Background:In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. Methods:A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Results:Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions:Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding PD-L1 to its receptor. T is a mAb directed against CTLA-4. PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. This randomized phase II study (NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs GEM and Nab-P (arm B) in patients (pts) with mPDAC (n=191). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) were eligible. A safety run in was conducted for 11 pts receiving GEM, Nab-P, D and T. The study then randomized 180 pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate (ORR) and quality of life. 180 pts were randomized (119 to arm A and 61 to arm B) between April 2017 and July 2018. Baseline characteristics were well balanced. With a median (med) follow-up of 28.5 months (mo) there was no significant difference in OS (med 9.8 mo in arm A vs. 8.8 mo in arm B, Hazard Ratio (HR)=0.94, 90% confidence interval (CI) 0.71-1.25, p=0.72). There was no significant difference in PFS (med 5.5 mo vs 5.4 mo respectively, HR=0.98, 90% CI 0.75-1.29, p=0.91). ORR was not significantly different, 30.3% vs. 23.0% respectively (Odds Ratio=1.49, 90% CI 0.81-2.72, p=0.28). Disease control rate (DCR) was 70.6% vs 57.4% respectively (difference=13.2%, 90% CI 0.7-25.7%, p=0.096). The only significant difference in grade 3 or greater adverse events was lymphopenia (38% vs 20% respectively, p=0.02). The addition of dual immune checkpoint inhibitors to Gem and Nab-P did not result in a significant improvement in OS, PFS, or ORR. There is a trend to improved DCR. Correlative analyses to assess biomarkers that may predict immune sensitivity in this setting are underway.

Therapeutic options for chemorefractory metastatic colorectal cancer (mcrc) have significantly expanded since 2009. The oral targeted therapies regorafenib and trifluridine/tipiracil have been established to be efficacious and safe in patients with mcrc who have progressed beyond 2 or more lines of chemotherapy. Evidence for the use of immunotherapy in a subgroup of this patient population is also encouraging, particularly in patients with mcrc that exhibits high microsatellite instability or deficient mismatch repair. Those significant advances have led to Health Canada approval of 3 novel therapeutic options for the treatment of patients with chemorefractory mcrc. However, the limited clinical efficacy of those treatments underscores the need for ongoing development of systemic therapy options for this unique cohort of patients. Here, we review the current and emerging treatment landscape for chemorefractory mcrc.

Background Evidence from a retrospective analysis of multiple large phase iii trials suggested that primary tumour location (ptl) in RAS wild-type metastatic colorectal cancer (wtRAS mcrc) might have predictive value with respect to response to drug therapies. Recent studies also show a potential preferential benefit for epidermal growth factor inhibitors (egfris) for left-sided tumours. In the present study, we aimed to determine the incremental costeffectiveness ratio (icer) for the first-line use of an egfri for patients with left-sided wtRAS mcrc. Methods We developed a state-transition model to determine the cost effectiveness of alternative treatment strategies in patients with left-sided mcrc: ■ Standard of care ■ Use of an egfri in first-line therapy The cohort for the study consisted of patients diagnosed with unresectable wtRAS mcrc with an indication for chemotherapy and previously documented ptl. Model parameters were obtained from the published literature and calibration. The perspective was that of a provincial ministry of health in Canada. We used a 5-year time horizon and an annual discount rate of 1.5%. Results Selecting patients for first-line egfri treatment based on left-sided location of their colorectal primary tumour was more effective than the standard of care, resulting in an increase in quality-adjusted life-years (qalys) of 0.226 (or 0.644 life-years gained). However, the strategy was also more expensive, costing an average of $60,639 more per patient treated. The resulting icer was $268,094 per qaly. A 35% price reduction in the cost of egfri would be needed to make this strategy cost-effective at a willingness-to-pay threshold (wtp) of $100,000 per qaly. Conclusions Selective use of an egfri based on ptl was more cost-effective than unselected use of those agents; however, based on traditional wtp thresholds, it was still not cost-effective. While awaiting the elucidation of more precise predictive biomarkers that might improve cost-effectiveness, the price of egfris could be reduced to meet the wtp threshold.

