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The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients M.A. West a,b,f,*, L. Loughney a,b,d, C.P. Barben a, R. Sripadam e, G.J. Kemp f, M.P.W. Grocott b,c,d, S. Jack b,d a Colorectal Surgery Research Group, Aintree University Hospitals NHS Foundation Trust, Liverpool, United Kingdom Critical Care Research Area, Southampton NIHR Respiratory Biomedical Research Unit, Southampton, United Kingdom c Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom d Anaesthesia and Critical Care Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom e Clatterbridge Cancer Centre, Wirral, United Kingdom f Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom b
Accepted 22 March 2014 Available online - - -
Abstract Background: Neoadjuvant chemoradiotherapy (NACRT) followed by surgery for resectable locally advanced rectal cancer improves outcome compared with surgery alone. Our primary hypothesis was that NACRT impairs objectively-measured physical fitness. We also wished to explore the relationship between fitness and postoperative outcome. Method: In an observational study, we prospectively studied 27 consecutive patients, of whom 25 undertook cardiopulmonary exercise testing (CPET) 2 weeks before and 7 weeks after standardized NACRT, then underwent surgery. In-hospital post-operative morbidity and mortality were recorded. Patients were followed up to 1 year for mortality. Data was analysed blind to clinical details. Receiver-operating characteristic (ROC) analysis defined the predictive value of CPET for in-hospital morbidity at day 5. Results: Oxygen uptake (V_ O2 in ml kg1 min1) at estimated lactate threshold ðb q L Þ and at peak exercise (V_ O2 at peak in ml kg1 min1) b both significantly decreased post-NACRT: V_ O2 at q L 12.1 (pre-NACRT) vs. 10.6 (post-NACRT), p < 0.001 (95%CI 1.7, 1.2); V_ O2 at peak 18.1 vs. 16.7, p < 0.001 (95%CI 3.1, 1.0). Optimal V_ O2 at b q L and peak pre-NACRT for predicting postoperative morbidity were b _ 12.0 and 18.1 (V O2 at q L e AUC ¼ 0.71, 77% sensitive and 75% specific; V_ O2 at peak e AUC ¼ 0.75, 78% sensitive and 76% specific). Optimal V_ O2 at b q L and peak post-NACRT for predicting postoperative morbidity were 10.7 and 16.7 (V_ O2 at b q L e AUC ¼ 0.72, 77% sensitive and 83% specific; V_ O2 at peak e AUC ¼ 0.80, 85% sensitive and 83% specific). Conclusion: NACRT before major rectal cancer surgery significantly decreased physical fitness as assessed by CPET. Trials Registry Number: NCT01334593. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Neoadjuvant chemoradiotherapy; Cardiopulmonary exercise testing; Cancer surgery; Morbidity; Rectal cancer; Physical fitness
Introduction
* Corresponding author. Aintree University Hospitals, Clinical Sciences Centre, 3rd Floor, Longmoore Lane, Liverpool L97AL, United Kingdom. Tel.: þ44 151 529 5882. E-mail addresses: [email protected], [email protected] (M.A. West), [email protected] (L. Loughney), chris.barben@ aintree.nhs.uk (C.P. Barben), [email protected] (R. Sripadam), [email protected] (G.J. Kemp), mike.grocott@ soton.ac.uk (M.P.W. Grocott), [email protected] (S. Jack).
