Sarah T O'Dwyer

Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis

BACKGROUND Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and are thought to be important in tumour development. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk. METHODS We did a systematic review and meta-regression analysis of case-control studies, including studies nested in cohorts, of the association between concentrations of IGF-I and IGFBP-3 and prostate, colorectal, premenopausal and postmenopausal breast, and lung cancer. Study-specific dose-response slopes were obtained by relating the natural log of odds ratios for different exposure levels to blood concentrations normalised to a percentile scale. FINDINGS We identified 21 eligible studies (26 datasets), which included 3609 cases and 7137 controls. High concentrations of IGF-I were associated with an increased risk of prostate cancer (odds ratio comparing 75th with 25th percentile 1.49, 95% CI 1.14-1.95) and premenopausal breast cancer (1.65, 1.26-2.08) and high concentrations of IGFBP-3 were associated with increased risk of premenopausal breast cancer (1.51, 1.01-2.27). Associations were larger in assessments of plasma samples than in serum samples, and in standard case-control studies compared with nested studies. INTERPRETATION Circulating concentrations of IGF-I and IGFBP-3 are associated with an increased risk of common cancers, but associations are modest and vary between sites. Although laboratory methods need to be standardised, these epidemiological observations could have major implications for assessment of risk and prevention of cancer.

Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials

Abstract Objective: To review the evidence from clinical trials of follow up of patients after curative resection for colorectal cancer. Design: Systematic review and meta-analysis of randomised controlled trials of intensive compared with control follow up. Main outcome measures: All cause mortality at five years (primary outcome). Rates of recurrence of intraluminal, local, and metastatic disease and metachronous (second colorectal primary) cancers (secondary outcomes). Results: Five trials, which included 1342 patients, met the inclusion criteria. Intensive follow up was associated with a reduction in all cause mortality (combined risk ratio 0.81, 95% confidence interval 0.70 to 0.94, P=0.007). The effect was most pronounced in the four extramural detection trials that used computed tomography and frequent measurements of serum carcinoembryonic antigen (risk ratio 0.73, 0.60 to 0.89, P=0.002). Intensive follow up was associated with significantly earlier detection of all recurrences (difference in means 8.5 months, 7.6 to 9.4 months, P<0.001) and an increased detection rate for isolated local recurrences (risk ratio 1.61, 1.12 to 2.32, P=0.011). Conclusions: Intensive follow up after curative resection for colorectal cancer improves survival. Large trials are required to identify which components of intensive follow up are most beneficial. What is already known on this topic There is a lack of direct evidence that intensive follow up after initial curative treatment for colorectal cancer leads to increased survival Guidelines are inconclusive and clinical practice varies widely What this study adds The cumulative analysis of available data supports the view that intensive follow up after curative resection for colorectal cancer improves survival If computed tomography and frequent measurements of serum carcinoembryonic antigen are used during follow up mortality related to cancer is reduced by 9-13% This survival benefit is partly attributable to the earlier detection of all recurrences, particularly the increased detection of isolated recurrent disease

Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis

BACKGROUND Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). METHODS Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. FINDINGS 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months [IQR 19-43]), 44 (34%) had local regrowths (3-year actuarial rate 38% [95% CI 30-48]); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% [95% CI 75-94] with watch and wait vs 78% [63-87] with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% [88-98] vs 87% [77-93]; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% [95% CI 64-82] vs 47% [37-57]; hazard ratio 0·445 [95% CI 0·31-0·63; p<0·0001), with a 26% (95% CI 13-39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. INTERPRETATION A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. FUNDING Bowel Disease Research Foundation.

Patterns of local disease failure and outcome after salvage surgery in patients with anal cancer.

Salvage surgery for anal cancer is usually reserved for local disease failure, but issues relating to the prediction of local failure and surgical outcome are ill defined.

Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer.

This study explored the relationships of serum insulin-like growth factors, IGF-I and IGF-II, and their binding proteins (IGFBP)-2 and IGFBP-3, with key clinicopathological parameters in 92 patients with colorectal cancer (cases). Comparisons were made with 57 individuals who had a normal colonoscopy (controls). Serial changes were examined in 27 cases. As IGF-related peptides are age- and sex-dependent, absolute concentrations were converted to standard deviation scores (SDS). Mean IGF-II SDS were elevated in Dukes A (n= 12P< 0.001) and Dukes B (n= 25P< 0.001) cases compared with controls, but not in advanced disease. Compared with controls, mean IGFBP-2 SDS were significantly elevated in patients with Dukes B (P< 0.001), Dukes C (n= 13P< 0.001) and advanced disease (n= 42P< 0.0001), with a significant trend from early to advanced disease (one-way ANOVAP< 0.001). Furthermore, IGFBP-2 SDS were positively related to tumour size (P= 0.01) and fell significantly in patients following curative resection (P= 0.04), suggesting that circulating levels reflect tumour load. We tested the potential tumour marker characteristics of IGFBP-2 SDS against three endpoints: metastasis alone; local pelvic recurrence alone; and metastasis and recurrence combined. The sensitivities for IGFBP-2 alone (≥ + 2SD) were modest at 55%, 46%, and 52%, but in combination with CEA, increased substantially to 90%, 77% and 86%, respectively. We conclude that the serum IGF-II and IGFBP-2 profiles may provide insights into underlying biological mechanisms, and that serum IGFBP-2 may have an adjunct role in cancer surveillance in patients with colorectal cancer.

