International variation in oesophageal and gastric cancer survival 2012–2014: differences by histological subtype and stage at diagnosis (an ICBP SURVMARK-2 population-based study)

ObjectiveTo provide the first international comparison of oesophageal and gastric cancer survival by stage at diagnosis and histological subtype across high-income countries with similar access to healthcare.MethodsAs part of the ICBP SURVMARK-2 project, data from 28 923 patients with oesophageal cancer and 25 946 patients with gastric cancer diagnosed during 2012–2014 from 14 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were included. 1-year and 3-year age-standardised net survival were estimated by stage at diagnosis, histological subtype (oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC)) and country.ResultsOesophageal cancer survival was highest in Ireland and lowest in Canada at 1 (50.3% vs 41.3%, respectively) and 3 years (27.0% vs 19.2%) postdiagnosis. Survival from gastric cancer was highest in Australia and lowest in the UK, for both 1-year (55.2% vs 44.8%, respectively) and 3-year survival (33.7% vs 22.3%). Most patients with oesophageal and gastric cancer had regional or distant disease, with proportions ranging between 56% and 90% across countries. Stage-specific analyses showed that variation between countries was greatest for localised disease, where survival ranged between 66.6% in Australia and 83.2% in the UK for oesophageal cancer and between 75.5% in Australia and 94.3% in New Zealand for gastric cancer at 1-year postdiagnosis. While survival for OAC was generally higher than that for OSCC, disparities across countries were similar for both histological subtypes.ConclusionSurvival from oesophageal and gastric cancer varies across high-income countries including within stage groups, particularly for localised disease. Disparities can partly be explained by earlier diagnosis resulting in more favourable stage distributions, and distributions of histological subtypes of oesophageal cancer across countries. Yet, differences in treatment, and also in cancer registration practice and the use of different staging methods and systems, across countries may have impacted the comparisons. While primary prevention remains key, advancements in early detection research are promising and will likely allow for additional risk stratification and survival improvements in the future.

MRI and targeted biopsies compared to transperineal mapping biopsies for targeted ablation in recurrent prostate cancer after radiotherapy: Primary outcomes of the FORECAST trial.

5009 Background: Radiotherapy is a common and effective treatment for localised prostate cancer. However, recurrence of cancer can occur in 10-15% of men in the following 5 years. Most patients with recurrence are managed using hormonal therapy with associated systemic side-effects and subsequent development of castrate resistance. Salvage prostatectomy confers a high risk of urine incontinence and rectal injury. Accurately localising and ablating only areas of recurrence within the prostate might be effective with fewer side-effects. The FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial assessed this diagnostic and treatment pathway for men with radiorecurrent cancer (NCT01883128). Methods: We first compared the accuracy of multi-parametric MRI (mp-MRI) and MRI-targeted biopsy in identifying areas of recurrent cancer to a transperineal template prostate mapping (TTPM) biopsy (Apr/2014-Jan/2018) in 181 patients from 6 UK centres. We then assessed the functional and cancer control outcomes of focally ablating areas of intraprostatic recurrence in 93 patients with localised or metastatic cancer (using cryotherapy or HIFU). Primary outcomes were sensitivity of mpMRI and MRI-targeted biopsies and urinary continence after focal ablation. A key secondary outcome was progression free survival (PFS) defined as no new metastases or hormone use (localised group only), or chemotherapy or further local treatment. Results: Of 181 men with suspicion of recurrence following radiotherapy, re-staging whole-body imaging (Choline PET and Bone Scan) showed localised disease in 128 (71%), nodal disease only in 13 (7%) and 38 (21%) metastatic. The sensitivity of MRI-targeted biopsy was 92% (95%CI 83-97%). Specificity, and positive and negative predictive values, were 75% (95%CI 45-92%), 94% (95%CI 86-98%) and 65% (95%CI 38-86%). 4/72 (6%) cancers were missed on TTPM biopsies alone and 6/72 (8%) were missed on MRI-targeted biopsies alone. Overall sensitivity of mpMRI was 81% (95%CI 73-88%) using Likert score 4-5 to denote a positive test. Specificity, and positive and negative predictive values, were 88% (95%CI 73-98%), 96% (95%CI 90-99%) and 57% (95%CI 42-70%). In the 93 men undergoing focal ablation, urinary continence was preserved in 78/93 (84%); 5/93 (5%) had a CTCAE grade 3+ adverse events. There were no rectal injuries. With a median follow-up of 27.8 [SD 1.3] months, PFS was 66% [54-75] at 24-months. Metastases-free survival in the 73 men with localised disease was 80% [95%CI 68–88] at 24-months. There were no cancer specific deaths. Conclusions: Prostate mpMRI and MRI-targeted biopsies can accurately detect and localise recurrent prostate cancer following radiotherapy. Focal ablation to areas of intra-prostatic recurrence preserves continence in the majority of men with good cancer control. Clinical trial information: NCT01883128.

Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression

Background DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Methods We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. Results Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2–4.8, p = 0.014). Conclusions CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.

Hormone replacement therapy and the risk of melanoma in post-menopausal women

Study Question Is hormone replacement therapy (HRT) associated with an increased risk of melanoma skin cancer or prognostic outcomes amongst post-menopausal women? SUMMARY ANSWER Whilst we found evidence of an association with melanoma risk, the lack of dose-response and associations observed with recent use, localised disease and intravaginal oestrogens suggests this is a non-causal association. WHAT IS KNOWN ALREADY Evidence on HRT and melanoma risk remains inconclusive, with studies providing conflicting results. Furthermore, evidence on melanoma survival is sparse, with only one previous study reporting protective associations with HRT use, likely attributable to immortal time bias. STUDY DESIGN, SIZE, DURATION We conducted a nation-wide population-based case-control study and a retrospective cohort study utilising the Danish healthcare registries. Case-control analyses included 8279 women aged 45–85 with a first-ever diagnosis of malignant melanoma between 2000 and 2015, matched by age and calendar time to 165 580 population controls. A cohort of 6575 patients with a diagnosis of primary malignant melanoma between 2000 and 2013 and followed through 2015 was examined to determine if HRT use had an impact on melanoma survival outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on prescriptions dispensed since 1995, ever-use of HRT was defined as having filled at least one prescription for HRT prior to the index date. In total, 2629 cases (31.8%) and 47 026 controls (28.4%) used HRT. Conditional logistic regression was used to calculate odds ratios (ORs) for melanoma risk according to HRT use, compared with non-use, adjusting for potential confounders. For cohort analyses, Cox proportional hazards models was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for second melanoma incidence and all-cause mortality associated with HRT. MAIN RESULTS AND THE ROLE OF CHANCE High use of HRT was associated with an OR of 1.21 (95% CI 1.13–1.29) for melanoma risk, with no evidence of a dose-response pattern. Results were most pronounced amongst recent high users (OR, 1.28; 95% CI 1.17–1.41), for localised disease (OR, 1.25; 95% CI 1.15–1.36) and for intravaginal oestrogen therapy (OR, 1.38; 95% CI 1.13–1.68). Compared with non-use, there was no evidence of an association for secondary melanoma for post-diagnostic new-use (fully adjusted HR, 1.56; 95% CI 0.64–3.80) or continuous HRT use (fully adjusted HR, 1.26; 95% CI 0.89–1.78). Similar associations were observed for all-cause mortality. LIMITATIONS, REASONS FOR CAUTION Despite the large sample size and the use of robust population-based registries with almost complete coverage, we lacked information on some important confounders including sun exposure. WIDER IMPLICATIONS OF THE FINDINGS Whilst we cannot rule out an association between HRT use and melanoma risk, the associations observed are also compatible with increased healthcare utilisation and thus increased melanoma detection amongst HRT users. No association between HRT use and melanoma survival outcomes was observed. This should provide some reassurance to patients and clinicians, particularly concerning the use of HRT in patients with a history of melanoma. STUDY FUNDING/COMPETING INTEREST(S) B.M.H. is funded by a Cancer Research UK Population Research Postdoctoral Fellowship. The funding source had no influence on the design or conduct of this study. A.P. reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Servier, Novo Nordisk and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this article. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Cancer treatment and the risk of cancer death among Aboriginal and non-Aboriginal South Australians: analysis of a matched cohort study

