text:
Horticulture/Suburban Forestry

Maintaining a healthy population of trees in a suburban setting shares much in common with maintaining a "woodlot" or resource forest, but there are of course a number of differences as well. The best "wooded gardens" actually have relatively few large trees, since these areas are also expected to support small trees, shrubs, garden plants, and lawns. Managing these small woodlots takes planning and a realistic sense of what woodlands look like.

Natural woodlands are bound by the laws of ecological succession, where a disturbed area (in nature disturbed by fire or storm) will first be colonized by herbaceous plants and other "pioneer species" such as fast-growing trees and shrubs adapted to sunny environments. In many regions, the mature forest will be primarily one or a few species of climax trees, and a very sparse understory of ferns, mosses, ephemeral plants, and slow-growing shrubs: an ecosystem which is too sparse and delicate for regular use as an entertainment space for humans and their pets.

Ecologically speaking, the goal in having a woodland garden is to "freeze" the ecological succession at the stage where there is a fairly extensive canopy (between 50% and 30% enclosed), which limits the amount of shade and water competition form the trees to allow us to have ornamental plants and lawns beneath. Maintaining that balance is a never-ending task, because the trees will continue to grow unless constantly suppressed. The main question is whether to prune or to cull the trees.

Culling (or "thinning")
In situations where the woodland garden was not planned in advance, there will often be decisions to be made about what trees to keep and what trees to remove. As a rule, it's best to remove trees as soon as they begin to pose a problem, because the trees will only get larger, more problematic, and more difficult to remove as they continue to grow or perhaps die (live trees are much easier to remove than dead trees).

1. Hazardous trees: Trees that pose an obvious hazard should be the first to go. Rotten trees and hollow trees are the most obvious, but a number of other factors can be just as important, such as trees from weak-wooded species, trees growing through utility lines, or even trees with dangerous fruits (such as walnuts, osage orange, or horse chestnuts and buckeyes if they are growing in an area where people, cars, or outdoor furniture is below).

2. Diseased trees: Trees with serious diseases (such as ../Phytophthora/, ../Verticillium/, or other fatal diseases should in most cases be removed, unless there are no other trees around that could catch the disease and the garden owner would like to maintain a snag for woodpeckers and cavity-nesting birds.

3. Invasive trees: Trees that are invasive in a particular region should in most cases be culled to protect the health of other trees and prevent seed production, although in some areas close to urban centers invasive species may represent almost all the trees present, and it may be better to keep some of them.

4. Trees with bad growth habits: When trees are not carefully managed "from the start", they can often have growth habits that are aesthetically undesirable or in many cases will eventually become hazardous. Trees that have grown up underneath larger neighbors will often lean perilously, for example, and other trees may have dangerously narrow crotches. Removing these trees reduces the competition for the trees that will be kept, and helps prevent hazards later on.

5. Overcrowded trees: The last step is to see if the healthy trees are competing with one another, and make a decision as to whether to allow them to compete, or pick the best specimens and cull the second best.

Pruning ("lightening the canopy")
After any culling has been done, or if there are no trees needing culling, the next step is to prune the remaining trees to allow light to reach the ground and reduce the water consumption of the larger trees. Limbing up is often the best option, but other methods of structural or reductive pruning can be used if low branches are desirable.

Trunk protection
If the trees are growing in a lawn, it is generally a good idea to create tree rings around the base of the trunks to prevent damage from mowing equipment. Small rings can simply be maintained as mulched soil, or larger rings can be created and plenatd with ground covers, shrubs, or herbaceous plants adapted to competition with tree roots.

Soil maintenance
/Techniques

title: Horticulture/Suburban Forestry


text: User talk:74.236.29.252

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: User talk:74.236.29.252


text: User talk:68.194.183.245

title: User talk:68.194.183.245


text: User talk:207.144.91.149

title: User talk:207.144.91.149


text:
User talk:Wim b

 * Talk: my user talk on it.wikt
 * Info: my user page on Meta

You can contact me also :
 * #wiktionary-it
 * #wikipedia-it
 * #wikibooks-it
 * #wikivoyage-it
 * #wikimedia-admin
 * #wikimedia-gs

title: User talk:Wim b


text:
User talk:76.238.177.161

Join Us!
--Laleena (talk) 00:13, 5 March 2008 (UTC)

title: User talk:76.238.177.161


text: User talk:208.120.204.132

title: User talk:208.120.204.132


text:
Radiation Oncology/Bladder/Randomized

Bladder Cancer Level I Evidence

In the process of being cross-linked ...

Superficial Bladder Cancer

 * MRC T1 Bladder (1991-2003)
 * Randomized, 2 strata. 210 patients with pT1G3 TCC after TURBT
 * Unifocal disease & no Tis: Arm 1) observation vs. Arm 2) RT 60/30
 * Multifocal disease and/or Tis: Arm 1) intravesical therapy (MMC or BCG) vs. Arm 2) RT 60/30
 * 2007 PMID 17631326 -- "A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder." (Harland SJ, J Urol. 2007 Sep;178(3 Pt 1):807-13; discussion 813. Epub 2007 Jul 16.)
 * Outcome: No difference in PFS, OS, or cystectomy rate
 * Conclusion: No evidence that adjuvant RT after TURBT is better than more conservative treatment; prognosis poor regardless

Definitive RT vs Preop RT + Cystectomy

 * Danish National Bladder Cancer Group, DAVECA 8201 (1983-1986) -- Definitive RT vs Preop RT + cystectomy
 * Randomized. 183 patients. cT2-T4a. Arm 1) Pre-op RT 40 Gy + cystectomy vs Arm 2) Radical RT 60 Gy with cystectomy for salvage.
 * 1991 PMID 1785004 — "Treatment of advanced bladder cancer category T2 T3 and T4a. A randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor. DAVECA protocol 8201. Danish Vesical Cancer Group." (Sell A, Scand J Urol Nephrol Suppl. 1991;138:193-201.) Median F/U 4.2 years
 * Outcome: Salvage cystectomy 28%. Local/pelvic failure Cystectomy 7% vs RT 35%, no difference in DM. No difference in OS (29% vs 23%)
 * No difference in OS (29% vs 23%). Local/pelvic recurrence lower (6.8% surgery vs 35% RT). No difference in DM.
 * Conclusion: Improved pelvic control with surgery, but no difference in survival

 * MD Anderson (1964-1970) -- Definitive RT vs Preop RT + cystectomy
 * Randomized. 67 patients, Stage B2-C. Arm 1) definitive RT 60 Gy vs Arm 2) Preoperative RT 50 Gy followed by cystectomy
 * 1977 PMID 402205 -- "Bladder cancer: superiority of preoperative irradiation and cystectomy in clinical stages B2 and C." (Miller LS, Cancer. 1977 Feb;39(2 Suppl):973-80.)
 * Outcome: 5-year OS RT 16% vs preop RT + cystectomy 46% (SS)
 * Conclusion: Institutional policy has changed to preoperative RT with planned cystectomy, except for patients declining or medically unfit for surgery

RT Alone vs Chemo-RT

 * NCI Canada (1985-1989) -- RT vs RT + concurrent cisplatin
 * Randomized. 99 patients. cT2-T4b, either definitive therapy or pre-cystectomy (selected a priori). Arm 1) RT 40/20 or 60/30 vs Arm 2) Same RT with concurrent cisplatin 100 mg/m2 Q2W x3 cycles
 * 1996 PMID 8918486 — "Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group." (Coppin CM, J Clin Oncol. 1996 Nov;14(11):2901-7.) Median F/U 6.5 years
 * Outcome: 5-year pelvic failure RT 59% vs chemo-RT 40% (SS), first site pelvic failure 52% vs chemo-RT 29% (SS), held in both definitive and preop groups. No difference in DM. 3-year OS 47% vs 33% (NS). If definitive treatment, bladder preservation RT 36% vs chemo-RT 70% (NS)
 * Conclusion: Concurrent cisplatin may improve pelvic control and bladder preservation, but not overall survival.

Induction MCV chemotherapy

 * RTOG 89-03 (1990-93) -- Selective chemo-RT bladder sparing +/- induction MCV x2 cycles
 * Phase III. Stopped prematurely due to severe neutropenia and sepsis. 123 of 174 patients. cT2-T4a. Randomized to Arm 1) 2 cycles of MCV before, or Arm 2) no MCV before RT 39.6/22 with concurrent cisplatin 100 mg/m2 q3w x2 courses (per RTOG 88-02), cystoscopy 4 weeks later. If CR, consolidative RT 25.2/14 with concurrent cisplatin 100 mg/m2, else radical cystectomy. Total RT dose 64.8/36
 * 1998 PMID 9817278 — "Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03." (Shipley WU, J Clin Oncol. 1998 Nov;16(11):3576-83.) Median F/U 5 years
 * Outcome: pCR MCV+ 61% vs MCV- 55%. 5-year bladder preservation 36% vs 40% (NS). DM 33% vs 39% (NS). 5-year OS 48% vs 49% (NS) Predictors for worse outcome hydronephrosis and incomplete TURBT
 * Conclusion: 2 cycles of MCV did not increase CR rate, change DM rate, or impact OS. High toxicity.

Partial bladder irradiation

 * Christie Hospital, UK (1993-99) -- whole bladder 52.5/20 vs partial bladder 57.5/20 or 55/16
 * Randomized. 149 patients. T2-T3N0M0, unifocal TCC <= 7cm. Randomized to whole bladder conformal RT (52.5/20, 2.63 Gy/fx) or partial bladder RT (CTV + 1.5 cm) in 4 wks (57.5/20, 2.88 Gy/fx) or 3 wks (55 Gy/16, 3.44 Gy/fx). No chemo
 * 2004 PMID 15093917 — "Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy." (Cowan RA, Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):197-207.) Median F/U 5.8 years for living patients
 * Outcome: 5-year local control WBRT 58% vs PBRT4 59% vs PBRT3 34% (NS), overall 50%. 87% of recurrences within irradiated tumor volume. DM 17% vs 25% vs 22% (NS). 5-year OS 58% (NS)
 * Toxicity: Well tolerated. 85% of patients alive at 5 years preserved their bladder
 * Conclusion: Comparable outcome between whole bladder RT and partial bladder RT

Accelerated irradiation

 * Cooperative Urological Oncology Group, UK (1988-1998) -- AHFX 60.8/32 BID vs CF 64/32 QD
 * Randomized. 229 patients with T2-T3 N0-N1 bladder cancer. Arm 1) AF split-course 60.8/32 BID (22.8/12 + 19/10 + 19/10) vs. Arm 2) Conventional CF 64/32. Primary endpoint local control
 * 2005 PMID 15878099 -- "A randomised trial of accelerated radiotherapy for localised invasive bladder cancer." (Horwich A, Radiother Oncol. 2005 Apr;75(1):34-43. Epub 2004 Nov 25.)
 * Outcome: LR AF 32% vs. CF 29% (NS); 3-year OS 47% vs. 54% (NS); 5-year OS 40% vs. 37% (NS)
 * Toxicity: Acute AF 44% vs. CF 26% (SS); Late toxicity (if FFR 2 years): Grade 2+ AHFX 44% vs. conventional 38% (NS). 2 treatment-related deaths on AHFX arm
 * Conclusion: No benefit for AHFX over conventional fractionation, worse acute GI toxicity

title: Radiation Oncology/Bladder/Randomized


text:
C++ Programming/Code/Standard C Library/Functions/tmpfile

tmpfile
The function tmpfile opens a temporary file with a unique filename and returns a pointer to that file. If there is an error, null is returned.

 * Related topics: tmpnam


text:
C++ Programming/Code/Standard C Library/Functions/tmpnam

tmpnam
The tmpnam function creates a unique filename and stores it in name. tmpnam can be called up to TMP_MAX times.