Therapeutic options for chemorefractory metastatic colorectal cancer (mcnc) have significantly expanded since 2009. The oral targeted therapies regorafenib and trifluridine/tipiracil have been established to be efficacious and safe in patients with mcnc who have progressed beyond 2 or more lines of chemotherapy. Evidence for the use of immunotherapy in a subgroup of this patient population is also encouraging, particularly in patients with mcnc that exhibits high microsatellite instability or deficient mismatch repair. Those significant advances have led to Health Canada approval of 3 novel therapeutic options for the treatment of patients with chemorefractory mcnc. However, the limited clinical efficacy of those treatments underscores the need for ongoing development of systemic therapy options for this unique cohort of patients. Here, we review the current and emerging treatment landscape for chemorefractory mcRc.

Assessment of the clinical benefit of cancer treatments can be highly subjective, influenced by both perspective and context. Such assessments are required in regulatory and policy decision-making, but consistency between jurisdictions is often lacking. Clear and consistent standards for determining when a treatment offers a meaningful benefit, relative to the current standard of care, can help to address issues of equity and transparency in health technology assessment. For metastatic colorectal cancer (MCRC), no standardized Canadian definition of clinically meaningful benefit has yet been proposed. Colorectal Cancer Canada therefore convened a group of medical oncologists expert in colorectal cancer to review the literature about clinical significance. The resulting consensus is intended to apply to any therapeutic agent being considered in the setting of chemotherapy-refractory MCRC. It was agreed that overall survival is the appropriate measure of clinical efficacy in chemorefractory MCRC. As quantitative targets for efficacy, an improvement of 2 months or more in median overall survival or a hazard ratio for survival of 0.75 or lower (or both) are proposed as the threshold for clinically meaningful benefit. That threshold could be influenced by a treatment’s effect on quality of life. Treatment toxicity is also relevant to the assessment of clinical benefit in this setting, specifically when significant differences in treatment tolerability are evident.

The legalization of medical assistance in dying (maid) in June 2016 expanded options for end-of-life care in Canada [...]

Background: Evidence from a retrospective analysis of multiple large phase iii trials suggested that primary tumour location (ptl) in RAS wild-type metastatic colorectal cancer (wtRAS mcrc) might have predictive value with respect to response to drug therapies. Recent studies also show a potential preferential benefit for epidermal growth factor inhibitors (egfris) for left-sided tumours. In the present study, we aimed to determine the incremental cost-effectiveness ratio (icer) for the first-line use of an egfri for patients with left-sided wtRAS mcrc. Methods: We developed a state-transition model to determine the cost effectiveness of alternative treatment strategies in patients with left-sided mcrc: 1. Standard of care; 2. Use of an egfri in first-line therapy. The cohort for the study consisted of patients diagnosed with unresectable wtRAS mcrc with an indication for chemotherapy and previously documented ptl. Model parameters were obtained from the published literature and calibration. The perspective was that of a provincial ministry of health in Canada. We used a 5-year time horizon and an annual discount rate of 1.5%. Results: Selecting patients for first-line egfri treatment based on left-sided location of their colorectal primary tumour was more effective than the standard of care, resulting in an increase in quality-adjusted life-years (qalys) of 0.226 (or 0.644 life-years gained). However, the strategy was also more expensive, costing an average of $60,639 more per patient treated. The resulting icer was $268,094 per qaly. A 35% price reduction in the cost of egfri would be needed to make this strategy cost-effective at a willingness-to-pay threshold (wtp) of $100,000 per qaly. Conclusions: Selective use of an egfri based on ptl was more cost-effective than unselected use of those agents; however, based on traditional wtp thresholds, it was still not cost-effective. While awaiting the elucidation of more precise predictive biomarkers that might improve cost-effectiveness, the price of egfris could be reduced to meet the wtp threshold.

