PET/MRI Assessment of Acute Cardiac Inflammation 1 Month After Left-Sided Breast Cancer Radiation Therapy.

Our purpose was to investigate the utility of 18F-FDG PET/MRI and serial blood work to detect early inflammatory responses and cardiac functionality changes at 1 mo after radiation therapy (RT) in patients with left-sided breast cancer. Methods: Fifteen left-sided breast cancer patients who enrolled in the RICT-BREAST study underwent cardiac PET/MRI at baseline and 1 mo after standard RT. Eleven patients received deep-inspiration breath-hold RT, whereas the others received free-breathing RT. A list-mode 18F-FDG PET scan with glucose suppression was acquired. Myocardial inflammation was quantified by the change in 18F-FDG SUVmean (based on body weight) and analyzed on the basis of the myocardial tissue associated with the left anterior descending, left circumflex, or right coronary artery territories. MRI assessments, including left ventricular functional and extracellular volumes (ECVs), were extracted from T1 (before and during a constant infusion of gadolinium) and cine images, respectively, acquired simultaneously during the PET acquisition. Cardiac injury and inflammation biomarker measurements of high-sensitivity troponin T, high-sensitivity C-reactive protein, and erythrocyte sedimentation rate were measured at the 1-mo follow-up and compared with preirradiation values. Results: At the 1-mo follow-up, a significant increase (10%) in myocardial SUVmean in left anterior descending segments (P = 0.04) and ECVs in slices at the apex (6%) and base (5%) was detected (P ≤ 0.02). Further, a significant reduction in left ventricular stroke volume (-7%) was seen (P < 0.02). No significant changes in any circulating biomarkers were seen at follow-up. Conclusion: Myocardial 18F-FDG uptake and functional MRI, including stroke volume and ECVs, were sensitive to changes at 1 mo after breast cancer RT, with findings suggesting an acute cardiac inflammatory response to RT.

A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles.

PURPOSE: The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. METHODS: An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. RESULTS: Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. CONCLUSIONS: Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.

Redefining postmastectomy radiation contouring in the era of immediate breast reconstruction: An accurate assessment of local recurrence risk.

INTRODUCTION: Most studies report post-mastectomy local recurrences as chest wall recurrences without clarifying whether the recurrence is in the subcutaneous tissue, muscle or underlying rib. Post-mastectomy chest wall radiation is recommended in patients at increased risk of locoregional recurrence. Chest wall radiation-related fibrosis has become an important clinical consideration in the era of immediate implant-based breast reconstruction. In patients with commonly performed subpectoral implant-based reconstruction, the pectoralis major becomes relocated anterior to the implant and just deep to skin, therefore raising the question of value in radiating deep chest wall structures. This study assessed the rate of recurrence in each anatomical region of chest wall in post-mastectomy patients. METHODS: A comprehensive breast cancer database of 4287 patients at a single regional cancer center from 2006 to 2018 was retrospectively analyzed to identify 1571 mastectomy patients. Recurrences were classified as local skin/subcutaneous, pectoralis muscle (pectoralis major), deep chest wall (pectoralis minor, intercostal muscle or rib) or regional axillary recurrence. RESULTS: A total of 26 patients with locoregional recurrence were identified. Most recurrences were in the skin/subcutaneous level. Of 1571 mastectomy patients, only one patient developed a local recurrence posterior to pectoralis major. Our literature search and meta-analysis revealed that local recurrences post-mastectomy are much more likely to be in subcutaneous tissues/pectoralis major versus deeper chest wall. CONCLUSION: A reduced clinical target volume which encompasses skin/subcutaneous and pectoralis muscle layers without treating deep chest wall may be more appropriate to reduce radiation-associated toxicity since avoiding circumferential radiation of an implant may prevent capsular contracture without compromising treatment benefit.

DCE-MRI assessment of response to neoadjuvant SABR in early stage breast cancer: Comparisons of single versus three fraction schemes and two different imaging time delays post-SABR.

PURPOSE: To determine the effect of dose fractionation and time delay post-neoadjuvant stereotactic ablative radiotherapy (SABR) on dynamic contrast-enhanced (DCE)-MRI parameters in early stage breast cancer patients. MATERIALS AND METHODS: DCE-MRI was acquired in 17 patients pre- and post-SABR. Five patients were imaged 6-7 days post-21 Gy/1fraction (group 1), six 16-19 days post-21 Gy/1fraction (group 2), and six 16-18 days post-30 Gy/3 fractions every other day (group 3). DCE-MRI scans were performed using half the clinical dose of contrast agent. Changes in the surrounding tissue were quantified using a signal-enhancement threshold metric that characterizes changes in signal-enhancement volume (SEV). Tumour response was quantified using Ktrans and ve (Tofts model) pre- and post-SABR. Significance was assessed using a Wilcoxin signed-rank test. RESULTS: All group 1 and 4/6 group 2 patients' SEV increased post-SABR. All group 3 patients' SEV decreased. The mean Ktrans increased for group 1 by 76% (p = 0.043) while group 2 and 3 decreased 15% (p = 0.028) and 34% (p = 0.028), respectively. For ve, there was no significant change in Group 1 (p = 0.35). Groups 2 showed an increase of 24% (p = 0.043), and Group 3 trended toward an increase (23%, p = 0.08). CONCLUSION: Kinetic parameters measured 2.5 weeks post-SABR in both single fraction and three fraction groups were indicative of response but only the single fraction protocol led to enhancement in the surrounding tissue. Our results also suggest that DCE-MRI one-week post-SABR may be too early for response assessment, at least for single fraction SABR, whereas 2.5 weeks appears sufficiently long to minimize confounding acute effects.