 * Related topics: tmpfile


text:
C++ Programming/Code/Standard C Library/Functions/vprintf, vfprintf, and vsprintf

vprintf, vfprintf, and vsprintf
These functions are very much like printf, fprintf, and sprintf. The difference is that the argument list is a pointer to a list of arguments. va_list is defined in cstdarg, and is also used by (Other Standard C Functions) va_arg.

For example:


text:
User talk:Isis~enwikibooks

Welcome!
Welcome, !

Come introduce yourself at the new users page. If you have any questions, you can ask there or contact me personally.--Whiteknight (Page) (Talk) 01:13, 5 March 2008 (UTC)

Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Isis. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Isis~enwikibooks that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name.

Your account will still work as before, and you will be credited for all your edits made so far, but you will have to use the new account name when you log in.

Sorry for the inconvenience.

Yours, Keegan Peterzell Community Liaison, Wikimedia Foundation 23:14, 17 March 2015 (UTC)

Renamed
 This account has been renamed as part of single-user login finalisation. If you own this account you can |log in using your previous username and password for more information. If you do not like this account's new name, you can choose your own using this form after logging in: . -- Keegan (WMF) (talk) 05:03, 19 April 2015 (UTC)

title: User talk:Isis~enwikibooks


text:
User talk:Andybee

Welcome!
Welcome, !

Come introduce yourself at the new users page. If you have any questions, you can ask there or contact me personally.--Whiteknight (Page) (Talk) 01:14, 5 March 2008 (UTC)

Thanks for all your work!
Andybee,

I noticed that you have made many contributions to the human physiology textbook. Thanks for working to improve upon this book! I'm sorry I have not been active in this project for quite some time, but I would enjoy interacting with you and working together to improve upon the text. It appears that you are very knowledgeable when it comes to physiology, and it is an honor that you would contribute your time and efforts to this book. Provophys (talk) 18:01, 24 March 2008 (UTC)

title: User talk:Andybee


text:
User talk:Monoxide~enwikibooks

Welcome!
Welcome, !

Come introduce yourself at the new users page. If you have any questions, you can ask there or contact me personally.--Laleena (talk) 01:35, 5 March 2008 (UTC)

Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Monoxide. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Monoxide~enwikibooks that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name.

Your account will still work as before, and you will be credited for all your edits made so far, but you will have to use the new account name when you log in.

Sorry for the inconvenience.

Yours, Keegan Peterzell Community Liaison, Wikimedia Foundation 23:31, 17 March 2015 (UTC)

Renamed
 This account has been renamed as part of single-user login finalisation. If you own this account you can |log in using your previous username and password for more information. If you do not like this account's new name, you can choose your own using this form after logging in: . -- Keegan (WMF) (talk) 05:16, 19 April 2015 (UTC)

title: User talk:Monoxide~enwikibooks


text:
Video Game Design/About the Book/Foreword

Foreword
This book is designed to teach people what video game design is, how video games work, and enable them to create them, from chumming up ideas and figuring out how to structure them to teaching them how a game engine can be designed to satisfy their requirements. You do not need any prior knowledge of video games to understand this book's subject, up to the implementation part that will expand upon game development techniques for many different types of media. Programming may not be required. Depending on what your goal is, you will need to understand how to program if you intend on going from design to production. You will also need to comprehend Object Oriented Programming to understand modular designs, and be able to understand C/C++ APIs, and have some basic 2D/3D graphics concepts like what a bitmap or a texture is and how they can be used. We will not deal with a specific API or programming language but C/C++ and ASM will be used for examples. The intention is to provide you with a broad vision of the possibilities available to create Video Games.

Guide to Readers
This is a wikibook (en.wikibooks.org), as such you should learn a bit about what it is and how it does its magic.

The book is organized into different parts, but as this is a work that is always evolving, things may be missing or just not where they should be, you are free to become a writer and contribute to fix things up...

Reader Comments
If you have comments about the technical accuracy, content, or organization of this document, please tell us (e.g. by using the "discussion" pages or by email). Be sure to include the section or the part title of the document with your comments and the date of your copy of the book. If you are really convinced of your point, information or correction then become a writer (at Wikibooks) and do it, it can always be rolled back if someone disagrees.

Guide to Writers
Authors/Contributors should register if intending to make non-anonymous contributions to the book (this will give more value and relevance to your opinions and views on the evolution of the work and enable others to talk to you) and try to follow the structure. If you have major ideas or big changes use the discussion area; as a rule just go with the flow.

 * Conventions : A set of conventions have been proposed to adoption on this book, please read about them before you contribute any content on the book's talk page.


text: Video Game Design/About the Book/Authors


text:
Talk:Fringe Psychology

Mental health: Is it mind over matter? In a sense, yes. But not in every case. Pysical and mind can't be separated. They both have influence on each other. Because of my long term physical health problem, my mental health/depression has triggered. I tried to control my mind not to have that kind of feeling. But can only control for a certain amount. For my case, I found out one thing. It is true for me. It is nothing to use or buy and no side affect. That is to exercise your nerve. How to exercise? It is simple. You sit down on your leg (not in the chair) and squeeze your chest while keeping your head down. Squeeze means the same thing you do when you go to restroom. Try a few times everyday. Don't squeeze too much and a long time. It can cause low blood pressure. It is sound strange. It does work.

Can you find a common thread?
What might be a common thread for this book that we could use to tie it all together and then be used expand upon it? --Remi (talk) 09:18, 3 June 2008 (UTC)

Most of this material falls into a category which usually appears in books or chapters as 'themes in psychology' or 'approaches to psychology' or the like. These are more schools of thoughts than 'topics' as the term is commonly used. I think that as an 'Approaches' text it could be useful and relevant. Lord Spring Onion (talk) 00:03, 26 March 2009 (UTC)

Material for possible integration
Laing argued that the strange behavior and seemingly confused speech of people undergoing a psychotic episode were ultimately understandable as an attempt to communicate worries and concerns, often in situations where this was not possible or not permitted. Laing stressed the role of society, and particularly the family, in the development of "madness" (his term). He argued that individuals can often be put in impossible situations, where they are unable to conform to the conflicting expectations of their peers, leading to a 'lose-lose situation' and immense mental distress for the individuals concerned. (In 1956, in Palo Alto, Gregory Bateson and his colleagues Paul Watzlawick, Donald Jackson, and Jay Haley articulated a related theory of schizophrenia as stemming from double bind situations where a person receives different or contradictory messages.) The perceived symptoms of schizophrenia were therefore an expression of this distress, and should be valued as a cathartic and trans-formative experience.

Laing saw psychopathology as being seated not in biological or psychic organs -- whereby environment is relegated to playing at most only an accidental role as immediate trigger of disease (the 'stress diathasis model' of the nature and causes of psychopathology) -- but rather in the social cradle, the urban home, which cultivates it, the very crucible in which selves are forged. This re-evaluation of the locus of the disease process-- and consequent shift in forms of treatment-- was, indeed still is, perhaps now more than ever, in stark contrast to psychiatric orthodoxy (in the broadest sense we have of ourselves as psychological subjects and pathological selves). Psychiatrist and philosopher Karl Jaspers had previously pronounced, in his seminal work General Psychopathology, that many of the symptoms of mental illness (and particularly of delusions) were 'un-understandable', and therefore were worthy of little consideration except as a sign of some other underlying primary disorder. Laing was revolutionary in valuing the content of psychotic behavior and speech as a valid expression of distress, albeit wrapped in an enigmatic language of personal symbolism which is meaningful only from within their situation. According to Laing, if a therapist can better understand his or her patient, the therapist can begin to make sense of the symbolism of the patient's psychosis, and therefore start addressing the concerns which are the root cause of the distress.

Laing never denied the existence of mental illness, but simply viewed it in a radically different light from his contemporaries. For Laing, mental illness could be a trans-formative episode whereby the process of undergoing mental distress was compared to a shamanic journey. The traveler could return from the journey with important insights, and may even have become a wiser and more grounded person as a result.

There is already an entry for Laing in Wikipedia. (see http://en.wikipedia.org/wiki/R._D._Laing ). There it is noted that his ideas are not part of mainstream Psychology. A series on Topics in Psychology should mostly (not entirely) represent the prevailing view. Ideally this would be accompanied by references to the scientific literature rather than a description of ones personal views and experience. DJM77bci (talk) 00:14, 20 December 2009 (UTC)

Nature of the content here
Much of what I see in this section seems to be "fringe Psychology" rather than the mainstream point of view. One would not find this sort of description in a standard textbook of Psychology. DJM77bci (talk) 00:19, 20 December 2009 (UTC)

Lead section: what is the point?
The lead section seems to ramble on aimlessly with a potted history of the universe before even mentioning the topic in a general way. What is the point of this? It mentions psychology as one of the things 'not immediately related to survival' - so does this mean that every book about any of the myriad arts or sciences should start out like this? Surely the lead section should summarise what the book is about and define the topic but it does not do this as 'Fringe' psychology is not even mentioned. Smcg8374 (discuss • contribs) 09:01, 28 December 2011 (UTC)

title: Talk:Fringe Psychology


text:
Talk:Video Game Design/Content

 *  See also: Talk:Video Game Design/Conventions and Talk:Video Game Design/Q&A
 * This space is for contents planning and to provide a direction for continued contributions.

= TO ADD to TOC =

Merges
I have reset the talk page (not archived, posts are still present on the history log). I intend on starting merging the works, will give 7 days to any to present objections or ideas on the subject before starting... --Panic (talk) 04:14, 9 February 2008 (UTC)

 * Proceeding with the merges. --Panic (talk) 00:54, 5 March 2008 (UTC)

 * Still reorganizing the content from top to bottom... --Panic (talk) 20:37, 6 March 2008 (UTC)

 * I think I have place the content in the right locations and streamlined the flow of the book, some of the content does need lots of work and there is a lot missing and probably still out of place. I will come to it again if I have the time to, but this is not my topmost priority in the list of books I'm working on... --Panic (talk) 03:21, 9 March 2008 (UTC)

title: Talk:Video Game Design/Content


text:
Radiation Oncology/Pancreas/Staging

Pancreatic Cancer Staging

AJCC 7th Edition (2010) Primary Tumor:
 * T1 - confined to pancreas, 2 cm or less
 * T2 - confined to pancreas, > 2 cm
 * T3 - extends beyond pancreas
 * T4 - invades SMA or celiac axis (unresectable primary tumor)

Regional Lymph Nodes:
 * N0 - no
 * N1 - yes
 * NX - regional lymph nodes cannot be assessed
 * Note 1: Histopathological assessment of minimum 12 regional lymph nodes is recommended. However, in cases where surgery results in examination of less than the ideal minimum number, N staging is performed if at least one node has been examined.
 * Note 2: Direct extension of primary tumor into regional node is classified as node positive.

Distant Metastases:
 * M0 - none
 * M1 - yes

Stage Grouping:
 * IA - T1 N0
 * IB - T2 N0
 * IIA - T3 N0
 * IIB - T1-3 N1
 * III - T4 Any N
 * IV - M1

Changes from the 6th Edition:
 * Now staging includes neuroendocrine tumors of the pancreas (including carcinoid)
 * No changes in TNM or Overall Stage

Instead of using the AJCC staging system, many simply divide pancreatic cancer into resectable, unresectable, and metastatic.

