Thanks maryvz, I didn't know that.  I've downloaded all 15,229 of the cholangiocarcinoma cases in the SEER.  I checked the SEER registry for those cases and none of them are from the Veterans Administration, so perhaps they just don't include them in their public database anymore.

I wouldn't say this is a flaw in their data since many cancer facilities in the United States don't report their cases to the SEER.  The cancer facilities in your state of Virginia don't report.  SEER estimates they cover about 28% of the US population, but when they started in 1973, they didn't have anywhere near that percentage.  The cancer facilities in my state of Louisiana started in 2000.

Bruce

Percy, the 12 locations for the positive nodes are:

Abdomen
Abdomen
Celiac
Diaphragm
Gall Bladder
Gall Bladder
Hilar
Liver
Liver
Near liver
Pancreas
Pericardial, etc.

I believe that most of those patients who did not report lymph node status did not have positive LNs.  Assuming that this was the case for all who did not report LN status, the percentage of all patients with positive LN status would be 14.5%.  I'll have to check other sources to see if this is about what should be expected.

Bruce

Hi Percy,

I keep track of the number of positive lymph nodes and their regions.  I don't think anyone has ever reported the next organ that will be affected based on the region, but if someone did, I would add a column and record that also.

Of the 498 cc patients for which I have recorded data, 117 have reported their lymph node status, and 12 reported the location of the affected LNs.  The 117 was divided into 45 with 0 positive LNs, 44 with an exact count of the positive LNs, and 28 with more than 1 positive LNs.

Bruce

I previously thought that the Roux-en-Y procedure was just done for extrahepatic cholangiocarcinoma.  However, while reviewing the article "Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma," by R. Dhanasekaran, et al,

http://www.spandidos-publications.com/or/29/4/1259

I found the statement, "Extrahepatic bile duct resection with Roux-en-Y reconstruction was carried out in patients (ie IHCC patients) with bile duct invasion or lymph node metastases." My wife had IHCC with a single positive LN and I remember the surgeon telling us that he was going to do something beyond a simple resection, and it would be more like surgery for extrahepatic cholangiocarcinoma.  I checked the pathology report and the extrahepatic bile duct was listed as a specimen.  I'll ask the surgeon about it at our next meeting.

Bruce

Thanks Marion. I was able to download Patel's paper off the Medscape site.  I set up my account with them months ago.  The paper was proceeded by almost 3 pages of Medscape stuff, but it was there.  Altogether, there were 24 pages.

Also, thanks for the advice on the unpublished phase II clinical trial results.  I haven't written the clinical investigator about the results, but I intend to.

Bruce

Eli, here's another. 

The AJCC Staging Manual, 7th edition describes the three geographical regions for cholangiocarcinoma as intrahepatic, perihilar, and extrahepatic.  Others have referred to perihilar as Klatskin and extrahepatic as distal.  Perihilar (Klatskin) and extrahepatic (distal) together have been referred to as extrahepatic, which is very confusing since the same name is used to describe two different locations.

Now, some authors refer to intrahepatic cc as consisting of peripheral cc and hilar cc, with hilar cc originating from a main hepatic duct or from the bifurcation of the common hepatic duct.

Is there any difference between the hilar cc that is referred to as being intrahepatic cc and the perihilar cc that is referred to as being extrahepatic cc?

Bruce

I just noticed that the clinical trial, NCT00123825, "A Phase II Trial of Gemcitabine and Cisplatin in Unresectable Or Metastatic Biliary Tract and Gallbladder Cancers," sponsor Dana-Farber Cancer Institute, was completed on 10/01/2007, but there was no published paper on its results.

Is this common practice?

Bruce

Thanks Eli for the distinction between ampullary and periampullary.  I missed that completely.

There appears to be something left out of the following sentence in the paper.  Are they trying to say something like distal cholangiocarcinoma account for 27% of the extrahepatic cholangiocarcinomas and perihilar cholangiocarcinoma accounts for 60-80%, or maybe 73% if the 27% is correct.

