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Riders who have chosen to go bitless over the last ten years have been able to select from an increasingly wide range of products. It can be difficult to know which bitless bridle is best suited to both your riding style and to your horse. This list attempts to group products in terms of the action on the horse and to describe how each group of products functions
Crossunders
Bosals
Sidepulls
Crossunder Bridles
These bridles have emerged and been developed in the last decade and are one of the most popular bitless bridles available. These bridles are easily identified by the straps which cross from just below the ears and pass under the jaw to the side of the nose on the opposite side of the face. The main reason for this is that the bridle contacts around the whole head with a gentle action, as opposed to contact being concentrated on specific areas.
The simplest, and most popular, of these is the Dr Cook Bitless Bridle which has been in production for almost ten years, and is available in a variety of sizes and materials.
The Nurtural No-Bit Bridle has two additional distinctive features - the noseband is lined with a textured rubber (to help with horses who throw their head up or lean a little on the bridle) and has the circle x (a circular section that the cross straps pass through that sits under the jaw and keeps the cross straps on the widest part of the face). This prevents the straps twisting and fully tightening around the face which can be helpful with sensitive horses.
The British designed Be-Kind Bridle has rolled cross straps to aid in the quick release of pressure. It has a highly padded noseband and headpiece for maximum comfort and the cheekpieces incorporate elasticated sections to minimise any pressure on the poll.
Other variations include rope versions such as the Crazy Ropes Bridle, the Gawani Pony Boy Bridle and the Free Rein.
Be Kind Bitless Bridle - www.equinewhispers.co.uk
Nurtural Bitless Bridle - www.nurturalhorse.com
Dr Cook Bitless Bridle - www.bitlessbridle.co.uk
Crazy Ropes Bridle - www.crazyropes.com
IV Horse Cross Under - www.4horse.co.uk
Australian No-Bit Bridle - www.nobitbridles.com
Gawani Pony Boy Bridle
Barefoot Bridle
Mechanical Hackamores, which include the German Hackamore and the Blair's Pattern (also known as the English Hackamore) all employ leverage in their action. Pulling on the rein causes the shanks to pivot, applying pressure on the poll, the nose and the chin. The severity of the action is increased by the length of the shanks. The amount of force created by the leverage that these bridles produce has the potential to be severe and care must be used as in extreme cases horse's noses have been calloused from the pressure and even the nasal bones have been damaged
Little S – A small design change from a mechanical hackamore but the action is still similar.
German Hackamore
American Hackamore
Blairs pattern – English Hackamore
Little S Hackamore
The main identifying feature of this group is that the reins are attached at a single point behind the horse's jaw and neck reining is the favoured method of guiding the horse.
The Western Bosal is a rawhide loop which sits on the nose and is balanced by the fiador in order to create the correct effect and is typically used for starting young horses in western riding. These bridles have existed for centuries and there are many texts describing their construction and use.
The Rope Hackamore consists of a rope halter with the reins attached to the knot behind the chin. It produces a mild action on the nose and is usually favoured in natural horsemanship methods (including Parelli) as it is a simple transition from the rope halter used for groundwork.
The half bosal riding halter is an enhancement of the rope hackamore developed by Lodge Ropes in Australia, the rope-bound noseband is more rigid to give the bridle stability and enable clear communication, whilst still being softer than rawhide.
Gentle control – The gentle control hackamore is a noseband with a fulcrum plate underneath the jaw which it also attached to the throatlatch to give three points of suspension. The plate puts pressure on the left or right hand side of the jaw and underneath the jaw depending on how the reins are used.
The other two bridles in this group are the Meroth and the Indian Bosal which have a similar action to each other in that the noseband continues and crosses behind the jaw before passing through loops or rings on the opposite side of the nose, where it is attached to the reins. The Indian Bosal is traditionally made using rope and whereas the Meroth makes use of leather with a short section between the side of the nose and the ring that the strap passes through.
Western Bosal
Indian Bosal
Meroth Bridle
Rope Hackamore (lodgeropes, parelli)
Half Bosal Riding Halter - www.lodgeropes.com
Gentle Control Hackamore
The Enduro Bridle, another development by Lodge Ropes, is similar in appearance to a halter, with the addition of rope loops at each end of the noseband, to which the reins and chinpiece are attached. As the reins are not attached to solid rings any action on the rein causes the chin piece to lift and contact with the back of the jaw. It provides a gentle and subtle cue that produces a positive response in many horses.
The Dually is similar to a headcollar with a second noseband made of rope which passes through rings on either side. The noseband has rings at each end that attach to the reins, providing contact with the top and sides of the nose. The Dually can be used for riding but is often used as a training aid or in conjunction with a bitted bridle to aid young horse with transition from a halter to a bit.
Riding halter – Very simple riding halter which is a regular rope halter with rings attached below the side of the noseband and allows the halter to be used with two reins.
Light Rider Bitless Bridle – Currently made of rope, though a beta and a leather version are being developed, it features a soft webbing stabilising strap that passes behind the jaw, through rings either side of the noseband and attaches to reins. The noseband is padded for extra comfort and is one of the lightest, softest bridles available. Also like many rope bridles it incorporates a halter for leading making it excellent for Endurance or Trec.
Aeron Mack Riding Halter - www.naturalhorsemanship.biz
Enduro Bridle - www.lodgeropes.com
ALL-IN-ONE Training Halter Bitless Bridle (missy wynn)
The Light Rider Bitless Bridle - www.naturalhorseworld.com
The sidepull is more common in the USA than in the UK and is available in a wide range of materials and configurations. In its simplest form it can be described as a bridle with rings at either side to which the reins are attached. Its action is similar to attaching reins to either side of a headcollar and acts by using the reins to pull the head towards the direction that the rider wants to go.
Pluvinel Bridle
Vienna cavesson
All In One Bridle (kaarenjordan)
Lindell Bridle
The Equibridle has a plain leather strap across the nose and a curb chain with a leather guard. The cheekpieces are rolled leather and pass around a pulley situated at either side of the noseband and then to the reins. The purpose of the pulleys is to distribute the contact on the poll, nose and chin.
The Orbitless Bridle is designed to produce the most versatility of all the bitless bridles while retaining excellent release properties, it is designed to have a neutral state. Comprising of elliptical side pieces the noseband and the chinstrap can be moved to give greater emphasis on the nose or on the poll. The rein position can be altered from a simple sidepull through varying degrees to a strong action.