Older staging systems
AJCC 6th Edition (2002)
 * Same as AJCC 7th Edition for TNM
 * Excluded neuroendocrine tumors

title: Radiation Oncology/Pancreas/Staging


text:
Radiation Oncology/Pancreas/Resectable

Resectable Pancreatic Cancer

Treatment Overview

 * Historically, surgery alone was used to treat resectable pancreatic cancer. Unfortunately, 5-year OS at the time of the first GITSG trial was only 6%
 * GITSG 9173 randomized patients to adjuvant chemo-RT with concurrent/adjuvant 5-FU vs. no adjuvant treatment. The study closed prematurely due to slow accrual, but showed a dramatic benefit for DFS and OS. RT was given as split course (20 Gy + 20 Gy). Adjuvant chemo-RT became the standard of care in the US
 * In a follow-up trial (RTOG 97-04), the role of induction and adjuvant gemcitabine compared with 5-FU as a sandwich to concurrent chemo-RT was evaluated. There was a trend for improved survival with gemcitabine (particularly for head of pancreas tumors) but also significantly more toxicity. This trend dissipated at 5 year follow up (p=0.12)
 * In the US, NCCN.org considers both chemo-RT and chemotherapy to be valid choices (evidence 2A)
 * In Europe, EORTC 40891 attempted to confirm the GITSG results. It randomized patients to adjuvant chemo-RT vs. no adjuvant treatment. RT schedule was the same; chemo schedule was concurrent C.I. 5-FU only, without 2 years of further adjuvant treatment. It also included patients with peri-ampullary cancers (45%), who have significantly better prognosis. There was no benefit for LRR or OS. On exploratory subset analysis, there was also no benefit for the pancreatic cancer subset. In this trial, ~80% of patients died of their disease, but 8% survived >10 years
 * ESPAC-1 included 3 separate randomization (2x2, +/- chemo, +/- chemo-RT) trying to further determine the role of the various adjuvant options. On combined analysis, there was no survival benefit for adjuvant chemo-RT, but significant benefit for adjuvant chemotherapy. A further analysis of only the 2x2 patients again showed a survival benefit for adjuvant chemotherapy, and a deleterious effect of chemo-RT. However, this trial was widely criticized for its methodology
 * A further meta-analysis of individual patient data from available randomized trials (Europe, Japan) confirmed a survival benefit for adjuvant chemotherapy and suggested trend to worse survival with chemo-RT. The one exception was patients with R1 resection, where chemo-RT appeared beneficial over chemotherapy alone
 * Based on the combined results of EORTC 40891 and ESPAC-1, adjuvant chemo-RT is not indicated in Europe. Adjuvant chemotherapy is considered standard of care
 * A German trial (CONKO-001) demonstrated a significant survival advantage for adjuvant gemcitabine over observation alone; there was no benefit in a Japanese trial of adjuvant cisplatin/5-FU
 * Ongoing ESPAC-3 trial attempts to compare observation only to adjuvant 5-FU (ESPAC-1) to adjuvant gemcitabine (CONKO-001)
 * to be continued...

Surgery

 * Only ~10-20% of patients surgical candidates
 * Based on Johns Hopkins experience (2007), ~20% will have N0 disease and ~80% will have N1 disease. Lymph node ratio (positive/examined) most powerful predictor of survival
 * Perioperative mortality with modern techniques is low (<4%)
 * Upon laparoscopy small liver mets and peritoneal implants are found in ~10% of head tumors and up to 40% of body/tail tumors, leading to aborted surgery

 * Whipple procedure - invented in 1935 by Dr. Allen Whipple, an American surgeon.
 * Remove: head of pancreas, duodenum, proximal jejunum, gall bladder, distal common bile duct, regional lymph nodes
 * Reconstruction: pancreaticojejunostomy, choledochojejunostomy, gastrojejunostomy
 * NCCN criteria for resectability:
 * Resectable - no distant mets, clear fat plane around celiac/SMA, patent SMV
 * Borderline Resectable - severe unilateral SMV/portal impingement, abut SMA, gastroduodenal artery encasement up to hepatic artery, limited involvement of IVC, colonic invasion, SMV occlusion
 * Unresectable - distant mets (including celiac/para-aortic), SMA/celiac encasement, SMV/portal occlusion, aortic/IVC invasion, SMV invasion below transverse mesocolon

Preoperative Biliary Drainage

 * The Netherlands (2003–2008) -- preop biliary drainage vs. surgery only
 * 2010 PMID 20071702 -- "Preoperative biliary drainage for cancer of the head of the pancreas." (van der Gaag NA, N Engl J Med. 2010 Jan 14;362(2):129-37.)
 * Randomized. 202 patients, obstructive jaundice and bilirubin 2.3 - 14.6 mg/dl. Arm 1) Preoperative biliary drainage for 4–6 weeks vs. Arm 2) No drainage. Both arms followed by surgical resection. Drainage primarily by ERCP placed endoprosthesis. Primary outcome rate of serious complications
 * Outcome: Complications drain 74% vs. no drain 39% (RR 0.54, SS). Mortality and LOS no difference
 * Conclusion: Routine pre-op biliary drainage increases rate of complications

Surgical Results

 * Kuala Lumpur, 1997 (1980–1993) PMID 9372373 -- "Carcinoma of the pancreas: resection outcome at the University Hospital Kuala Lumpur." (Shahrudin MD, Int Surg. 1997 Jul-Sep;82(3):269-74.)
 * Retrospective. 236 patients with curative intent. 75% PD, 15% total pancreatectomy, 10% distal pancreatectomy, 3% distal subtotal. Extra-pancreatic invasion in 75%, PNI 83%
 * Median OS: 14 months (vs. 5 months if no resection). 5-year OS: 10%. Op mortality 3.4%.
 * Recurrences: 10 patients recurred/died >5 years.
 * Hopkins, 1995 (1970–1994) PMID 7794076 -- "Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients." (Yeo CJ, Ann Surg. 1995 Jun;221(6):721-31; discussion 731-3.)
 * Retrospective. 201 patients with head of pancreas.
 * In-hospital mortality: 5%, but 0.7% for last 149 patients
 * 5-year OS: 21%. SM- 26% vs. SM+ 8% (SS). LN- 36% vs. LN+ 14% (SS). OS in 1990s 36%
 * Starting in 1991, 56 received RT (>45 Gy) + 5-FU, 22 declined: 2-year OS RT+ 35% vs. RT- 0%
 * Predictors of survival: diameter <3 cm, LN-, SM-, diploid DNS
 * MGH, 1993 (1978–1991) PMID 8094952 -- "Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy." (Willett CG, Ann Surg. 1993 Feb;217(2):144-8.)
 * Retrospective. 72 patients with head of pancreas. 39 received RT (40/22 - 50/28 Gy) + 5-FU
 * Margins: 51% SM+ (73% peripancreatic soft tissue, 38% pancreatic transection line). LN+: 65%
 * 5-year: OS 13%, LC 34%, FFDM 29%.
 * 2-year impact of margin (SM+ vs. SM-): OS 18% vs. 37%; LC 44% vs. 60%; FFDM 38% vs. 52%
 * No benefit to RT/5-FU

Patterns of failure

 * Local failure 50-80%, sole site of failure ~25%
 * Liver failure ~50%, commonly together with local failure, rarely as sole site
 * Peritoneal failure ~30%
 * Distant failure rare without local failure
 * Note: most series are older without benefit of modern imaging and CA19-9 monitoring

 * Tochigi, 2006 (Japan) PMID 16627216 -- "Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings." (Hishinuma S, J Gastrointest Surg. 2006 Apr;10(4):511-8.)
 * Retrospective. Autopsy findings. 27 patients after curative resection. Recurrence classified as 1) local, 2) hepatic, 3) peritoneal, 4) para-aortic LN, 5) other distant mets
 * Recurrence: 75% local (15% undetectable on CT), 50% hepatic mets, 46% local+hepatic, peritoneal 33%, para-aortic LN 21%, other distant mets 75%
 * Local disease direct cause of death only in 17%
 * Padua, 1997 (Italy) PMID 8995078 -- "Recurrence after resection for ductal adenocarcinoma of the pancreas." (Sperti C, World J Surg. 1997 Feb;21(2):195-200.)
 * Retrospective. 78 patients.
 * Recurrence: local component 72%, hepatic component 62%, both 97%. Majority within 24 months
 * Median DFS: 8 months; predictors: grade, size, SM, LN
 * Conclusion: surgery alone inadequate
 * Kanazawa, 1993 (Japan) PMID 8104092 -- "An evaluation of radical resection for pancreatic cancer based on the mode of recurrence as determined by autopsy and diagnostic imaging." (Kayahara M, Cancer. 1993 Oct 1;72(7):2118-23.)
 * Retrospective. 45 patients. Recurrence classified as 1) retroperitoneal (local and/or LN), 2) hepatic, 3) peritoneal, 4) distant
 * 15 postmortem: local 80%, retroperitoneal LN 47%, hepatic 66%, peritoneal 53%
 * 15 antemortem: retroperitoneal 87%, hepatic 53% (almost all had also local recurrence)
 * Lund, 1993 PMID 8406311 -- "Recurrence of exocrine pancreatic cancer--local or hepatic?" (Westerdahl J, Hepatogastroenterology. 1993 Aug;40(4):384-7.)
 * Retrospective. 74 patients with recurrent disease
 * Recurrence: 8% local only, 78% local + liver, 14% liver only
 * U Penn, 1991 (1981–1989) PMID 1938511 -- "Adjuvant therapy of resected adenocarcinoma of the pancreas." (Whittington R, Int J Radiat Oncol Biol Phys. 1991 Oct;21(5):1137-43.)
 * Retrospective. 72 patients; initially 33 surgery only, then 19 surgery + RT, then 20 surgery + chemo-RT (CI 5-FU)
 * Local recurrence: 85% vs. 55% vs. 25%. Peritoneal 23%. Liver 23%.
 * 2-year OS: 35% vs. 30% vs. 43%; very poor survival if SM+
 * Kansas, 1990 (1977–1987) PMID 2354408 -- "Patterns of failure after curative resection of pancreatic carcinoma." (Griffin JF, Cancer. 1990 Jul 1;66(1):56-61.)
 * Retrospective. 36 patients with curative resection of pancreatic CA, 26 Whipple, 7 total pancreatectomy, 3 distal pancreatectomy
 * Outcome: 26 recurred, 4 died of initial disease, 6 cured. Median OS 11 months, 5-year OS 17%
 * Initial failures: 27% local only (50% local component), 15% liver only (50% liver component), peritoneal 30%, distant 23% (never sole site)
 * Ultimate failures: 19% local only (73% local component), 12% liver only (62% liver component), peritoneal 42%, distant 27% (never sole site)
 * High local failure risk: age >60, T2-T3, location in body/tail
 * Adjuvant treatment: 10/36 received RT 45-60 Gy and 5-FU; had unfavorable characteristics (SM+, LN+, T2-3)
 * MGH, 1976 (1963–1973) PMID 1260670 -- "Carcinoma of the pancreas: review of MGH experience from 1963 to 1973. Analysis of surgical failure and implications for radiation therapy." (Tepper J, Cancer. 1976 Mar;37(3):1519-24.)
 * Retrospective. 145 patients considered for definitive surgery, 21% with radical surgery, 43% palliative, 36% biopsy alone. 9 patients received RT (30-45 Gy); 5-FU given occasionally
 * Median OS: 4 months, 2-year OS: 7%. For radical surgery median OS: 10.5 months
 * Radical surgery failures: LR most common site of failure (50%), mets without LR 13%

Extent of surgical resection

 * Extent of surgery
 * Initial Whipple procedure included distal gastrectomy
 * Randomized trial from Johns Hopkins of peri-ampullary tumors concluded that pylorus-sparing pancreaticoduodenectomy has comparable outcomes to pancreaticoduodenectomy with gastrectomy and extended lymph node dissection
 * Extent of lymph node dissection
 * Extended lymph node dissection initially described in 1973, since standard LND doesn't remove LNs frequently involved with microscopic disease and many patients die with local recurrence
 * It became widely adopted in Japan, but because of complexity and no apparent improvement in survival, was not adopted by Western surgeons
 * Japanese retrospective series showed superior survival rates to Western series, and prospective randomized trials were undertaken
 * Three randomized trials were published, and none showed a survival benefit for extended LND. Meta-analysis published in 2007 also didn't find a survival benefit, and found a trend to worse morbidity
 * Lymph node ratio (positive/examined) appears to be the most potent prognostic factor for survival after surgery

