Prevalence and Prognostic Significance of PIK3CA Mutation and CNV Status and Phosphorylated AKT Expression in Patients With Cervical Cancer Treated With Primary Surgery.

Currently, there are limited and conflicting reports on the prognostic utility of PIK3CA and associated pathway markers for cervical cancers treated with primary surgical management. Moreover, current studies are lacking complete characterization of adjuvant treatment with RT and/or chemotherapy. We aimed to document the prevalence, clinicopathologic, adjuvant treatment details, and prognostic value of PI3K/AKT pathway mutations and copy number variation and phosphorylated AKT status in patients with cervical cancers treated with primary surgery. A clinicopathologic review was performed on a retrospective cohort of 185 patients with cervical cancer, treated with primary surgery at a single tertiary institution. Next-generation sequencing and digital PCR was used to determine PI3K/AKT pathway mutational status and PIK3CA copy number variation, respectively, and fluorescent immunohistochemistry measured phosphorylated AKT expression. In all, 179 of 185 (96.8%) of tumors were successfully sequenced; 48 (26.8%) were positive for PI3K/AKT pathway mutations-the majority (n=37, 77.1%) PIK3CA mutations. PIK3CA mutation was associated with pathologically positive lymph nodes [12 (32%) vs. 22 (16%); P =0.022] and indication for postoperative chemoradiotherapy [17 (45.9%) vs. 32 (22.5%); P =0.004]. On multivariable analysis, PIK3CA status was not associated with overall survival ( P =0.103) or progression-free survival ( P =0.240) at 5 yrs, nor was PIK3CA copy number variation status. phosphorylated AKT ≤ median significantly predicted for progression-free survival [multivariable hazard ratio 0.39 (0.17-0.89; P =0.025)] but not overall survival ( P =0.087). The correlation of PIK3CA with pathologic positive lymph node status yet lack of association with survival outcomes may be due to the use of adjuvant postoperative therapy. PIK3CA assessment before radical hysterectomy may help identify patients with a higher risk of node-positive disease.

The Choosing Wisely Oncology Canada Cancer List: An Update.

BACKGROUND: Choosing Wisely (CW) Canada is a national campaign to identify unnecessary or harmful services that are frequently used in Canada. The original CW Oncology Canada Cancer list was developed in 2014. A CW Oncology Canada working group was established to review new evidence and guidelines and to update the current CW Oncology Canada Cancer List. METHODS: Between January and March 2022, we conducted a survey of members of the Canadian Association of Medical Oncology (CAMO), Canadian Association of Radiation Oncology (CARO) and the Canadian Society of Surgical Oncology (CSSO). We took the feedback from the survey, including potential new recommendations as well as those that were thought to be no longer relevant and up to date, and conducted a literature review with the assistance of the Canadian Agency for Drugs and Technology in Health (CADTH). The final updated list of recommendations was made by the CW Oncology Canada working group based on a consensus process. RESULTS: We reviewed two potential recommendations to add and two potential recommendations to remove from the existing CW Oncology Canada Cancer List. The recommendation "Do not prescribe whole brain radiation over stereotactic radiosurgery for patient with limited brain metastases (≤4 lesions)" was supported by several evidence-based guidelines with the strength of recommendations ranging from strong to moderate and the quality of evidence ranging from level 1 to level 3. After reviewing the evidence, the working group felt that the other potential recommendation to add and the two potential recommendations to remove did not have sufficient strength and quality of evidence at this time to be added or removed from the list. CONCLUSION: The updated Choosing Wisely Oncology Canada Cancer List consists of 11 items that oncologists should question in the treatment of patients with cancer. This list can be used to design specific interventions to reduce low value care.

Are the Choosing Wisely Canada Cancer recommendations relevant and up to date with the current evidence?