"Carcinoma of the distal bile duct: Cholangiocarcinoma is a rare malignancy of the biliary tract occurring in 27% in the distal bile duct, however the hepatic bifurcation is the most frequent involved site (60–80% of the cases)."

I'm still trying to find out where the 1973-2009 distal bile duct cancer is located in the SEER.  I figure it must be there, but just coded unusually.  I thought this may have something to do with it.

Bruce

Between 1987 and 1995, a phase III trial of the EORTC (European Organization for Research and Treatment of Cancer) Gastrointestinal Tract Cancer Cooperative Group to determine the effectiveness of adjuvant radiotherapy and 5-Fluorouracil after curative resection of cancer of the pancreas and periampullary region.  The results are presented at the following link:

http://www.ncbi.nlm.nih.gov/pmc/article … 06p776.pdf

The author state that the cancer in the periampullary region is periampullary carcinoma and it occurs in the ampulla of Vater, duodenum, and the distal common bile duct.  The authors also state that in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the group that had adjuvant therapy, however p=0.737 for their analysis which means that the results were not statistically significant.

I became interested in this because it was a phase III test involving adjuvant therapy and the distal common bile duct was mentioned.  My problem was that I couldn't find if periampullary carcinoma was cholangiocarcinoma.  The paper "Adjuvant treatment in biliary tract cancer: To treat or not to treat?" has 11 references to periampullary cancer including adenocarcinoma of ampulla of Vater (4), periampullary cancer (2) ampulla of Vater cancer (1) ampullary carcinoma (2), and ampullary adenocarcinoma (2), the second most references for a paper on biliary tract cancer, the first being gallbladder.  I could not find mention of periampullary, ampulla or Vater in ICD-O-3 (International Classification of Diseases for Oncology, 3rd edition) although I did find it as Code 156.2 in the 1st edition, and C24.1 in the 2nd edition.  In the 1st edition, it was coded with the "gallbladder and extrahepatic bile ducts" and in the 2nd edition, it was coded with "other and unspecified parts of biliary tract."

Page 74 of the paper,

http://www.ncbi.nlm.nih.gov/pmc/article … 02-070.pdf

states, "However, only 75% of periampullary tumours are truly of pancreatic origin . . . " but doesn't mention what the other 25% are.

Does anyone have more information about periampullary tumours and could they be cholangioncarnoma?

Bruce

Marion - OK, I fully understand the need for larger Phase III studies for chemo.  But then, let me pose the question, "Where is the Phase III study that proves resection is better than no resection?"  I think it is almost universally accepted that resection is better.  What is that based on?

Bruce

Marion - If you mean there are no large (phase 3) randomized studies reflecting survival benefit derived from post resection adjuvant therapy, I agree with that.

However, there are small retrospective studies, based on small to large populations, that show there is a benefit.  There are others that also say there is no benefit.  Maybe others even show a negative impact.

Just glancing at some of the papers on my desk:

1. Murakami, "Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma,", 2009, 42 patients, "Five-year actuarial survival rates of patients who did or did not receive adjuvant gemcitabine-based chemotherapy were 57% and 23%, respectively (P=0.026)."

2. Shinohara, "Radiotherpy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas", 2009, 4,758 patients, "The median overall survival time was 16 months for surgery and RT and 9 months for surgery alone.

3. Nakeeb, "Radiation therapy, chemotherapy and chemoradiation in hilar cholagiocarcinoma", 2005, "A carefully controlled trial from the John Hopkins Hospital did not demonstrate any benefit for adjuvant radiation therapy. A number of phase II trials of chemotherapy have demonstrated modest response rates (20-40%)...... Neither radiation therapy nor chemotherapy alone has been proven to prolong survival in completely or partially resected patients or in unresected patients."

4. Cereda, "Adjuvant treatment in biliary tract cancer: To treat or not to treat?", 2011, "A retrospective series of 73 patients with gallbladder cancer treated between 1985 and 2004 at Mayo Clinic suggested that adjuvant CRT may obtain a statistically significant improvement in OS only for patients with lymph node involvement ..... A more recent phase III trial exploring the role of single agent adjuvant chemotherapy with either gemcitabine or 5-fluorouracil, in 304 patients with ampullary adenocarcinoma submitted to curative resection did not demonstrate a survival benefit for any of the adjuvant therapy arms when compared to surgery alone."

