MANUAL Theses | Books | Design www.ridderprint.nl
MANUAL
Ohmweg 21 2952 BD Alblasserdam T +31 (0)180 463962 E info@ridderprint.nl I www.ridderprint.nl © Ridderprint | 2021
About us Who are we? Ridderprint is a family business which has specialised in the printing of dissertations (and other books) for many years. From day one, the vision is to deliver an exceptional final product in close consultation with the PhD. Everything is possible. After all, it is the conclusion of an exciting period and this deserves a beautiful dissertation. Using the latest techniques, we always strive to deliver the highest quality at an appropriate price. In consultation with PhD students, we ensure that the best options are chosen for printing and layout. Everyone has their own preferences and our aim is to get as much as possible out of every budget. As a team, we believe it is important to have short lines of communication. In your own online portal environment, all information can be found regarding your order; specifications, planning, progress and final delivery. If there are any questions, we are there for you. We look forward to a great collaboration! The Ridderprint Team
Content About Us 3 Chapter 1 | Procedure 7 Procedure 9 Chapter 2 | Layout packages 13 Layout 15 The Packages - Inside Work 16 The Packages - Total Package 19 The Packages - Cover 20 Chapter 3 | Online Publishing 23 Online Publishing 25 The Packages - Online 26 Chapter 4 | General 29 Production Methods 31 Use of Colour 32 Image Quality 33 What is ‘Bleed’? 36 Chapter 5 | Start your layout 39 The inside 41 Applying for an ISBN 41 Ridderprint in Colophon 42 Layout of the Inside Work 44 Front Matter 46 Layout in Microsoft Word 50 Layout in Indesign 58 The cover 61 Layout your cover 62 Layout in Indesign, Illustrator or Photoshop 62 Cover variations 66 Special cover finishing 68
Additional material 70 Propositions, bookmark, extra invitation, summary booklet 70 Chapter 6 | Create PDF 73 Submitting PDF files 75 Ridderprint portal / Sending Files 76 Creating a PDF file using Word 78 Creating a PDF file in Mac OS X 84 Creating a PDF file using Adobe Acrobat 86 Creating a PDF file using Adobe InDesign 88 Creating a PDF file using Adobe Illustrator 90 Creating a PDF file using Adobe Photoshop 92 Types of Paper 101
1 Procedure
Ridderprint stands for service and quality, but without the high costs. With clear agreements, proper guidance and quality print, we aim for 100% customer satisfaction. #Ridderprint
9 Procedure Procedure You can submit a request for an offer on our website www.ridderprint.nl. A group discount may be offered if you employ our services together with other colleagues. If you are submitting the files yourself, the entire procedure can take 3 to 4 weeks. When the layout is arranged by us, the procedure takes 5 to 6 weeks. The method in this procedure is explained during a call. 1. Request an offer Request an offer without any obligations. We will personally deal with your offer. You can expect to receive an offer within two working days. The offer is all-inclusive, with the exception of VAT. We will be happy to amend our offer in response to your questions or suggested changes. 2. Planning and finalising order If the offer is approved, you will receive a login to your Ridderprint portal. We will ask you to fill in some more details to finalize your order such as; prefered delivery date, need for an ISBN, etc. On the basis of your prefered delivery date, we will make a time schedule. After your order is scheduled you will receive an email with information. 3. Submitting files Upload your files in your Ridderprint portal according to the time schedule. You will find here all your order specifications and help for submitting your files. 4. Checking and feedback We will check your files for: • Image resolution • Embedding fonts • Size • Layout and pagination After we have checked your files, you will receive feedback if necessary. You receive the feedback by e-mail.