INTRODUCTION: The Choosing Wisely (CW) Canada campaign was launched in 2012 to identify low-value, unnecessary and/or harmful services that are frequently used. The CW Canada Cancer list was developed in 2014 by a task force convened by the Canadian Partnership Against Cancer. The list outlines ten harmful or low-value practices that oncologists should avoid. We conducted a study of oncologists to understand the familiarity with the current recommendations and whether these continue to be relevant and up to date. METHODS: An electronic survey was developed by the members of the CW Oncology Working Group and distributed to practicing oncologists. The survey consisted of questions on 1) the familiarity of the existing CW Canada Cancer list 2) the relevance of the current list to current evidence and 3) any recommendation(s) that could be added or removed from the existing list. Descriptive statistics were used to analyze responses and narrative analysis was used to identify themes in open-ended questions. RESULTS: Between January 14 and May 3, 2022, 151 survey responses were received (overall response rate of 20 %) from 68 medical oncologists (45 % of study cohort, response rate 32 %), 54 radiation oncologists (36 % of study cohort, response rate 14 %) and 29 surgical oncologists (19 % of study cohort, response rate 18 %). Seventy-nine percent (120/151) of respondents were familiar with the current list and 65 % (78/119) said they implemented the recommendations "always" or "most of the time". Eight recommendations had > 80 % agreement that they were relevant and up to date with current evidence. There was interest in adding a new recommendation to avoid whole brain radiation and consider stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases. CONCLUSIONS: There is excellent familiarity with the CW Canada Cancer list amongst the survey respondents and most recommendations continue to be relevant and up to date with current evidence. There is an opportunity to educate physicians about the intent of the campaign and to add a new recommendation on the use of SRS for patients with a limited number of brain metastases. There is also an opportunity to identify barriers at the patient, provider and institution level that are hindering adoption of the CW Canada Cancer list POLICY SUMMARY: This survey will impact implementation and publication of an updated CW Canada Cancer list.

Radiation Therapy for Endometrial Cancer: An American Society for Radiation Oncology Clinical Practice Guideline.

PURPOSE: With the results of several recently published clinical trials, this guideline informs on the use of adjuvant radiation therapy (RT) and systemic therapy in the treatment of endometrial cancer. Updated evidence-based recommendations provide indications for adjuvant RT and the associated techniques, the utilization and sequencing of adjuvant systemic therapies, and the effect of surgical staging techniques and molecular tumor profiling. METHODS: The American Society for Radiation Oncology convened a multidisciplinary task force to address 6 key questions that focused on the adjuvant management of patients with endometrial cancer. The key questions emphasized the (1) indications for adjuvant RT, (2) RT techniques, target volumes, dose fractionation, and treatment planning aims, (3) indications for systemic therapy, (4) sequencing of systemic therapy with RT, (5) effect of lymph node assessment on utilization of adjuvant therapy, and (6) effect of molecular tumor profiling on utilization of adjuvant therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for quality of evidence grading and strength of recommendation. RESULTS: The task force recommends RT (either vaginal brachytherapy or external beam RT) be given based on the patient's clinical-pathologic risk factors to reduce risk of vaginal and/or pelvic recurrence. When external beam RT is delivered, intensity modulated RT with daily image guided RT is recommended to reduce acute and late toxicity. Chemotherapy is recommended for patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to II with high-risk histologies and those with FIGO stage III to IVA with any histology. When sequencing chemotherapy and RT, there is no prospective data to support an optimal sequence. Sentinel lymph node mapping is recommended over pelvic lymphadenectomy for surgical nodal staging. Data on sentinel lymph node pathologic ultrastaging status supports that patients with isolated tumor cells be treated as node negative and adjuvant therapy based on uterine risk factors and patients with micrometastases be treated as node positive. The available data on molecular characterization of endometrial cancer are compelling and should be increasingly considered when making recommendations for adjuvant therapy. CONCLUSIONS: These recommendations guide evidence-based best clinical practices on the use of adjuvant therapy for endometrial cancer.

The prognostic impact of PD-L1 and CD8 expression in anal cancer patients treated with chemoradiotherapy.