 * Meta-Analysis; 2007 PMID 17318801 -- "Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer." (Michalski CW, Br J Surg. 2007 Mar;94(3):265-73.)
 * Meta-analysis. 4 randomized trials identified, 3 analyzed. Standard vs extended procedures
 * Outcome: Weighted mean HR for OS 0.93 (NS)
 * Toxicity: Comparable, trend to higher delayed gastric emptying with extended
 * Conclusion: Extended lymphadenectomy doesn't benefit OS, and may trend to increased morbidity

 * Johns Hopkins; 2007 (1995–2005) PMID 17462460 -- "Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer." (Pawlik TM, Surgery. 2007 May;141(5):610-8. Epub 2007 Mar 23.)
 * Retrospective. 905 patients, pancreaticoduodenectomy (classic 29%, pylorus-preserving 71%). R0 resection in 59%. Median LN removed 17. Median F/U 2 years
 * Outcome: 21% N0 vs. 79% N1 disease. Median OS 17 months, N0 25 months vs N1 16 months (SS). Lymph node ration most compelling independent predictor of survival: LNR=0 25 months, LNR <0.2 22 months, LNR 0.2-0.4 15 months, LNR >0.4 12 months (SS)
 * Extent of dissection: N0 patients and <12 LNs 22 months vs. >12 LNs 33 months (p=0.09, but fairly small sample size). N0 and <12 LN survival comparable to N1
 * Conclusion: Lymph node ratio powerful predictor of survival; patients with <12 lymph nodes may be understaged
 * Mayo Clinic (1997–2003) -- standard vs. extended LND
 * Randomized. 79 patients with resectable pancreatic head cancer, peri-ampullary and islet cell excluded. Distal gastrectomy, pylorus preservation not allowed. Arm 1) standard LND (D1) removed first-echelon lymph nodes en bloc vs. Arm 2) extended LND (D2) which in addition dissected second-echelon lymph nodes
 * 2005 PMID 16269290 -- "A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma." (Farnell MB, Surgery. 2005 Oct;138(4):618-28; discussion 628-30.)
 * Outcome: Median OR time D1 6.2 hrs vs. D2 7.6 hrs (SS), blood transfusions 22% vs. 44% (SS), median LN resected 15 vs. 36 (SS), LOS ~11 days (NS). Median OS 2.2 years vs. 1.6 years (NS), 1-year OS 82% vs. 71% (NS)
 * Toxicity: Diarrhea, body appearance, bowel control better (SS) with D1 resection
 * Conclusion: No difference, extended LND unattractive for further evaluation
 * Johns Hopkins (1996–2001) - Pancreaticoduodenectomy: pylorus preservation vs. distal gastrectomy with retroperitoneal LN dissection
 * Randomized. 299 patients with periampullary carcinoma (57% pancreatic, 22% ampullary, 17% distal bile duct, 3% duodenal). Initially treated with pylorus-preserving pancreaticoduodenectomy then Arm 1) pylorus preservation and standard LND (distal gastrectomy only if inadequate margin) vs. Arm 2) radical resection with gastrectomy and extended LND
 * 2002 PMID 12192322 -- "Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality." (Yeo CJ, Ann Surg. 2002 Sep;236(3):355-66; discussion 366-8.)
 * Complication rate: standard 29% vs. radical 43%
 * LN+ 74%, SM+ 10% (standard 21% vs. radical 5%)
 * 5-years; 2005 PMID 16332474 -- "Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival." (Riall TS, J Gastrointest Surg. 2005 Dec;9(9):1191-204; discussion 1204-6.). Median live F/U 5.3 years
 * Outcome: 5-year OS standard 25% vs. radical 31% (NS); pancreatic CA - standard 13% vs. radical 29% (NS). SM+ standard 21% vs. radical 5% (SS)
 * Conclusion: Pylorus-preserving pancreaticoduodectomy without retroperitoneal lymphadenectomy procedure of choice, but higher SM+ in standard resection
 * Milan (Italy)(1991–1994) -- standard LND vs extended LND
 * Randomized. 81 patients with resectable head of pancreas CA. Pancreatoduodenectomy, then Arm 1) standard LND vs. Arm 2) extended LND and retroperitoneal soft-tissue clearance (hepatic hilum, along aorta from the diaphragm to the IMA, laterally to both renal hila, with clearance of the celiac axis and SMA). IORT in 19 patients (NS)
 * 1998 PMID 9790340 -- "Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group." Pedrazzoli S, Ann Surg. 1998 Oct;228(4):508-17.)
 * Outcome: No difference in peri-operative outcomes. LN sampled standard 13 vs. extended 20 (SS). Median OS standard 11.0 months vs. 16.4 (NS)
 * Post-hoc analysis: N1 patients significantly better survival if extended vs standard; no difference in N0 patients
 * Predictors of survival: Grade, size (>2.0 cm), N1, >=4 transfused units of blood
 * Conclusion: Extended resection doesn't improve survival, although trend in N1 patients

Extensive Peritoneal Lavage

 * Kumamoto, 2005 PMID 16211228 -- "EIPL (extensive intraoperative peritoneal lavage) therapy significantly reduces peritoneal recurrence after pancreatectomy in patients with pancreatic cancer." (Yamamoto K, Int J Oncol. 2005 Nov;27(5):1321-8.)
 * Retrospective. 39 consecutive patients, treated without EIPL (1995–2000) or with EIPL (2001–2003)
 * Recurrence (EIPL vs. non-EIPL): local 13% vs. 29%, LN 27% vs. 29%, hepatic 40% vs. 50%, peritoneal 7% vs. 46%, distant 13% vs. 21%

Neoadjuvant Chemo-RT

 * PREOPANC Trial (2013 - 2017) -- NACRT + surgery + ACT vs surgery + ACT
 * Randomized. Dutch 16 centers. 246 patients, resectable/borderline resectable pancreatic cancer. Arm 1) Neoadjuvant chemoRT (Gemcitabine x 3 cycles, with RT 36/15fx during second cycle) followed by surgery, and adjuvant gemcitabine x 4 cycles vs Arm 2) Upfront surgery, followed by adjuvant gemcitabine x 6 cycles. Primary outcome OS
 * Long Term; 2022 PMID 35084987 -- "Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial" (Versteijne E, J Clin Oncol. 2022 Apr 10;40(11):1220-1230.doi: 10.1200/JCO.21.02233. Epub 2022 Jan 27.)
 * Outcome: Median OS NACRT 15.7 months vs S 14.3 months (SS); 5-year OS 20% vs 6% (SS)
 * Conclusion: Neoadjuvant chemoRT followed by surgery improves long term OS compared to upfront surgery

Proton Therapy

 * Harvard; 2010 (2006–2008) PMID 20421151 -- "Phase I Study of Preoperative Short-Course Chemoradiation with Proton Beam Therapy and Capecitabine for Resectable Pancreatic Ductal Adenocarcinoma of the Head." (Hong TS, Int J Radiat Oncol Biol Phys. 2010 Apr 24. [Epub ahead of print])
 * Phase I. 15 patients, localized, resectable, head of pancreas adenoCA. Proton therapy dose-escalation with capecitabine 825 mg/m2 BID x10 days. Level 1 30/10, Level II 25/5 in 2 weeks, Level III 25/5 in 1.5 weeks, Level IV 25/5 in 5 days
 * Outcome: Surgical resection in 11/15, others developed mets (n=4) or were unresectable (n=1)
 * Toxicity: No dose-limiting toxicity. Grade 3 in 4 patients (pain 1, stent obstruction/infection 3)
 * Conclusion: Preop chemo-RT with 1 week proton beam is feasible

Adjuvant Therapy Meta-Analysis

 * UK Clinical Trials Unit
 * Surgical margin; 2008 PMID 18209156 -- "Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials." (Butturini G, Arch Surg. 2008 Jan;143(1):75-83; discussion 83.)
 * Individual data from 4 randomized trials (GITSG, Norway, EORTC, Japan, ESPAC-1), 875 patients (R0 68%, R1 32%). Pooled hazards ratios calculated. Median F/U 3.7 years
 * Outcome: Surgical margin involvement not predictive for survival (HR 1.10, NS), median OS R0 16 months vs. R1 14 months (NS), 5-year OS 16% vs. 15%
 * Chemo-RT : If R0 pooled HR 19% increased risk of death with chemo-RT (NS), median OS chemo-RT 16 months vs. no chemo-RT 16 months (NS); if R1 pooled HR 28% reduction in risk of death (NS), median OS chemo-RT 15 months vs. no chemo-RT 11
 * Chemotherapy : If R0 pooled HR 35% reduction in risk of death with chemo (SS), median OS chemo 21 months vs. no chemo 14 months (SS); if R1 pooled HR 4% increased risk of death with chemo, median OS chemo 15 months vs. 13 months
 * Predictors of outcome: tumor size, grade, N-stage, not surgical margin
 * Conclusion: Adjuvant chemotherapy alone should be standard of care for either R0 or R1 resections. There may be a role for chemo-RT in R1 resection, but meta-analysis underpowered
 * Comment (same issue): widely disparate patients (IA-IIB), some subgroups don't make biological sense (e.g. R0 no chemo worse outcome than R1 no chemo)
 * 2005 PMID 15812554 -- "Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer." (Stocken DD, Br J Cancer. 2005 Apr 25;92(8):1372-81.)
 * 5 randomized trials (GITSG, Norway, EORTC, Japan, ESPAC-1), 4 recent trials (excluding GITSG) provided individual patient data (n=875). Previously unpublished F/U data on 261 ESPAC-1 patients. Overall median F/U 3.7 years
 * Chemo-RT : pooled HR 9% increase in risk of death with chemo-RT (NS), median OS chemo-RT 16 months vs. no chemo-RT 15 months; 2-year OS 30% vs. 34%, 5-year OS 12% vs. 17%
 * Chemotherapy : pooled HR 25% reduction in risk of death with chemotherapy (SS), median OS chemo 19 months vs. no chemo 13 months; 2-year OS 38% vs. 28%, 5-year OS 19% vs. 12%
 * Subgroup analysis: Chemo-RT may be more effective in patients with SM+
 * Conclusion: Chemotherapy is effective adjuvant treatment, chemoradiation is not. There may be benefit for chemo-RT in SM+