10 Chapter 1 5. Sending proof We will send you a complete proof if we think the files are ready. Check this proof thoroughly. This proof will be sent by mailbox mail. If you are not able to receive post or in order to save time, we can send a PDF proof by e-mail. You will receive a track and trace when the proof has been sent. 6. Corrections Are you satisfied with your proof, send us your approval by e-mail as soon as possible. Correct your files or send the corrections to your designer if needed. After receiving your final files, we will send a last final digital proof for approval production. 7. Approval / Order confirmation After you have approved the final files, you receive an order confirmation by e-mail. Check the final specifications of your order. After your confirmation we will start the printing process. 8. Production and Delivery The delivery of your books is in 8-10 working days, depending on your order specifications. Your books will be packed in boxes and shipped to the address you provide. The day before delivery, your books will be picked up here (end of the day) and you will receive an e-mail confirmation with a track and trace from the external carrier. This will show an estimated time of delivery. On the agreed delivery date, someone should be present between 09:00 and 16:00. If no one is present, the delivery will be offered a working day later. Please note, there will be an extra charge for this repeat delivery. You will receive the invoice by e-mail after receiving the books.
11 Procedure Process timelines SUBMIT YOUR OWN FILES (3-4 WEEKS) up to 1 week LETS TALK! PLANNING FILES PROOF APPROVAL PRODUCTION & DELIVERY 1 week 2 weeks COMPLETE LAYOUT (5-6 WEEKS) CONSULTATION LAYOUT PROOF APPROVAL PRODUCTION & DELIVERY LETS TALK! PLANNING up to 3 weeks 1 week 2 weeks
2 Layout packages
We provide several layout solutions for books and theses; a package for every budget! #Ridderprint
Layout packages 15 Layout We are specialized in the layout of all kinds of books, in particular theses. Our personal approach sets us apart. During a conversation we will take careful stock of your requirements using examples. With these requirements a design will be made. We will consult you about this design, making adjustments until it fully meets your requirements. This guarantees customer satisfaction. You are not obliged to follow fixed patterns: we can carry out any idea you may have! Experience has taught us that some people arrange the layout themselves, asking us to add just a few layout elements. Others ask us to arrange the complete layout. We also create the cover for most of our customers. We have therefore developed a number of different packages, offering different options. These range from basic to full-service solutions. Examples of the packages are available on our website. Or contact Ridderprint for more information.
Chapter 2 16 Complete Plus Check our website for up-to-date prices • A to Z layout of the inside pages • Based on templates • More than 30 tables Complete Check our website for up-to-date prices • A to Z layout of the inside pages • Based on templates • Up to 30 tables • Cover • Fonts, type size and line spacing • Use of headings • Header and footer • Contents • References (non-textual) • Tables and figures • Indexes • Chapter title-pages With the Complete Plus and Complete package, we will arrange the layout of the following items: The Packages | Inside Pages
Layout packages 17 Example layout chapter page Example layout inside
Chapter 2 18 Standard PDF Check our website for up-to-date prices • Adding 1, 2 or 3 layout elements to your PDF file • Choose different styling templates • Upload via a handy tool in your portal With this package you can choose one or more of the following layout elements: • Header and footer (short titles and page numbers) • Chapter indexes (on the side of the pages) • Chapter and title page (styling according a template) Basic packages | Inside
Layout packages 19 Total package PhD package Check our website for up to date prices • Customised design (book + cover) • Creativity of experienced designer • Also for additional material (bookmark, propositions etc.) Custom design of your interior and cover. Entirely according to your wishes and ideas in collaboration with the creativity of our designers. Also for additional material such as invitations. Your book, cover and ancillary material are processed as an overall concept.
Chapter 2 20 Standard The packages | Cover Check our website for up-to-date prices • A standard layout of your cover and bookmark according to a template. Including bookmark/invitation layout Design Check our website for up-to-date prices • Customized design together with the input and creativity of an experienced designer. Including bookmarker/invitation design In collaboration with the designer you create a plan of action. On the basis of, for example, a summary of the book, a concept can be made. You will be consulted at various stages in the design process. We combining images and text supplied by you. Send us an example and your wishes regarding color, positioning of the different aspects and style. We combine them to a technically correct cover .