The LG Bridle consists of a leather noseband and either a chain or leather chin strap. The wheel allows different settings ranging from a side pull action, to varying degrees of nose, chin and poll contact, through to an action similar to a mechanical hackamore, via a shank attachment.
The Scawbrig consists of a straight noseband and a chin piece which passes through rings on either side of the noseband and back to the reins. The main action it has is to tighten on the back of the jaw, but also produces some tightening around the nose.
Bitmore – The Bitmore bridle has straps which attach from the reins through rings at either side of the noseband and then up the cheeks to rings either side of the head below the ears. This puts pressure on the nose and the poll.
Micklem Multibridle – This is a combination bridle with the option of a sidepull, scawbrig and crossunder action as well as allowing for a bit for bit to bitless transition.
Callisto - a simple yet cleverly designed bridle. The reins attach to a chin strap which is designed to have pressure over the nose and/or under the chin depending on how the reins are attached. the bridle is designed to have good release and no poll pressure.
Equibridle
Orbitless bridle - www.orbitlessbridle.co.uk
LG bridle - www.lgbridle.com
Bitmore bridle
Scawbrig Bridle - www.libbys-tack.com
Micklem multibridle
Back to FAQs
If there is any bridle you think we may have missed on this list then please let us know


Wine tours and winery related experiences are very popular with culinary travellers. In many markets, spending on food and drink, including wine, is upwards of 30% of total spend. As a wine tour provider, you also want to make it easy for your customers to find you online and to make bookings in advance, even on the same day. By partnering with Rezgo you get a professional, trustworthy, and secure website as well as mobile interface that allows customers to make bookings on any device while in your destination or before they leave on their trip. Rezgo even includes a full retail point of sale so you can upsell customers with wine related merchandise. Best of all, you get all the tools you need to manage your bookings, keep track of your sales and customers, and drive more direct bookings to your business.
See why wine tour businesses around the World trust Rezgo.


Despite Pence's remarks, Trump doubled down on his allegations about the election via Twitter.
Republican vice presidential nominee Mike Pence said Sunday the Trump campaign would "absolutely accept" the results of the November 8 U.S. presidential election.
"We will absolutely accept the result of the election," Pence said during an interview on NBC's "Meet the Press," later adding that the Republican ticket will "accept the will of the American people."
Republican presidential nominee Donald Trump, who is trailing in the polls against Democrat Hillary Clinton, has warned supporters the election could be rigged against him and has called on them to monitor polling places for potential voter fraud.
But when pushed by host Chuck Todd on whether he believes the election could be subject to widespread voter fraud or whether talking about a rigged election could "undermine our democracy," Pence instead lambasted media coverage of the campaign, which he said was tilted in favor of Clinton.
"Look, the American people will speak in an election that will culminate on November the 8th. But the American people are tired of the obvious bias in the national media," Pence said. "That's where the sense of a rigged election goes here."
"One of the great traditions of America is the peaceful transfer of power. And elections ... always get pretty rough," the Indiana governor added. "But as Donald Trump said in that first debate, I'll say to you again today: We're going to accept the will of the American people."
Despite Pence's remarks, Trump doubled down Sunday afternoon on his allegations about the election via Twitter.
"The election is absolutely being rigged by the dishonest and distorted media pushing Crooked Hillary -- but also at many polling places -- SAD," he tweeted.


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(Reuters) – An independent review for fashion retailer Boohoo BOOH.L found many failings in its English supply chain after allegations about working conditions and low pay, the company said on Friday, setting out steps it was taking to tackle the issues.
FILE PHOTO: A shopper walks pass advertising billboards for Boohoo and for 'Pretty Little Things', a Boohoo brand, at Canary Wharf DLR station in central London, Britain, September 17, 2018. REUTERS/James Akena
Boohoo commissioned the review, headed by senior lawyer Alison Levitt, in July after a damaging British media reports about factory working conditions in the city of Leicester in central England.
"Ms Levitt is satisfied that Boohoo did not deliberately allow poor conditions and low pay to exist within its supply chain, it did not intentionally profit from them and its business model is not founded on exploiting workers in Leicester," Boohoo said in a statement.
Shares in the company, which sells own-brand clothing, shoes, accessories and beauty products targeted at 16- to 40-year-olds, were up 11% by 0835 GMT, on track to regain much of the market value they had lost since the July media report.
Boohoo said the review found that some workers in its supply chain had not always been properly compensated for their work and that many workers were not fully aware of their rights and their obligations.
It said it recognised that this was a widespread issue in the garment industry and committed to establishing and funding a Garment & Textiles Community Trust governed by independent trustees to address hardship.
'UNACCEPTABLE ISSUES'
Boohoo, which has grown into a company with a market value of over 4 billion pounds ($5.1 billion), acknowledged the need for change.
"This (review) has identified significant and clearly unacceptable issues in our supply chain and the steps we had taken to address them," Boohoo CEO John Lyttle said.
"It is clear that we need to go further and faster to improve our governance, oversight and compliance," he said.
The company laid out six steps it was taking to improve governance, including appointing new independent directors to its board, making supply chain compliance a standing item at board meetings and the formation of two committees to oversee risks to the business and its supply chain compliance.
"Overall, we see the results of the review as being broadly in line with our expectations, and think the changes being called out represent further steps forward on the path to rebuilding investor confidence in Boohoo's social responsibility," JP Morgan analysts said.
Graphic – Boohoo vs rivals:
Reporting by Muvija M in Bengaluru; editing by Patrick Graham and Jason Neely

redpajama_set_name: RedPajamaCommonCrawl


One of the most popular of the Benzodiazepines is the medication known as Ativan. Ativan is a prescription medication that is available locally and online through pharmacies. There are numerous generic versions of Ativan available as well, and generally these are sold at a reduced cost vs. the brand name pill. It is categorized as a sedative that slows normal brain functions. Specifically, Ativan attaches to the GABA receptor in the brain to provide a more calm state of mind to an individual suffering from anxiety related symptoms. The world wide web offers a bulk of information about Ativan, and often times you will easily be able to locate forums where individuals record there recent experiences with the medication.
It is very dangerous to take Ativan with alcohol. You can also develop dependence to Ativan, especially if you have a history of substance abuse. It is very important to let your doctor know if you have had episodes of severe depression in the past, suicidal thoughts or suffer from medical conditions such as glaucoma or severe liver disease.
Ativan is a form of drug that has been known to be addictive. Medications like these are not recommended for people that have a history of alcohol or drug abuse. The best way to ensure that you do not become dependant on Ativan is to use it for a short period of time and to follow all of your doctor's directions diligently. Do not stop taking Ativan without consulting with your doctor first. They will probably want to decrease your dosage over a period of time before you stop taking it completely.