BackgroundDespite the high incidence and burden of cancer in Canadians, medical oncology (mo) rotations are not mandatory in most Canadian internal medicine (im) residency training programs.MethodsAll im residents scheduled for a mo rotation at 4 Canadian teaching cancer centres between 1 January 2013 and 31 December 2015 were invited to complete an online survey before and after their rotation. The survey was designed to evaluate perceptions of oncology, comfort in managing cancer patients, and basic oncology knowledge.ResultsThe survey was completed by 68 im residents pre-rotation and by 48 (71%) post-rotation. Cancer-related learning was acquired mostly from mo physicians in clinic (35%). Self-directed learning, didactic teaching, and resident or fellow teaching accounted for 31%, 26%, and 10% respectively of learning acquisition. Comfort level in dealing with cancer patients and patients at end of life improved to 4.0/5 from 3.2/5 (p < 0.001) and to 4.0/5 from 3.6/5 (p = 0.003) respectively. Mean knowledge assessment score improved to 83% post-rotation from 76% pre-rotation (p = 0.003), with the greatest increase observed in general knowledge of common malignancies. The 3 topics ranked as most important to learn during a mo rotation were oncologic emergencies, common complications of treatment, and approach to diagnosis of cancer.ConclusionsA rotation in mo improves the perceptions of im residents about oncology and their comfort level in dealing with cancer patients and patients at end of life. Overall cancer knowledge is also improved. Given those benefits, im residency programs should encourage most of their residents to complete a mo rotation.

Surgical resection of colorectal cancer (CRC) metastases is an accepted standard of care option in select patients. Multi-site stereotactic body radiotherapy (SBRT) has emerged as another ablative therapy technique. The purpose of this study was to review the clinical outcomes of SBRT in patients with metastatic CRC from a large academic institution. Metastatic CRC patients treated with extracranial SBRT were identified from an institutional database. Treatment indications were: 1) oligometastases, where the goal was to treat all visible tumors (≤5), 2) oligoprogression, where the goal was to treat only the progressing tumors (≤5) while other metastases were stable, and 3) local control of dominant tumors, where the goal was to treat tumors in unfavorable locations to prevent or improve symptoms even while other metastases may be progressing. Endpoints calculated using Kaplan-Meier methodology included overall survival (OS), progression free survival (PFS), and time to starting/changing systemic therapy (SCST). Competing risk analysis was used to calculate cumulative incidence of local failure (LF). Univariate analyses were performed to look for predictive factors. One hundred sixty-five patients were treated. Median age of patients was 69.0 years, with 102 patients (61.8%) being male. SBRT was delivered for oligometastases in 130 patients, oligoprogression in 16 patients, and local control of dominant tumors in 19 patients. For the entire cohort, median OS was 39.4 months, with a 3-year OS rate of 56.3%. Median PFS and time to SCST was 9.9 months, and 34.5 months, respectively. In 72 patients who did experience SCST, the median time to the event was 14.5 months. Treatment indication, number of lines previous systemic therapy, pre-treatment CEA, primary tumor in situ or not, and location of metastases were all significant predictors of OS, PFS, and time to SCST (all p<0.05). Oligometastatic patients had the best outcomes with a median OS of 49.3 months, 3-year OS rate of 67.5%, median PFS of 12.4 months, and median time to SCST of 42.3 months. Two hundred sixty-two metastases were irradiated, which included 122 lung tumors, 95 liver tumors, and 25 spine tumors. The cumulative incidence of LF was 26.9% at 3 years for all tumors, with lung metastases having lowest cumulative incidence of LF of 15.2% at 3 years. Lung tumors, smaller PTV volume, and higher mean PTV dose were all significant predictors of lower LF (all p<0.05). Nine patients developed grade 3 toxicities. Oligometastatic CRC patients treated with SBRT have favorable OS, which is comparable to those historically treated with metastasectomy. Use of SBRT to treat select metastatic CRC patients may significantly delay the need for SCST. Higher SBRT doses may further optimize local control of CRC metastases.

BACKGROUND:The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (gist) is imatinib. However, most gists develop imatinib resistance, highlighting the need for new agents in the imatinib-refractory setting. Currently, no randomized studies have directly compared the available post-first-line treatments. METHODS:In a systematic review, the medline, embase, and central databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included gist patients treated with post-first-line therapies. Hazard ratios (hrs) for progression-free (pfs) and overall survival (os) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. RESULTS:Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved pfs, but not improved os. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo-controlled and the non-placebo-controlled trials showed significant heterogeneity (I2 = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for pfs was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any-grade toxicities and 19.5% for grades 3 and 4 toxicities. CONCLUSIONS:Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of pfs, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level.