Layout packages 21 Cover design
3 Online Publication
We offer various solutions for digital publishing; from PDF to Flipbook. #Ridderprint
Online Publication 25 Online Publishing Ridderprint is moving with the times and therefore offers exciting digital publishing capabilities. For example, a digital publication can make your work more accessible to more people on more devices (smartphone, e-reader, tablet, desktop computers), and can reduce costs because the paper print run can be a lot smaller. Or maybe you want your work to be easily found online through Google. You can also easily share it via different social media channels. Ask us about the possibilities and see some examples on www.publicationonline.com or scan the QR code! QR code A QR code is a type of barcode that can redirect your readers to your online book. For example, use it in your book or on an invitation card.
Chapter 3 26 Flipbook + PDF Check our website for up-to-date prices • Cover as first and last page in the PDF • Intuitive display on a smartphone or tablet • Protection with a password possible • Unlimited online hosting on www.publication-online.com PDF Check our website for up-to-date prices • Realistic page-turning on a desktop • Intuitive display on a smartphone or tablet • Clickable contents (Flipbook) • Protection with a password possible • Unlimited online hosting on www.publication-online.com The packages | Online Publishing It is not a requirement to make use of one of our layout packages. This package will be processed based on the approved PDF files of the inside work and cover. Inserting the cover as first and last page in the PDF is included. This package will be processed based on the approved PDF files of the inside work and cover. Creating the clickable contents is included. The online flipbook is not a physical file you can send by email. It’s only for online purpose.
Online Publication 27 ePub (OGC) € 395 • Alleen i.c.m. het ‘Volledig Lay-out Pakket’ • Dynamische weergave van pagina’s • Optie voor interactieve video en geluid • Online hosting op www.publicatie-online.nl Een van de laatste ontwikkelingen op het gebied van digitaal publiceren is de ePub. Wij werken hiervoor samen met Optima Grafische Communicatie. Zij zijn hierin gespecialiseerd en naar ons idee de beste partij om een ePub van uw boek of proefschrift te laten maken. Omdat een door Optima gemaakte ePub leesbaar is in een browser, is aanvullende software niet nodig om het bestand te lezen. Bij andere aanbieders is dit wel het geval. Online publication page Ridderprint
4 General
We aim to meet the requirements of our customers. By properly informing them about their options and taking careful stock, we get the most out of every budget. #Ridderprint
General 31 Production methods As thesis specialists, we keep a close eye on the latest developments in printing and are keen to have the best. Besides digital production, we also produce using conventional offset technology. Digital printing Characteristics: • Short delivery time. • Easy to order extra copies. • Ideal if you have colour pages. You pay per color page and are not affected by sections, as is the case in offset printing. Offset Printing Characteristics: • The delivery time exceeds that of digital printing by one week. • Favourable for higher print runs. • Colour pages can be expensive, depending on their position and number. This determines the number of sections that have to be printed in colour. Finishing Perfect bind (Soft cover) Separate sheets form a book block, which is roughened in a machine with a cutter. The cover is then bonded to the book block in flexible hot melt. 99% of our books are done this way. Sewn-glued (Hard cover) Sheets are folded into quires, which are sewn together and then glued to the cover. This gives an even stronger bond. This way is much more expensive than the perfect bind method.
