, p < 0.001) were significantly higher in P group. Point A dose, HR-CTV, stage, and use of an RR were significant predictors of rectal D 2cc on multivariate analysis. Conclusions: Our data show that use of an RR leads to lower rectal dose parameters compared with vaginal packing. Further study is needed to determine if this will lead to less long-term toxicity. [Copyright &y& Elsevier]

Abstract: Purpose: To document doses received by critical organs during adjuvant high-dose-rate (HDR) vaginal vault brachytherapy. Methods and Materials: Patients treated with HDR vaginal vault radiation between January 1, 2009, and January 31, 2012, who had a CT simulation with the treatment cylinder in situ were included. The CT scans were retrospectively reviewed and the rectum, sigmoid, small bowel, and bladder were contoured. Standardized plans treating the upper 4 cm of the vaginal vault were used to deliver a total of 21 Gy (Gy) at 0.5 cm from the apex of the vaginal vault in three fractions. Results: There were 41 patients. Median age was 62 years. The median vaginal cylinder diameter was 3 cm. The mean 2cc dose to the rectum, sigmoid, small bowel, and bladder were 5.7, 4.7, 4.0, and 5.6 Gy, respectively. Bladder volume ranged from 67–797cc. Assuming minimal interfraction organ variation, the equivalent dose in 2 Gy/fraction was extrapolated from data and may be near or beyond organ tolerance for rectum, sigmoid, and small bowel in some cases. Spearman correlation found that increased bladder volume was not associated with adjacent organs at risk dose but may be associated with a trend (p =0.06) toward increased bladder dose (R=0.30). Conclusions: This study describes the dose received by adjacent critical structures during vaginal vault HDR brachytherapy. This is important information for documentation in the rare setting of treatment-related toxicity or recurrence. Bladder volume was not associated with dose to adjacent organs. [Copyright &y& Elsevier]

Abstract: Background and purpose: The possibility of using γH2AX foci as a marker of DNA damage and as a potential predictor of tumour response to treatment was examined using biopsies from 3 sets of patients with advanced carcinoma of the cervix. The relation between endogenous γH2AX expression and hypoxia was also examined. Materials and methods: Set 1 consisted of 26 biopsies that included pre-treatment and 24h post-radiation treatment samples. Pre-treatment biopsies from 12 patients in Set 2 were used to develop image analysis software while pre-treatment biopsies from 33 patients in Set 3 were examined for the relation between staining for the hypoxia marker pimonidazole and endogenous γH2AX expression. Formalin-fixed paraffin-embedded sections were analyzed after antigen retrieval and fluorescence antibody labeling for the hypoxia markers CAIX or pimonidazole in combination with γH2AX staining. Results: Before treatment, 24±19% of cells contained γH2AX foci, with most positive cells containing fewer than 5 foci per nucleus. Twenty-four hours after exposure to the first fraction of 1.8–2.5Gy, 38±19% contained foci. CAIX positive cells were 1.4 times more likely to exhibit endogenous γH2AX foci, and pimonidazole-positive cells were 2.8 times more likely to contain γH2AX foci. For 18 patients for whom both pre-treatment and 24h post-irradiation biopsies were available, local control was unrelated to the fraction of cells that retained γH2AX foci. However, 24h after irradiation, tumours that had received 2.5Gy showed a significantly higher fraction of cells with residual γH2AX foci than tumours given 1.8Gy. Conclusions: Endogenous γH2AX foci are enriched in hypoxic tumour regions. Small differences in delivered dose can produce quantifiable differences in residual DNA damage that can overshadow inter-tumour differences in response. [Copyright &y& Elsevier]

Purpose: To examine whether modified radical mastectomy (MRM) improves outcomes compared with breast-conserving treatment (BCT) in young women. Methods and Materials: Women aged 20–49 years, diagnosed with early breast cancer between 1989 and 1998, were identified. Management with BCT or MRM was compared for local (L), locoregional (LR), and distant relapse-free survival (DRFS) and breast cancer–specific survival (BCSS) by age group (20–39 years, 40–49 years). The analysis was repeated for patients considered “ideal” candidates for BCT: tumor size ≤2 cm, pathologically negative axillary nodes, negative margins, and no reported ductal carcinoma in situ. Results: A total of 1,597 women received BCT, and 801 had MRM. After a median follow-up of 9.0 years, the outcomes (L, LR, BCSS) were worse for the younger age group; however, the outcomes were not statistically different by type of local treatment. For women aged 20–39 years considered “ideal” for BCT, those treated with BCT had slightly lower LRFS compared with those treated with MRM (p = 0.3), but DRFS and BCSS were similar. Conclusions: A difference in LRFS at 10 years potentially favored MRM among women aged 20–39 years considered “ideal” BCT candidates but was not statistically significant and did not translate into a noticeable difference in DRFS or BCSS. Our data suggest that young age alone is not a contraindication to BCT. [Copyright &y& Elsevier]

Abstract: Cigarette smokers have high carboxyhaemoglobin levels which can promote tumour radioresistance. Inhalation of carbogen gas shortens the half-life of carboxyhaemoglobin, increasing tumour radiosensitivity in animal models. Breathing 2.5% carbogen for 30min results in a greater reduction in venous blood COHb levels than breathing 5% carbogen for 7min. [Copyright &y& Elsevier]