•Few predictive biomarkers are in clinical use for colorectal and gastric cancers.•Integrative analysis has identified molecularly distinct subgroups of colorectal cancer and gastric ...cancer.•Molecular subclassification has laid the foundation for tailored therapies to be investigated.•Reproducibility and confirmation of clinical utility of molecular subclassification are now key issues.
Gastrointestinal (GI) malignancies comprise a diverse group of cancers with varying aetiology, clinical course, management and prognosis. Advances over the last decade in molecular diagnostics in colorectal cancer (CRC) have helped to improve our understanding of the underlying complex mechanisms in the development and progression of this highly heterogenous disease. Large scale integrative analysis has identified molecularly distinct subgroups of CRC with differing clinical behaviour. It was hoped that these discoveries would fuel the development of novel drug targets and new treatments to shift the management of advanced CRC from an empirical strategy to a biomarker driven approach based on underlying molecular characteristics. However, biomarkers in current clinical practice remain limited in CRC. Gastric cancer (GC) has also been slow to benefit from biomarker discovery and development and the successful utilisation of targeted therapies, with the exception of trastuzumab in HER2 positive cancers. More recently, molecular analysis of GC has also identified distinct subgroups within these cancers with differing behaviour and therapeutic targets. In addition, our deeper understanding of the underlying molecular biology of GI cancers has led to the consideration of alterations above and beyond gene mutations. The clonal, stromal and immune characteristics of GI malignancies are increasingly recognised as important in therapeutic targeting. The challenge remains to apply the data generated through molecular exploration into clinical practice in order to provide personalised treatment to each individual patient.
There is a lack of large-scale randomised data evaluating the impact of sex and age in patients undergoing chemotherapy followed by potentially curative surgery for oesophagogastric cancer.
...Individual patient data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival analysis, hazard ratios (HRs) were calculated for patients aged <70 and ≥ 70 years, as well as between males and females. Mandard tumour regression grade (TRG) and, ≥grade III toxicities were compared using logistic regression models to calculate odds ratios. All analyses were adjusted for the type of chemotherapy received.
3265 patients were included for survival analysis (2668 82% male, 597 18% female; 2627 (80%) <70 years, 638 (20%) ≥70 years). A significant improvement in overall survival (OS) (HR: 0.78; p < 0.001) and disease-specific survival (DSS) (HR: 0.78; p < 0.001) was observed in females compared with males. No significant differences in OS (HR: 1.11; p = 0.045) or DSS (HR: 1.01; p = 0.821) were observed in older patients compared with younger patients.
For patients who underwent resection, older patients (15% vs 10%; p = 0.03) and female patients (14% vs 10%, p = 0.10) were more likely to achieve favourable Mandard TRG scores. Females experienced significantly more ≥grade III nausea (10% vs 5%; p≤0.001), vomiting (10% vs 4%; p≤0.001) and diarrhoea (9% vs 4%; p≤0.001) than males.
In this large pooled analysis using prospective randomised trial data, females had significantly improved survival while experiencing more gastrointestinal toxicities. Older patients achieved comparable survival to younger patients and thus, dependent on fitness, should be offered the same treatment paradigm.
•Individual patient data pooled from four randomised trials in localised oesophagogastric cancer.•Female patients had significantly improved survival than male patients.•Females experienced more gastrointestinal toxicity from chemotherapy.•Older patients had comparable survival to younger patients.
No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma ...following neoadjuvant chemotherapy and the impact on survival.
Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis.
Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable.
Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.
Cisplatin-based radical chemoradiotherapy (CRT) is utilised in oesophagogastric (OG) cancer but the toxicity profile of cisplatin limits its use. This study aimed to evaluate the clinical ...characteristics and outcomes of patients treated with either cisplatin or carboplatin based CRT at our institution.
This is a retrospective analysis of patients with localised OG cancer undergoing CRT with cisplatin/fluoropyrimidine (CX/F) or carboplatin/fluoropyrimidine (CarboX/F) between January 2001 and December 2014.