Chapter 4 32 Color When using photos, diagrams or other image elements in colour, these are printed in ‘full colour’, CMYK (Cyan, Magenta, Yellow and Key=black). These are the 4 basic colours used for digital and offset printing. RGB versus CMYK RGB colours are used for display and website design. These colours have a very high range in black and brightness. A printer cannot print RGB colours and therefore converts the RGB colour to a CMYK colour. Because the CMYK colour range is much smaller than the RGB colour range (see image below), RGB colours will be converted to the nearest colours in CMYK that can be printed. However, this can cause colour surprises. Compared to the colours of your file (in RGB) on your screen, your file in CMYK on screen and especially in your print will be less bright and appear a bit ‘pale’. If you have access to professional software such as Adobe Indesign , Illustrator or Photoshop, try to work in CMYK colour mode as much as possible. This will give you a better visual representation of the final colours in your print. If your file is in RGB, we will automatically convert it to CMYK. So, your printed colours may look different compared to your screen. The different properties of various types of paper also mean that colours can look slightly different. In the back of this guide you can see what effect a particular paper has on a colour. The simplest and most effective solution to still know how your colour turns out, is a proof print. Use of black (rich black) When using large areas of black in your book or cover, use ‘rich’ black. This will give you a more deeper black color. Use these CMYK values; C60 / M50 / Y50 / K100
General 33 Image quality Resolution If your book contains images, make sure they are of good quality (resolution). We recommend a resolution of at least 300 dpi (dots per inch) to 600 dpi maximum. Of course, the quality of the images will be checked by us. Be careful when enlarging images, this will affect the resolution and thus quality. For example, if the resolution of the image is 300 dpi and you double its size, the effective resolution will be only 150 dpi. Reduce an image size however, can again improve the quality. Adobe Photoshop is an example of pixel-oriented software. Pixel-oriented file types can be; .psd, .jpg, .tiff, .png or .bmp. Vector figures So-called vector graphics are scalable without losing quality. They have no resolution and do not depend on the number of pixels. Therefore, vector figures are ideally suited for line figures, graphics, logos, etc. The small file size of vector figures also makes them easy to process. Adobe Illustrator is an example of vector-oriented software. Vector file types can be; .ai, .eps .pdf, .emf, .svg or .wmf. Should you have created figures in certain programmes, see if you can save them in a file type as described above. You can then place this file in, for example, your Word document or Indesign document. 300 DPI 72 DPI
Chapter 4 34 Paper proof The simplest and most effective solution to still know how your colour turns out is a proof print. When discussing the quote, mention that you would like to receive a proof print. Then you can judge for yourself whether the colours meet your requirements and adjust them if necessary. Special finishing of cover If you have a special finishing option such as; foil printing or spot UV etc., unfortunately we cannot show it in a proof. These finishes are done off-site. 95% of the costs are start-up costs and therefore it is not possible to provide one copy with foil or spot-UV. We can, however, send a sample along if required. Please indicate this when requesting. Viewing your PDF file We regularly send you PDF files as samples. Please do not judge these in a browser environment or in preview mode. This does not always give a correct display. View them in Acrobat pro or standard version. If these are not available, you can download a free Acrobat reader version from the Adobe Acrobat website http://www.adobe.com/products/reader.html. Set up your PDF viewer as below to properly review your inserts.
General 35 Colour or Black and White The total cost of your book is partly determined by the number of pages printed in colour or black and white. The cost of colour pages is higher. Therefore, try to convert content that can be black or gray (graphics, images) to grayscale. For example weblinks in Microsoft Word are often placed in blue. These could then be made black or gray so that these pages are not calculated as colour. If this is not (entirely) possible, we will do it for you as a service. Therefore, always send along a ‘PDF’ colour page list of the correct pages we need to print in colour. Write these down as follow; 12, 34, 56, etc. We use this list to convert the remaining pages to black and white (greyscale). If you have a designer creating the files for you, they will usually make sure that the correct pages are colour and all the rest are converted to black and white. Write down these page numbers Write down these page numbers if you have prelimanary page numbers