Buying Ativan in the US without RX is strictly prohibited. However some overseas online pharmacies are selling Ativan without prescription.


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Q: Where have I been? I'm trying to earn my Completist badges, but can't figure out how to tell where I have and haven't been.  I thought I saw a gameplay tip flash across the screen at one point about unvisited streets, but I can't find a way to see it again.  I even checked whether the API could be coaxed into telling me how many times I've visited a street, but no such luck.
There's also a complication: I'm colorblind.  If there's a visual difference between visited and unvisited streets, I can't see it.
So how can I figure out where I've been?

A: It doesn't look like the API supports retrieving how many times a Glitch has visited a street and the time of their last visit, but this information is tracked. If you look at the Encyclopedia of Locations when logged in, each street page will display this information.
So someone wrote a bookmarklet to get around it. It's here; drag it into your bookmarks to use it. Clicking on it will take you to the Locations page in the Encyclopedia, with a few new options. There's a link to 'check' a hub, which will step through each street in the hub and cross it out if you've been there, and besides each location it will add a link to set that location as your in-game destination.

A: This has now been implemented in the game. The in game map greys out any street you have not visited, and the updated encyclopedia now shows a checkmark besides every street you visit.
Note that this does not include all locations that counts for traveller and completist achievements, such as Seam Streets and hidden floors. For those you should refer Agent86's answer on this question: What streets have I not visited?

redpajama_set_name: RedPajamaStackExchange


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Home » Browse » Academic journals » Economics Journals » New England Economic Review » Article details, "Indexes of Economic Indicators: What Can They..."
Academic journal article New England Economic Review
Indexes of Economic Indicators: What Can They Tell Us about the New England Economy
By Clayton-Matthews, Alan; Kodrzycki, Yolanda K.; Swaine, Daniel
London: The University of Chicago Press.
Watson, Mark W. and Robert F. Engle. 1983. "Alternative Algorithms for the Estimation of Dynamic Factor, MIMIC, and Varying Coefficient Regression Models." Journal of Econometrics, vol. 23, August, pp. 385-400.
RELATED ARTICLE: Solving Unobservable Variable Time-Series Models
Dynamic factor analysis and the Kalman filter involve different algorithmic methods to estimate models that are intimately related.(14) As Engle and Watson (1981) and Watson and Engle (1983) point out, a wide spectrum of factor analysis models are special cases of the so-called state-space model, Each month, the Boston Federal Reserve publication New England Economic Indicators reaches about 6,000 subscribers. Many of these readers undoubtedly want to know: "How is the New England economy doing?" In response, Indicators offers a comprehensive compilation of timely data. Yet no one of these indicators can possibly provide an overall assessment of the New England economy. Nor can any other individual piece of information offered by other regional or state agencies.
This article explores the development of composite coincident indexes summarizing the condition of the economy of New England and its six states. While composite indexes have long been used to analyze the national economy, they may be needed even more for regions because of the lack of current comprehensive measures of state activity, as well as the frequent lack of clarity in indicators that are available. The article discusses two approaches to constructing composite indexes, the traditional averaging method used by the U.S. Department of Commerce and a latent variable method advanced by two academic researchers, James Stock and Mark Watson, and recently applied to states in a study conducted at the Federal Reserve Bank of Philadelphia. A general model for deriving a coincident economic index is described, along with its relationship to the Stock-Watson and Philadelphia Fed research. The Philadelphia Fed specification is then applied to the New England states in order to measure how regional business cycles have compared with national cycles. In addition, an alternative composite coincident index is constructed for Massachusetts, using as inputs newly developed data based on state tax collections, which have the advantage of being quite timely and not subject to revisions (in contrast to more commonly used indicators).
I. Motivations
Composite indexes of U.S. economic indicators have a long history. Originally developed a half century ago by researchers at the National Bureau of Economic Research, a private organization, such indexes are now issued monthly by the U.S. Department of Commerce. The government's index of leading indicators gets widespread attention when it is released. Less noticed, but released just as frequently, are the index of coincident indicators, which measures the current state of the national economy, and the index of lagging indicators.
Composite indexes are attractive because of their simplicity and compactness. Interest in economic trends is widespread, but most people have neither the time nor the inclination to try to interpret each individual piece of economic data that becomes available. Furthermore, even for professional observers of the macroeconomy, individual indicators may be problematic. Any particular economic series may give an ambiguous signal, or it may contradict another piece of data.
National composite indexes (and individual indicators) may be misleading for regions because regional business cycles do not parallel national cycles exactly. For example, the strongest recoveries from the early 1980s recessions occurred on the East and West Coasts, and several interior states lost employment or showed virtually no gain in employment for several years after the national economy had picked up (Bradbury and Kodrzycki 1992). By contrast, in the upturn from the most recent national recession of 1990-91, it is widely acknowledged that the New England states and California were laggards. …
Publication: New England Economic Review
Publication date: November-December 1994
Clayton-Matthews, Alan
Kodrzycki, Yolanda K.
