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

PurposeSeveral 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.ObjectiveWe aimed to assess the clinical and economic value of primary tumour identification in CUP using a retrospective matched cohort study.MethodsWe 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.ResultsOf 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.ConclusionIdentifying the primary tumour in CUP patients might enable the use of more effective therapies, improve OS and allow more efficient allocation of healthcare resources

OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy

Background: Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.Methods:Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.Results:SLCO1B1 521C was significantly associated with increased SN-38 exposure (P\u3c0.001), which was additive with UGT1A1∗28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2-24C/T (odds ratio (OR)=0.22, 0.06-0.85) and CES1 (rs2244613; OR=0.29, 0.09-0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2-24T/T and UGT1A1∗28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.Conclusions:Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers

Cost-effectiveness of using a gene expression profiling test to aid in identifying the primary tumour in patients with cancer of unknown primary.

We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget impact was$36.2 million per year. A value-of-information analysis revealed that the expected value of perfect information about the test\u27s clinical impact was $4.2 million per year. The 2000-GEP test should be considered for adoption in CUP. Field evaluations of the test are associated with a large societal benefit.The Pharmacogenomics Journal advance online publication, 29 March 2016; doi:10.1038/tpj.2015.94

A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC

Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada.

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology

The clinical significance of occult gastrointestinal primary tumours in metastatic cancer: A population retrospective cohort study

© 2018 by the Korean Cancer Association. Purpose The purpose of this study was to estimate the incidence of occult gastrointestinal (GI) primary tumours in patients with metastatic cancer of uncertain primary origin and evaluate their influence on treatments and overall survival (OS). Materials and Methods We used population heath data from Manitoba, Canada to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients to have occult primary tumour if the primary was found at least 6 months after initial diagnosis. Otherwise, we considered primary tumours as obvious. We used propensity-score methods to match each patient with occult GI tumour to four patients with obvious GI tumour on all known clinicopathologic features. We compared treatments and 2-year survival data between the two patient groups and assessed treatment effect on OS using Cox regression adjustment. Results Eighty-three patients had occult GI primary tumours, accounting for 17.6% of men and 14% of women with metastatic cancer of uncertain primary. A 1:4 matching created a matched group of 332 patients with obvious GI primary tumour. Occult cases compared to the matched group were less likely to receive surgical interventions and targeted biological therapy, and more likely to receive cytotoxic empiric chemotherapeutic agents. Having an occult GI tumour was associated with reduced OS and appeared to be a nonsignificant independent predictor of OS when adjusting for treatment differences. Conclusion GI tumours are the most common occult primary tumours in men and the second most common in women. Patients with occult GI primary tumours are potentially being undertreated with available GI site-specific and targeted therapies

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confi rmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratifi ed by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fl uorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defi ned retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identifi cation of patients and treatment. This trial is registered with ClinicalTrials. gov, number NCT00460265. Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11.1 months (95% CI 9.8-12.2) in the panitumumab group and 9.0 months (8.1-11.2) in the control group (hazard ratio [HR] 0.873, 95% CI 0.729-1.046; p = 0.1403). Median progression-free survival was 5.8 months (95% CI 5.6-6.6) in the panitumumab group and 4.6 months (4.1-5.4) in the control group (HR 0.780, 95% CI 0.659-0.922; p = 0.0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7-13.7] vs 8.6 months [6.9-11.1]; HR 0.73 [95% CI 0.58-0.93]; p = 0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3-12.9] vs 12.6 months [7.7-17.4]; 1.00 [0.62-1.61]; p = 0.998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0.70 [95% CI 0.47-1.04]). Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings

The impact of seasonal operating room closures on wait times for oral cancer surgery

Background Operating room slowdowns occur at specific intervals in the year as a cost-saving measure. We aim to investigate the impact of these slowdowns on the care of oral cavity cancer patients at a Canadian tertiary care centre. Methods A total of 585 oral cavity cancer patients seen between 1999 and 2015 at the London Health Science Centre (lhsc) Head and Neck Multidisciplinary Clinic were included in this study. Operating room hours and patient load from 2006 to 2014 were calculated. Our primary endpoint was the wait time from consultation to definitive surgery. Exposure variables were defined according to wait time intervals occurring during time periods with reduced operating room hours. Results Overall case volume rose significantly from 2006 to 2014 (p \u3c 0.001), while operating room hours remained stable (p = 0.555). Patient wait times for surgery increased from 16.3 days prior to 2003 to 25.5 days in 2015 (p = 0.008). Significant variability in operating room hours was observed by month, with lowest reported for July and August (p = 0.002). The greater the exposure to these months, the more likely patients were to wait longer than 28 days for surgery (odds ratio per day [or]: 1.07, 95% confidence interval [ci]: 1.05 to 1.10, p \u3c 0.001). Individuals seen in consultation preceding a month with below average operating room hours had a higher risk of disease recurrence and/or death (hazard ratio [hr]: 1.59, 95% ci: 1.10 to 2.30, p = 0.014). Conclusions Scheduled reductions in available operating room hours contribute to prolonged wait times and higher disease recurrence. Further work is needed to identify strategies maximizing efficient use of health care resources without negatively affecting patient outcomes