Chapter 4 58 Lay-out in Adobe Indesign Ceate a new document and set the ‘bleed area’ (see settings page 59). This bleed is indicated within Indesign by a red line outside the document. Every design element that needs to have bleed, will need to run up to this red line. NB. Note that this space is not part of content formatting, but will be cut off later. Do not place important text and image elements too close to the page edge. Keep a distance of 5 mm ‘safe zone’ from the page edge (black line). Setup Indesign document • Create new document 170 x 240 mm (or another book size) • Select ‘facing pages’ • Margins 20 mm (keep your text and tables inside this area) • Bleed area 3 mm • Headers, footers. Keep a minimum of 5 mm ‘safe zone’ distance from the page edge. See example below. Page setup in Indesign Chapter 1 Title chapter 4 5 (white) margins safe zone page edge document bleed area 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
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