Chapter 4 36 What is Bleed? It’s effectively a safety net. During the printing process, the paper may move in the machine or when trimming the pages, the stack of paper can shift slightly. If that happens when you have an image that goes right to the edge of your page and there is no bleed, you end up with an unsightly white line down the edge. (Assuming you are using white paper). So, that’s why we always want to receive a print file with a 3 mm bleed on all sides. This means that the top and bottom together will be 6 mm longer than the final size. This also applies, of course, to the left and right sides. So, if your book is A5 size (210 x 148 mm), your print file will have a size of 216 x 154 mm. Your design runs 3 mm over the page edge (final size), so to speak. By bleeding an image beyond the trim size (final size) – often called a full bleed image - if there is any movement in the process, there is more image in the bleed area to compensate. So, if the paper moves a little, the image in the bleed area will be pulled into the trim size. Bleeding background image 149602 Jongeneel BNW.indd 18 04-06-2021 13:47 Final size 17 x 24 cm Page size + bleed 17,6 x 24,6 cm Cut-off 3 mm Safe zone 5 mm (from final size)
General 37 Note: this extra space around will be cut-off later. Make sure text or other important image elements are not too close to this ‘trimming edge’. Keep 5 mm distance from the page edge (final size). So, if colour areas, pictures or other image elements are to continue to the edge of the page (see also the chapter pages and ‘tabs’ of this manual), the layout should be made with ‘bleed’. these elements need to ‘bleed’ 3 mm beyond the trim size. How to set up bleed in your document can be read from page 50. See also the examples below for illustration. Bleeding layout element 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 1 General introduction 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 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 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 149602 Jongeneel BNW.indd 19 04-06-2021 13:47 Bleeding tabs The number is 5 mm from the trim (final) size
Start your layout 5
We aim to meet the requirements of our customers. By properly informing them about their options and taking careful stock, we get the most out of every budget. #Ridderprint
Inside 41 Applying for an ISBN Please consult your university about the ISBN rules. We can request an ISBN for you if you want. You can indicate this in your quote request. After you have completed the ISBN request form in your portal you will find the ISBN in about two days on the ‘specifications’ page in your portal. What is an ISBN? The ISBN is a unique code that can be assigned to a book. The abbreviation stands for International Standard Book Number, consisting of 13 digits. When you apply for an ISBN, you indicate which category it falls into by means of a ‘NUR’ code. This makes editions findable worldwide for (online) bookshops, libraries and archives and for people who are searching specifically for the subject of your book. Is an ISBN mandatory? No. If you want to sell your book through your own website or through a social media platform, an ISBN is not necessary. However, the ISBN is useful for the findability of your book. An ISBN does not mean there will be a barcode on your book, it will only be mentioned in the colophon. If you want to sell your book through a (online) bookshop however, a barcode is necessary. Do i need an e-book ISBN? No. In fact, the same applies here. If you want to sell an e-book through mainstream online book retailers (including iBooks), your e-book will need an ISBN. Otherwise, an e-book ISBN has no added value. What is a DOI number? DOI (Digital Object Identifiers) numbers are unique numbers that can be assigned to a digital document. The purpose of the DOI is that with the help of this number, the referenced document can always be found online in a standard way, independent of any changes to an Internet address. For the findability of the book, a DOI as an identifier is nowadays more important than an ISBN. Please consult your university for the use of an ISBN, ISSN or DOI.
Chapter 4 42 Ridderprint in Colophon The colophon page, mostly the second page of your book but, can also add as last page in the book, list things like; copyright, ISBN number and sponsors etc. If you would like to list Ridderprint as your printer, we are very gratefull. This is commercially very important to us. Any notation is good to us but, we prefer the following options: Dutch • Druk: Ridderprint, www.ridderprint.nl or Ridderprint, Alblasserdam • Omslag ontwerp and/or boek layout: Ridderprint, www.ridderprint.nl or Ridderprint, Alblasserdam English • Printing: Ridderprint, www.ridderprint.nl or Ridderprint, the Netherlands • Cover design and/or book layout: Ridderprint, www.ridderprint.nl or Ridderprint, the Netherlands You can put the following information on the colophon page: • ISBN • Name of the printer and designer • Copyright • Sponsors • Etc.