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are members of the VEGF family of cytokines and have angiogenic and lymphangiogenic actions. In gastric adenocarcinoma, VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis and in some reports, venous invasion and reduced 5-year survival. Patients with gastric adenocarcinomas containing high levels of VEGF-C expression have significantly reduced 5-year survival rates, and VEGF-C expression is an independent prognostic risk factor for death. The role of VEGF-C in oesophageal squamous and colorectal cancer and VEGF-D in colorectal cancer is not clear, with conflicting reports in the published literature. In order to exploit potential therapeutic applications, further research is necessary to define the precise roles of these cytokines in health and disease.

Cost effectiveness analysis of intensive versus conventional follow up after curative resection for colorectal cancer.

Abstract Objective To determine the cost effectiveness of intensive follow up compared with conventional follow up in patients with colorectal cancer. Design Incremental cost effectiveness analysis recognising differences in follow up strategies, based on effectiveness data from a meta-analysis of five randomised trials. Setting United Kingdom. Main outcome measures Taking a health service perspective, estimated incremental costs effectiveness ratios for each life year gained for five trials and four trials designed for early detection of extramural recurrences (targeted surveillance). Results Based on five year follow up, the numbers of life years gained by intensive follow up were 0.73 for the five trial model and 0.82 for the four trial model. For the five trials, the adjusted net (extra) cost for each patient was £2479 (€3550;

Lymph node harvest in colon and rectal cancer: Current considerations

4288) and for each life year gained was £3402, substantially lower than the current threshold of NHS cost acceptability (£30 000). The corresponding values for the four trial model were £2529 and £3077, suggesting that targeted surveillance is more cost effective. The main predictor of incremental cost effectiveness ratios was surveillance costs rather than treatment costs. Judged against the NHS threshold of cost acceptability, the predicted incremental cost threshold was ninefold and the effectiveness threshold was 3%. Conclusions Based on the available data and current costs, intensive follow up after curative resection for colorectal cancer is economically justified and should be normal practice. There is a continuing need to evaluate the efficacy of specific surveillance tools: this study forms the basis for economic evaluations in such trials.

Early cellular events in colorectal carcinogenesis

The prognostic significance of identifying lymph node (LN) metastases following surgical resection for colon and rectal cancer is well recognized and is reflected in accurate staging of the disease. An established body of evidence exists, demonstrating an association between a higher total LN count and improved survival, particularly for node negative colon cancer. In node positive disease, however, the lymph node ratios may represent a better prognostic indicator, although the impact of this on clinical treatment has yet to be universally established. By extension, strategies to increase surgical node harvest and/or laboratory methods to increase LN yield seem logical and might improve cancer staging. However, debate prevails as to whether or not these extrapolations are clinically relevant, particularly when very high LN counts are sought. Current guidelines recommend a minimum of 12 nodes harvested as the standard of care, yet the evidence for such is questionable as it is unclear whether an increasing the LN count results in improved survival. Findings from modern treatments, including down-staging in rectal cancer using pre-operative chemoradiotherapy, paradoxically suggest that lower LN count, or indeed complete absence of LNs, are associated with improved survival; implying that using a specific number of LNs harvested as a measure of surgical quality is not always appropriate. The pursuit of a sufficient LN harvest represents good clinical practice; however, recent evidence shows that the exhaustive searching for very high LN yields may be unnecessary and has little influence on modern approaches to treatment.

Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer.

Colorectal cancer develops through a multistage process recognizable at a histopathological level by progression from normal mucosa to invasive carcinoma (the adenoma‐carcinoma sequence). For many years, it has been hypothesized that increased cell proliferation in the colonic crypt represents the earliest recognizable stage in this sequence. This perspective is now changing. While several human studies have reported increased crypt cell proliferation in samples from at‐risk patients, there are many inconsistencies and paradoxes in their conclusions. In addition, it is appreciated that the process of apoptosis (programmed cell death) is vital for normal crypt homeostasis and its impairment may be an early event in the neoplastic process. It is now believed that aberrant crypt foci (ACFs) represent the earliest step in colorectal carcinogenesis. Two ACF types are identifiable: hypercellular and dysplastic. Increased proliferative activity may be seen in both, but the dysplastic entity is most relevant to carcinogenesis. Animal and human studies support the notion that ACFs grow by crypt fission leading to the formation of microadenomas. Adenomas are monoclonal expansions of an altered cell, but very early lesions may be polyclonal. There are outward and inward theories of polypoid growth, and evidence to support both mechanisms. The ACF assay has become a useful tool to detect carcinogens in animal studies but has been less frequently used in human studies. For future cancer chemopreventive and risk assessment studies in humans, the identification and quantification of ACFs should be considered a more effective intermediate marker of risk than the determination of crypt cell proliferation alone.