Background: Programmed death-ligand 1 (PD-L1) expression has been shown to be prognostic in many cancer types and used in consideration of checkpoint inhibitor immunotherapy. However, there are very limited and conflicting data on the prognostic impact of PD-L1 in patients with anal squamous cell carcinoma (ASCC). The objectives of this study were to measure the expression of PD-L1 and CD8 in patients with ASCC treated with radical chemoradiotherapy (CRT) and to correlate tumor expression with progression-free survival (PFS) and overall survival (OS). Methods: Ninety-nine patients with ASCC treated with primary CRT at two tertiary care cancer centers between 2000 and 2013, with available pre-treatment tumors, were included. Tissue microarrays (TMAs) from pre-treatment tumor specimens were stained for PD-L1 and CD8. PD-L1 expression in the tumor and stroma was quantified using HALO image analysis software, and results were interpreted using quantitative methods. The density of CD8 cells within the tumor was interpreted by a trained pathologist semi-quantitatively, using a 0-4 scoring system. Kaplan-Meier analysis with log-rank was used to determine the significance in the association of tumor markers with PFS and OS. Cox multivariate analysis was used to explore independent predictors of PFS and OS. Results: Of the 99 patients, 63 (64%) had sufficient tumor samples available for full analysis. CD8 high status was documented in 32 of 63 (50.8%) % of cases. PD-L1 expression was positive in 88.9% of cases. Approximately half the patients had tumor PD-L1 ≥ 5%. Patients with tumor PD-L1 ≥ 5% had better OS vs those with lower expression, HR=0.32 (95% CI 0.11-0.87), p=0.027; 10 years OS: 84% for tumor PD-L1 ≥ 5% vs 49% for PD-L1 < 5%. PD-L1 expression was not associated with PFS. On multivariate analysis, tumor PD-L1 ≥ 5% showed a trend to statistical significance for better OS, HR=0.55 (95% CI 0.12- 1.00), p=0.052. Conclusions: Tumor PD-L1≥5% is associated with OS in patients with ASCC treated with CRT. PD-L1 expression status using this unique cut-point warrants further validation for prognostication in patients with this disease. Future studies are required to determine the benefit of alternative treatment strategies based on PD-L1 status.

Representation of Women in Canadian Radiation Oncology Trainees and Radiation Oncologists: Progress or Regress?

Purpose: The study objective was to determine the representation of women in Canadian radiation oncology (RO) trainees and the radiation oncologist workforce over time. Methods and Materials: Gender data for Canadian RO trainees (residents and fellows) and radiation oncologists were collected from the Canadian Post-MD Education Registry (1994-2021) and Canadian Medical Association (1994-2019). Visa trainees were excluded. Gender parity was defined as a 1:1 female-to-male ratio. Descriptive statistics were used to summarize the data. Results: Female trainee proportions varied with 2 rising trend periods (1994-1998: 38%-43%, P = .93; 2002-2014: 35%-51%, P = .53) and 2 regression trend periods (1998-2002: 43%-35%, P = .83; 2014-2021: 52%-35%, P = .011). Gender parity was observed in RO trainees between 2012 and 2016. The annual number of RO trainees ranged from 66 to 173 with 2 near-parallel periods of gender-associated growth (1994-1996; 2002-2008) and regression (1997-2001; 2009-2016) followed by gender divergence (2017-2021) with increasing male and decreasing female trainees. Nearly all Canadian regions, except Ontario, reached 50% or higher female representation in RO trainees during the study period. In the radiation oncologist workforce, female representation increased from 20% (54/271) to 37% (217/582) between 1994 and 2019, and all regions and age groups demonstrated higher female representation over time. Within radiation oncologist subgroups, age <35 years old and Quebec region cohorts reached gender parity. Conclusions: Representation of women varied in Canadian RO trainees and has fallen since 2014, whereas female representation generally increased in the radiation oncologist workforce over time. Gender parity was observed in RO trainees, radiation oncologists <35 years old, and radiation oncologists in Quebec. Recent declining female representation among RO trainees is worrisome, and further study is warranted to identify potential gender-based barriers in attracting women to the specialty.

Impact of the COVID-19 Pandemic on Canadian Radiation Oncology Practices.