Inside 43 Example colophon page Financial support for the printing of this thesis was kindly provided by Erasmus University Rotterdam Parkinson Vereniging Boehringer Ingelheim B.V. UCB Pharma B.V. Teva Nederland B.V. Abbott B.V. GRIPP B.V. ISBN: 978-90-5335-481-0 The studies in this thesis were financially supported by the Prinses Beatrix Fonds (grant number 01-0128). Cover design: Ridderprint, the Netherlands Printing: Ridderprint, the Netherlands Copyright © 2011 by L. Donker Kaat
Chapter 4 44 Layout of the inside work Starting the layout The layout will be done in most cases in Word. For Word, the standard formats A4 (21 x 29.7 cm) and B5 (17.6 x 25 cm) are the best choices. If you work with Indesign, set your document to 17 x 24 cm. See page 58 for setting up an Indesign document. If you use LaTeX set your document to 17,6 x 24,6 cm. Upload your documents as PDF files. Points of attention • White margins determine the width and height of the text box (this does not include the header and footer, which can be placed outside the box). Make sure the margins at the binding side of the book (inside) is at least 20 mm. • Headers and Footers positioned at the same height on every page. • On the left pages of an open book, the even pagenumbers are placed on the left outside of the pages. The right pages get the odd page numbers, which are placed on the right outside of the pages. See example page 45. • Important pages such as titles and chapters are positioned usually on an odd (right) page. • Make sure the ‘front matter’ pages are in the right order. See page 46. • Submitting the file in A4 format? We reduce your file to 81% for the format 17 x 24 cm. Make sure the core text is in a minimum type size of 12 points, for a recommended type size of 10 pnt. after resizing. • Do you have pictures or layout elements which extend to the edge of the page? Then you need “bleed”. See page 36 for more information about bleed. • Try to keep as many images, tables etc. within the layout width of the text as possible. This looks neater and improves the readability of the text. • We rotate landscape pages in an counterclockwise direction. Keep in mind that the side margins will become the top and bottom margins (and vice versa) as a result of rotating the pages.
Inside 45 Even page (left page in open book) Odd-page (right page in open book) Margins in Microsoft Word Page Layout Chapter 1 (header) 4 (footer) 5 Inside Inside Chapter Title Outside Outside TOP TOP BOTTOM BOTTOM RIGHT LEFT LEFT RIGHT
Chapter 4 46 Front Matter The front matter of a thesis should be placed in the right order. The content may vary from one university to another. Consult the doctorate regulations for the appropriate text. Page I - (Half) Title Page A short title, possibly with the addition of the author’s name, Page II - Copyright Page You can provide the following information here: • ISBN • The name of the printer (see page 42) • Copyright • Sponsors Page III - Thesis Title Page This page is compulsory. Consult the doctorate regulations for the appropriate text. Page IV - Doctoral Committee The doctoral committee members will be listed here. Consult the doctorate regulations for this. These pages are being included in the page count, but the page numbers are not visible on these pages.
Inside 47 Progressive Supranuclear Palsy expanding the clinical and genetic spectrum Laura Donker Kaat Financial support for the printing of this thesis was kindly provided by Erasmus University Rotterdam Parkinson Vereniging Boehringer Ingelheim B.V. UCB Pharma B.V. Teva Nederland B.V. Abbott B.V. GRIPP B.V. ISBN: 978-90-5335-481-0 The studies in this thesis were financially supported by the Prinses Beatrix Fonds (grant number 01-0128). Cover: Ridderprint BV, www.ridderprint.nl Lay-out: Ridderprint BV, www.ridderprint.nl Printed by: Ridderprint BV, www.ridderprint.nl Copyright © 2011 by L. Donker Kaat Progressive Supranuclear Palsy expanding the clinical and genetic spectrum Progressieve supranucleaire verlamming: verbreding van het klinisch en genetisch spectrum Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof. dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op vrijdag 2 december 2011 om 9:30 uur door Laura Donker Kaat geboren te Haarlem Promotiecommissie Promotoren: Prof.dr. P.A.E. Sillevis Smitt Prof.dr. P. Heutink Overige leden: Prof.dr.ir. C.M. van Duijn Dr. V. Bonifati Dr. T. van Laar I IV II III
Chapter 4 48 Continued page The pages following the preliminary work have no specific order but, below are some points of interest and tips: Place important pages like the start of a chapter, preface, CV etc. on an odd-numbered page. This is the right-hand side of the book. End of chapter If a chapter ends with an even page (left-hand page), place a blank page after it. (See example below). Blank page 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 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 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
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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