Swaine, Daniel
Indexation (Economics)--Analysis
Economic Indicators--Analysis
New England--Economic aspects
Guide to Economic Indicators By Norman Frumkin M. E. Sharpe, 1990
Latinos in New England By Andrés Torres Temple University Press, 2006
The Rural Economy of New England: A Regional Study By John Donald Black Harvard University Press, 1950
Indexes of Economic Indicators: What Can They Tell Us about the New England Economy By Clayton-Matthews, Alan Kodrzycki, Yolanda K. Swaine, Daniel New England Economic Review, November-December 1994
Quantification of Relationship between Cardiovascular Diseases Mortality Rate and Selected Socio-Economic Indicators - Comparative Analysis of the Czech Republic and the Slovak Republic By Gavurová, Beáta Huculová, Eva Kovác, Viliam Economics & Sociology, Vol. 12, No. 2, 2019
Economic Indicators: A Comparative Analysis of Human - Centric Development Index By Hasan, Wan Norhaniza Wan Researchers World, Vol. 6, No. 4, 2015
Stoking Hearths; New England Is Not Likely to Rush into Nationwide Banking Relationships By Fraust, Bart American Banker, Vol. 151, March 18, 1986
New England: On Cutting Edge of Regional Banking Movement By Syron, Richard F. American Banker, Vol. 149, July 11, 1984
Yankee Ingenuity - New England Cut Taxes, Controlled Costs, and Used High Tech to Diversify Its Economy By Tuerck, David G. The World and I, Vol. 16, No. 8, August 2001
Mervyn Must Turn on Printing Presses Now; Our New Economics Correspondent Warns Bank of England Needs to Inject More Cash to Avoid Double-Dip; ECONOMIC ANALYSIS By Lynch, Russell The Evening Standard (London, England), September 7, 2010
BRAVE NEW ENGLAND GO DOWN WITH A FIGHT; ENGLAND V NEW ZEALAND SECOND ODI, THE KIA OVAL NEW ZEALAND WON BY 13 RUNS ON DL; Yes, England Lost, but, Boy, Did They Put Up an Almighty Scrap in Pursuit of a Huge 399 By Wilson, Dean The Mirror (London, England), June 13, 2015
New England in Bloom; Swedish Stoicism and Discipline Has Sparked the National Side's Exuberance England's New Confidence Could Net Us the World Cup, Says Chief Football Writer Hyder Jawad By Jawad, Hyder The Birmingham Post (England), September 14, 2001
FREE! New England The Columbia Encyclopedia, 6th ed., 2018
FREE! New England Confederation The Columbia Encyclopedia, 6th ed., 2018
FREE! New England Primer The Columbia Encyclopedia, 6th ed., 2018


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What I'm For (BNA, 2009)
Pat Green
Reviewed by Rick Bell
Despite his Texas roots and a career that started over a decade ago in the clubs and honky tonks across the Southwest, Pat Green still can't shake the comparisons to heartland songwriters like John Mellencamp and Tom Petty.
Maybe Green is cool with that, because his latest album does little to establish an identifiable sound. And Dann Huff's production clutters several cuts with overblown rock guitar riffs.
The song "Country Star" may be a wink-and-nod ode to being a Nashville hitmaker, but after listening to this 10-song collection, it sounds like an unwitting admission to Green's career path. "Carry On" and "What I'm For" are unimpressive explanations of who Green thinks he is, and the overproduced "Footsteps of Our Fathers" draws directly from the Mellencamp playbook. The San Antonio-born Green's at his best on his two acoustic cuts, "Lucky" and "In the Middle of the Night."
With so many songs here offering glimpses into Green's beliefs and ideals, it's still hard to distinguish just who he is as a country music singer and songwriter.
CDs by Pat Green


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Articles by Stefan Boeck
Between 2008 and 2019, S. Boeck wrote the following 55 articles about Pancreatic Neoplasms.
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018
Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.
ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.
2 Review Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. 2018
Auernhammer, Christoph J / Spitzweg, Christine / Angele, Martin K / Boeck, Stefan / Grossman, Ashley / Nölting, Svenja / Ilhan, Harun / Knösel, Thomas / Mayerle, Julia / Reincke, Martin / Bartenstein, Peter. ·Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany. Electronic address: christoph.auernhammer@med.uni-muenchen.de. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 3, Ludwig-Maximilians-University of Munich, Munich, Germany. · Neuroendocrine Tumour Centre, Royal Free Hospital, London, UK. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 2, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Munich, Germany. ·Lancet Diabetes Endocrinol · Pubmed #29229497.
ABSTRACT: In this Review, we discuss clinical developments and controversies in the treatment of neuroendocrine tumours (NETs) that are relevant for clinicians and clinical researchers. We describe advances in genetics, blood-based biomarkers, functional imaging, and systemic therapy of advanced NETs and discuss results of recent phase 3 studies, systemic treatment of advanced disease with peptide receptor radionuclide therapy, biotherapy, chemotherapy, and molecularly targeted therapy, and the potential role of immunotherapy in the treatment of NETs. Suggested treatment algorithms for NETs of ileal or jejunal origin and of pancreatic origin are presented.
3 Review Safety of palliative chemotherapy in advanced pancreatic cancer. 2016
Westphalen, C Benedikt / Kruger, Stephan / Haas, Michael / Heinemann, Volker / Boeck, Stefan. ·a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany. ·Expert Opin Drug Saf · Pubmed #27070177.
ABSTRACT: INTRODUCTION: Pancreatic cancer is a major health burden. Currently, the majority of patients is diagnosed at advanced stages and thus qualifies for palliative chemotherapy. Gemcitabine monotherapy has been the gold standard for many years. Recently, more effective chemotherapeutic regimens have shown meaningful clinical activity in patients with metastatic pancreatic cancer. AREAS COVERED: In this review we have aimed to give an overview on the treatment options for patients diagnosed with metastatic pancreatic cancer with an emphasis on the safety and toxicity of the applied regimens. We have conducted a pubmed search using the terms 'metastatic pancreatic cancer', 'palliative chemotherapy', 'safety' and 'toxicity'. Our special focus rested on randomized phase III trials to provide readers with the highest level of available evidence. EXPERT OPINION: The emergence of new and more effective chemotherapy regimens gives clinicians more freedom in the treatment of metastatic pancreatic cancer. While being more effective, these regiments have a considerable degree of toxicity. Choosing the right treatment for any individual will be the next major challenge treating patients with pancreatic cancer.
4 Review Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. 2014
Kruger, Stephan / Haas, Michael / Ormanns, Steffen / Bächmann, Sibylle / Siveke, Jens T / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Stephan Kruger, Michael Haas, Sibylle Bächmann, Volker Heinemann, Stefan Boeck, Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. ·World J Gastroenterol · Pubmed #25152580.
ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.
5 Review Neoadjuvant treatment of borderline resectable and non-resectable pancreatic cancer. 2013
Heinemann, V / Haas, M / Boeck, S. ·Department of Medical Oncology and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany. ·Ann Oncol · Pubmed #23852311.
ABSTRACT: Neoadjuvant therapy is increasingly becoming a valid treatment option for patients with locally advanced pancreatic cancer (LAPC). In borderline resectable disease, neoadjuvant therapy is employed to improve the probability of margin-clear resections. In non-metastatic, non-resectable pancreatic cancer, treatment primarily aims to induce disease control, but may achieve conversion to surgical resectability in some patients. Several treatment modalities including chemotherapy, chemoradiotherapy (CRT) or the sequential use of both have been investigated in numerous, mostly small and non-randomized studies. Nevertheless, there is a consistent finding that neoadjuvant therapy can induce resectability in up to 30%-40% of LAPC patients. Once resection has been achieved, overall survival appears to be comparable to that observed for primarily resectable patients. Thus, patient selection evolves as an important aspect of neoadjuvant therapy; retrospective analyses identified induction chemotherapy as an appropriate tool to define LAPC patients who may benefit most from subsequent treatment with CRT. The clinical importance of induction chemotherapy may further increase once highly active protocols such as the FOLFIRINOX or the gemcitabine plus nab-paclitaxel regimen are introduced into novel multimodality treatment concepts.