And there are many more.  I should look at all this in detail and try and figure out why the results vary so much.

Bruce

The following survival plot is for resected SEER cholangiocarcinoma patients.  As for the intrahepatic cholangiocarcinoma plot,   I used the database "Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2012 Sub (1973-2010 varying)" and the Site and Morphology "CS Schema v0204."   This site has data coded as BileDucts Perihilar, BileDuctsDistal, BileDuctsIntraHepat, and BiliaryOther.  Unfortunately, Klatskin data has been incorrected coded and placed in all four lists plus other unidentified locations.  However, it appears all the Klatskin data is also coded in the site ICD-O-3 Hist/behav.  There were 1362 cases of Klatskin in this site. These were duplicated in the other lists with 779 in the BilesDuctIntraHepat, 527 in the BilesDuctPerihilar (where they all should have been), 1 in BileDuctDistal, 31 in OtherBiliary, and 24 in unknown lists.  The analyzed database for ECC was Perihilar & Distal without Klatskin and the Klatskin list form ICD-O-3 Hist/behav.

Again the survival curves below show that a single postive node substantially reduces survival for patients who have resected extrahepatic  cholangiocarcinoma, although the reduction is not as much as for intrahepatic cholangiocarcinoma, 63.1% for ECC vs. 38.9% for ICC for median survivals.

Patients in the database were eliminated from the analysis based on the same criteria used for the intrahepatic cholangiocarcinoma analysis.  A total of 336 patients were used in the analysis.  These patients were diagnosed with extrahepatic cc from 1998 - 2010, median 2006.  Their ages ranged from 12 - 87, median 65 years.

Median survival is 2.25 years for 0 positive LNs and 1.42 years for 1 positive LN.   Statistical parameters for the analysis are Chsq = 17, 1 degree of freedom, p = 3.82 e-05.

The longest survivor in the database was a deceased man from Alameda County, CA with a resected Klatskin tumor, 22.8 years.  He is not included in the analsis.

Bruce Baird

https://sites.google.com/site/bbairdsr/seer2.png

Marion - According to the literature, the BILCAP trial is studying the effects of capecitabine (Xeloda), not Gemzar, vs. no capecitabine, for R0 & R1 resected intrahepatic cc, extrahepatic cc (Klatskin, hilar), lower common bile duct cc (distal), and muscle invasive gallbladder cancer.  As stated in their literature, the primary objective is an increase in 2-year survival from 20% to 32%.  Patients are from England and Wales.

Right now GemCis seems to be the "standard" for adjuvant therapy, even thought many oncologists are still prescribing other chemo therapies.  This "standardizaton" is most likely based on the results of ABC-02 trial which compared the results of GemCis with those of Gemzar alone for 410 patients from the United Kingdom with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer.  The results were a median overall survival of 11.7 months for the GemCis group vs. 8.1 months for the Gemzar group.  Time started from the date of randomization, not from the date of diagnosis.

Now, my SEER data plots of survival for resected IHCC & ECC (Klatskin + distal), shows that in the USA, 2-year survival is about 55% for 0 positive node, and about 30% for 1 positive node.  These results include patients who are R0, R1, and R2, may or may not have had chemo and/or radiation.  So what's the big deal about trying to improve 2-year survival from 20% to 32%.  One of my previous analyses showed that the USA leads the rest of the world in achieving increases in survival for cholangiocarcinoma patients, and maybe that is the case here.

In any case, unless the BILCAP results are much better than expected, I don't see how a USA oncologist could prescribe Xeloda over GemCis for R0 & R1 resected cholangiocarcinoma patients.

Eventually, I will gather enough cc.org board data to produce statistically significant survival plots showing the effectiveness of chemo adjuvant therapy for resected R0 patients.