PURPOSE: To survey Canadian radiation oncology (RO) practice leaders to determine the effect of the COVID-19 pandemic on radiation services and patient and staff issues in the early phase of the pandemic and 1 year later. METHODS AND MATERIALS: The RO leader (department or division head) from every Canadian cancer center with radiation services was identified. Two surveys were circulated to the identified leader via email from the Canadian Association of Radiation Oncology central office, using the SurveyMonkey survey tool: the first closed in June 2020 and the second (expanded) survey in June 2021, representing 2 points in time of the COVID-19 pandemic. Questions included patient volume, service interruptions and delays, and changes in scheduling and telemedicine use. Additional questions were included in the follow-up survey to determine further effects on disease presentation, volume, vaccination and access, and personnel issues. RESULTS: Telemedicine was widely adopted early in the pandemic and continued to be a common technique to communicate and connect with patients. Although many centers were deferring or delaying certain disease sites early in the pandemic, this was not as prevalent 1 year later. Reduced cancer screening and patients presenting with more advanced disease were concerns documented in the 2021 survey. A high level of concern regarding stress among health care professionals was identified. CONCLUSIONS: Canadian RO centers have faced numerous challenges during the COVID-19 pandemic but continued to provide timely and essential cancer care for patients with cancer. Future evaluation of RO center practices will be important to continue to document and address the effect of the COVID-19 pandemic on issues relevant to RO leaders, patients, and staff.

Changing Landscape of Radiation Therapy for Advanced Cervical Cancer With a Focus on Interstitial Brachytherapy: A Canadian Practice Patterns Survey.

PURPOSE: To document the evolution of radical radiation therapy and interstitial brachytherapy (ISBT) utilization practice patterns across Canada, including use of imaging, technical details, and usage of anesthesia/analgesia, and to compare advanced (AC) versus nonadvanced (nAC) brachytherapy (BT) center practices. METHODS AND MATERIALS: All Canadian centers with BT services were identified. One gynecology radiation oncologist per center was sent a 64-item questionnaire regarding the center's practice for patients with cervical cancer. Centers were categorized based on availability of advanced BT expertise (AC) versus those referring patients to other centers for advanced BT techniques (nAC). Aggregate responses are reported and compared with practice patterns identified in our previous survey. Descriptive statistics were used to summarize data, and the Fisher exact test, Fisher-Freeman-Halton, or Mann-Whitney-Wilcox test was used for comparisons. RESULTS: Thirty-seven of 38 respondents completed the survey (response rate: 97.4%). Compared with 2015, there has been an increase in utilization of magnetic resonance imaging as the sole imaging modality for BT planning: 3 of 26 (11%) versus 12 of 37 (32%; P = .03). The number of centers with the ability to perform ISBT increased in 2020 compared with 2015 (26/37 [70%] vs 13/26 [50%], P = .710); this trend is likely due to an increase in use of hybrid (Vienna, Utrecht, Venezia) applicators (36% [2015] vs 84% [2020]; P = .175). Fifteen (40%) centers had the ability to perform perineal-ISBT (P-ISBT). Sixteen and 21 centers were identified as AC and nAC, respectively. All 16 AC centers had the ability to perform ISBT, compared with only 10 nAC centers (P < .001). A higher proportion of AC centers had fellowship-trained radiation oncologists performing brachytherapy, compared with nAC centers (94% vs 14%, P < .001). In terms of anesthesia, conscious sedation was the only available choice at low-patient-volume centers (8/37, 21%) performing intracavitary BT only. Those performing ISBT had choice of general, spinal, and epidural anesthesia. CONCLUSIONS: In Canada, high-quality, modern management radiation therapy practices are consistently offered to patients with cervical cancer. There is a trend toward increased utilization of ISBT. Accumulation of evidence toward the use of ISBT, increased utilization of high-quality imaging modalities such as magnetic resonance imaging, and availability of hybrid applicators are potential contributors for this upward trend.

PIK3CA mutation and CNV status and post-chemoradiotherapy survival in patients with cervical cancer.