Background: The immune system is believed to have an important role in solid tumor progression. The development of monoclonal antibodies targeting immune checkpoints, such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have revolutionized the treatment of some cancers. Recent efforts have attempted to elucidate the relevance of the PD-1/PD-L1 pathway in gastrointestinal stromal tumors (GIST). Methods: Formalin-fixed, paraffin-embedded specimens were obtained from resected GIST at Sunnybrook Health Sciences Centre between March 2008 and August 2015. PD-L1 analysis was based off a tissue microarray of the cases using the Roche Ventana SP263 antibody. Each case had 1mm cores taken from different areas of the tumor block. Normal controls used for PD-L1 were placenta and tonsil (epithelial and inflammatory). CD117 was assessed via immunohistochemistry in all tumor specimens. Results: Of twenty-nine patients who underwent surgical resection, eight had insufficient tumor tissue for analysis, and three cases were excluded due to CD117 negativity after preoperative imatinib treatment, leaving 18 patients for analysis. Three of these 18 cases were positive for PD-L1 expression: 2 patients with moderate PD-L1 staining in 85% of the stromal cells and 1 with weak staining in 15% of the stromal cells. Fifteen patients were negative for PD-L1 expression. Analysis of PD-L1 expression in tumor-infiltrating lymphocytes was not feasible due to the lack of inflammatory cells in tumor environment. The patients whose samples had significant PD-L1 expression had gastric primaries, with tumour size <10cm. They did not require preoperative treatment, and did not have metastatic disease despite two having a high mitotic rate. The clinicopathologic characteristics of patients by PD-L1 expression status is demonstrated in Table 1.Table1517PPD-L1 negative (N = 15)PD-L1 positive (N = 3)Age (± SD)62 (14)63 (14)Gender M F10 51 2Location Gastric Small Bowel Colon Rectum7 5 - 33 - - -Metastasis No Yes11 43 -Preoperative Imatinib No Yes7 83 -Size (cm) Preoperative imatinib Upfront surgery6.2 (1.3-16) 5.8(1.5-11)− 9.5 (1.5-9.5)Mitotic Rate (50 HPF) < 5 = or > 512 31 2 Open table in a new tab Conclusions: In this cohort, PD-L1 may be a favorable prognostic biomarker. Further studies to examine the clinical benefit of immunotherapy in GIST patients with or without PD-L1 expression are warranted. Legal entity responsible for the study: Ana Beatriz Kinupe Abrahao Funding: Glenita Mungcal GIST Research Award from the Life Raft Group Canada Disclosure: All authors have declared no conflicts of interest.

e15653 Background: Several staging systems and models (TNM, BCLC, Okuda, CLIP and ALBI) have been developed to estimate the prognosis of patients with HCC. Most of these were developed prior to the prevalent use of sorafenib. The purpose of this study was to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib. Methods: Patients who received sorafenib for the treatment of HCC between January 1, 2008 and June 30, 2015 in the provinces of British Columbia and Alberta, as well as Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre in Toronto, Ontario were included. Survival outcomes for each model were assessed with Kaplan-Meier (KM) curves and compared with the log-rank test. Time dependent area under the curve (t-AUC) was used to test the discriminatory power of each model (higher t-AUC = more discriminatory power). Akaike information criterion (AIC), a measure of goodness-of fit of models while penalizing overly complex models, was used to compare the models (lower AIC = better model). Results: A total of 681 patients were included in this analysis. Median age was 64 years (range 8-91). Majority were males (80%), had a Child-Pugh score A (86%), ECOG performance status 0 (30%) and 1 (60%). 37% of patients were of East Asian ethnicity. Most common etiology for liver disease was hepatitis B (33%) and C (29%). At start of sorafenib, most patients were BCLC stage C (92%) and TNM stage IV (61%). The median overall survival for the entire cohort was 9.2 months (95% CI 8-10.4). See table below for t-AUC and AIC results. Conclusions: According to ourlarge multi-center study, CLIP appears to be the most informative in predicting survival in HCC patients treated with sorafenib. Prospective studies are needed to determine its role in patient selection for clinical trials and in guiding treatment decisions. The TNM and BCLC staging systems were the least useful in predicting survival in this population. [Table: see text]