Background Aboriginal and Torres Strait Islander Australians have poorer cancer outcomes than other Australians. Comparatively little is known of the type and amount of cancer treatment provided to Aboriginal and Torres Strait Islander people and the consequences for cancer survival. This study quantifies the influence of surgical, systemic and radiotherapy treatment on risk of cancer death among matched cohorts of cancer cases and, the comparative exposure of cohorts to these treatments. Methods Cancers registered among Aboriginal South Australians in 1990–2010 (N = 777) were matched with randomly selected non-Indigenous cases by sex, birth and diagnostic year, and primary site, then linked to administrative cancer treatment for the period from 2 months before to 13 months after diagnosis. Competing risk regression summarised associations of Indigenous status, geographic remoteness, comorbidities, cancer stage and treatment exposure with risk of cancer death. Results Fewer Aboriginal cases had localised disease at diagnosis (37.2% versus 50.2%) and they were less likely to: experience hospitalisation with cancer diagnosis, unadjusted odds ratio (UOR) = 0.76; 95%CI = 0.59–0.98; have surgery UOR = 0.65; 95%CI = 0.53–0.80; systemic therapies UOR = 0.64; 95%CI = 0.52–0.78; or radiotherapy, UOR = 0.76; 95%CI = 0.63–0.94. Localised disease carried lower risk of cancer death compared to advanced cases receiving surgery or systemic therapies, SHR = 0.34; 95%CI = 0.25–0.47 and SHR = 0.35; 95%CI = 0.25–0.48. Advanced disease and no treatment carried higher risk of cancer death, SHR = 1.82; 95%CI = 1.26–2.63. Conclusion The effects of treatment did not differ between Aboriginal and non-Indigenous cohorts. However, comparatively less exposure to surgical and systemic treatments among Aboriginal cancer cases further complicated the disadvantages associated with geographic remoteness, advanced stage of disease and co-morbid conditions at diagnosis and add to disparities in cancer death. System level responses to improving access, utilisation and quality of effective treatments are needed to improve survival after cancer diagnosis.

Carcinosarcoma prostate with osteosarcomatous differentiation: a rare de novo presentation

Carcinosarcoma is a rare histological event in the history of prostatic malignancies. Historically aggressive tumours with dismal outcomes reported in scarce literature available so far. Very few recent studies suggest good outcomes with modern era surgery and radiotherapy techniques in localised disease. The case presented here had no history of known risk factors like prior adenocarcinoma or prior radiation therapy. This case presented with obstructive urinary symptoms with no prostate-specific antigen elevation, diagnosed with imaging, managed aggressively with robotic surgery. Detailed immunohistochemistry and pathological review suggested diagnosis as carcinosarcoma with osteosarcomatous differentiation. Very rare such cases were reported in the past with complete clinical, radiological, pathological details and managed aggressively with good outcomes. The patient is disease free after 6 months of follow-up.

Using Linked Lung Cancer Registry and Hospital Data for Guiding Health Service Improvement

Objective: To use linked NSW Cancer Registry and hospital lung cancer (LC) data for raising discussion points on how to improve outcomes. Design: Historical cohort – cases diagnosed in 2003-2007. Setting: New South Wales, Australia Outcome Measures: Relative odds (OR) of localised disease and resection of non-small cases (NSCLC) using multiple logistic regression. Comparisons of risk of NSCLC death using competing risk regression. Findings: (1) Older patients have fewer resections of localised NSCLC [adjusted OR 95% CLs; 80+Vs <60 years; 0.20 (0.14, 0.28)]. Cases with co-morbidity have fewer resections [adjusted OR, 0.74 (0.61, 0.90)] and have more conservative resections. Question: Is there the best balance between resection and avoiding surgery to accommodate frailty and co-morbidity? (2) Compared with public patients, the health insured: have higher odds of localised LC [adjusted OR, 1.23 (1.12, 1.35] and resection for localised NSCLC [adjusted OR, 2.08 (1.70, 2.54)]; are more likely to have lobectomies than wedge/segmental resections (p<0.001); and have a lower risk of LC death [adjusted SHR, 0.89 (0.85, 0.93)]. Question: Are there opportunities for improving publicpatient outcomes? (3) Patients born in non-English speaking countries have lower odds of localised disease [adjusted OR, 0.88 (0.79, 0.99)]. – Question: Could this difference be decreased by reducing cultural and language barriers? (4) Cancers of pulmonary lobes rather than the main bronchus pose lower risks of LC death. Question: Could outcomes for main bronchus cancers be improved by up-skilling or referral to higher-volume centres? (5) Greater extent of disease is strongly predictive of case fatality – Question: Could LC deaths be reduced by earlier treatment? (6) Use of lobectomies varies – Question: Could survival be increased through greater use of lobectomies for localised NSCLC? Conclusions: Linked cancer registry and hospital data can increase system-wide understanding of local health-service delivery and prompt discussion points on how to improve outcomes. Abbreviations: APDC – Australian Patient Data Collection; CHeReL – Centre for Health Record Linkage; EOD – Extent of Disease; LC – Lung Cancer; NSCLC – Non-Small Cell Cancers; NSWCR – New South Wales Cancer Registry; OR – Relative Odds; SEIFA – Socio-Economic Index for Areas; SES – Socio- Economic Status.

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.