PURPOSE: This study aimed to describe the prognostic value of PI3K/AKT pathway mutations in a large cohort of patients with cervical cancer. EXPERIMENTAL DESIGN: Patients with pre-treatment archival specimens, diagnosed with FIGO stages IB-IVA cervical cancer between 1998 and 2014 and treated with radical, curative intent chemoradiotherapy (CRT) at a single center were identified. Mutational status was determined by next generation sequencing and PIK3CA copy number (CNV) was assessed by digital PCR. RESULTS: 190 patients with available pre-treatment tumor specimens were identified. Median OS and PFS were 57.4 and 46.0 months, respectively. A total of 161 tumors were successfully sequenced; 60 (37.3%) had PI3K/AKT pathway mutations, with 50 (30.1%) having PIK3CA hotspot mutations. PIK3CA CNV gain was noted in 79 (59.2%) of the 154 successfully analyzed. On univariate analysis, PIK3CA mutation was associated with poor OS (HR 1.73; 95% CI: 1.03-2.92; p = .037) but not PFS (HR 1.38; 0.84-2.28; p = .204). Absence of any PI3K/AKT pathway mutation was associated with improved OS (HR 1.68; 1.01-2.81; p = .046) but not PFS (HR 1.50; 0.93-2.43; p = .202). Associations were not maintained when adjusting for clinical factors. On univariate analysis, PIK3CA mutation positive, CNV normal tumors were associated with poorer OS (HR 2.55; 1.18-5.50; p = .017) and trend to worse PFS (HR 1.87; 0.90-3.83; p = .094) when compared to those with CNV gain and wildtype PIK3CA. CONCLUSIONS: PI3K/AKT pathway mutations are common in cervical cancer. Consideration of PIK3CA mutational status with CNV status may be important in predicting outcome in cervical cancer patients.

National Trends and Dynamic Responses in the Canadian Radiation Oncology Workforce From 1990 to 2018.

PURPOSE: To report radiation oncology (RO) workforce and cancer incidence trends in Canada and explore the relationship between the two. METHODS AND MATERIALS: Canadian radiation oncologist, trainee, and cancer incidence data from 1990 to 2018 were collected from the following publicly accessible administrative and health information databases: Canadian Post-MD Education Registry (1990-2018), Canadian Medical Association Physician Data Centre (1994-2018), Canadian Institute for Health Information/Scott's Medical Database (1990-2017), Canadian Cancer Registry (1990-2017), and Statistics Canada (1990-2017). Descriptive statistics were used to summarize the data. RESULTS: The Canadian RO workforce grew from 240 radiation oncologists in 1990 to 567 in 2018, with the largest growth period from 2005 to 2015 adding 207 radiation oncologists. Regional analyses revealed steady or stepwise growth in all Canadian regions, except in Québec, where the number of radiation oncologists decreased from 86 in 1990 to 57 in 2003 before rising to 139 by 2018. Trainee totals were between 54 and 173 per year with 2 periods of growth (1990-1996 and 2001-2008) and regression (1996-2001 and 2008-2018), signifying trainee supply variability. Female proportions of the workforce and trainees, respectively, rose steadily from 18% to 38% and 28% to 50%, while the workforce proportion with non-Canadian medical degrees decreased from 40% to 26%. Radiation oncologists younger than 40 years increased from 70 to 171, whereas those age 60 years and older decreased from 85 in 1990 to 31 in 2002 and then increased to 108 in 2017. Annual cancer incidence rose steadily from 103,780 to 206,290 cases/year. The annual cancer incidence-to-provider ratio fluctuated (364-475:1) and trended lower with time, and proportional cancer incidence-to-provider ratios varied between 0.7:1 and 1.6:1 in Canada's regions before approaching 1:1. CONCLUSIONS: Our study demonstrates the challenges and successes of managing the Canadian radiation oncologist workforce. These data will inform policy makers and other stakeholders to ensure that the profession meets the current and future needs of Canadian cancer patients.

Taking Stock: The Canadian Association of Radiation Oncology 2017 Radiation Oncologist Workforce Study.

PURPOSE: To identify and report radiation oncologist (RO) workforce demographics, clinical workload trends, and equipment inventory in Canada. METHODS AND MATERIALS: The Canadian Association of Radiation Oncology (CARO) distributed an online survey to RO administrative leaders at 47 Canadian cancer centers providing radiation therapy services from June to December 2017. The survey queried RO staff demographics, clinical workload, and equipment inventory from 2014 to 2016. RESULTS: The response rate was 98% and represented 46 of 47 centers for analysis. In 2016, 510 ROs were in practice, with 98 ROs (19.2%) having <1.0 full-time equivalent (FTE) clinical work activities because of administration, research, or part-time employment. Most ROs worked full-time (92.0%), were affiliated with a university (77.5%), and worked in communities with a population >200,000 (84.9%). Approximately half (52.3%) were ≥46 years old. The male-to female ratio was 1.5:1 or higher in all regions of Canada except for Quebec, where there was no gender gap. Part-time employment was more common among female ROs (P < .01). Although FTE staff levels rose steadily between 2014 (456.3) and 2016 (475.8), an increase in patient workload resulted in a rise in the average annual consults per FTE-RO (from 257 to 267). Over a 2-year period, there were 63.5 FTE-recruitments and 44.0 FTE-departures (18.3 FTE-retirements; 25.7 FTE-migration) for a net gain of 19.5 RO-FTEs. An 8.4% increase in FTE staffing to 516 RO-FTEs in 2019 is anticipated, with 22 ROs expected to retire by 2019. There were 251 megavoltage linear accelerators across Canada, with most (39.8%) located in Ontario. Approximately one-fifth (20.7%) of these were older than 10 years and operating beyond the equipment's recommended life span. CONCLUSIONS: The Canadian RO workforce demonstrated incremental growth, but rising annual caseloads suggest that radiation therapy demand outpaced RO supply gains. Government funding is required to replace aging equipment in Canada.

Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811.

PURPOSE: To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. METHODS AND MATERIALS: EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. RESULTS: A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. CONCLUSIONS: High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.

Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer.

Several of the cancer immunotherapies under investigation or in clinical use target the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling axis. PD-L1 expression in tumor samples has been used as a predictive marker for response to these therapeutics, and may also have independent prognostic utility when assessed along with immune cell markers. Our objectives were to assess the expression of PD-L1 in tumor specimens from a uniformly treated patient cohort with locally advanced cervical cancer, and to determine its prognostic significance along with the density of tumor-infiltrating T cells. We identified 120 patients with locally advanced cervical cancer treated with radical chemoradiotherapy, and built tissue microarrays from their formalin-fixed, paraffin-embedded pre-treatment biopsies. We used conventional brightfield and fluorescence immunohistochemistry to detect PD-L1, and quantified protein expression using both manual pathologist scoring and automated software analysis. We also evaluated the effect of PD-L1 expression in tumors, along with the presence and density of intra-tumoral CD8+ T cells, on patient survival outcomes. Approximately 96% of the tumor samples expressed PD-L1, as determined using quantitative software analysis. Neither expression of PD-L1 nor density of CD8+ T cells was associated with progression-free or overall survival. However, there was a trend towards worse progression-free survival in patients whose tumors expressed PD-L1 but lacked CD8+ T cells (hazard ratio=0.43 (0.18-1.01), P=0.053). Nevertheless, the high percentage of cervical cancer tumor samples expressing PD-L1 suggests that anti-PD-L1 or anti-PD-1 therapies are potential treatment options for this patient population.

Anemia, leukocytosis and thrombocytosis as prognostic factors in patients with cervical cancer treated with radical chemoradiotherapy: A retrospective cohort study.

INTRODUCTION: Anemia has long been associated with poor prognosis in patients with cervical cancer. Recently, additional hematologic parameters have emerged as potential indicators of worse outcome in this patient group. In a cohort of cervical cancer patients treated with chemoradiotherapy (CRT) and brachytherapy, we report on the prognostic significance of hematologic parameters including anemia, leukocytosis, neutrophil to lymphocyte ratio (NLR), and thrombocytosis, the effect of combining anemia with other hematologic parameters, and the effect of changes in hemoglobin levels during treatment. MATERIALS AND METHODS: Two-hundred fifty-seven cervical cancer patients were retrospectively identified from a single cancer institution's database. Hematologic parameters were categorized as: anemia (hemoglobin ≤115 g/L), leukocytosis (white blood cell count >10 × 109/L), thrombocytosis (platelets >400 × 109/L), and NLR (ratio >5). The association between clinical factors and hematologic parameters on progression-free survival (PFS) and overall survival (OS) were assessed at 5 years. RESULTS: At 5 years, both pre-treatment anemia (PFS: 60% vs 34%, p < 0.0001; OS: 68% vs 41%, p < 0.0001) and on-treatment anemia (PFS: 62% vs 40%, p < 0.0001; OS: 70% vs 48%, p < 0.0001) were significantly associated with worse survival. This adverse effect on 5-year PFS and OS was increased in patients with both pre-treatment anemia and leukocytosis (PFS: 72% vs 42%, p < 0.0001; OS: 68% vs 37%, p < 0.0001) and pre-treatment anemia and elevated NLR (PFS: 61% vs 30%, p < 0.0001; OS: 68% vs 37%, p < 0.0001). Five-year PFS (50% vs 31%) and OS (60% vs 36%) was better in patients whose pre-treatment anemia improved to normal hemoglobin levels on treatment vs those patients who were anemic both pre- and on-treatment. CONCLUSION: Pre-treatment and on-treatment anemia were significant, independent predictors of worse PFS and OS. Anemia and other hematologic parameters remain prognostic markers for cervical cancer patients. Improvement in PFS and OS was seen in patients with normalization of hemoglobin.