Surgery +/- Chemo-RT

 * Erasmus MC (2000–2007) -- intra-arterial chemo-RT vs observation
 * Randomized. 120 patients, pancreatic head (52%) or periampullary (48%) cancer. After pancreaticoduodenectomy, randomized to Arm 1) intra-arterial mitoxantrone, 5-FU, leucovoring, and cisplatin x6 cycles with RT 54/30 after first cycle vs Arm 2) observation
 * 2008 PMID 19092348 -- "Adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: a prospective randomized controlled trial." (Morak MJ, Ann Surg. 2008 Dec;248(6):1031-41.) Median F/U 1.5 years
 * Outcome: Median OS 19 months vs 18 months (NS), PFS 37% vs 20% (SS). Significantly fewer liver mets on subgroup analysis
 * Conclusion: Intra-arterial chemo-RT prolongs time to progression, but no impact on survival
 * QoL; 2010 PMID 20029974 -- "Quality of life after adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: a prospective randomized controlled study." (Morak MJ, Cancer. 2010 Feb 15;116(4):830-6.)
 * Subset analysis, 103 patients, 355 responses. QoL C30 questionnaires
 * Outcome: No impact on physical, emotional, or social functioning. Less pain, nausea and vomiting with chemo-RT
 * Conclusion: Intra-arterial chemo-RT improved QoL compared with observation
 * ESPAC-1 (1994–2000) -- 2x2 surgery +/- chemotherapy and +/- chemo-RT
 * Randomized, 2x2 design + 2 other randomizations to improve accrual. 541 patients total, treated with pancreaticoduodenectomy (R0 81%, R1 19%). Physicians could choose a randomization. 285 patients randomized to 2x2 factorial (observation, chemotherapy x6 cycles, chemo-RT, chemo-RT followed by adjuvant chemo x6 cycles). 68 patients randomized to +/- adjuvant chemo-RT. 188 patients randomized to +/- adjuvant chemo. Patients could be given other "background" therapy, which could be chemo or RT. RT AP/PA split course 20/10 + 20/10 (GITSG regimen, although up to 60 Gy could be given). Chemotherapy concurrent bolus 5-FU 500 mg/m2 + leucovorin, adjuvant 5-FU 425 mg/m2 x6 months
 * All patients; 2001 PMID 11716884 -- "Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial." (Neoptolemos JP, Lancet. 2001 Nov 10;358(9293):1576-85.) Median F/U of alive patients 10 months
 * Analysis: Combined group chemo-RT (n=178) vs. no chemo-RT (n=175); combined group chemo (n=235) vs. no chemo (n=238).
 * Outcome: median OS chemo-RT 15 months vs. no chemo-RT 16 months (NS); median OS chemo 20 months vs. no chemo 14 months (SS)
 * Conclusion: No survival benefit for adjuvant chemo-RT, significant benefit for adjuvant chemo
 * Comment : Physicians were able to choose which randomization to put a patient on. Also, physicians were able to give additional "background" therapy which means that patientss randomized to no chemotherapy could still get chemotherapy and those randomized to chemotherapy only could still get RT. No central audit.
 * 2x2 subset; 2004 PMID 15028824 — "A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer" (Neoptolemos JP, N Engl J Med. 2004 Mar 18;350(12):1200-10.)
 * Analysis of 2x2 factorial patients only. 289 patients, not powered for individual group comparison. 82% deaths recorded. Median F/U 3.9 years
 * Outcome: median OS observation 17 months vs. chemo-RT 14 months vs. 22 months chemo vs. 20 months chemo-RT + chemo (not powered for statistics)
 * Chemo-RT comparison: median OS chemo-RT 16 months vs. no chemo-RT 18 months (NS), 5-year OS chemo-RT 10% vs. no chemo-RT 20% (p=0.05); no benefit regardless of chemo
 * Chemo comparison: median OS chemo 20 months vs. no chemo 15 months (SS), 5-year OS chemo 21% vs. no chemo 8% (p=0.009); benefit regardless of RT
 * Pattern of failure: LR 35%, LR+DM 27%, DM 34%
 * Conclusion: Adjuvant chemotherapy significant survival benefit; adjuvant chemo-RT had deleterious effect on survival
 * Editorial: PMID 15028829: Analysis of 2x2 not straightforward due to low power, worse survival of chemo-RT group probably due to toxicity
 * Commentary: PMID 15752874 — "A challenge to the therapeutic nihilism of ESPAC-1." (2005): Substandard RT used, inappropriate toxicity reporting, longer time-to-treatment in chemo-RT group, inclusion of R1 patients
 * EORTC 40891 (1987–95) -- surgery +/- chemo-RT
 * Randomized. 218 patients. Pancreatic T1-2 N0-1a (55%) or periampullary (ampulla, distal CBD, duodenum) T1-3 N0-1a (45%). Arm 1) Chemo-RT vs. Arm 2) observation. RT split course 20/10 + 20/10 (GITSG regimen). Chemo 5-FU C.I. 25 mg/kg over 5 days at the beginning of each RT course. No maintenance (vs. 2 years in GITSG). SM+ 21%, LN+ 50%
 * 1999 PMID 10615932 — "Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group." (Klinkenbijl JH, Ann Surg. 1999 Dec;230(6):776-82.)
 * For all tumors: Median PFS chemo-RT 17 months vs observation 16 months (NS); median OS 24 months vs 19 months (NS). 2-year OS 51% vs 41%, 5-year OS 28% vs 22% (NS)
 * Pancreas tumor subset: median OS 17 months vs 13 months (NS). 2-year OS 37% vs 23%, 5-year OS 20% vs 10% (p=0.09).
 * Periampullary tumor subset: median OS 39 months vs 40 months (NS). 5-year OS 38% vs. 36% (NS)
 * Site of failure: LR both arms 15% (NS), LRR+DM ~20%, DM ~30%
 * Conclusion: Routine use of post-op chemo-RT not warranted
 * 12-years; 2007 PMID 17968163 -- "Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891." (Smeenk HG, Ann Surg. 2007 Nov;246(5):734-40.) Median F/U 11.7 years
 * Outcome: Death reported in 79% (malignant disease cause of death in chemo-RT 79% vs. observation 86%, but only 1 death >7 years); median OS chemo-RT 1.8 years vs. observation 1.6 years (NS), 5-year OS 25% vs. 22% (NS), 10-year OS 17% vs. 18% (NS) - pancreatic subset 8% vs. periampullary subset 29%; median PFS 1.5 years vs. 1.2 years (NS)
 * Site of failure: LR both arms 20%, LR+distant 30% (LR a component in 50% of failures), DM ~50% (liver 50%)
 * Conclusion: No benefit for adjuvant chemo-RT
 * Criticisms: No maintenance chemotherapy. About 20% of pts assigned to chemo-RT arm did not receive that treatment, although 93% received RT. Benefit was diluted by inclusion of favorable periampullary cancers, although on exploratory pancreatic cancer subset analysis there was no difference.
 * GITSG 9173 (1974–82) -- surgery +/- chemo-RT
 * Randomized. Terminated early due to poor accrual. 42 patients with adenocarcinoma of the pancreas (ampulla excluded), who were resected, margins negative, no peritoneal mets. Head of pancreas 95%, contigous disease 38%, LN+ 28%, Grade 3 5%. Subtotal Whipple 68%, Stage I 35%. Randomized to Arm 1) RT + 5-FU vs Arm 2) observation. RT was supravoltage 40/20 split course (2 week break after 20/10). Fields included the pancreatic bed and regional nodes AP/PA. 5-FU (500 mg/m2) bolus on days 1-3 of each cycle. Adjuvant chemotherapy given weekly x 2 years beginning 1 month after RT.
 * Original study; 1985 PMID 4015380 — "Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection." (Kalser MH, Arch Surg. 1985 Aug;120(8):899-903.) Median F/U 5.5 years
 * Median OS: chemo-RT 20 months vs observation 11 months (SS). 2-year OS 42% vs 15%; 5-yr OS vs 15% and 5%; median DFS 11 months vs. 9 months (SS)
 * Recurrence: overall 71% vs. 86%; local 47%; hepatic 32% vs. 50%; DM 40% vs 52%.
 * Conclusion: Adjuvant chemo-RT may prolong survival time
 * Confirmatory study; 1987: PMID 3567862 — "Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer." Gastrointestinal Tumor Study Group. Cancer. 1987 Jun 15;59(12):2006-10.
 * Not randomized. 30 additional patients, same characteristics, received chemo-RT protocol.
 * Outcome: MS 18 months. 2-yr OS 46%, 5-yr OS 17%. Similar results to chemo/RT arm from randomized study.
 * Conclusion: Use of adjuvant chemo-RT is preferred to no adjuvant treatment

Non-randomized
 * Hopkins, 2008 (1993–2005) PMID 18640931 -- "Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital." (Herman JM, J Clin Oncol. 2008 Jul 20;26(21):3503-10.)
 * Retrospective review 616 patients with adenoCA of head/neck/uncinate. 345 (56%) did not receive chemoRT, while 271 (44%) received 5-FU based chemoRT (median dose 50 Gy), including 2–6 months maintenance 5-FU.
 * Outcomes: chemoRT had superior MS (21.2 mo vs 14.4 mo), 2-yr OS (43.9% vs 31.9%) and 5-yr OS (20.1% vs 15.4%) (all SS)
 * Poor predictors: tumor >3 cm, SM+, and postop complications
 * Pts receiving chemoRT were younger, less comorbid disease, and less perioperative complications
 * Competing risk factor MVA performed, chemoRT still demonstrated significant beneficial effect
 * Conclusion: suggests that adjuvant concurrent FU-based CRT significantly improves survival after Whipple for resectable pancreatic CA.

 * Mayo, 2008 (1975–2005) PMID 18640932 -- "Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005)." (Corsini MM, J Clin Oncol. 2008 Jul 20;26(21):3511-6.)
 * Retrospective review of 472 pts who underwent R0 resection (+ margins, unresectable, indolent tumor types excluded)
 * Median f/u 32.4 mo. Median RT dose was 50.4 Gy in 28 fractions; 98% of RT patients also received concurrent 5-FU.
 * Median OS improved w/ adjuvant chemoRT (25.2 vs 19.2 months) (SS). Two-year OS was 50% versus 39%, and 5-year OS was 28% versus 17%.
 * ChemoRT arm had more LN-positive, high-grade tumors and more tumors with extension beyond the pancreas
 * MVA revealed lack of adjuvant therapy to be an independent negative prognostic factor
 * Conclusion: OS better in patients who received adjuvant chemoRT.

Surgery + Chemo-RT: Adjuvant Chemo Alternatives

 * RTOG 97-04 / Intergroup (1998–2002) -- sandwich 5-FU vs. gemcitabine
 * Randomized. 451 patients, with complete GTR of pancreas (R0 or R1). Head of pancreas 86%. SM+ 34%, SM- 42% and unknown 25%. Arm 1) CI 5-FU (250 mg/m2) x3 weeks -> chemo-RT -> CI 5-FU (250 mg/m2) x12 weeks vs. Arm 2) gemcitabine (1000 mg/m2) x3 weeks -> chemo-RT -> gemcitabine (1000 mg/m2) x12 weeks. Chemo-RT was same for both arms (RT 50.4 Gy + concurrent 5-FU 250 mg/m2), 1–2 weeks after induction chemo. Compliance with both >85%
 * 3-years; 2008 PMID 18319412 -- "Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial." (Regine WF, JAMA. 2008 Mar 5;299(9):1019-26.) Median F/U 1.5 years for all, 4.7 years for surviving
 * Outcome: median OS 5-FU 17 months vs. gemcitabine 20 months (p=0.09); 3-year OS 22% vs. 31%
 * Toxicity: Grade 4 hematologic 5-FU 1% vs. gemcitabine 14% (SS)
 * Conclusion: Trend to survival for gemcitabine (but NS), but GEM significantly more toxic
 * CA 19-9; 2008 PMID 19029412 -- "Postresection CA 19-9 Predicts Overall Survival in Patients With Pancreatic Cancer Treated With Adjuvant Chemoradiation: A Prospective Validation by RTOG 9704." (Berger AC, J Clin Oncol. 2008 Nov 24. [Epub ahead of print])
 * Secondary outcome. 385 patients with assessable CA 19-9. Analyzed as dichotomized variable (<=90 vs >90 and =180). Overall, >180 in 9% and >90 in 14%
 * Outcome: CA 19-9 <=90 significantly better (HR 3.4 SS); CA 19-9 <180 also (HR 3.5, SS). No patients with CA 19-9 >180 survived 3 years
 * Conclusion: Post-op CA 19-9 highly significant predictor of OS
 * 5-years; 2011 PMID 21499862 -- "Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial." (Regine WF, Ann Surg Oncol. 2011 May;18(5):1319-26.)
 * Outcome: No difference in OS. Pancreatic head patients had a median survival of 20.5 months and 5-year OS of 22% with gemcitabine versus 17.1 months and 18% with 5-FU.
 * Conclusion: No difference in OS between Gemcitabine and 5-FU.
 * Editorial: Argues that post-op data difficult to interpret due to surgical and path issues resulting in lack of standardization of trial data.

Non-randomized
 * Picozzi - single institution experience using XRT, 5FU, and alpha-interferon regimen following surgery
 * PMID12727570 — Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma., Picozzi et al. Am J Surg. 2003 May;185(5):476-80.
 * 42% were hospitalized during chemoradiation, virtually all due to gastrointestinal toxicity.
 * At mean follow-up time of 31.9 months, 67% of the patients are alive.
 * Actuarial overall survival for the 1-, 2-, and 5-year periods was 95%, 64%, and 55%.