Cost-effectiveness analysis of multigene expression profiling assays to guide adjuvant therapy decisions in women with invasive early-stage breast cancer.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays' utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

The Potential Clinical and Economic Value of Primary Tumour Identification in Metastatic Cancer of Unknown Primary Tumour: A Population-Based Retrospective Matched Cohort Study.

PURPOSE: Several genomic tests have recently been developed to identify the primary tumour in cancer of unknown primary tumour (CUP). However, the value of identifying the primary tumour in clinical practice for CUP patients remains questionable and difficult to prove in randomized trials. OBJECTIVE: We aimed to assess the clinical and economic value of primary tumour identification in CUP using a retrospective matched cohort study. METHODS: We used the Manitoba Cancer Registry to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients as having CUP if their primary tumour was found 6 months or more after initial diagnosis or never found during the course of disease. Otherwise, we considered patients to have metastatic cancer from a known primary tumour (CKP). We linked all patients with Manitoba Health databases to estimate their direct healthcare costs using a phase-of-care approach. We used the propensity score matching technique to match each CUP patient with a CKP patient on clinicopathologic characteristics. We compared treatment patterns, overall survival (OS) and phase-specific healthcare costs between the two patient groups and assessed association with OS using Cox regression adjustment. RESULTS: Of 5839 patients diagnosed with metastatic cancer, 395 had CUP (6.8%); 1:1 matching created a matched group of 395 CKP patients. CUP patients were less likely to receive surgery, radiation, hormonal and targeted therapy and more likely to receive cytotoxic empiric chemotherapeutic agents. Having CUP was associated with reduced OS (hazard ratio [HR] 1.31; 95% confidence interval 1.1-1.58), but this lost statistical significance with adjustment for treatment differences. CUP patients had a significant increase in the mean net cost of initial diagnostic workup before diagnosis and a significant reduction in the mean net cost of continuing cancer care. CONCLUSION: Identifying the primary tumour in CUP patients might enable the use of more effective therapies, improve OS and allow more efficient allocation of healthcare resources.

Negative pressure wound therapy use to decrease surgical nosocomial events in colorectal resections (NEPTUNE): study protocol for a randomized controlled trial.

BACKGROUND: Surgical site infections (SSIs) are the second most common form of nosocomial infection. Colorectal resections have high rates of SSIs secondary to the inherently contaminated intraluminal environment. Negative pressure wound therapy dressings have been used on primarily closed incisions to reduce surgical site infections in other surgical disciplines. No randomized control trials exist to support the use of negative pressure wound therapy following elective open colorectal resection to reduce surgical site infection. METHODS/DESIGN: In this single-center, superiority designed prospective randomized open blinded endpoint controlled trial, patients scheduled for a colorectal resection via a laparotomy will be considered eligible. Patients undergoing laparoscopic resection will be enrolled but only randomized and included if the operation is converted to an open procedure. Exclusion criteria are patients receiving an abdominoperineal resection or a palliative procedure, as well as pregnant patients and those with an adhesive allergy. After informed consent, 300 patients will be randomized to the use of a standard adhesive gauze dressing or to a negative pressure wound device. Patients will be followed in hospital and reassessed on post-operative day 30. The primary outcome measure is SSI within the first 30 post-operative days. Secondary outcomes include the length of hospital stay, the number of return visits related to a potential or actual SSI, cost, and the need for homecare. The primary endpoint analysis follows the intention-to-treat principle. DISCUSSION: NEPTUNE is the first randomized controlled trial to investigate the role of incisional negative pressure wound therapy in decreasing the rates of surgical site infections in the abdominal incisions of patients following an elective, open colorectal resection. This low-risk intervention may help decrease the morbidity and costs associated with the development of an SSI in our patients. TRIAL REGISTRATION: NCT02007018--clinicaltrials.gov; 5 December 2013.

Cost effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in post-menopausal women with early-stage estrogen or progesterone-receptor-positive, axillary lymph-node positive breast cancer.