In the United Kingdom colorectal cancer is the third commonest cause of cancer death.1 In 2009, 33 600 new cases were registered in England (w1/3 rectal), with w13 000 deaths in 2010.2 In 2012, of w9000 diagnosed with rectal cancer (35% over 75 years), 75% underwent major resection, 76% of whom had no worse than mild systemic disease (American Society of Anaesthesiologists (ASA) score of 1 or 2), with 90-day post-operative
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.03.021 Please cite this article in press as: West MA, et al., The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.021
2
M.A. West et al. / EJSO xx (2014) 1e8
mortality of 3.2%.3 The 2012 UK National Bowel Cancer Audit reported ASA score (a categorical descriptor of fitness for surgery) as the strongest predictor of death within 30 days of surgery.3 Twenty-five per cent of rectal cancers are locally advanced (T3/T4 Nþ), and these are considered for neoadjuvant chemoradiotherapy (NACRT) to control local disease, improve operability, achieve tumour downsizing and negative resection margins.4,5 However, standard NACRT based on external beam radiation and oral or intravenous fluoropyrimidines causes dose-limiting toxicity (most commonly diarrhoea, handfoot syndrome, cardiotoxicity and haematological toxicity) reaching Grade 3e5 in w20% (Common Terminology Criteria for Adverse Events, Version 3.0).6 It is less clear whether there are further metabolic adverse effects from cancer therapies which could impact outcome after surgery. Cardiorespiratory fitness, assessed by cardiopulmonary exercise testing (CPET), reliably predicts outcome following major surgery.7,8 CPET provides an integrated quantitative assessment of the cardiorespiratory system at rest and under the stress of maximal exercise, testing the physiological reserve required to withstand the stress of surgery. Knowledge of the effects of cancer and cancer therapies on physical fitness is critical to develop interventions targeted at improving fitness prior to surgery. Subjective assessment tools have been used to predict surgical outcomes, but there is little evidence linking objectivelymeasured physical fitness and surgical outcome in this group. Only two trials suggest that rectal cancer patients with a lower subjective performance status or physical fitness (WHO score >1) have worse post-operative outcome after combined chemotherapy or chemoradiation and surgery.6,9 We hypothesised that standardised NACRT prior to elective surgery for locally advanced rectal cancer would impair objectively-measured physical fitness; specifically oxygen uptake ðV_ O2 Þ measured at estimated lactate threshold ðb q L Þ and at peak exercise. We also explored the relationship of V_ O2 at b q L and V_ O2 at peak in predicting in-hospital post-operative morbidity. Patients and methods Patients and study design This single-centre, prospective, observational cohort study, based in a tertiary referral NHS University Teaching Hospital, was approved by the Northwest Research Ethics Committee (11/H1002/12) and registered with ClinicalTrials.gov (NCT01334593). Written informed consent was obtained from all patients. We recruited consecutive patients between August 2011 and July 2012 referred to the Colorectal Multi-Disciplinary Team (MDT), age 18 years, with locally advanced (circumferential resection margin threatened) resectable rectal cancer, who were scheduled for standardised NACRT (see below) on
the basis of Tumour, Node, Metastasis (TNM) classification >T2/Nþ with no metastasis10 and WHO Performance Status 5 mm in all cases. No patients had complete pathological response. Chemoradiotherapy and acute toxicity The mean cumulative dose of capecitabine was 96% (range 84e100%) of the planned treatment dose; 3 patients needed dose reduction. All but 1 patient received at least 45 Gy radiotherapy, and all completed the full 25 fractions. 7 patients (including 3 receiving a diverting stoma because of obstructive symptoms prior to starting NACRT) experienced grade 3 toxicity, notably diarrhoea and radiation dermatitis, but no grade 4 toxicity. No hepatic toxicity was encountered. The effect of NACRT on physical fitness Table 3 shows CPET-derived variables pre- and postNACRT. Post-NACRT, both absolute (ml min1) and relative (ml kg1 min1) V_ O2 at b q L and V_ O2 at peak exercise were significantly decreased ( p < 0.001): Fig. 1 and Fig. 2 e online show pair-plots of individual patients’ relative V_ O2 at b q L and relative V_ O2 at peak pre- and postNACRT. Oxygen pulse at b q L and at peak (ml beat1) were also significantly decreased ( p ¼ 0.005 and p ¼ 0.002 respectively). V_ E =V_ CO2 did not change. There