Surgery +/- Adjuvant Chemo

 * CONKO-001 (Germany)(1998–2004) - adjuvant gemcitabine vs observation
 * Randomized. 354/368 patients. Pancreas carcinoma T1-4 N0-1 M0 s/p gross complete resection (R0 or R1 allowed). Arm 1) adjuvant gemcitabine (1000 mg/m2) x 6 cycles vs Arm 2) no adjuvant treatment. R0 resection in 80%
 * 2007 PMID 17227978 — "Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer." (Oettle H, JAMA. 2007 Jan 17;297:267-277.) Median F/U 4.4 years
 * Relapse: chemo 74% vs control 92%; LR (with/without DM) in 34% vs 41%. DM alone in 56% vs 49%.
 * Survival: Median DFS 13 vs 7 months (SS); 1-year DFS 58% vs. 31%, 3-year 23% vs. 7%, 5-year 16% vs. 5%. Median OS 22 months vs. 20 months (NS) but 5-year OS 22% vs. 11% (p=0.06)
 * Subgroup analysis shows benefit for gemzar for DFS for all subgroups. In subgroup analysis, OS benefit thus far for gemzar for R0 resection and T3-4 and N- pts.
 * Conclusion: Adjuvant Gemzar significantly improved DFS (primary endpoint), and support its use as adjuvant therapy
 * Final; 2008 ASCO Abstract "CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC)." (Neuhaus P, J Clin Oncol 26: 2008 (May 20 suppl; abstr LBA4504))
 * Outcome: 83% deaths. Median DFS GEM 13.4 months vs OBS 6.9 months (SS), benefit in all subgroups. Median OS 23 months vs. 20 months (SS), 3-year OS 37% vs. 20%, 5-year OS 21% vs. 9% (SS)
 * Conclusion: Adjuvant Gemcitabine x6 months significantly increases DFS and OS compared with observation
 * JSAP (Japan)(1992–2000) -- adjuvant cisplatin/5-FU vs. observation
 * Randomized. 85 patients, s/p complete resection (R1 not allowed). Arm 1) adjuvant cisplatin 80 mg/m2 + 5-FU 500 mg/m2 x2 cycles. Intraop RT used but not discussed.
 * 2006 PMID 16490736 -- "A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer." (Kosuge T, Jpn J Clin Oncol. 2006 Mar;36(3):159-65. Epub 2006 Feb 20.)
 * Outcome: median OS chemo 12 months vs. observation 16 months (NS); 5-year OS chemo 26% vs. observation 15%
 * Prognostic factors: Grade 1, no LN+. T-stage, size not prognostic
 * Toxicity: Grade 3+ 16%
 * Conclusion: Postop adjuvant cisplatin/5-FU safe, but no survival benefit
 * Japan (1986–1992) -- adjuvant Mitomycin C/5-FU vs. observation
 * Randomized. 508 patients ( pancreatic n=173, cholangio n=139, gallbladder n=140, ampulla n=56), s/p surgery. Stage II-IV, pancreas LN+ 80%, liver+ 10%, curative resection 58%. Arm 1) adjuvant chemo with mitomycin C + 5-FU C.I. x2 courses, followed by 5-FU until recurrence vs. Arm 2) observation
 * 2002 PMID 12365016 -- "Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma." (Takada T, Cancer. 2002 Oct 15;95(8):1685-95.)
 * Outcome: 5-year OS pancreatic chemo 11% vs. observation 18%; for curative resection chemo 18% vs. observation 27% (NS)
 * Conclusion: No benefit for adjuvant systemic chemotherapy in pancreatic cancer
 * Norway (1984–1987) -- adjuvant AMF vs. observation
 * Randomized. 61 patients with pancreatic (77%) or papilla (23%), s/p radical resection. Arm 1) adjuvant chemo (AMF) x6 cycles vs. Arm 2) control.
 * 1993 PMID 8471327 -- "Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater--results of a controlled, prospective, randomised multicentre study." (Bakkevold KE, Eur J Cancer. 1993;29A(5):698-703.)
 * Outcome: median OS chemo 23 months vs. observation 11 months (SS); 2-year OS 43% vs. 32% (NS); 5-year OS 4% vs. 8% (NS)
 * Conclusion: Adjuvant chemo postpone incidence of recurrence during first 2 years; no difference on ultimate cure rate

Surgery + Chemo: Adjuvant Chemo Alternatives

 * ESPAC-3 (2000–2007) -- adjuvant 5-FU vs. adjuvant gemcitabine
 * 1088 pts, R0 or R1 resection. No RT.
 * Trial originally included observation arm, which was later closed to accrual.
 * 2009 - ASCO Abstract 2009 -- "ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma" (Neoptolemos J, Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings, Vol 27, No 18S (June 20 Supplement), 2009: LBA4505)
 * No OS diff. Median OS 23.0 mo (5-FU) vs 23.6 mo (GEM), NS. Improved toxicity profile with gem (but higher thrombocytopenia rate).

Ongoing:
 * ESPAC-4 - adjuvant gemcitabine + capecitabine vs gemcitabine alone

Surgery vs. Chemo-RT

 * Japan Pancreatic Cancer Study Group -- Surgery vs. Chemo-radiation
 * Randomized. Stopped early after survival benefit to surgery. 42/150 patients, locally advanced but resectable pancreatic cancer, no involvement of SMA or common hepatic artery, no para-aortic LN+. Arm 1) Surgery (pancreaticoduodenectomy or distal pancreatectomy + dissection of regional lymphatics) vs. Arm 2) Concurrent RT 50.4/28 and C.I. 5-FU 200 mg/m2 to primary tumor + 1–3 cm margin to cover regional lymph nodes
 * 5-years; 2008 PMID 18958561 -- "Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: Final results of a randomized multi-institutional trial." (Doi R, Surg Today. 2008 Nov;38(11):1021-1028. Epub 2008 Oct 29.) Minimum F/U alive patients 5 years
 * Outcome: median OS surgery 12 months vs. chemo-RT 9 months (NS); 3-year OS 20% vs. 0% (SS); 5-year OS 10% vs. 0% (NS)
 * Conclusion: Locally invasive resectable pancreatic cancer is treated more effectively by resection than by chemo-radiation

Adjuvant Chemo vs. Adjuvant Chemo-RT

 * Intergroup EORTC 40013-22012 / FFCD-9203 / GERCOR (2004–2007) -- gemcitabine vs gemcitabine followed by chemo-RT
 * Randomized Phase II. 90 pts with R0 resection randomized to: 1) Control arm - gemcitabine x 4 cycles, or 2) gemcitabine x 2 cycles followed by chemo-RT 50.4 Gy with weekly gemcitabine
 * 2010 PMID 20837948 -- "Adjuvant Gemcitabine Alone Versus Gemcitabine-Based Chemoradiotherapy After Curative Resection for Pancreatic Cancer: A Randomized EORTC-40013-22012/FFCD-9203/GERCOR Phase II Study" (Van Laethem JL, J Clin Oncol. 2010 Oct 10;28(29):4450-6.)
 * Primary objectives: treatment completed per protocol in 86.7% vs 73.3%. Grade 4 toxicity 0% vs 4.7%.
 * Grade 3 late toxicity in 3 pts in RT arm. Median DFS 11 months vs 12 months. Median OS 24 months in both arms. First local recurrence 24% vs 11%.
 * Conclusion: adjuvant gemcitabine-based chemo-RT is feasible and well-tolerated.
 * ESPAC-1
 * See full details above at

Official Guidelines

 * 2009 - American Hepato-Pancreato-Biliary Association
 * PMID 19390900 PDF -- "Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus statement." (Abrams RA, Ann Surg Oncol. 2009 Jul;16(7):1751-6.)

Radiation Technique

 * RTOG Postoperative Pancreas Atlas

Other Resources

 * ARRO Case - Borderline Resectable Pancreatic Cancer
 * ARRO Contour Borderline Resectable Pancreas
 * Multiple Choice Questions on Pancreas

title: Radiation Oncology/Pancreas/Resectable


text:
Radiation Oncology/Pancreas/Unresectable

Unresectable Pancreatic Cancer

Epidemiology

 * 30-40% are locally advanced, unresectable (30-40% are metastatic, 15-20% resectable)

Treatment Overview
Gem alone dose is 1000mg/m2. Gem dose is reduced to 300-600mg/m2 concurrently with RT. 5FU dose is 250mg/m2. Capecitabine dose is 825mg/m2 bid M - F concurrent with RT (rtog 0848).
 * Median survival for untreated patients is ~4 months, and ~7 months with palliative bypass
 * EBRT alone had survival ~6 months in 1960's.
 * A randomized trial from Mayo Clinic in unresectable GI tumors (Moertel, 1969) showed that combined chemo-RT is superior to RT alone
 * GITSG 9273 confirmed that chemo-RT is superior over RT alone. The outcome of chemo-RT 40/20 split-course was comparable to chemo-RT 60/30 split-course
 * GITSG 9283 then compared RT + 5-FU to SMF chemotherapy alone and determined chemoRT was superior to chemo alone.
 * Conversely, ECOG trial published around the same time compared 5-FU alone to 5-FU + RT and found no benefit for addition of RT, with more toxicity
 * In the US, concurrent 5-FU and RT became standard of care
 * Gemcitabine became treatment of choice in metastatic pancreatic cancer, and efforts are made to evaluate its role in unresectable locally advanced disease
 * A Taiwan trial showed that gemcitabine + RT is superior to 5-FU + RT, with comparable toxicity
 * A French trial was closed prematurely, after 5-FU + RT arm had significantly worse survival compared with gemcitabine alone. Median OS of the chemo-RT arm was comparable to the original GITSG data, despite modern RT and infusional 5-FU
 * An ECOG trial (published thus far as abstract), showed that gemcitabine + RT may be superior to gemcitabine alone; however, the trial closed early due to nonaccrual
 * At the moment (12/2008), it is not entirely clear what the best strategy is for unresectable patients
 * A reasonable strategy may be that proposed by MDACC (see below) of using induction chemotherapy to exclude patients with rapid distant progression, and select patients who benefit from local consolidative chemo-RT

Palliative bypass
Median survival is 4 months for untreated patient, 7 months with palliative bypass (gastric or biliary), and 16 months with a Whipple procedure.

RT +/- Chemotherapy

 * ECOG E8282  -- RT alone vs. RT + 5-FU + Mitomycin-C
 * Randomized. 114 patients with locally advanced adenocarcinoma of the pancreas. Arm 1) EBRT 59.4 Gy vs. Arm 2) Same EBRT + concurrent 5-FU (1,000 mg/m2/day by continuous infusion on Days 2-5 and 28-31) and MMC (10 mg/m2 on Day 2)
 * 2005 PMID 16029791 -- "A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282." (Cohen SJ, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1345-50.)
 * Outcome: Response rate RT alone 6% vs. chemo-RT 9%; DFS 5 months vs. 5.1 months (p=0.19); OS 7.1 months vs 8.4 months (p=0.16)
 * Conclusion: Addition of 5-FU and MMC increased toxicity without improving DFS or OS. Alternative drugs for radiosensitization may improve outcome.