BACKGROUND: A 21-gene recurrence score (RS) assay provides a method of guiding treatment decisions in women with early-stage breast cancer (ESBC). We investigated the cost effectiveness of using the RS assay versus current clinical practice (CCP) in post-menopausal women with estrogen- or progesterone-receptor-positive, one to three positive axillary lymph-node ESBC from the perspective of the Canadian public healthcare system. METHODS: We developed a decision analytic model to project the lifetime clinical and economic consequences of ESBC. We assumed that the RS assay would classify patients among risk levels (low, intermediate and high) and corresponding adjuvant treatment regimens. The model was parameterized using 7-year follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. Costs are presented in 2012 Canadian dollars, and future costs and benefits were discounted at 5 %. RESULTS: In the base case analysis, the RS assay compared with CCP led to an increase of 0.08 quality-adjusted life-year (QALY) and an increase in cost of Can$36.2 per person, resulting in an incremental cost-effectiveness ratio (ICER) of Can$464/QALY gained. The ICER was most sensitive to the proportion of women classified to intermediate risk by the RS assay who received adjuvant chemotherapy, and absolute risk of relapse among patients receiving the RS assay. CONCLUSIONS: The RS assay is likely to be cost effective in the Canadian healthcare system. Field evaluations of the assay in this patient population will help reduce uncertainty in clinical guidelines for intermediate-range RS-assay values and specific disease outcomes by the RS assay, which are important drivers of ICER.

Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer.

BACKGROUND: A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor-positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system. METHODS: We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post-menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%. RESULTS: The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS-assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model. CONCLUSIONS: The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted.

Telephone contact intervention in women undergoing treatment for breast cancer.

The chemotherapy received by breast cancer patients is complicated by many side effects. At our centre, a health care professional is accessible at all times, yet we hypothesize that most breast cancer patients suffer in silence rather than phone for assistance. This study sought to assess the value of and perceived need for a telephone call to breast cancer patients following the initiation of chemotherapy. The women's side effects were also documented, and the level to which they were educated about symptoms to expect and available assistance was evaluated. Overall, the weekend calls were well received because they provided information and support to the patients. It was determined that further research is required to determine if and how such a call should be best implemented at our cancer centre.

Variation in the use of percutaneous biopsy for diagnosis of breast abnormalities in Ontario.

BACKGROUND: Preoperative diagnosis of breast abnormalities is currently the standard of care. A population-based study to determine the use of percutaneous needle biopsy for breast diagnosis in Ontario was performed. METHODS: A total of 17,068 women undergoing breast tissue sampling (percutaneous needle biopsy or surgical excision) for diagnosis between April 1, 2002, and December 31, 2002, and without a previous cancer diagnosis were identified. Univariate and multivariate analyses examined the association of age, residence in a particular local health integration network (LHIN), income quintile, urban or rural residence, primary care provider, any prior mammogram, and prior regular screening mammography, as well as whether the biopsy was initiated by a screening mammogram with different methods of tissue diagnosis. RESULTS: A total of 10,459 women (61%) underwent percutaneous biopsy for diagnosis. A total of 10,131 women underwent surgery, of whom 6,637 received a benign diagnosis and 3,494 had cancer, for a benign-to-malignant ratio of 1.9:1. Women with cancer were slightly more likely to undergo percutaneous biopsy than women without (64.7% vs. 60.3%). There was variation among LHINs in the use of percutaneous biopsy (range, 24%-72%). Women with the highest incomes, urban residence, a primary care provider, or history of any prior mammography were more likely to receive percutaneous biopsy. On multivariate analysis, age 50 to 69 years, LHIN, urban residence, primary care provider, and screen-initiated evaluation were associated with percutaneous biopsy. CONCLUSIONS: Variation in the use of percutaneous biopsy by factors unrelated to indications for biopsy indicate that strategies to identify and overcome barriers to its use are needed.

Surgical case costing: trauma is underfunded according to resource intensity weights.

OBJECTIVE: To determine whether rate-based funding using resource intensity weights (RIWs) adequately represents trauma case costs. DESIGN: A prospective time-in-motion resource utilization pilot study to assure the effectiveness of the computerized hospital Transition-One data acquisition system, followed by a retrospective observational case costing study. Patient costs with no identifing data were used, and all costs were tabulated as mean cost per group. SETTING: London Health Sciences Centre, London, Ont., a tertiary care "lead" trauma hospital. PATIENTS: A modified random selection of 4 control case mix groups (CMGs) of surgical patients for the fiscal year 1996-97. The trauma group was selected as a representative resource-intensive CMG. Each patient was assigned to a CMG by Health Records according to the most responsible diagnosis. OUTCOMES MEASURES: Total case costs were tabulated for each patient then combined for a mean case cost per CMG. The RIW assignments for each patient were combined to create a mean RIW per CMG and mean length of stay per CMG. RESULTS: There was no statistically significant difference between the control surgical CMGs and the trauma CMG for mean RIW-adjusted length of stay per CMG, but there was a significant difference (p < 0.0001) between the control CMGs and the trauma CMG for RIW-adjusted mean case cost per CMG. CONCLUSIONS: RIWs underrepresent trauma case costs by a factor of 3.5, which could result in underfinding and potential fiscal difficulties for leading trauma hospitals as has occurred in the United States.