Andre Lopes

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer

BACKGROUND Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.

Clinical endpoints in trials of chemoradiation for patients with anal cancer

This Review examines the reporting of endpoints in randomised controlled trials (RCTs) of radical chemoradiation for treatment of squamous cell carcinoma of the anus. The types, frequency, and definitions of clinical primary and secondary endpoints, and patient-reported outcome measures, reported in the methods and results sections of papers (and protocols, if available) were examined. Only six published RCTs comprising 2877 patients were identified. Primary outcome measures varied across the trials analysed: two used disease-free survival, one used progression-free survival, two used local failure, and one used colostomy-free survival. Secondary endpoints included overall survival, complete clinical response, quality of life, toxicity, and compliance. The definitions for primary and secondary endpoints were not consistent across trials, particularly for treatment failure (local, regional, and distant). We conclude that the quality of outcome reporting in RCTs of squamous cell carcinoma of the anus is inconsistent. A core set of outcomes, including clinical and patient-reported outcome measures with standardised definitions, is needed to improve the reporting of RCTs examining chemoradiation for treatment of patients with squamous cell carcinoma of the anus.

Quality of life, long-term survivors and long-term outcome from the ABC-02 study

Background:The ABC-02 (Advanced Biliary Tract Cancer) study established cisplatin and gemcitabine (CisGem) as the standard first-line chemotherapy for patients with locally advanced or metastatic biliary tract cancer (BTC). We examine quality of life (QoL), describe the long-term survivors and provide a long-term outcome.Methods:A total of 410 BTC patients were randomised to receive either CisGem or gemcitabine alone (Gem); 324 patients consented to complete EORTC QLQ-C30 and EORTC QLQ-PAN26 QoL questionnaires; 268 (83%) patients returned at least one QoL questionnaire (134 in each arm). Long-term survivors were defined as those surviving over 2 years and we performed a final analysis of the primary outcome; overall survival (OS).Results:Most QoL scales showed a trend favouring the combined CisGem arm, including functional and symptomatic scales, although the differences were not statistically significant. Forty-five (11%)) patients survived at least 2 years (34 received CisGem and 11 Gem) and 21 (5%) 3 years or more (14 received CisGem and 7 Gem). After a median follow-up of 9.2 months and 398 deaths, the median OS was 11.7 months for CisGem and 8.1 months for Gem (hazard ratio (HR)=0.65, 95% CI: 0.53–0.79, P<0.001).Conclusions:The survival advantage of CisGem compared to Gem was not associated with an improvement or deterioration of QoL. Long-term survivors were more likely to have received CisGem and the long-term OS is identical to that previously described.

Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations

Background:The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain.Methods:In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen.Results:Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73–88%) (four patients with clinical complete response declined surgery). Twenty–four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05–1.03, P=0.055).Conclusions:This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.

Abstract C32: PTEN and p53 expression in endometrial cancer correlated with clinicopathological phenotype.

p53 overexpression and loss of PTEN expression have been implicated in the pathogenesis of endometrial cancer. Our aim was to correlate expression levels of these proteins with clinicopathological parameters to characterise their utility as biomarkers. Immunohistochemistry was done on 49 cases of formalin fixed paraffin embedded endometrial cancer tissue for p53 and 47 for PTEN expression. For p53 staining the Hue Saturation and Intensity mathematical model was used to evaluate different degrees of positivity of the immunohistochemical stain. The quick score was used for p53 and immunoreactive score for PTEN was done to score immunoreactivity. For PTEN, average percentage of positive cells and intensity was evaluated and the immunoreactive score was calculated. Both these scoring methods incorporated percentage of positive cells and staining intensity. Univariate Cox regression analysis for cause specific survival showed a hazard ratio of 9.2 for p53 overexpression (P<0.05). High levels of P53 were significantly associated with histologic type, grade, LVI and recurrent disease. There was no significant association between PTEN expression and clinicopathological features but it was noted that the 8 patients who relapsed were PTEN negative. Cause specific survival could not be assessed for PTEN expression due to the lack of events in this group. PTEN and p53 (n=46) combined analysis failed to demonstrate a significant association on prognostic features in this group. ![Figure][1] Overexpression of P53 has a negative effect on disease specific survival and was associated with poor prognostic features. We did not demonstrate a significant association with clinicopathological features assessed and PTEN expression. However of the 8 patients who relapsed all were PTEN negative and 7 were p53 positive. Dual assessment of p53 and PTEN warrants further investigation as a prognostic indicator. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C32. Citation Format: Bihani Kularatne, Arrigo Capitanio, Rupali Arora, Philippa Jones, Andre Lopes, Jennifer Paterson, Rebecca Kristeleit. PTEN and p53 expression in endometrial cancer correlated with clinicopathological phenotype. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C32. [1]: pending:yes

BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC)

Background Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). Methods/design This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on “T” and “N” downstaging were calculated. Findings Twenty patients aged 18–75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%–85%). Interpretation The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.

Whole-body MRI for staging and interim response monitoring in paediatric and adolescent Hodgkin’s lymphoma: a comparison with multi-modality reference standard including 18 F-FDG-PET-CT

ObjectivesTo prospectively investigate concordance between whole-body MRI (WB-MRI) and a composite reference standard for initial staging and interim response evaluation in paediatric and adolescent Hodgkin’s lymphoma.MethodsFifty patients (32 male, age range 6–19 years) underwent WB-MRI and standard investigations, including 18F-FDG-PET-CT at diagnosis and following 2–3 chemotherapy cycles. Two radiologists in consensus interpreted WB-MRI using prespecified definitions of disease positivity. A third radiologist reviewed a subset of staging WB-MRIs (n = 38) separately to test for interobserver agreement. A multidisciplinary team derived a primary reference standard using all available imaging/clinical investigations. Subsequently, a second multidisciplinary panel rereviewed all imaging with long-term follow-up data to derive an enhanced reference standard. Interobserver agreement for WB-MRI reads was tested using kappa statistics. Concordance for correct classification of all disease sites, true positive rate (TPR), false positive rate (FPR) and kappa for staging/response agreement were calculated for WB-MRI.ResultsThere was discordance for full stage in 74% (95% CI 61.9–83.9%) and 44% (32.0–56.6%) of patients against the primary and enhanced reference standards, respectively. Against the enhanced reference standard, the WB-MRI TPR, FPR and kappa were 91%, 1% and 0.93 (0.90–0.96) for nodal disease and 79%, < 1% and 0.86 (0.77–0.95) for extra-nodal disease. WB-MRI response classification was correct in 25/38 evaluable patients (66%), underestimating response in 26% (kappa 0.30, 95% CI 0.04–0.57). There was a good agreement for nodal (kappa 0.78, 95% CI 0.73–0.84) and extra-nodal staging (kappa 0.60, 95% CI 0.41–0.78) between WB-MRI readsConclusionsWB-MRI has reasonable accuracy for nodal and extra-nodal staging but is discordant with standard imaging in a substantial minority of patients, and tends to underestimate disease response.Key Points• This prospective single-centre study showed discordance for full patient staging of 44% between WB-MRI and a multi-modality reference standard in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI underestimates interim disease response in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI shows promise in paediatric and adolescent Hodgkin’s lymphoma but currently cannot replace conventional staging pathways including18F-FDG-PET-CT.

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

BackgroundAdvanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes.MethodsChanges in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC).ResultsSamples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P < 0.001 and P = 0.02, respectively).ConclusionsRising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study

In the original version of this article, the mention of ‘ifosfamide 1500 mg/m2 days 1–3’ should, in fact, read ‘ifosfamide 1500 mg/m2 bd days 1–3’. This has now been updated in the original version of the article.

Sacroiliac Joint Ankylosis In Young Spondyloarthritis Patients Receiving Biologic Therapy: Observation of Serial MRI scans

To assess the temporal relationship between initiating biologic therapy and magnetic resonance imaging (MRI) scores of inflammation and structural damage in young patients with spondyloarthritis.