 * GITSG 9273 (1970's) -- RT 60 Gy vs. RT 40 Gy + 5-FU vs. RT 60 Gy + 5-FU
 * Randomized, 3 arms. 194 patients with locally unresectable pancreatic CA. Arm 1) RT alone 60/30 Gy split course (On interim analysis found inferior and was discontinued) vs. Arm 2) RT 40/20 Gy split course + concurrent 5-FU vs. Arm 3) RT 60/30 Gy split course + concurrent 5-FU. Concurrent 5-FU 500 mg/m2, followed by maintenance 5-FU 500 mg/m2 x2 years
 * 1981 PMID 7284971 "Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group," Moertel CG et al. Cancer. 1981 Oct 15;48(8):1705-10.
 * Outcome: DFS RT-60 2.9 months vs. C-RT-40 7.0 months vs. C-RT 60 7.6 months (SS); median OS 5.3 months vs. 9.7 months vs. 9.3 months (SS); 1-year OS 10% vs. 35% vs. 46%
 * Toxicity: No severe GI toxicity >10%
 * Conclusion: Concurrent chemo-RT superior to RT alone; C-RT 40 Gy comparable to C-RT 60 Gy

 * Mayo Clinic (1960's) -- RT alone vs. RT + 5-FU
 * Randomized. 64 patients with unresectable cancers of the stomach, pancreas, and large bowel. Arm 1) EBRT 35-37.5 Gy vs. Arm 2) Same EBRT + concurrent 5-FU bolus 45 mg/kg
 * 1969 PMID 4186452 -- "Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer." (Moertel CG, Lancet. 1969 Oct 25;2(7626):865-7.)
 * Outcome: median OS RT alone 6.3 months vs. chemo-RT 10.4 months (SS); 1-year OS 6% vs. 22%
 * Conclusion: Concurrent chemo-RT significantly augments RT alone

Choice of Concurrent Chemotherapy
Randomized Trials
 * PACT -- 5-FU + RT +/- TNFerade
 * Randomized. 330 patients with locally advanced pancreatic CA. Treated with 1) TNFerade (adenoviral vector carrying TNF-a regulated by radiation-inducible promoter Egr-1) + C.I. 5-FU 200 mg/m2/d + RT 50.4 Gy vs 2) 5-FU + RT, randomized 2:1
 * 2007 ASCO Abstract -- "Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)." (Posner M, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4518)
 * First 50 patients assessed for response. 1-year OS (primary endpoint): 71% vs. 28%; median OS 1.4 years vs. 0.9 years
 * Conclusion: Preliminary data encouraging
 * 2010 -- "GenVec Press Release - GenVec discontinues Phase 3 Clinical Trial Of TNFerade"
 * Interim analysis indicated that PACT trial did not provide sufficient evidence of the clinical effectiveness of TNFerade to warrant completion of the trial.
 * Taipei (1998-2001) -- 5-FU + RT vs. GEM + RT
 * Randomized. 34 patients. Unresectable pancreatic CA. Arm 1) 5-FU 500 mg/m2 + RT vs. Arm 2) Gemcitabine 600 mg/m2 + RT. RT 50.4 - 61.2 Gy @ 1.8 Gy/fx. All patients received maintenance GEM 1000 mg/m2 thereafter
 * 2003 PMID 12909221 "Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study." (Li CP, Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):98-104.)
 * Outcome: median OS 5-FU 7 months vs. GEM 14 months (SS). 1-year OS 31% vs. 56%. 2-year OS 0% vs. 15%. Also improvement in pain control, performance status, and QoL
 * Toxicity: No difference
 * Conclusion: Gemcitabine + RT more effective than 5-FU + RT, comparable tolerability
 * Comment: Small size, poor outcome in control group

 * GITSG 9277 (1980's) -- RT + 5-FU vs. RT + adriamycin
 * Randomized. 143 patients with locally unresectable pancreatic CA, surgically staged. Arm 1) RT 60/30 split course + concurrent 5-FU bolus 500 mg/m2 + maintenance 5-FU vs Arm 2) RT 40/20 continuous course + concurrent adriamycin 10 mg/m2 + maintenance adriamycin x5 courses + maintenance 5-FU
 * 1985 PMID 2864997 "Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group," ([No Authors Listed], Cancer. 1985 Dec 1;56(11):2563-8.)
 * Outcome: Median OS 5-FU 8.5 months vs. adriamycin 7.6 months (NS). Initial recurrence LRR 5-FU 58% vs. adriamycin 51%
 * Toxicity: 5-FU 36% vs. adriamycin 53% (SS)
 * Conclusion: No difference in outcome, but adriamycin significantly more toxic

Non-Randomized
 * RTOG 98-12 PMID 14758134 - "Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12." Rich T, Am J Clin Oncol. 2004 Feb;27(1):51-6.
 * 122 patients w/ unresectable pancreatic CA by imaging criteria tx'd w/ weekly Taxol + XRT (50.4 Gy) for unresectable pancreatic cancer.
 * 26% PR, 6% CR, 43% 1yr OS, 13% 2yr OS. 40% grade 3 toxicity, 5% grade 4
 * Conclusion: tolerable regimen w/ outcomes that appear better than historical data w/ concurrent 5FU

 * Michigan; 2001 - PMID 11709563 "Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer." McGinn CJ et al. J Clin Oncol. 2001 Nov 15;19(22):4202-8.
 * 37 pts w/ unresectable or incompletely resected pancreatic CA tx'd w/ full dose gemcitabine and xrt.
 * Dose escalation of fraction size, keeping duration of xrt at 3 wks. 2/6 pts experienced dose limiting toxicity at 42 Gy (2.8 Gy fractions) (grade 4 vomiting and grade 4 gastric/duodenal ulceration)

 * M.D. Anderson; 2000 (1996-2000) - PMID 11955742 — "Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?" Crane CH et al. Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1293-302.
 * Retrospective. 114 pts with localized unresectable dz. Treated with chemo/RT (median RT dose 30 Gy in 10 fx). Compared pts treated with weekly gemcitabine vs C.I. 5-FU.
 * No difference in OS, LR, or DM. Higher toxicity rate with gemcitabine.

Chemo-RT vs. Chemo Alone

 * LAP07 -- 1) Randomize: induction chemo (4 mo) gemcitabine vs. gemcitabine + erlotinib. 2) 2nd randomization: 2 additional months of the same chemo vs chemo/RT (54 Gy, capecitabine)
 * 449 pts. Locally advanced. 4 mo induction chemo. 2nd randomization for non-progressing pts: 2 months of same chemo vs chemo/RT (54 Gy plus capecitabine).
 * 2016 PMID 27139057 -- "Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. The LAP07 Randomized Clinical Trial" (Hammel P, JAMA. 2016 May 3;315(17):1844-53.)
 * Conclusion: "There was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy."
 * ECOG E4201 (2003-2005) -- gemcitabine vs. gemcitabine + RT
 * Randomized. Closed early due to slow accrual. 69 of planned 316 patients with unresectable disease. Arm 1) Gemcitabine alone 1000 mg/m2 x7 cycles vs. Arm 2) RT 50.4/28 + gemcitabine 600 mg/m2, then gemcitabine alone 1000 mg/m2 x5 cycles
 * 2011 PMID 21969502 --"Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial." (Loehrer PJ, J Clin Oncol 29:4105-4112, 2011)
 * Outcome: PFS GEM 6.7 months vs. GEM/RT 6.0 months (NS). Median OS 9.2 months vs. 11.1 months (SS)
 * Toxicity: Grade 4 or 5 GEM 9% vs. GEM/RT 41% (SS) (1 grade 5 toxicity in each arm)
 * Conclusion: Gem+RT had increased but generally manageable toxicity, with improved OS
 * Editorial PMID 21969514 (Philip PA, JCO 29:4066-4068, 2011) Moderate OS benefit with small patient number (wide CI) and no PFS benefit. In future, need consensus on clinical trial priorities and better systemic therapy.

 * FFCD-SFRO (2000-2005) -- RT + 5-FU vs. gemcitabine alone
 * Randomized. Stopped prematurely due to worse survival in Chemo-RT arm. 119 patients with unresectable pancreatic CA. Arm 1) 3D-RT 60/30 + concurrent 5-FU C.I. 300 mg/m2 + cisplatin 20 mg/m2 vs Arm 2) Gemcitabine 1000 mg/m2 alone x7 weeks. Both arms then maintenance Gemcitabine 1000 mg/m2 until disease progression/toxicity. RT technique: GTV = tumor + probably involved LNs. CTV = tumor + peripancreatic, celiac, and hepatic hilar LNs. PTV = CTV + 2cm. Only 42% of Chemo-RT group received at least 75% of planned RT and CT (though 83% received at least 75% of RT); 73% of GEM group received at least 75% of CT
 * 2008 PMID 18467316 -- "Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study." (Chauffert B, Ann Oncol. 2008 May 7. [Epub ahead of print])
 * Outcome: median OS Chemo-RT 8.6 months vs. GEM 13 months (SS); 1-year OS 32% vs. 53%. Median OS in Chemo-RT patients who received >75% of planned dose still only 9.5 months
 * Toxicity: higher in Chemo-RT arm 36% vs. GEM 22% (SS)
 * Conclusion: RT/5-FU is more toxic and less effective than Gemcitabine alone. May be due to dose intensity

 * GITSG 9283 (1980's) -- Chemo-RT vs. SMF (Streptozocin, mytomycin, 5-FU)
 * Randomized. 43 patients with locally unresectable pancreatic CA. Arm 1) Streptozocin + mitomycin + 5FU (SMF) vs Arm 2) RT 54 Gy + concurrent 5FU, followed by SMF.
 * 1988 PMID 2898536 "Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group," ([No Authors Listed], J Natl Cancer Inst. 1988 Jul 20;80(10):751-5.)
 * Outcome: median OS Chemo-RT 9.7 months vs. SMF alone 7.4 months (SS); 1-year OS 41% vs. 19% (SS)
 * Conclusion: Combined chemo-RT superior to SMF chemotherapy alone

 * ECOG (1980's) -- 5-FU alone vs. 5-FU + concurrent RT
 * Randomized. 148/191 patients with locally unresectable adenoCA of stomach (n=57) or pancreas (n=91). Arm 1) 5-FU 600 mg/m2 alone vs. Arm 2) RT 40/20 + concurrent 5-FU bolus 600 mg/m2 + adjuvant 5-FU 600 gm/m2
 * 1985 PMID 3973648 -- "Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study." (Klaassen DJ, J Clin Oncol. 1985 Mar;3(3):373-8.)
 * Outcome: median OS 5-FU 6.5 months vs. chemo-RT 5.1 months (NS); pancreas subgroup 8.2 months vs. 8.3 months (NS)
 * Toxicity: 5-FU alone 27% vs. chemo-RT 51% (SS)
 * Conclusion: Adding RT to 5-FU didn't improve survival, and was more toxic

Induction Chemotherapy + Chemo-RT

 * MD Anderson; 2007 (1993-2005) PMID 17538975 -- "Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy." (Krishnan S, Cancer. 2007 Jul 1;110(1):47-55.)
 * Retrospective. 323 patients locally advanced. 247 patients with initial chemo-RT (concurrent 5-FU or GEM), 76 patients induction GEM followed by RT 30/10 concurrent with chemo (5-FU, GEM, or capecitabine). RT 4 field; originally ENI (69%) but since 2001 primary tumor only (31%) to reduce toxicity. Median F/U 5 months
 * Outcome: Median OS CRT group 8 months vs. induction-CRT group 12 months (SS). Median time to local progression 6 months vs. 9 months (SS). No difference in patterns of failure
 * Conclusion: Induction chemo (2-3 months) may select patients who may optimally benefit from consolidative chemo-RT, by identifying patients who already have micrometastatic disease

Hypofractionated RT
With Concurrent Chemotherapy:
 * UT-San Antonio; 2005 (1993-2001) PMID 15923793 -- "Radiation dose considerations in the palliative treatment of locally advanced adenocarcinoma of the pancreas." (Wong AA, Am J Clin Oncol. 2005 Jun;28(3):227-33.)
 * Retrospective. 107 pts with locally advanced dz.
 * Concurrent C.I. 5-FU.
 * Low dose group (30 Gy in 10 fractions): 86 pts
 * High dose group (50.4 Gy): total of 21 pts. 18 pts received 50.4. 3 others received: 33 Gy, 36 Gy, 52.2 Gy.
 * MS: 8 months (30 Gy) vs 9 months (standard dose), NS. 6-mo local disease progression rate: 45% vs 50%, NS; distant metastasis: 54% vs 50%
 * Conclusion: "Compared with higher doses given over 5 to 6 weeks, chemoradiation (30 Gy in 10 fractions in 2 weeks with concurrent infusional 5-FU) results in a similar median survival, and local disease progression rates in patients with locally advanced pancreatic cancer apparently do not substantially improve local disease control or median survival time. Because higher doses of radiotherapy can lead to increased acute treatment-related morbidity, we recommend using 30 Gy in 10 fractions unless the patient is part of a prospective study evaluating novel biologic or cytotoxic radiosensitizers."