In the BOND trial (Cunningham et al, NEJM 2004) for refractory mCRC, the addition of I to an EGFR antibody improved tumor response rate and time to progression but not overall survival (OS). We assessed the "real world" efficacy and toxicity of combination versus monotherapy in i) all-comers and ii) older patients (pts) who are under-represented in randomized trials. In Ontario, universal public funding is available for either Cmab + I combination or Pmab monotherapy only in pts with refractory non-mutated Kras mCRC. All pts diagnosed before Dec 2012 and treated with an EGFR antibody for mCRC were identified from the Ontario drug database and linked to the Ontario Cancer Registry and other administrative databases to ascertain baseline characteristics, health services utilization and outcomes. Multivariable Cox and logistic models were constructed to compare the time to treatment discontinuation, overall survival (OS), ED or hospital visits between Cmab + I and Pmab, adjusting for observable confounders (including age, gender, year of diagnosis, stage at presentation, duration of prior treatment in 1st and 2nd line, previous liver resection, rural residence and income quintile) using propensity score methods. 1081 pts were identified (Cmab + I: 278, Pmab: 803); median age: 60 (21.1% >age 70), 36.4% female, 36.2% rectal cancer and 60.1% stage IV at presentation. After adjusting for confounders, the use of Cmab + I as compared to Pmab alone was associated with a prolonged time to treatment discontinuation [median: 3.5 mos vs. 2.8 mos, HR 0.63, 95%CI 0.53-0.75, p < 0.001]and an improved OS compared to Pmab alone [median: 8.8 mos vs. 5.9 mos, HR 0.62, 95% CI 0.53-0.73, p < 0.001]. Both had similar 14-day mortality and incidence of ED or hospital visits. Interaction tests of treatment effect and age were >0.05. "Real world" data suggest a possible OS benefit with Cmab + I compared to Pmab alone, without an associated increase in toxicity. Pts age ≥70 appear to experience similar benefit and toxicity from combination therapy. These results suggest a need for adequately powered randomized trials to compare Cmab + I and Pmab like the ongoing ICECREAM study.

A recent review article expressed caution in the combination of stereotactic body radiation therapy and antiangiogenic agents in terms of risk of gastrointestinal toxicities. This is a prospective study evaluating the feasibility and toxicities of combining liver stereotactic body radiation therapy (SBRT) and bevacizumab in the treatment of colorectal liver metastases. This was a single-center, single-arm, open-label proof-of-concept study. Ethics approval was received by our institution. Eligible patients included any patient with metastatic colorectal cancer to liver (1-3 lesions) that was to receive SBRT. Patients received 2 doses of bevacizumab (5mg/kg) separated by 2 weeks. SBRT was commenced within 48 hours of the second dose of bevacizumab, and was up to 60 Gy in 6 fractions (alternating weekdays). Toxicities were assessed by NCI CTCAE v4.0. Efficacy of the SBRT was measured by CT and/or MRI and used RECIST v1.1 criteria. This study enrolled 11 patients. One patient withdrew consent shortly after accrual. Ten patients and 11 liver lesions were treated. Median follow-up was 12.3 months (6.4-25.3 months). Median age was 70 years (44-94 years). There were 7 males and 4 females. All 10 patients completed bevacizumab without dose modifications. All 10 patients completed SBRT (median dose: 54 Gy, range 36-60) in 6 fractions. Median BED10 was 95.57. Acute adverse events attributable to bevacizumab included one grade 3 (hypertension) and two grade 2 (hypertension, paresthesia) toxicities. For SBRT, there were two grade 2 (fatigue, nausea), but no grade 3 toxicities. No late term toxicities attributable to bevacizumab or SBRT have been seen so far. In our pilot study, the combination of SBRT and Bevacizumab appeared to be feasible with an acceptable acute toxicity profile and no severe gastrointestinal toxicities. More research is needed to define biomarkers predicting for the potential benefit of this combination.