6 Review Systemic treatment of advanced pancreatic cancer. 2012
Heinemann, Volker / Haas, Michael / Boeck, Stefan. ·Klinikum Grosshadern, Department of Oncology and Comprehensive Cancer Center, Ludwig-Maximilians-Universität München, Germany. Volker.Heinemann@med.uni-muenchen.de ·Cancer Treat Rev · Pubmed #22226241.
ABSTRACT: Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX-regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel.
7 Review The role of second-line chemotherapy after gemcitabine failure in patients with advanced pancreatic cancer. 2008
Boeck, Stefan / Heinemann, Volker. ·Ludwig-Maximilians-University of Munich, Department of Internal Medicine III, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany. stefan.boeck@med.uni-muenchen.de ·Future Oncol · Pubmed #18240999.
ABSTRACT: Systemic chemotherapy with single-agent gemcitabine or a gemcitabine-based regimen still remains a standard of care for the treatment of patients with locally advanced and metastatic pancreatic cancer. To date, no standard treatment approach for patients that show progressive disease during gemcitabine therapy is defined. Several clinical trials have evaluated the safety and efficacy of second-line chemotherapy after gemcitabine failure in this patient population. Based on the currently available data, there is increasing evidence that selected patients may derive clinical benefit from salvage chemotherapy, also with regard to survival. However, results from large randomized Phase III trials are still lacking and therefore no evidence-based treatment recommendation can be given for patients with advanced pancreatic cancer after failure of first-line gemcitabine.
8 Clinical Trial Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'. 2018
Haas, M / Siveke, J T / Schenk, M / Lerch, M M / Caca, K / Freiberg-Richter, J / Fischer von Weikersthal, L / Kullmann, F / Reinacher-Schick, A / Fuchs, M / Kanzler, S / Kunzmann, V / Ettrich, T J / Kruger, S / Westphalen, C B / Held, S / Heinemann, V / Boeck, S. ·Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Electronic address: michael.haas@med.lmu.de. · 2nd Medical Department, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Solid Tumor Translational Oncology (DKTK, Partner Site Essen), West German Cancer Center, University Hospital Essen, Essen, Germany. · Department of Haematology and Oncology, Hospital Barmherzige Brüder, Regensburg, Germany. · Department of Medicine A, Universitätsmedizin Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. · Department of Internal Medicine I, Klinikum Ludwigsburg, Ludwigsburg, Germany. · Practice for Haematology and Oncology, Dresden, Germany. · Department of Oncology, Gesundheitszentrum St. Marien, Amberg, Germany. · Department of Medicine I, Klinikum Weiden, Weiden, Germany. · Department of Haematology and Oncology, St. Josef-Hospital, Ruhr University, Bochum, Germany. · Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Klinikum Bogenhausen, Munich, Germany. · Department of Internal Medicine II, Leopoldina Krankenhaus Schweinfurt, Schweinfurt, Germany. · Department of Medical Oncology, University Hospital of Wuerzburg, Wuerzburg, Germany. · Department of Internal Medicine I, University of Ulm, Ulm, Germany. · Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. · ClinAssess GmbH, Leverkusen, Germany. ·Eur J Cancer · Pubmed #29549862.
ABSTRACT: INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).
9 Clinical Trial The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy. 2017
Ormanns, Steffen / Haas, Michael / Remold, Anna / Kruger, Stephan / Holdenrieder, Stefan / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. steffen.ormanns@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. michael.haas@med.uni-muenchen.de. · Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. annaremold@yahoo.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. annaremold@yahoo.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. stephan.kruger@med.uni-muenchen.de. · Institute of Laboratory Medicine, German Heart Centre Munich, Technische Universität München, 80333 Munich, Germany. holdenrieder@dhm.mhn.de. · Institute of Clinical Chemistry and Clinical Pharmacology, Universitätsklinikum Bonn, 53127 Bonn, Germany. holdenrieder@dhm.mhn.de. · Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. thomas.kirchner@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. thomas.kirchner@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. volker.heinemann@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. volker.heinemann@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. stefan.boeck@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. stefan.boeck@med.uni-muenchen.de. ·Int J Mol Sci · Pubmed #28534865.
ABSTRACT: The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (
10 Clinical Trial Impact of hand-foot skin reaction on treatment outcome in patients receiving capecitabine plus erlotinib for advanced pancreatic cancer: a subgroup analysis from AIO-PK0104. 2015
Kruger, Stephan / Boeck, Stefan / Heinemann, Volker / Laubender, Ruediger P / Vehling-Kaiser, Ursula / Waldschmidt, Dirk / Kettner, Erika / Märten, Angela / Winkelmann, Cornelia / Klein, Stefan / Kojouharoff, Georgi / Gauler, Thomas C / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Geissler, Michael / Greten, Tim F / Hegewisch-Becker, Susanna / Modest, Dominik P / Stintzing, Sebastian / Haas, Michael. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany. ·Acta Oncol · Pubmed #25924969.
ABSTRACT: BACKGROUND: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated. METHODS: Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross-over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles. RESULTS: Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first- and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056). CONCLUSION: The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine-treated patients with advanced PC.
11 Clinical Trial pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. 2014
Ormanns, Steffen / Siveke, Jens T / Heinemann, Volker / Haas, Michael / Sipos, Bence / Schlitter, Anna Melissa / Esposito, Irene / Jung, Andreas / Laubender, Rüdiger P / Kruger, Stephan / Vehling-Kaiser, Ursula / Winkelmann, Cornelia / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Gauler, Thomas C / Märten, Angela / Geissler, Michael / Greten, Tim F / Kirchner, Thomas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, München, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #25164437.
ABSTRACT: BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).
12 Clinical Trial Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: a dose-finding study. 2014
Joka, Mareile / Boeck, Stefan / Zech, Christoph J / Seufferlein, Thomas / Wichert, Goetz von / Licht, Thomas / Krause, Annekatrin / Jauch, Karl-Walter / Heinemann, Volker / Bruns, Christiane J. ·aDepartment of Surgery bDepartment of Internal Medicine III cInstitute of Radiology, LMU, Munich dDepartment of Internal Medicine I, University Ulm, Ulm eBRK Schlossbergklinik, Oberstaufen fNovartis Pharma GmbH, Nürnberg gDepartment of Surgery, University of Magdeburg, Magdeburg, Germany hDepartment of Radiology and Nuclear Medicine, University Basel, Basel, Switzerland. ·Anticancer Drugs · Pubmed #25029236.