 * Germany; 2005 PMID 15783041 -- "Dose escalation of concurrent hypofractionated radiotherapy and continuous infusion 5-FU-chemotherapy in advanced adenocarcinoma of the pancreas." (Zimmermann FB, Hepatogastroenterology. 2005 Jan-Feb;52(61):246-50.)
 * 26 pts. Locally advanced (20 pts) or metastatic (6).
 * Concurrent C.I. 5-FU. RT Dose-escalation (all at 4 fractions per week): 1) 24 Gy in 8 fractions (3 Gy/fx); 2) 30 Gy in 10; 3) 36 Gy in 12.
 * Toxicity: gr 3 mucositis - 1 pt. gr 2 nausea - 12 pts (46%). gr 2 weakness - 1. No treatment interruption or dose reduction.
 * Pain improved in 70% of pts. MS: 8 months (all pts); 9 months (loc adv); 5 mos (metastatic).
 * Conclusion: "Dose escalation to 36 Gy in a hypofractionated manner proved to be feasible with low toxicity in patients with locally advanced and metastatic adenocarcinoma of the pancreas and warrants further investigation aiming at optimal tailoring in these two subgroups of patients."

IMRT/IGRT

 * San Antonio; 2007 PMID 19262697 "Image-Guided Intensity-Modulated Radiotherapy for Pancreatic Carcinoma" (Fuss M, Gastrointestinal Cancer Research,1 (1), p. 2)
 * Retrospective. 41 patients treated with ultrasound IGRT, doses of 55 Gy (range, 45-64 Gy).
 * Acute upper GI toxicity was grade 0–1 in 22 patients (53.7%), grade 2 in 16 patients (39%), and grade 3 in 3 patients (7.3%). Lower GI grade 0–1 in 32 patients (78%), grade 2 in 7 patients (17.1%), and grade 4 in 2 patients (4.9%). Treatment was stopped early in 4 patients.
 * Conclusion: Daily image-guidance during delivery of IMRT for pancreatic carcinoma is clinically feasible. Safety margin reduction and moderate dose escalation yields preliminary outcomes at least comparable with published survival data.

 * Washington University; 2005 ASTRO Abstract "4D CT for Hepatobiliary Malignancies: Organs at Risk and Implications for Gating" (Ma D, ASTRO 2005, Abstract 2550)
 * 11 patients (1 CCA, 1 ampullary, 9 pancreas) reviewed for end-expiration, mid-inspiration, end inspiration, and mid-expiration respiratory phases. Estimated V18 for RT and LT kidney and V20/V30 for liver
 * Liver received more dose during inspiration, max (V20 10%, V30 9%), mean (6% V20, 5% V30); Kidney dose varied
 * Conclusion: Individualized patient protocols using gating treatment during inspiration or expiration could potentially reduce dose to liver and kidneys, allowing dose escalation or increased chemotherapy during radiation.

 * Wayne State; 2004 PMID 15145162 — "Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer." Ben-Josef E et al. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):454-9.
 * Retrospective. 15 pts (7 post-surgical, 8 unresectable). IMRT in 25 fx - 45 Gy to lymph nodes, and 45-54 Gy (post-op) or 54 Gy (unresectable) to tumor bed or tumor.
 * Well tolerated.

SBRT boost

 * Stanford, 2005 - PMID 16168826 "Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer," Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):320-3.
 * 16 pts tx'd w/ 45 Gy IMRT + concurrent 5FU + 25 Gy SRS boost.
 * 2 pts had grade 3 toxicity, none had grade 4 toxicity.
 * 15/16 pts free of local progression until death.

Primary SBRT

 * Stanford
 * Retrospective; 2009 (2002-2007) PMID 19117351 -- "Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas." (Chang DT, Cancer. 2009 Feb 1;115(3):665-72.)
 * Retrospective. 77 patients, no surgery (58% locally advanced, 14% medically inoperable, 19% metastatic, 8% locally recurrent), <7.5 cm diameter. GEM-based regimens in 96%. SBRT 25/1. Prior EBRT 45-54 Gy in 16%. Median F/U 6 months (12 months among surviving patients).
 * Outcome: LC 6-months 91%, 12-months 84%. Isolated local failure 5%, 5%. Regional failure 12%, but 8/9 concurrent distant failure. PFS 26%, 9%. OS 56%, 21%.
 * Toxicity: Acute Grade 2+ in 5%; Late Grade 3+ 9% (3/10 in patients with prior EBRT). 12-month actuarial late toxicity 25%
 * Conclusion: SBRT effective for local control; efforts to reduce complications warranted. Distant mets vast majority of disease-related mortality
 * Phase II; 2008 (2004-2006) PMID 18395362 -- "Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer." (Schellenberg D, Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):678-86. Epub 2008 Apr 18.)
 * Phase II. 16 patients, locally advanced. GEM 1000 mg/m2 x1 cycle, SBRT 25/1, GEM 1000 mg/m2 until disease progression (median 4 cycles). SBRT to ITV (respiratory expanded GTV) + 2-3 mm margin using fiducial markers. Median F/U 9 months (22 months for living patients)
 * Outcome: LC 81%. Median OS 11 months
 * Toxicity: Acute GI toxicity mild; Late GI toxicity Grade 2 (ulcers) 5/16, Grade 3 (duodenal stenosis) 1/16, Grade 4 (duodenal perforation) 1/16
 * Conclusion: SBRT with GEM resulted in comparable survival to conventional CRT. However, late toxicity was significant
 * Phase I; 2004 PMID 15001240 -- "Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer." (Koong AC, Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1017-21.)
 * Dose-escalation study. Locally advanced pancreas. Single fractions 15 Gy (3 patients) -> 20 Gy (5 patients) -> 25 Gy (7 patients). Trial stopped early prior to reaching MTD due to 100% local control at 25 Gy
 * Toxicity: No Grade 3+
 * Conclusion: SRS is feasible; recommend 25 Gy in single fraction
 * Aarhus, Denmark; 2005 (2000-2001) PMID 15990186 -- "Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma." (Hoyer M, Radiother Oncol. 2005 Jul;76(1):48-53.)
 * Phase II. 22 patients, unresectable. SBRT Dmax 45/3
 * Outcome: LF 27%, but only 5% isolated LF. Median OS 6 months; 1-year OS 5%
 * Toxicity: Acute toxicity: severe mucositis, ulceration, or perforation 22%
 * Conclusion: SBRT poor outcome, unacceptable toxicity, and questionable palliative effect

Brachytherapy

 * Rome 1988-91 PMID 7538501 -- Intraluminal brachytherapy in the treatment of pancreas and bile duct carcinoma. (1995 Montemaggi P, Int J Radiat Oncol Biol Phys. 1995 May 15;32(2):437-43.)
 * Retrospective. 12 patients with billiary or pancreatic CA with obstructive jaundice treated with ILRT (20-50 Gy @ 1cm) +/- 5-FU
 * Median OS 14 months. 3 patients developed GI toxicity
 * Conclusion : "Further experience is necessary to determine whether ILBT in the common bile duct and/or in the duct of Wirsung may be, in pancreatic head patients, an alternative boost technique to Interstitial Brachy-therapy (IBT) or Intraoperative Electron Beam Radiation Therapy (IOEBRT)."

P-32

 * South Florida; 2008 PMID 18266048 -- "(32)P as an Adjunct to Standard Therapy for Locally Advanced Unresectable Pancreatic Cancer: A Randomized Trial." (Rosemurgy A, J Gastrointest Surg. 2008 Feb 12 [Epub ahead of print])
 * Randomized. Stopped early. 30 patients out of expected 80, biopsy proven unresectable adenoCA. Treated with 5-FU + RT (45 Gy nodal basin, pancreatic boost to 59.4 Gy), followed by Arm 1) intratumoral injection of colloidal chromic P-32 0.5 mCi/g tumor vs. Arm 2) observation. Both arms were followed by gemcitabine.
 * Outcome: median OS P-32 7 months vs. control 11 months (NS)
 * Severe toxicity: P-32 4% vs. control 2% (SS)
 * Conclusion: Intratumoral P-32 did not improve survival, and was associated with more serious adverse events

Advanced Stage

 * 5-FU alone was historically the main treatment; no combination of 5-FU based regimens has shown a benefit
 * Gemcitabine became standard treatment in 1997, after showing better symptom control and a modest survival benefit over 5-FU
 * Multiple trials evaluating combinations of agents with gemcitabine have not resulted in improved survival
 * NCI Canada trial with gemcitabine + erlotinib (Tarceva) suggests a modest survival benefit over gemcitabine alone

 * Swiss, 2007 (2001-2004) -- Gemcitabine +/- capecitabine
 * Randomized. 319 patients with advanced/metastatic Ca. Gemcitabine 1000 mg/m2 + Capecitabine 650 mg/m2 vs. Gemcitabine alone
 * 2007 PMID 17538165 -- "Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group." (Herrmann R, J Clin Oncol. 2007 Jun 1;25(16):2212-7.)
 * Median OS: 8.4 months vs. 7.2 months (NS). Subgroup KPS 90-100 10.1 months vs. 7.4 months (SS). Toxicity comparable
 * Conclusion: No overall benefit to GemCap; subgroup survival benefit with good KPS

 * NCI Canada CTG PA.3 -- Gemcitabine +/- erlotinib
 * Randomized. 569 patients with unresectable, locally advanced, or metastatic pancreatic CA. Gemcitabine 1000 mg/m2, erlotinib 100 or 150 mg/d
 * 2007 PMID 17452677 -- "Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group." (Moore MJ, J Clin Oncol. 2007 May 20;25(15):1960-6.)
 * Outcome: Median OS: Gem alone 5.9 months vs. Gem + Tarceva 6.2 months (SS); 1-year OS: 17% vs. 23% (SS); PFS also longer
 * Toxicity: higher incidence, but most Grade 1-2
 * Conclusion: Significantly improved survival

 * Multi-institutional -- 5-FU vs. Gemcitabine
 * Randomized. 126 patients, advanced symptomatic pancreatic CA. Treated with Gemcitabine 1000 mg/m2 vs. 5-FU 600 mg/m2
 * 1997 PMID 9196156 -- "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial." (Burris HA, J Clin Oncol. 1997 Jun;15(6):2403-13.)
 * Outcome: Clinical benefit: Gem 24% vs. 5-FU 5% (SS); Median OS: Gem 5.6 months vs. 5-FU 4.4 months (SS); 1-year OS: Gem 18% vs. 5-FU 2%
 * Toxicity: well tolerated
 * Conclusion: Gemcitabine more effective than 5-FU

Patterns of care

 * National Patterns of Care Study
 * PMID 8604906 Full text, 1996 — "National patterns of care for pancreatic cancer. Results of a survey by the Commission on Cancer." Janes RH Jr et al. Ann Surg. 1996 Mar;223(3):261-72.
 * Two study periods: 1983-85 and 1990. 16,942 total case reports.

Ongoing Trials

 * RTOG PA 00-20 (Closed) — Phase II, weekly gemcitabine + paclitaxel + XRT followed by farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer
 * RTOG P04-11 — Phase II, Bevacizumab + Capecitabine + RT, followed by maintenance Gemcitabine + Bevacizumab for locally advanced pancreatic cancer