Inside 49 *Blank page or image/illustration This thesis focuses on the evaluation of the optimal allocation and duration of adjuvant chemotherapy in stage II colon cancer. Using decision-analytic modelling, we evaluated the cost-effectiveness of different strategies to allocate adjuvant chemotherapy in stage II colon cancer patients. In addition, we evaluated the optimal treatment duration in these patients. This chapter briefly describes colon cancer epidemiology and the importance of optimizing treatment strategies in stage II colon cancer. Subsequently, it explains why adjuvant chemotherapy allocation is considered as a medical dilemma in stage II colon cancer by discussing treatment effectiveness, the selection of high-risk patients, the optimal treatment duration and the health risks of adjuvant chemotherapy. Furthermore, the advantages of decision-analytic modelling to address the challenge of adjuvant chemotherapy allocation and optimal treatment duration in stage II colon cancer are discussed. Finally, the aims and outline of this thesis are described. Colon cancer Colon cancer is the fourth most commonly diagnosed cancer worldwide, after lung-, breast- and prostate cancer, with around 1.1 million new cases and 0.6 million deaths in 2018.1 The incidence of colon cancer varies widely by world region and is highest in western countries, which is probably due to differences in lifestyle compared to non-Western countries.1 Worldwide, the incidence and mortality rates are higher in men compared to women. In the Netherlands, colon cancer is an important health problem as well. The incidence has more than doubled in the last thirty years; from 4,600 new cases in 1989 to 9,800 cases in 2018.2 The average age of a colon cancer patient is 69 years at the moment of diagnosis. In addition, more than 30% of all newly diagnosed patients are aged 75 or older.2 Thus, colon cancer mainly affects elderly patients. Given the aging population in the Netherlands in combination with an unfavourable change in lifestyle, such as a decrease in physical activity and an increase in alcohol consumption, the risk to develop colon cancer is increasing. On the other hand, the Dutch colorectal cancer screening program was introduced in 2014, which hopefully will ensure a decrease in colon cancer mortality in the long term. Shift in colon cancer stage distribution Using the tumor-node-metastasis (TNM) system, four disease stages are distinguished to classify the extensiveness of colon cancer.3 In this thesis, we focus on stage II colon cancer, which means that the tumor has grown through the colon wall, but has not spread to regional lymph nodes or distant organs. The proportion of stage II colon cancer patients was 26% in 2018 in the Netherlands. Due to the introduction of the Dutch national colorectal cancer screening program, the proportion of stage II colon cancer patients slightly decreased. To illustrate, in 2013 28% of the colon cancer patients were diagnosed with stage II disease.4 Medical dilemma’s in stage II colon cancer treatment The standard treatment of stage II colon cancer patients is surgical resection. The overall prognosis after surgical resection is relatively good. To illustrate, the QUASAR trial reported in 2007 5-year survival rates of 76% and 80% for disease-free survival (DFS) and overall survival (OS), respectively.5 However, the stage II colon cancer population is heterogeneous regarding the risk to develop a recurrence. Therefore, adjuvant chemotherapy is recommended in national and international guidelines to optimize survival probabilities for those patients with a high risk of recurrence.6-8 Notwithstanding these recommendations, there are still three important knowledge gaps. Firstly, 8 1 Chapter 1 149602 Jongeneel BNW.indd 8 04-06-2021 13:47 CHAPTER 2 Estimating adjuvant treatment effects in stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data Gabriëlle Jongeneel, Thomas Klausch, Felice N. van Erning, Geraldine R. Vink, Miriam Koopman, Cornelis J.A. Punt, Marjolein J.E. Greuter and Veerle M.H. Coupé International Journal of Cancer. 2020 Jun 1;146(11):2968-2978 Estimating adjuvant treatment effects in stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data Gabrielle Jongeneel, Thomas Klausch, Felice N. van Erning, Geraldine R. Vink, Miriam Koopman, Cornelis J.A. Punt, Marjolein J.E. Greuter and Veerle M.H. Coupé International Journal of Cancer. 