ABSTRACT: Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.
13 Clinical Trial Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody. 2014
Ormanns, Steffen / Heinemann, Volker / Raponi, Mitch / Isaacson, Jeff / Laubender, Rüdiger P / Haas, Michael / Kruger, Stephan / Kleespies, Axel / Mann, Elaina / Bartosiewicz, Mike / Kirchner, Thomas / Boeck, Stefan. ·Department of Pathology, Ludwig-Maximilians-University of Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Clovis Oncology Inc., San Francisco, CA, USA. · German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. · Department of Pathology, Ludwig-Maximilians-University of Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. Electronic address: stefan.boeck@med.uni-muenchen.de. ·Eur J Cancer · Pubmed #24857044.
ABSTRACT: BACKGROUND: The role of human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker for gemcitabine efficacy in advanced pancreatic cancer remains unclear to date. PATIENTS AND METHODS: AIO-PK0104 was a German multicenter phase III trial comparing gemcitabine/erlotinib followed by capecitabine (GEC) with capecitabine/erlotinib followed by gemcitabine (CEG) in advanced pancreatic cancer. Archival tumour tissue from 169 of the 274 eligible study patients was available for a central and standardised immunohistochemistry staining for hENT1 expression using the SP120 rabbit monoclonal anti-hENT1 antibody. Within a retrospective translational subgroup analysis, biomarker data were correlated with efficacy end-points. RESULTS: Thirty-nine out of 130 fresh-cut slides were scored as hENT1(high) (30%), whereas 91 samples were classified as hENT1(low) (70%). For the 62 patients randomised to CEG median overall survival was estimated with 6.4 months in the hENT1(low) compared to 6.9 months in the hENT1(high) subgroup (Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.48-1.61, p=0.67). For the 68 patients randomised to GEC survival was 5.7 months in the hENT1(low) compared to 4.4 months in the hENT1(high) subgroup (HR 1.16, 95% CI 0.69-1.96, p=0.57). In 101 patients receiving gemcitabine at any time during study treatment (either within the 1st- or 2nd-line setting) hENT1(low) cases had a median overall survival of 7.5 months and hENT1(high) patients an overall survival of 4.4 months (HR 1.30, 95% CI 0.84-2.03, p=0.24), respectively. CONCLUSION: Within this subgroup analysis from Arbeitsgemeinschaft Internistische Onkologie-pancreatic cancer (AIO-PK0104), no evidence supporting the use of hENT1 as a predictive biomarker for gemcitabine efficacy in patients with advanced pancreatic cancer was found.
14 Clinical Trial Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. 2013
Poplin, Elizabeth / Wasan, Harpreet / Rolfe, Lindsey / Raponi, Mitch / Ikdahl, Tone / Bondarenko, Ihor / Davidenko, Irina / Bondar, Volodymyr / Garin, August / Boeck, Stefan / Ormanns, Steffen / Heinemann, Volker / Bassi, Claudio / Evans, T R Jeffrey / Andersson, Roland / Hahn, Hejin / Picozzi, Vince / Dicker, Adam / Mann, Elaina / Voong, Cynthia / Kaur, Paramjit / Isaacson, Jeff / Allen, Andrew. ·Elizabeth Poplin, Cancer Institute of New Jersey, New Brunswick, NJ · Mitch Raponi, Elaina Mann, Cynthia Voong, and Andrew Allen, Clovis Oncology, San Francisco, CA · Hejin Hahn and Vince Picozzi, Virginia Mason Medical Center, Seattle, WA · Adam Dicker, Radiation Therapy Oncology Group, Philadelphia, PA · Jeff Isaacson, Clovis Oncology, Boulder, CO · Harpreet Wasan, Hammersmith Hospital, London · Lindsey Rolfe and Paramjit Kaur, Clovis Oncology UK, Cambridge · T.R. Jeffrey Evans, University of Glasgow, Glasgow, United Kingdom · Tone Ikdahl, Oslo Universitetssykehus, Oslo, Norway · Ihor Bondarenko, Dnipropetrovsk State Medical Academy, Dnipropetrovsk · Volodymyr Bondar, Donetsk Regional Antitumor Center, Donetsk, Ukraine · Irina Davidenko, Clinical Oncology Center 1, Krasnodar · August Garin, Blokhin Russian Cancer Research Center, Moscow, Russia · Stefan Boeck, Steffen Ormanns, and Volker Heinemann, Ludwig-Maximilians-University of Munich, Munich, Germany · Claudio Bassi, Ospedale Policlinico G.B. Rossi, Verona, Italy · and Roland Andersson, Lund University, Lund, Sweden. ·J Clin Oncol · Pubmed #24220555.
ABSTRACT: PURPOSE: Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. PATIENTS AND METHODS: Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. RESULTS: Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). CONCLUSION: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.
15 Clinical Trial Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer. 2013
Boeck, S / Wittwer, C / Heinemann, V / Haas, M / Kern, C / Stieber, P / Nagel, D / Holdenrieder, S. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. stefan.boeck@med.uni-muenchen.de ·Br J Cancer · Pubmed #23579210.
ABSTRACT: BACKGROUND: CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated. METHODS: Within a prospective single-centre study serial blood samples were collected from patients with confirmed advanced PC. Pre-treatment values and weekly measurements of CYFRA 21-1, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (assessed by Elecsys 2010, Roche Diagnostics) during palliative first-line chemotherapy were obtained. Biomarker data were correlated with objective response (determined by RECIST) as well as time to progression (TTP) and overall survival (OS) using uni- and multivariate analyses. RESULTS: Seventy-eight patients were included, 45% of these received treatment in prospective clinical trials. Median TTP was 3.9 months, median OS 7.7 months. Pre-treatment CYFRA 21-1 levels were significantly associated with performance status (P=0.0399) and stage of disease (P=0.0001). Marker values before chemotherapy and at the 2-month staging of all three markers were considered significant predictors for objective treatment response. Pre-treatment CYFRA 21-1 levels, as well as CA 19-9 values, could be applied to define subgroups (categorised by tertiles) with a different OS outcome (CYFRA: 14.8 vs 7.1 vs 4.8 months, CA 19-9: 14.2 vs 7.1 vs 5.2 months; P<0.0001). CYFRA 21-1 and CA 19-9 (both as categorised and as continuous variables) showed a highly significant correlation with TTP and OS at nearly all-time points assessed in univariate analysis. In multivariate analysis, only CYFRA 21-1 and performance status were independent predictors for OS. CONCLUSIONS: CYFRA 21-1 may serve as a valuable tool for monitoring treatment response and assessing prognosis in advanced PC.
