Evaluation of prognosis and treatment response in colorectal cancer with focus on biomarkers

Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer death in Finland. Improvements in surgical techniques, diagnostics, pathological evaluation of the specimen and oncological treatments have all improved its 5-year survival. Early diagnosis, proper surgery and multidisciplinary teamwork are the keys to a cure. Improvements in the oncological treatment of metastatic CRC (mCRC) have prolonged survival, but in oligometastatic disease, only metastasectomies are curative. Biomarkers are useful in follow-up of CRC patients and in prediction of prognosis and treatment response, both in radically operated CRC patients and in mCRC. In this thesis, the patients included were from four different trials: the randomised LIPSYT trial investigating bolus versus infusional 5-fluorouracil-based adjuvant treatment for radically operated stage II to IV CRC patients at the Department of Oncology at Helsinki University Hospital and the multicentre French GERCOR C96.1 trial with the same design in radically operated stage II to III colon cancer patients. In addition were the MEPSYT TNF trial consisting of mCRC patients treated with three different chemotherapy regimens and the MEPSYT phase I to II trial with raltitrexed combined with peroral carmofur for mCRC, which both took place at the Department of Oncology at Helsinki University Hospital. Study I included 147 patients from the LIPSYT trial with archived post-operative blood samples available for biomarker assessment, YKL-40 (also known as chintinase-3-like protein 1 (CHI3L1)), and interleukin-6 (IL-6), combined with routine measurement of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and c-reactive protein (CRP). The study aim was to look at relapses, disease-free survival (DFS), and overall survival (OS) in the group of elevated versus normal post-operative markers. Study II included 153 stage II to III CRC patients from the LIPSYT trial and 880 stage II to III colon cancer patients from the GERCOR C96.1 trial eligible for analysis of adverse events and their impact on DFS and OS. Study III included 60 patients from the MEPSYT- TNF trial who were treated with fluoropyrimidines (n=20), raltitrexed alone (n=20), or raltitrexed combined with the peroral fluoropyrimidine carmofur (n=20); weekly CEA values, liver function tests, and inflammatory markers during one chemotherapy cycle were available for evaluation regarding fluctuation and correlation with prognosis. Study IV included 66 patients from the MEPSYT trial with CEA values and computed tomography (CT) examinations available for evaluation at baseline (before chemotherapy) and at 2-month intervals regarding the possibility of replacing CT with CEA in treatment response evaluation. Study I showed that post-operatively elevated CEA had a high positive predictive value (PPV) of 89% (CI95% 65-99%) and specificity 97% (CI95% 91-100%) and sensitivity 31% (CI95% 21-48%). Post-operatively elevated CEA was a significant marker for relapses (HR 7.91; CI95% 3.43-18.24), DFS (HR 8.63; CI95% 3.82-19.50), and OS (HR 10.17; CI95% 4.35-23.79) in multivariate analysis. Normal post-operative CEA combined with elevated YKL-40 was linked with impaired DFS (HR 2.30; CI95% 1.27-4.16) and OS (HR 2.40; CI95% 1.28-4.52) or CRP with impaired DFS (HR 3.54; CI95% 1.57-8.02) and OS (HR 3.10; CI95% 1.29-7.45). An elevated CEA combined with an elevated CA19-9, YKL-40, CRP, or IL-6 was linked to very high relapse rates: CA19-9 with PPV 100%, YKL-40 with PPV 90%, CRP with PPV 100%, and IL-6 with PPV 100%. In Study II, 47% of the patients receiving adjuvant 5-FU chemotherapy developed neutropenia, 54% developed nausea/vomiting, and 43% developed mucositis. Those patients experiencing these adverse events, especially if mild to moderate, had the best outcome. On the other hand, patients experiencing no adverse events had the worst survival rates. In Study III, CEA fluctuated during a fluorouracil-based chemotherapy cycle. A non-significant decrease occurred at day 7 and an increase at day 14. A significant CEA increase occurred during the evaluation cycle (55.4 μg/l vs. 148.2 μg/l; P=0.024) in progressive disease, but in patients with disease control, their CEA level was stable (10.6 μg/l vs. 17.8 μg/l; P=0.58). Study IV showed that at a certain measuring point, a decreasing CEA or a CEA at the same level compared to baseline (before chemotherapy) or the lowest value noticed was equivalent to disease control. In 23% to 47% of the cases, CEA could replace CT in the response evaluation of mCRC. In radically operated stage II to IV CRC patients, a post-operatively elevated CEA or a normal CEA combined with an elevated YKL-40 or an elevated CRP may aid us in finding high-risk patients who would benefit from more aggressive adjuvant therapy and more intensive follow-up. Moreover, adverse events during adjuvant chemotherapy may serve as clinical markers for the evaluation of treatment efficacy. Because CEA fluctuates during a chemotherapy cycle, measurement of CEA should not take place during the cycle, but just before the next cycle is due. If CEA replaces CT in response evaluation of mCRC during chemotherapy for mCRC, response evaluation becomes easier for the patient and cost-saving becomes possible for the health care system.