Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long-term outcomes in patients with locally advanced rectal cancers

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Abstract

Aim

The study was carried out to investigate whether pretreatment haemoglobin (Hb) levels act as a biomarker in the management of patients with locally advanced rectal cancer.

Method

We prospectively collected data on all patients within our cancer network with localized low rectal cancer treated with preoperative radiotherapy/chemoradiotherapy at Mount Vernon Centre for Cancer Treatment between March 1994 and July 2008. Pretreatment Hb level was assessed as an independent variable for the whole study sample and dichotomised at a value of 12 g/dl. A multivariate analysis of covariance (MANCOVA) was conducted on parameters that had significant association on univariate analysis of covariance (ANCOVA) and correlational (Kendall tau/Pearson) analyses. Kaplan–Meier survival analysis and Cox proportional hazard models were used to determine significant prognostic markers. Statistical significance was set at 0.05.

Results

463 patients (male/female 2:1; median age = 66 years, interquartile range = 56.5–73.0) were included in the analysis. There was significant tumour response of T stage ( P < 0.001) and N stage ( P < 0.001), with 17.6% of patients achieving a pathological complete response. Pretreatment Hb value was inversely related to the craniocaudal vertical tumour length ( P = 0.02) and pretreatment T stage of the tumour ( P = 0.01). Patients with Hb levels of < 12 g/dl and moderately differentiated adenocarcinoma were less responsive. Local recurrence was more common in patients with a pretreatment Hb of < 12 g/dl (hazard ratio = 1.78) over a median follow up of 24 months, but this was not statistically significant ( P = 0.08).

Conclusion

The pretreatment Hb level might be used as a biomarker of rectal tumour morphology, response to neoadjuvant chemoradiation and risk of local recurrence.

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Most cited references 29

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Hypoxia in cancer: significance and impact on clinical outcome.

Peter Vaupel, Arnulf Mayer (2007)

Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.

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Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial

Phil Quirke, Robert Steele, John Monson … (2009)

Summary Background Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved. Methods In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842. Findings 128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0·32 (95% CI 0·16–0·63, p=0·0011) with 3-year local recurrence rates of 6% (5–8%) and 17% (10–26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0·32 (0·16–0·64) and 0·48 (0·25–0·93), respectively. At 3 years, the estimated local recurrence rates were 4% (3–6%) for mesorectal, 7% (5–11%) for intramesorectal, and 13% (8–21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0·30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%. Interpretation In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.

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Impact of tumor hypoxia and anemia on radiation therapy outcomes.

Kyle Hill, Kenneth Hu, Manjeet Chadha … (2001)

Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.

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Author and article information

Journal

Journal ID (nlm-ta): Colorectal Dis

Journal ID (iso-abbrev): Colorectal Dis

Journal ID (publisher-id): codi

Title: Colorectal Disease

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 1462-8910

ISSN (Electronic): 1463-1318

Publication date (Print): October 2013

Publication date (Electronic): 24 October 2013

Volume: 15

Issue: 10

Pages: 1232-1237

Affiliations

[* ]Department of Gastrointestinal Research, Mount Vernon Cancer Treatment and Research Centre London, UK

[† ]Faculty of Health and Wellbeing, Centre for Sports and Exercise Science, Sheffield Hallam University Sheffield, UK

[‡ ]Department of Clinical Oncology, Minia University Hospital Al-Minia, Egypt

Author notes

Correspondence to: Mr Aftab A. Khan, Surgical Research Fellow, Department of GI Research, Mount Vernon Hospital, Northwood, Herts HA6 2RN, UK. E-mail: aftab.khan@ 123456ucl.ac.uk

What does this paper add to the literature? Pretreatment Hb level may distinguish rectal cancer subtypes and could contribute to management.

Article

DOI: 10.1111/codi.12307

PMC ID: 4204517

PubMed ID: 23710579

SO-VID: c7a610fc-40b1-4193-b9dd-771d4248564d

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long-term outcomes in patients with locally advanced rectal cancers

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Karger: Gastroenterology

Most cited references 29

Hypoxia in cancer: significance and impact on clinical outcome.

Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial

Impact of tumor hypoxia and anemia on radiation therapy outcomes.

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