16 Clinical Trial KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. 2013
Boeck, Stefan / Jung, Andreas / Laubender, Rüdiger P / Neumann, Jens / Egg, Rosalind / Goritschan, Clara / Ormanns, Steffen / Haas, Michael / Modest, Dominik P / Kirchner, Thomas / Heinemann, Volker. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany. stefan.boeck@med.uni-muenchen.de ·J Gastroenterol · Pubmed #23435671.
ABSTRACT: BACKGROUND: It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). METHODS: AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS: KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION: This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.
17 Clinical Trial Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. 2013
Heinemann, V / Ebert, M P / Laubender, R P / Bevan, P / Mala, C / Boeck, S. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, D-81377 Munich, Germany. volker.heinemann@med.uni-muenchen.de ·Br J Cancer · Pubmed #23412098.
ABSTRACT: BACKGROUND: To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS). RESULTS: Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea. CONCLUSION: In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.
18 Clinical Trial Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. 2013
Haas, Michael / Heinemann, Volker / Kullmann, Frank / Laubender, Rüdiger P / Klose, Christina / Bruns, Christiane J / Holdenrieder, Stefan / Modest, Dominik P / Schulz, Christoph / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377 Munich, Germany. ·J Cancer Res Clin Oncol · Pubmed #23315099.
ABSTRACT: PURPOSE: CA 19-9 is the only established tumor marker in pancreatic cancer (PC); the prognostic role of other serum markers like CEA, CRP, LDH or bilirubin has not yet been defined. METHODS: We pooled pre-treatment data on CA 19-9, CEA, CRP, LDH and bilirubin levels from two German multicenter randomized phase II trials together with prospective patient data from one high-volume German Cancer Center. Marker levels were assessed locally before the start of palliative first-line therapy for advanced PC and serially during treatment (for CA 19-9 only). Clinical and biomarker data (overall 12 variables) were correlated with the efficacy endpoints time-to-progression (TTP) and overall survival (OS) by using uni- and multivariate Cox models. RESULTS: Data from 291 patients were included in this pooled analysis; 253 patients (87 %) received treatment within prospective clinical trials. Median TTP in the study cohort was 5.1 months and median OS 9.0 months. In univariate analysis, pre-treatment CA 19-9 (HR 1.55), LDH (HR 2.04) and CEA (HR 1.89) levels were significantly associated with TTP. Regarding OS, baseline CA 19-9 (HR 1.46), LDH (HR 2.07), CRP (HR 1.69) and bilirubin (HR 1.62) were significant prognostic factors. Within multivariate analyses, pre-treatment log [CA 19-9] (as continuous variable for TTP) and log [bilirubin] as well as log [CRP] (for OS) had an independent prognostic value. A CA 19-9 decline of ≥25 % during the first two chemotherapy cycles was predictive for TTP and OS, independent of the applied CA 19-9 assay. CONCLUSION: Baseline CA 19-9 and CA 19-9 kinetics during first-line chemotherapy are prognostic in advanced PC. Besides that finding other serum markers like CRP, LDH and bilirubin can also provide prognostic information on TTP and OS.
19 Clinical Trial EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. 2013
Boeck, S / Jung, A / Laubender, R P / Neumann, J / Egg, R / Goritschan, C / Vehling-Kaiser, U / Winkelmann, C / Fischer von Weikersthal, L / Clemens, M R / Gauler, T C / Märten, A / Klein, S / Kojouharoff, G / Barner, M / Geissler, M / Greten, T F / Mansmann, U / Kirchner, T / Heinemann, V. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr 15, Munich D-81377, Germany. stefan.boeck@med.uni-muenchen.de ·Br J Cancer · Pubmed #23169292.
ABSTRACT: BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.
20 Clinical Trial Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104). 2013
Heinemann, Volker / Vehling-Kaiser, Ursula / Waldschmidt, Dirk / Kettner, Erika / Märten, Angela / Winkelmann, Cornelia / Klein, Stefan / Kojouharoff, Georgi / Gauler, Thomas C / von Weikersthal, Ludwig Fischer / Clemens, Michael R / Geissler, Michael / Greten, Tim F / Hegewisch-Becker, Susanna / Rubanov, Oleg / Baake, Gerold / Höhler, Thomas / Ko, Yon D / Jung, Andreas / Neugebauer, Sascha / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, D-81377 Munich, Germany. volker.heinemann@med.uni-muenchen.de ·Gut · Pubmed #22773551.
ABSTRACT: OBJECTIVE: AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. METHODS: 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. RESULTS: Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2-4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005). CONCLUSION: Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.
21 Clinical Trial Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. 2012
Harder, J / Ihorst, G / Heinemann, V / Hofheinz, R / Moehler, M / Buechler, P / Kloeppel, G / Röcken, C / Bitzer, M / Boeck, S / Endlicher, E / Reinacher-Schick, A / Schmoor, C / Geissler, M. ·Medizinische Klinik II, Hegau- Bodensee Klinikum, Virchowstraße 10, D-78224 Singen, Germany. jan.harder@hbh-kliniken.de ·Br J Cancer · Pubmed #22374460.
ABSTRACT: BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.
22 Clinical Trial Prognostic relevance of CA 19-9, CEA, CRP, and LDH kinetics in patients treated with palliative second-line therapy for advanced pancreatic cancer. 2010
Haas, Michael / Laubender, Rüdiger P / Stieber, Petra / Holdenrieder, Stefan / Bruns, Christiane J / Wilkowski, Ralf / Mansmann, Ulrich / Heinemann, Volker / Boeck, Stefan. ·Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377 Munich, Germany. ·Tumour Biol · Pubmed #20480409.
ABSTRACT: The objective of this study was to define prognostic serum biomarkers that could serve as surrogate survival endpoints during second-line treatment for advanced pancreatic cancer. This retrospective single-center study included patients treated with second-line therapy for advanced exocrine pancreatic cancer. A pretreatment value and at least one serial measurement during the first two cycles of second-line chemotherapy for CA 19-9, CEA, CRP, and LDH had to be available in order to evaluate the prognostic role of kinetics on overall survival. A cutoff of a >20% increase from baseline during treatment was defined in order to form groups with suspected different outcomes. The effect of serial biomarker changes on survival was modeled by Cox proportional hazards regression in univariate and multivariate analyses. Overall, 70 patients treated with second-line therapy for advanced disease were included; 94% had distant metastases at treatment initiation. Median time to progression was 2.7 months and median survival 5.4 months. Univariate analysis found that an increase of >20% during treatment was significantly associated with a worse overall survival for CA 19-9 (HR 2.00, p = 0.018), CEA (HR 2.38, p = 0.004), and CRP (HR 3.06, p < 0.001). These associations remained significant within multivariate analysis for CEA (HR 2.86, p = 0.001) and CRP (HR 3.20, p = 0.001). Serum biomarker kinetics might serve as useful prognostic tools during second-line chemotherapy in advanced pancreatic cancer.