Cervical cancer brachytherapy in Canada: A focus on interstitial brachytherapy utilization.

PURPOSE: Brachytherapy (BT) techniques for cervical cancer in Canada have changed over the last decade, with evolution to high-dose-rate and image-guided BT. However, there are currently no national data on the use of interstitial BT (IBT). The purpose of this study was to document IBT utilization in Canadian centers, as well as update details of cervical cancer BT practices. METHODS AND MATERIALS: All Canadian centers with gynecologic BT services (n = 33) were identified, and one gynecology radiation oncologist per center was sent a 33-item e-mail questionnaire regarding their center's practice for cervical cancer BT in 2015. Responses were reported and compared with practice patterns identified in a 2012 Canadian survey. RESULTS: The response rate was 85% (28/33 centers). The majority (93%) of respondents used high-dose-rate BT, similar to the 2012 survey; 96% of centers had transitioned to three-dimensional (MRI/CT)-based planning in 2015 vs. 75% in 2012 (p = 0.03); 57% centers incorporated MRI for treatment planning in 2015 compared to 38% in 2012 (p = 0.15); the majority (13/16) using a combination of MRI and CT; 50% (14/28 centers) had the capacity to perform IBT, whereas 71% of those that did not referred patients to other centers. Of centers performing IBT, the majority (11/14) used template-based techniques with a median of 6 (range 2-20) needles/catheters and an average of 4 (range 1-5) fractions. Catheters were placed using: strategy based on pre-op imaging (21%), intra-op ultrasound (50%), intra-op MRI (7%), and intra-op CT (21%). The most common dose/fractionation schedules were 6 Gy × 5 fractions (40%), 8 Gy × 3 fractions (19%), and 7 Gy × 4 fractions (15%). CONCLUSIONS: In Canada, treatment of cervical cancer continues to evolve. IBT has been adopted by half of the responding centers. As more centers move to MRI-based image-guided treatment planning, IBT will become an even more integral part of cervical cancer treatment.

Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells.

The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA. The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA-E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy.

Implementation and validation of a combined MRI-CT-based cervical cancer brachytherapy program using existing infrastructure.

PURPOSE: To describe the implementation of an MRI-CT-based cervical cancer brachytherapy (BT) program using existing infrastructure. To evaluate its impact on treatment planning. METHODS AND MATERIALS: A step-wise method was used to design and implement three-dimensional-based planning. Prospective risk analysis was used to create a process map and planning protocol. To evaluate the program, charts of cervical cancer patients treated curatively between January 2013 and December 2014, with at least one MRI during BT planning, were reviewed. Dosimetric comparisons were made between prescription point used and that of the traditional Point A and between MRI-planned treatments and CT-planned treatments. They were evaluated for differences between plans as well as adherence to Groupe Européen de Curiethérapie-European Society for Radiotherapy & Oncology (GEC-ESTRO) recommendations for high-risk clinical target volume coverage and organs-at-risk constraints. RESULTS: Implementation of the MRI-CT planning program occurred using existing infrastructure. Key to the implementation was communication between departments and the use of a process map to document the workflow. Eighty percent of treatments were prescribed to a point other than Point A, there were no major differences between the MRI-planned and CT-planned (with MRI guidance) treatments, and GEC-ESTRO recommendations were met for target coverage and organs at risk dose constraints. CONCLUSIONS: It was feasible to implement an MRI-CT-based cervical cancer BT planning program using existing infrastructure and that resulting plans meet GEC-ESTRO recommendations.

Intensity-Modulated Radiotherapy (IMRT) vs Helical Tomotherapy (HT) in Concurrent Chemoradiotherapy (CRT) for Patients with Anal Canal Carcinoma (ACC): an analysis of dose distribution and toxicities.