2020 Jun 1;146(11):2968-2978 CHAPTER 2 149602 Jongeneel BNW.indd 19 04-06-2021 13:47 despite the large number of RCTs that have evaluated adjuvant treatment effectiveness in colon cancer patients, the effectiveness in the stage II population remains unclear, mainly due to insufficient power in the studies for the stage II population. Furthermore, over the years the number of examined regional lymphnodes per patients increased as this provides important information about the patients’ prognosis, which resulted in a migration of disease stage.9 That is, a patient that was classified as stage II before the increasing number of evaluated lymphnodes, could possibly be classified as stage III in a more recently conducted study. Secondly, there is no consensus on which high-risk features should be taken into account to select stage II colon cancer patients for adjuvant chemotherapy. Thirdly, there is less convincing data for the optimal duration of adjuvant treatment in stage II colon cancer patients compared to stage III colon cancer. Moreover, when deliberating on the optimal treatment choice in stage II colon cancer, it is important to explicitly take into account the fact that there are also health risks associated with adjuvant chemotherapy. To guide the clinical decision making process, the potential health gain of adjuvant treatment should be carefully balanced against the potential harms. Summarizing, the identification of patients that require adjuvant chemotherapy as well as the optimal treatment duration remains challenging. Below the three knowledge gaps are discussed in more detail. The effect of adjuvant chemotherapy in stage II colon cancer The treatment effect of adjuvant chemotherapy in stage II colon cancer has been evaluated in several randomized clinical trials (RCTs) during the last decades. IMPACT was the first collaboration that conducted a pooled analysis of 1,016 patients with stage II colon cancer from 5 RCTs, which compared a fluorouracil-leucovorin (FU-LV) treated group to a control group. The group that was treated with FU-LV demonstrated a small, statistically non-significant improvement in 5-year DFS and OS. The DFS rates were 76% versus 73% and the OS rates were 82% versus 80% for the FU-LV group compared to the control group, respectively.10 Subsequently, in 2004 another meta-analysis was conducted in which 3,302 patients were included with stage II or III colon cancer from 7 RCTs (the 5 RCTs included in IMPACT and two additional RCTs), which compared FU-LV to a control group. In a stage II colon cancer subgroup analysis (n=1,440), a small but significant difference of 4% (76% versus 72%, p=0.049) was found for DFS and a small non-significant difference of 1% in OS (81% versus 80%, p=0.113).11 In 2007, results of the QUASAR trial became available. In the QUASAR trial, 3,239 resected stage I (1%), II (91%) and III (8%) patients were included of which 71% was diagnosed with colon cancer and 29% with rectal cancer. Patients were randomized to a FU-LV arm (with or without levamisole) or a control arm. The QUASAR trial demonstrated a relative risk of recurrence of 0.78 (95% CI, 0.67-0.91) and a relative risk of OS of 0.82 (95% CI, 0.70-0.95) for FU-LV treated patients compared to observation. The authors reported an improvement in OS of 3.6% for FU-LV compared to observation within 5-year follow-up, which was assessed as having limited clinical impact.5 After the QUASAR trial, the MOSAIC and NSABP-07 trials were conducted to evaluate the benefit of the addition of oxaliplatin to FU-LV (FOLFOX) in stage II and III colon cancer. In the secondary analysis of stage II colon cancer patients only (n=899), the MOSAIC trial reported a statistically non-significant improvement in DFS with a hazard ratio (HR) of 0.84 (95%CI: 0.62-1.14) for FOLFOX compared to FU-LV. However, the HR for OS was 1 (95% CI: 0.70-1.41), indicating equal survival probabilities in both groups.12 In the NSABP C-07 trial, 2,409 patients (29% stage II and 71% stage III) were included. In a separate stage II analysis (n=695), HRs of 0.94 (95% CI: 0.70-1.26) and 1.04 (95%: 0.72-1.50) for DFS and OS, respectively, were found when comparing FOLFOX to FU-LV.13 1 9 General introduction 149602 Jongeneel BNW.indd 9 04-06-2021 13:47 Start new chapter If the previous chapter ended with an odd page (right-hand page), place a *blank, even page before the start of a new chapter. (See example below). This ensures that this chapter starts with an odd page (right) again. Of course, this can also be applied to the preface, CV, etc. Of course, it does not have to be a blank page but can also be a page with an image or illustration. Note! Once these pages are added, your page numbering will also change. Therefore, check your table of contents after adding these pages. CHAPTER 3
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