23 Clinical Trial Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the 'Arbeitsgemeinschaft Internistische Onkologie'. 2010
Boeck, Stefan / Vehling-Kaiser, Ursula / Waldschmidt, Dirk / Kettner, Erika / Märten, Angela / Winkelmann, Cornelia / Klein, Stefan / Kojouharoff, Georgi / Gauler, Thomas / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Geissler, Michael / Greten, Tim F / Hegewisch-Becker, Susanna / Neugebauer, Sascha / Heinemann, Volker. ·Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. ·Anticancer Drugs · Pubmed #19770635.
ABSTRACT: To date, only limited toxicity data are available for the combination of erlotinib with either capecitabine or gemcitabine as front-line therapy for advanced pancreatic cancer. Within a randomized phase III trial, 281 treatment-naive patients were randomly assigned between capecitabine (2000 mg/m/day, for 14 days, once every 3 weeks) plus erlotinib (150 mg/day, arm A) and gemcitabine (1000 mg/m as a 30-min infusion) plus erlotinib (150 mg/day, arm B). In case of treatment failure, patients were crossed over to a second-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was the time to treatment failure of second-line therapy (TTF2). This interim analysis of toxicity contains safety data from the first 127 randomized patients. During first-line therapy, patients received a median number of three treatment cycles (range 0-13) in both the arms. Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18 and 27% of treatment cycles, respectively. Erlotinib dose reductions were performed in 6 and 11% of all cycles. Grade 3/4 hematological toxicity was <10% in both the arms; major grade 3/4 toxicities in arms A and B were diarrhea (9 vs. 7%), skin rash (4 vs. 12%), and hand-foot syndrome (7 vs. 0%). No treatment-related death was observed. In conclusion, this interim safety analysis suggests that treatment with erlotinib 150 mg/day is feasible in combination with capecitabine or gemcitabine.
24 Clinical Trial Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer--a multi-centre randomised phase II study. 2009
Wilkowski, R / Boeck, S / Ostermaier, S / Sauer, R / Herbst, M / Fietkau, R / Flentje, M / Miethe, S / Boettcher, H D / Scholten, T / Bruns, C J / Rau, H G / Hinke, A / Heinemann, V. ·Department for Radiotherapy and Radiooncology, Klinik Bad Trissl, Oberaudorf, Germany. ·Br J Cancer · Pubmed #19904268.
ABSTRACT: BACKGROUND: No standard treatment for locally advanced pancreatic cancer (LAPC) is defined. PATIENTS AND METHODS: Within a multi-centre, randomised phase II trial, 95 patients with LAPC were assigned to three different chemoradiotherapy (CRT) regimens: patients received conventionally fractionated radiotherapy of 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m(-2) per day on each day of radiotherapy, RT-5-FU arm), concurrent gemcitabine (300 mg m(-2)), and cisplatin (30 mg m(-2)) on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m(-2)) and cisplatin (50 mg m(-2)) every 2 weeks (RT-GC+GC arm). Primary end point was the overall survival (OS) rate after 9 months. RESULTS: The 9-month OS rate was 58% in the RT-5-FU arm, 52% in the RT-GC arm, and 45% in the RT-GC+GC arm. Corresponding median survival times were 9.6, 9.3, and 7.3 months (P=0.61) respectively. The intent-to-treat response rate was 19, 22, and 13% respectively. Median progression-free survival was estimated with 4.0, 5.6, and 6.0 months (P=0.21). Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms, no grade 3/4 febrile neutropaenia was observed. CONCLUSION: None of the three CRT regimens tested met the investigators' definition for efficacy; the median OS was similar to those previously reported with gemcitabine alone in LAPC.
25 Article POLE gene hotspot mutations in advanced pancreatic cancer. 2018
Guenther, Michael / Veninga, Vivien / Kumbrink, Joerg / Haas, Michael / Westphalen, C Benedikt / Kruger, Stephan / Heinemann, Volker / Kirchner, Thomas / Boeck, Stefan / Jung, Andreas / Ormanns, Steffen. ·Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Comprehensive Cancer Center Munich (CCCM), Munich, Germany. · Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany. steffen.ormanns@med.uni-muenchen.de. ·J Cancer Res Clin Oncol · Pubmed #30194485.
ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, lacking relevant prognostic and predictive biomarkers. DNA polymerase epsilon (POLE) has important functions in the maintenance of genetic stability during DNA replication and has previously been associated with favorable prognosis in endometrial and colorectal cancer. However, its relevance in advanced pancreatic cancer (aPDAC) has not been examined to date. METHODS: Using pyrosequencing on tumoral DNA extracted from 60 samples from the AIO-PK0104 study as well as 55 samples from completed translational trials, we examined POLE hotspot mutations in exon 9 (P286R) and exon 13 (V411R/L/M) in the POLE gene exonuclease domain. DNA extracted from 37 endometrial carcinomas were tested as positive controls. Publically available sequencing databases were searched for POLE mutations in PDAC samples. RESULTS: Fifty-three patients (pts) were men, 62 pts were women, median age was 61.2 years. Median overall survival (OS) was 7.4 months and median progression free survival (PFS) was 4.0 months. In four of the 37 endometrial carcinomas POLE mutations were detected in exon 9 (10.8%) and none in exon 13. In none of the overall 115 aPDAC tumors POLE gene hotspot mutations could be detected. CONCLUSION: Mutations in the hotspot regions of exon 9 and 13 of the POLE gene are very rare events in advanced pancreatic cancer. Thus, it is unlikely that POLE gene mutations contribute to genetic instability in the vast majority of aPDAC. POLE mutation does not serve as a relevant biomarker and should not be tested on a regular basis in PDAC.


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Lycoriella eflagellata är en tvåvingeart som beskrevs av Risto Kalevi Tuomikoski 1960. Lycoriella eflagellata ingår i släktet Lycoriella, och familjen sorgmyggor. Arten är reproducerande i Sverige.

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