A total of 91 eligible patients were included. Median age was 65 years (IQR=57-75) for CX/F and 77 years (IQR=69-80) for CarboX/F. Adenocarcinoma histology and Charlson comorbidity index were higher in the CarboX/F group. Endoscopic complete response (CR) was achieved in 64% of CX/F group and 48% of CarboX/F group (p=0.19). The median PFS for CX/F was 31.0 months (95%CI=18.2-NE) vs. 18.7 months for CarboX/F (95%CI=13.5-30.4; HR=1.49, p=0.21).
Despite significant differences in baseline clinical characteristics, patients treated with carboplatin CRT demonstrated no significant difference in PFS or endoscopic CR rate, compared to those treated with cisplatin.
IntroductionMesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with ...mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left.Methods and analysisThe MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery—(extended) pleurectomy decortication—versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.Ethics and disseminationResearch ethics approval was granted by London – Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal.Trial registration numbersISRCTN—ISRCTN44351742 and ClinicalTrials.gov—NCT02040272.
Background.
This study had two aims: (a) to evaluate the utility of fluorine 18‐fluorodeoxyglucose (FDG) positron emission tomography (PET)‐computed tomography (CT) in detecting occult disease ...recurrence with raised carcinoembryonic antigen (CEA) and (b) to establish the prognostic effects of early detection of disease recurrence in patients with colorectal cancer (CRC).
Patients and Methods.
Clinico‐pathological data were obtained from all consecutive patients undergoing CRC surveillance from 2004 to 2010 who had an elevated CEA level (>3 ng/mL in nonsmokers, >5 ng/mL in smokers) but normal or equivocal conventional investigations. Histopathological confirmation or a minimum of 12 months' clinical and radiological follow‐up were required to ascertain disease relapse.
Results.
A total of 1,200 patients were screened; of those, 88 (59% men; mean age, 66 years SD, 9.6) eligible patients (67 with normal and 21 with equivocal results on conventional investigations) were identified. Recurrent disease was detected in 56 of 88 patients (64%). The sensitivity of FDG PET‐CT to detect recurrence was 49 of 56 (88%; 95% confidence interval CI, 76%–95%) and specificity was 28 of 32 (88%; 95% CI, 71%–97%). Twenty‐seven of 49 (55%) patients with PET‐CT‐detected relapsed disease were deemed eligible for further curative therapy; 19 (70%) went on to receive potentially curative therapy. The median time to progression (8.8 months interquartile range (IQR), 4.5–19.1 months vs. 2.2 months IQR, 0.7–5.6), median overall survival (39.9 months IQR, 23.6–65.4 months vs. 15.6 months IQR, 7.3–25.7 months), and 5‐year survival (36.8% 95% CI, 16.5%–57.5% vs. 6.1% 95% CI, 1.1%–17.6%; p ≤ .001) were higher in patients who received potentially curative therapy than in those who received noncurative therapy.
Conclusion.
FDG PET‐CT is a highly sensitive and specific tool for the detection of occult CRC recurrence. In >50% of patients, recurrent disease may still be potentially amenable to curative therapy. Long‐term survival can be achieved in such patients.
Implications for Practice:
Colorectal cancer (CRC) patients who, on follow‐up, have normal or equivocal results on clinical investigations but raised carcinoembryonic antigen (CEA) levels pose a significant challenge to treating physicians. This study supported the notion that the early use of fluorodeoxyglucose (FDG) positron emission tomography (PET)‐computed tomography (CT) may have predictive and prognostic value in management of such patients. Long‐term disease control and cure can be achieved in a subgroup of this patient population with low‐volume disease relapse who are amenable to potentially curative treatment strategies. Reassuringly, the sensitivity and specificity for recurrence did not significantly vary as a function of the CEA level, suggesting that even with a minimal CEA rise, benefit can be attained by conducting FDG PET‐CT in a timely manner.
This study showed that fluorine 18‐fluorodeoxyglucose positron emission tomography–computed tomography was highly sensitive and specific for the detection of occult recurrence of colorectal cancer in patients with a raised carcinoembryonic antigen level and normal results on conventional investigations.
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