Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

Cardiopulmonary reserve as determined by cardiopulmonary exercise testing correlates with length of stay and predicts complications after radical cystectomy.

OBJECTIVE: To investigate whether poor preoperative cardiopulmonary reserve and comorbid state dictate high-risk status and can predict complications in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: In all, 105 consecutive patients with transitional cell carcinoma (TCC; stage T1-T3) undergoing robot-assisted (38 patients) or open (67) RC in a single UK centre underwent preoperative cardiopulmonary exercise testing (CPET). Prospective primary outcome variables were all-cause complications and postoperative length of stay (LOS). Binary logistic regression analysis identified potential predictive factor(s) and the predictive accuracy of CPET for all-cause complications was examined using receiver operator characteristic (ROC) curve analysis. Correlations analysis employed Spearman's rank correlation and group comparison, the Mann-Whitney U-test and Fisher's exact test. Any relationships were confirmed using the Mantel-Haenszel common odds ratio estimate, Kaplan-Meier analysis and the chi-squared test. RESULTS: The anaerobic threshold (AT) was negatively (r = -206, P = 0.035), and the ventilatory equivalent for carbon dioxide (VE/VCO2) positively (r = 0.324, P = 0.001) correlated with complications and LOS. Logistic regression analysis identified low AT (<11 mL/kg/min), high VE/VC02 (≥33) and hypertension as significant factors, such that, in their presence patients were 5.55-times more likely to have complications at 90 days postoperatively [P = 0.001, 95% confidence interval (CI) 2.2-13.9]. ROC analysis showed a high significance (area under the curve 0.78, 95% CI 0.69-0.87; P < 0.001). In addition, based on CPET criteria >50% of patients presenting for RC had significant heart failure, whereas preoperatively only very few (2%) had this diagnosis. Analysis using the Mann-Whitney test showed that a VE/VCO2 ≥33 was the most significant determinant of LOS (P = 0.004). Kaplan-Meier analysis showed that patients in this group had an additional median LOS of 4 days (P = 0.008). Finally, patients with an American Society of Anesthesiologists grade of 3 (ASA 3) and those on long-term ß-blocker therapy were found to be at particular risk of myocardial infarction (MI) and death after RC with odds ratios of 4.0 (95% CI 1.05-15.2; P = 0.042) and 6.3 (95% CI 1.60-24.8; P = 0.008). CONCLUSION: Patients with poor cardiopulmonary reserve and hypertension are at higher risk of postoperative complications and have increased LOS after RC. Heart failure is known to be a significant determinant of perioperative death and is significantly under diagnosed in this patient group.

Characterising recovery from renal transplantation and live-related donation using cardiopulmonary exercise testing.

BACKGROUND: An association between end-stage renal failure and exercise intolerance exists. Whether live kidney donation impacts on exercise tolerance is unknown. Here recovery post renal transplant and donation using cardiopulmonary exercise testing is investigated. METHODS: Renal donors (n = 28) and recipients (n = 24) undertook a cardiopulmonary exercise test, Duke activity score index and patient reported health score questionnaires pre-operatively and in the 7th and 14th week post-operatively. Anaerobic threshold, peak oxygen uptake and ventilatory equivalents were measured in relation to activity and reported health scores. Haemoglobin and renal function was recorded. RESULTS: Recipients showed impaired cardiopulmonary function compared to donors with lower anaerobic threshold (10.5 vs. 14.4 ml/kg/min) and peak oxygen uptake (18.5 vs 23.0 ml/kg/min). Post-operatively the anaerobic threshold of recipients improved and normalised by the 14th week, whereas that in donors fell by ∼20% by the 7th (mean 11.4 ml/kg/min), recovering by the 14th (mean 15.6 ml/kg/min). Reported health but not activity scores showed similar changes. CONCLUSIONS: Recovery following renal transplantation and donation differ. Transplantation improves renal function resulting in an increase in anaerobic threshold and peak oxygen uptake which essentially normalise by the 14th week post-operatively. Donors suffer a 20% reduction in cardiopulmonary reserve post-operatively, which recovers by the 14th week, suggesting no associated chronic exercise intolerance.IMPLICATIONS FOR REHABILITATIONCardiopulmonary exercise testing is a real-time predictor of functional capacity and thus is used as a pre-operative tool to measure physiological fitness and predict outcomes.Renal failure is associated with exercise intolerance and transplantation is transformational in terms of quality of life, longevity and healthcare cost.Live - related renal donation is increasingly available but whether donation itself carries a long-term health burden has not been previously well established.This study suggests that renal donation is not associated with long-term cardiopulmonary compromise and patients who donate their kidneys recover their previous fitness within 14 weeks.