Bruce

Percy - If it was survival analysis, I would have picked HR (hazard ratio).  I've read several technical papers on cholangiocarcinoma survival and CI is usually not even mentioned.  I took a quick look at the papers and found one by Yamashita, et al. "The Impact of Surgical Treatment and Poor Prognostic Factors for Patients with Intrahepatic Cholangiocarcinoma: Retrospective Analysis of 60 Patients."  Table III in it is "Multivariate analysis to determine poor prognosis factors.  Here's part of it:

Overall survival     Hazard ratio     95% CI        p-factor
n(+)                          28.3           5.4-148.0       <0.01
ly(+)                            8.5           2.3-30.5           0.01
Poorly diff.                    8.3           2.4-29.2           0.01
R1/2                             6.4           1.4-28.7           0.01

First of all confidence interval, by itself, means nothing.  It is only meaningful in that it gives you a measure of how much the Hazard ratio can vary.  Likewise, p-factor is only significant in that it tells you the calculation of Hazard ratio was statistically significant.

Now, I'm not familiar with measures of efficacy,OS and toxicities for your drug combo.  Efficacy is the capacity to produce an effect.  If that effect is a longer life, then it appears to me that Hazard ratio, CI, and p-factor would have the same role as in overall survival.

I'm probably missing something here.

Bruce

I have corrected the original post with the plot of survival for Resected SEER Intrahepatic CC Patients.  Median survival increased from 2.50 years to 3.42 year for 0 positive node patients and 1.25 to 1.33 years for 1 positive node patients.

Percy - I tried to include 95% confidence intervals for the two curves, but had trouble.  However, I do have 95% confidence intervals for the median survivals.  For the 0 positive node case, the 95% confidence interval is 2.33 - 4.50 years and for the 1 positive node case, it is 1.17 - 1.67 years.

Bruce

Percy - There are a lot of explanations on the web (Wikipedia, You Tube, etc.) concerning the "95% confidence interval," "null hypothesis," and p-value, but they generally involve statistical terms and numbers and are not representative of survival analysis.

The survival curves I've plotted so far are based on samples of cholangiocarcinoma.org data and the SEER data.  Both of these databases are themselves only a sample of all the cholangiocarcinoma cases in the cholangiocarcinoma universe, which would be the world for cc.org and the USA for the SEER data.  The curves are all approximate, since I'm working with a sample and not the whole universe.  If I used another sample of the same size, I would get a different curve.  If I had 100 samples, each the same size, I would get 100 different curves.  On average, 95 of these curves would lie between an upper curve and a lower curve.  This is the 95% confidence interval.  The R statistical software I use plots the 95% confidence interval for each curve and I will do that for my corrected SEER IHCC curves to better illustrate this.  I haven't shown them in the past because they clutter up the plot.

The "null hypothesis" assumes there is no relationship between two measured phenomena.  For example, in my last plot, the "null hypothesis" assumes that survival will be be the same with 0 or 1 positive node.  If this was the case, the curves would lie on top of each other, but they could be separated solely because they are two independent samples.  The question, are they separated because they are just two different samples, or are they separated because survival is dependent on positive nodes.  The answer is in the p-value, which gives the probabilitiy that they are different because they are just two independent samples.  Generally researchers would use a p-value equal to or less than 0.05 as evidence that the difference is because survival is dependent on positive nodes (>=95%) and not just different samples (<=5%)

Bruce

I couldn't find surgical margin or chemo data in SEER so I emailed them about it.  Their response, in short, was that they do not collect surgical margin data and the limited chemo data they collect are not released to the public but may be available through special request.  Radiation data is in SEER.

I was hoping to use SEER data to determine the effectiveness of adjuvant therapy for cc, but I suppose I will have to depend on posts to these discussion boards to calculate this.

Bruce

Below are histology codes and malignant tumors found in SEER which are not intrahepatic cholangiocarcinoma but are considered as intrahepatic bile duct cancers.