Background Previous Canadian cost-effectiveness analyses in cancer based on the EQ-5D-3L (EuroQoL, Rotterdam, Netherlands) have commonly used U.K. or U.S. tariffs because the Canadian equivalent only just recently became available. The implications of using non-Canadian tariffs to inform decision-making are unclear. We aimed to re-evaluate an earlier cost-effectiveness analysis of therapies for metastatic pancreatic cancer (originally performed using U.S. tariffs) with tariffs from Canada and various other countries to determine the impact of using non-country-specific tariffs.Methods We used tariffs from Canada, the United States, the United Kingdom, Denmark, France, Germany, Japan, the Netherlands, and Spain to derive EQ-5D-3L utilities for the 10 health states in the pancreatic cancer model. Quality-adjusted life years (QALYS) and incremental cost-effectiveness ratios (ICERS) were generated, and probabilistic sensitivity analyses (PSAS) were performed.Results Canadian utilities are generally lower than the corresponding U.S. utilities and higher than those for the United Kingdom. Compared with the Canadian-valued scenarios, U.S. and U.K. estimates were statistically different for 3 and 9 scenarios respectively. Overall, 35% of the non-Canadian utilities (28 of 80) were significantly different, clinically, from the Canadian values. Canadian QALYS were 6% lower than those for the United States and 6% higher than those for the United Kingdom. When comparing the QALYS of each treatment with those of gemcitabine alone, the average percent change was + 6.8% for a U.S. scenario and -7.5% for a U.K. scenario compared with a Canadian scenario. Consequently, Canadian ICERS were approximately 5.4% greater than those for the United States and 8.6% lower than those for the United Kingdom. Based on the PSAS and compared with the Canadian threshold value, the minimum willingness-to-pay threshold at which the combination chemotherapy regimen of gemcitabine-capecitabine is the most cost-effective is $5,239 less than in the United States and $11,986 more than in the United Kingdom.Conclusions The use of non-country-specific tariffs leads to significant differences in the derived utilities, ICERS, and PSA results. Past Canadian EQ-5D-3L-based cost-effectiveness analyses and related funding decisions might need to be re-visited using Canadian tariffs.

Introduction: Bevacizumab, an anti-VEGF, has been shown to normalize vasculature of tumors by changing tumor blood perfusion and tumor microvessel density, and therefore improve its oxygenation. This may have potential benefits as a radiosensitizer and indeed has been reported in several clinical trials with chemoradiation for locally advanced rectal cancer. To explore the effects of tumour perfusion, blood flow and cell death in vivo (on liver metastasis) as measured by dynamic contrast-enhanced (DCE-) CT and contrast-enhanced ultrasound (CEUS), efficacy and toxicities after bevacizumab and post-SBRT in patients with colorectal liver metastases. Methods: This was a single-centre, single-arm, open-label proof-of-concept study. Ethics approval was received by our institution. Eligible patients included any patient with metastatic colorectal cancer to liver (1-3 lesions) that was to receive SBRT. Patients received 2 doses of bevacizumab (5mg/kg) separated by 2 weeks. SBRT was commenced within 48 hours of the second dose of bevacizumab, and was up to 60 Gy in 6 fractions (alternating weekdays). DCE-CT and CEUS were performed at baseline, after the second dose of bevacizumab (but before SBRT) and within 7 days of completing SBRT. Toxicities were assessed by NCI CTCAE v4.0. Efficacy of the SBRT was measured by CT and/or MRI and used RECIST v1.1 criteria. Results: This study enrolled 11 patients. One patient withdrew consent shortly after accrual. Median follow-up was 329 days (8-426). Median age was 64 (44-94) years. There were 7 males and 4 females. All 10 patients completed the bevacizumab and SBRT (median 60 Gy, range 36-60) without dose modifications. Adverse events attributable to bevacizumab included one grade 3 (hypertension), two grade 2 (hypertension, paresthesia) toxicities. For SBRT, there were two grade 2 (fatigue, nausea), but no grade 3 toxicities. By RECIST criteria, the response to the SBRT treated lesions was (n): stable disease (5), partial response (2), progressive disease (2), and not evaluable (2). To date, 5 have died. Eight patients underwent all 3 DCE-CT and were available for analyses. From baseline, median tumor perfusion decreased by 24.8% (-64%-120%) after bevacizumab (but before SBRT) and decreased by 3.3% (-40%-247%) after SBRT. Similarly, median blood flow decreased by 25% (-70%-163%) and 50.2% (-70-24%), respectively. Conclusion: In our pilot study, we found that bevacizumab can be safely given immediately prior to SBRT for colorectal liver metastases with little toxicities. Tumor perfusion and blood flow decreased after bevacizumab and SBRT, though significant heterogeneity was seen.

Background: A higher incidence of second primary cancer (SPC) has been reported in patients diagnosed with gastrointestinal stromal tumors (GIST). We aimed to identify patients with GIST who develop a SPC, quantify the risk of additional malignancy and evaluate the impact upon survival.