Please cite this article in press as: West MA, et al., The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.021
M.A. West et al. / EJSO xx (2014) 1e8
5
Table 3 Cardiopulmonary exercise testing variables. q L (ml kg1 min1)a V_ O2 at b _V O2 at b q L (ml min1)b V_ O2 at peak (ml kg1 min1)a V_ O2 at peak (ml min1)b O2 pulse at b q L (ml beat1)b O2 pulse at peak (ml beat1)b qL b V_ E =V_ CO2 at b V_ E =V_ CO2 at peakb Baseline heart rate (beats min1)a Peak heart rate (beats min1)a Work load at b q L (W)a Work load at peak (W)a
Pre-NACRT
Post-NACRT
Mean difference (95% CI)
P-value
12.1 905.2 18.1 1370 8.7 11.2 33.5 35.8 85 124 46 104
10.6 (8.2e12.0) 803.0 (323.5) 16.7 (12.1e19.2) 1180 (690) 8.1(2.7) 10.1 (3.0) 33.1 (5.1) 35.8 (6.1) 83 (70e88) 122 (110e139) 46 (24e55) 96 (60e116)
1.5 (1.7, 1.2) 102.2 (75.7, 128.7) 1.4 (3.1, 1.0) 190 (86.7, 252.1) 0.7 (1.2, 0.2) 1.1 (1.8, 0.4) 0.4 (1.7, 0.9) 0 (1.2, 1.2) 2 (4.7, 2.1) 2 (6.4, 10.5) 5 (10.0, 0.1) 8 (13.4, 2.7)
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The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients M.A. West a,b,f,*, L. Loughney a,b,d, C.P. Barben a, R. Sripadam e, G.J. Kemp f, M.P.W. Grocott b,c,d, S. Jack b,d a Colorectal Surgery Research Group, Aintree University Hospitals NHS Foundation Trust, Liverpool, United Kingdom Critical Care Research Area, Southampton NIHR Respiratory Biomedical Research Unit, Southampton, United Kingdom c Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom d Anaesthesia and Critical Care Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom e Clatterbridge Cancer Centre, Wirral, United Kingdom f Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom b
Accepted 22 March 2014 Available online - - -
Abstract Background: Neoadjuvant chemoradiotherapy (NACRT) followed by surgery for resectable locally advanced rectal cancer improves outcome compared with surgery alone. Our primary hypothesis was that NACRT impairs objectively-measured physical fitness. We also wished to explore the relationship between fitness and postoperative outcome. Method: In an observational study, we prospectively studied 27 consecutive patients, of whom 25 undertook cardiopulmonary exercise testing (CPET) 2 weeks before and 7 weeks after standardized NACRT, then underwent surgery. In-hospital post-operative morbidity and mortality were recorded. Patients were followed up to 1 year for mortality. Data was analysed blind to clinical details. Receiver-operating characteristic (ROC) analysis defined the predictive value of CPET for in-hospital morbidity at day 5. Results: Oxygen uptake (V_ O2 in ml kg1 min1) at estimated lactate threshold ðb q L Þ and at peak exercise (V_ O2 at peak in ml kg1 min1) b both significantly decreased post-NACRT: V_ O2 at q L 12.1 (pre-NACRT) vs. 10.6 (post-NACRT), p < 0.001 (95%CI 1.7, 1.2); V_ O2 at peak 18.1 vs. 16.7, p < 0.001 (95%CI 3.1, 1.0). Optimal V_ O2 at b q L and peak pre-NACRT for predicting postoperative morbidity were b _ 12.0 and 18.1 (V O2 at q L e AUC ¼ 0.71, 77% sensitive and 75% specific; V_ O2 at peak e AUC ¼ 0.75, 78% sensitive and 76% specific). Optimal V_ O2 at b q L and peak post-NACRT for predicting postoperative morbidity were 10.7 and 16.7 (V_ O2 at b q L e AUC ¼ 0.72, 77% sensitive and 83% specific; V_ O2 at peak e AUC ¼ 0.80, 85% sensitive and 83% specific). Conclusion: NACRT before major rectal cancer surgery significantly decreased physical fitness as assessed by CPET. Trials Registry Number: NCT01334593. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Neoadjuvant chemoradiotherapy; Cardiopulmonary exercise testing; Cancer surgery; Morbidity; Rectal cancer; Physical fitness
Introduction
* Corresponding author. Aintree University Hospitals, Clinical Sciences Centre, 3rd Floor, Longmoore Lane, Liverpool L97AL, United Kingdom. Tel.: þ44 151 529 5882. E-mail addresses: [email protected], [email protected] (M.A. West), [email protected] (L. Loughney), chris.barben@ aintree.nhs.uk (C.P. Barben), [email protected] (R. Sripadam), [email protected] (G.J. Kemp), mike.grocott@ soton.ac.uk (M.P.W. Grocott), [email protected] (S. Jack).