PURPOSE: Intensity-modulated radiotherapy (IMRT) and helical tomotherapy (HT) have been adopted for radiotherapy treatment of anal canal carcinoma (ACC) due to better conformality, dose homogeneity and normal-tissue sparing compared to 3D-CRT. To date, only one published study compares dosimetric parameters of IMRT vs HT in ACC, but there are no published data comparing toxicities. Our objectives were to compare dosimetry and toxicities between these modalities. METHODS AND MATERIALS: This is a retrospective study of 35 ACC patients treated with radical chemoradiotherapy at two tertiary cancer institutions from 2008-2010. The use of IMRT vs HT was primarily based on center availability. The majority of patients received fluorouracil (5-FU) and 1-2 cycles of mitomycin C (MMC); 2 received 5-FU and cisplatin. Primary tumor and elective nodes were prescribed to ≥54Gy and ≥45Gy, respectively. Patients were grouped into two cohorts: IMRT vs HT. The primary endpoint was a dosimetric comparison between the cohorts; the secondary endpoint was comparison of toxicities. RESULTS: 18 patients were treated with IMRT and 17 with HT. Most IMRT patients received 5-FU and 1 MMC cycle, while most HT patients received 2 MMC cycles (p<0.01), based on center policy. HT achieved more homogenous coverage of the primary tumor (HT homogeneity and uniformity index 0.14 and 1.02 vs 0.29 and 1.06 for IMRT, p=0.01 and p<0.01). Elective nodal coverage did not differ. IMRT achieved better bladder, femoral head and peritoneal space sparing (V30 and V40, p ≤ 0.01), and lower mean skin dose (p<0.01). HT delivered lower bone marrow (V10, p<0.01) and external genitalia dose (V20 and V30, p<0.01). Grade 2+ hematological and non-hematological toxicities were similar. Febrile neutropenia and unscheduled treatment breaks did not differ (both p=0.13), nor did 3-year overall and disease-free survival (p=0.13, p=0.68). CONCLUSIONS: Chemoradiotherapy treatment of ACC using IMRT vs HT results in differences in dose homogenity and normal-tissue sparing, but no significant differences in toxicities.

The prognostic value of HPV status and p16 expression in patients with carcinoma of the anal canal.

BACKGROUND: In anal cancer studies, the detection frequency of high-risk HPV (human papillomavirus) is variable, depending on the method used. There are limited data reporting results of different HPV detection techniques in the same clinical series, and very few correlating results with clinical outcome. OBJECTIVES: To evaluate tumor expression of p16/HPV16 using three different methods, and to determine their association with clinical outcome in patients with anal canal squamous cell carcinomas (SCC). DESIGN: This retrospective study included patients with anal canal SCC treated with definitive radiotherapy or chemoradiotherapy at a single institution between 1992 and 2005. Formalin-fixed paraffin-embedded tumor samples from 53 of the 89 (60%) patient pre-treatment biopsies were adequate for tissue microarray construction. HPV status was determined using: p16 expression by conventional immunohistochemistry (IHC) and quantitative IHC (AQUA), HPV genotype analysis by chromogenic in situ hybridization (CISH) and HPV linear array sub-typing. Expression status was correlated with clinical outcome. RESULTS: 80% (28/35) of patient tumors had high p16 expression using conventional IHC. HPV16 CISH was positive in 81% (34/42) of tumors, and 78% (28/36) of tumors were HPV subtype 16. HPV16 CISH correlated with p16 evaluated by conventional IHC (correlation coefficient 0.46; p = 0.01) and by p16 AQUA score (correlation coefficient 0.49; p = 0.001). A subset of cases (15%) had very high p16 quantitative IHC scores (>244) and were associated with a higher incidence of local or distant recurrence (p = 0.04). CONCLUSIONS: The vast majority (80%) of anal canal SCC in our series were positive for HPV16/p16, regardless of the testing method used. The exploratory analysis of automated quantitative IHC scoring was the only technique to define a subset of patients with a worse prognosis by p16 expression status on univariate analysis. Further exploration of the molecular mechanisms of treatment resistance in association with very high p16 expression is warranted.