Colorectal cancer with liver metastases:Neoadjuvant chemotherapy,surgical resection first or palliation alone?

Colorectal cancer(CRC) is one of the commonest cancers with 1.2 million new cases diagnosed each year in the world.It remains the fourth most common cause of cancer-related mortality in the world and accounts for > 600000 cancer-related deaths each year.There have been significant advances in treatment of metastatic CRC in last decade or so,due to availability of new active targeted agents and more aggressive approach towards the management of CRC,particularly with liver-only-metastases;however,these drugs work best when combined with conventional chemotherapy agents.Despite these advances,there is a lack of biomarkers to inform us about the accurate management of the patients with metastatic CRC.It is therefore imperative to carefully select the patients with comprehensive multi-disciplinary team input in order to optimise the management of these patients.In this review we will discuss various treatment options available in management of colorectal liver metastases with potential guidance on how and when to choose these options along with consideration on future directions in management of this disease.

HER2 inhibition in gastro-oesophageal cancer:A review drawing on lessons learned from breast cancer

Human epidermal growth factor receptor 2(HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer(GOC).A significant proportion of GOC patients display HER2 amplification,yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer.Much of the current evidence surrounding HER2 has been obtained from studies in breast cancer,and we are only recently beginning to improve our understanding of HER2-amplified GOC.Whilst there are numerous licensed HER2 inhibitors in breast cancer,trastuzumab remains the only licensed HER2 inhibitor for HER2-amplified GOC.Clinical trials investigating lapatinib,trastuzumab emtansine,pertuzumab and MM-111 in GOC have demonstrated disappointing results and have not yet changed the treatment paradigm.Trastuzumab deruxtecan may hold promise and is currently being investigated in phase Ⅱ trials.HER2 amplified GOC differs from breast cancer due to inherent differences in the HER2 amino-truncation and mutation rate,loss of HER2 expression,alterations in HER2 signalling pathways and differences in insulin-like growth factor-1 receptor and MET expression.Epigenetic alterations involving different micro RNA profiles in GOC as compared to breast cancer and intrinsic differences in the immune environment are likely to play a role.The key to effective treatment of HER2 amplified GOC lies in understanding these mechanisms and tailoring HER2 inhibition for GOC patients in order to improve clinical outcomes.

Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer

AIM To investigate the impact of histology on outcome in advanced oesophageal cancer treated with first-line fluoropyrimidine-based chemotherapy.METHODS Individual patient data were pooled from three randomised phase Ⅲ trials of fluoropyrimidine-based chemotherapy ± platinum/anthracycline in patients with advanced, untreated gastroesophageal adenocarcinoma or squamous cell carcinoma(SCC) randomised between 1994 and 2005. The primary endpoint was overall survival of oesophageal cancer patients according to histology. Secondary endpoints were response rates and a toxicity composite endpoint.RESULTS Of the total 1836 randomised patients, 973 patients(53%)were eligible(707 patients with gastric cancer were excluded), 841(86%) had adenocarcinoma and 132(14%) had SCC. There was no significant difference in survival between patients with adenocarcinoma and SCC, with median overall survivals of 9.5 mo vs 7.6 mo(HR = 0.85, 95%CI: 0.70-1.03, P = 0.09) and one-year survivals of 38.8% vs 28.2% respectively. The overall response rate to chemotherapy was 44% for adenocarcinoma vs 33% for SCC(P = 0.01). There was no difference in the frequency of the toxicity composite endpoint between the two groups. CONCLUSION There was no significant difference in survival between adenocarcinoma and SCC in patients with advanced oesophageal cancer treated with fluoropyrimidine-based chemotherapy despite a trend for worse survival and less chemo-sensitivity in SCC. Tolerance to treatment was similar in both groups. This analysis highlights the unmet need for SCC-specific studies in advanced oesophageal cancer and will aid in the design of future trials of targeted agents.

Antibody drug conjugate development in gastrointestinal cancers:hopes and hurdles from clinical trials

Gastrointestinal(GI)cancers represent the leading cause of cancer-related mortality worldwide.Antibody drug conjugates(ADCs)are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival.ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy.Currently,only two ADCs[brentuximab vedotin and trastuzumab emtansine(T-DM1)]have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer,respectively.Clinical research evaluating ADCs in GI cancers has shown limited success.In this review,we will retrace the relevant clinical trials investigating ADCs in GI cancers,especially ADCs targeting human epidermal growth receptor 2,mesothelin,guanylyl cyclase C,carcinogenic antigen-related cell adhesion molecule 5(also known as CEACAM5)and other GI malignancy specific targets.We will review potential hurdles for their success and provide new perspective for future treatment.