In the United Kingdom colorectal cancer is the third commonest cause of cancer death.1 In 2009, 33 600 new cases were registered in England (w1/3 rectal), with w13 000 deaths in 2010.2 In 2012, of w9000 diagnosed with rectal cancer (35% over 75 years), 75% underwent major resection, 76% of whom had no worse than mild systemic disease (American Society of Anaesthesiologists (ASA) score of 1 or 2), with 90-day post-operative
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.03.021 Please cite this article in press as: West MA, et al., The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.021
2
M.A. West et al. / EJSO xx (2014) 1e8
mortality of 3.2%.3 The 2012 UK National Bowel Cancer Audit reported ASA score (a categorical descriptor of fitness for surgery) as the strongest predictor of death within 30 days of surgery.3 Twenty-five per cent of rectal cancers are locally advanced (T3/T4 Nþ), and these are considered for neoadjuvant chemoradiotherapy (NACRT) to control local disease, improve operability, achieve tumour downsizing and negative resection margins.4,5 However, standard NACRT based on external beam radiation and oral or intravenous fluoropyrimidines causes dose-limiting toxicity (most commonly diarrhoea, handfoot syndrome, cardiotoxicity and haematological toxicity) reaching Grade 3e5 in w20% (Common Terminology Criteria for Adverse Events, Version 3.0).6 It is less clear whether there are further metabolic adverse effects from cancer therapies which could impact outcome after surgery. Cardiorespiratory fitness, assessed by cardiopulmonary exercise testing (CPET), reliably predicts outcome following major surgery.7,8 CPET provides an integrated quantitative assessment of the cardiorespiratory system at rest and under the stress of maximal exercise, testing the physiological reserve required to withstand the stress of surgery. Knowledge of the effects of cancer and cancer therapies on physical fitness is critical to develop interventions targeted at improving fitness prior to surgery. Subjective assessment tools have been used to predict surgical outcomes, but there is little evidence linking objectivelymeasured physical fitness and surgical outcome in this group. Only two trials suggest that rectal cancer patients with a lower subjective performance status or physical fitness (WHO score >1) have worse post-operative outcome after combined chemotherapy or chemoradiation and surgery.6,9 We hypothesised that standardised NACRT prior to elective surgery for locally advanced rectal cancer would impair objectively-measured physical fitness; specifically oxygen uptake ðV_ O2 Þ measured at estimated lactate threshold ðb q L Þ and at peak exercise. We also explored the relationship of V_ O2 at b q L and V_ O2 at peak in predicting in-hospital post-operative morbidity. Patients and methods Patients and study design This single-centre, prospective, observational cohort study, based in a tertiary referral NHS University Teaching Hospital, was approved by the Northwest Research Ethics Committee (11/H1002/12) and registered with ClinicalTrials.gov (NCT01334593). Written informed consent was obtained from all patients. We recruited consecutive patients between August 2011 and July 2012 referred to the Colorectal Multi-Disciplinary Team (MDT), age 18 years, with locally advanced (circumferential resection margin threatened) resectable rectal cancer, who were scheduled for standardised NACRT (see below) on
the basis of Tumour, Node, Metastasis (TNM) classification >T2/Nþ with no metastasis10 and WHO Performance Status 5 mm in all cases. No patients had complete pathological response. Chemoradiotherapy and acute toxicity The mean cumulative dose of capecitabine was 96% (range 84e100%) of the planned treatment dose; 3 patients needed dose reduction. All but 1 patient received at least 45 Gy radiotherapy, and all completed the full 25 fractions. 7 patients (including 3 receiving a diverting stoma because of obstructive symptoms prior to starting NACRT) experienced grade 3 toxicity, notably diarrhoea and radiation dermatitis, but no grade 4 toxicity. No hepatic toxicity was encountered. The effect of NACRT on physical fitness Table 3 shows CPET-derived variables pre- and postNACRT. Post-NACRT, both absolute (ml min1) and relative (ml kg1 min1) V_ O2 at b q L and V_ O2 at peak exercise were significantly decreased ( p < 0.001): Fig. 1 and Fig. 2 e online show pair-plots of individual patients’ relative V_ O2 at b q L and relative V_ O2 at peak pre- and postNACRT. Oxygen pulse at b q L and at peak (ml beat1) were also significantly decreased ( p ¼ 0.005 and p ¼ 0.002 respectively). V_ E =V_ CO2 did not change. There
Please cite this article in press as: West MA, et al., The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.021
M.A. West et al. / EJSO xx (2014) 1e8
5
Table 3 Cardiopulmonary exercise testing variables. q L (ml kg1 min1)a V_ O2 at b _V O2 at b q L (ml min1)b V_ O2 at peak (ml kg1 min1)a V_ O2 at peak (ml min1)b O2 pulse at b q L (ml beat1)b O2 pulse at peak (ml beat1)b qL b V_ E =V_ CO2 at b V_ E =V_ CO2 at peakb Baseline heart rate (beats min1)a Peak heart rate (beats min1)a Work load at b q L (W)a Work load at peak (W)a
Pre-NACRT
Post-NACRT
Mean difference (95% CI)
P-value
12.1 905.2 18.1 1370 8.7 11.2 33.5 35.8 85 124 46 104
10.6 (8.2e12.0) 803.0 (323.5) 16.7 (12.1e19.2) 1180 (690) 8.1(2.7) 10.1 (3.0) 33.1 (5.1) 35.8 (6.1) 83 (70e88) 122 (110e139) 46 (24e55) 96 (60e116)
1.5 (1.7, 1.2) 102.2 (75.7, 128.7) 1.4 (3.1, 1.0) 190 (86.7, 252.1) 0.7 (1.2, 0.2) 1.1 (1.8, 0.4) 0.4 (1.7, 0.9) 0 (1.2, 1.2) 2 (4.7, 2.1) 2 (6.4, 10.5) 5 (10.0, 0.1) 8 (13.4, 2.7)