8000/3: Neoplasm, malignant
8001/3: Tumor cells, malignant
8010/3: Carcinoma, NOS
8012/3: Large cell carcinoma, NOS
8020/3: Carcinoma, undifferentiated type, NOS
8031/3: Giant cell carcinoma
8032/3: Spindle cell carcinoma
8033/3: Pseudosarcomatous carcinoma
8041/3: Small cell carcinoma, NOS
8046/3: Non-small cell carcinoma
8050/3: Papillary carcinoma, NOS
8070/3: Squamous cell carcinoma, NOS
8124/3: Cloacogenic carcinoma
8140/3: Adenocarcinoma, NOS
8141/3: Scirrhous adenocarcinoma
8161/3: Bile duct cystadenocarcinoma
8180/3: Combined hepatocellular ca. & cholangiocarcinoma
8240/3: Carcinoid tumor, malignant
8246/3: Neuroendocrine carcinoma
8260/3: Papillary adenocarcinoma, NOS
8310/3: Clear cell adenocarcinoma, NOS
8440/3: Cystadenocarcinoma, NOS
8453/3: Intraductal papillary-mucinous carcinoma, invasive
8470/3: Mucinous cystadenocarcinoma, NOS
8480/3: Mucinous adenocarcinoma
8481/3: Mucin-producing adenocarcinoma
8490/3: Signet ring cell carcinoma
8500/3: Infiltrating duct carcinoma, NOS
8560/3: Adenosquamous carcinoma
8800/3: Sarcoma, NOS
8980/3: Carcinosarcoma, NOS
9100/3: Choriocarcinoma
9120/3: Hemangiosarcoma

Bruce

Eli - Thanks for the information on the Klatskin tumors being incorrectly cross-references to intrahepatic cc.  The articles were written in 2006 and 2007, so I would have thought that the problem had been corrected in the Collaborative Stage Data Collection System version 2:0204, dated 12/5/11, which I used.  Unfortunately, it hasn't been corrected.  I hadn't downloaded histology data for the intrahepatic bile duct cancer data, but I found it as one of the parameters available and downloaded it.  It refers to ICD-0-3.  There were 779 patients coded 8162/3 Klatskin and included in the intrahepatic bile duct data.

I also noticed that there were 2,200 other patients among the 11,789 I downloaded as intrahepatic bile duct cancer, which were not coded as cholangiocarcinoma.  I'll need to eliminate the Klatskin and these other patients from the analysis and revise the above plots.  Evidently bile duct cancer and cholangiocarcinoma are not the same.

Bruce

I haven't done the extrahepatic CC cases yet, but I should be able to do those. 

I was hoping to find SEER data to do the two components of extrahepatic cc separately.  These two components are refererred to in the 7th edition of the AJCC as perihilar (aka Klatskin) and extrahepatic (aka distal). 

CS Schema v0204 shows bile duct data as Bile Ducts Intrahepatic (11,789 patients), Bile Ducts Perihilar (13,099 patients) and Bile Ducts Distal (387 patients).  Most of the Bile Ducts Distal data is from 2010, which was the year the 7th edition of the AJCC became effective and extrahepatic cc was divided into perihilar and distal.  For 2010, bile duct data in CS Schema v0204 is divided into intrahepatic (881, 51.0%), perihilar (510, 29.5%), & distal (337, 19.5%).   The distribution for extrahepatic cc is, perihilar (60.2%) and distal (39.8%).  Using 39.8% for distal, I would have expected to see about 5,367 cases of distal bile duct cancer in CS Schema v0204, instead of the very small 387 cases that are there, so something is definitely wrong with the process in which pre-2010 cases of extrahepatic cc has been divided into perihilar and distal.

Bruce

EDIT [The original post was made after the original survival analysis.  The woman referred to actually had cystadenocarcinoma, not cholangiocarcinoma.  The longest surviving cholangiocarcinoma patient was a San Francisco County, CA man who died 26.6 years after his diagnosis.]


I forgot to mention that the longest surviving patient in the CS Stema v0204 intrahepatic cc section is a woman, diagnosed in January, 1977 in Alameda County, CA, who was still alive on 12/31/2010, a 33.9 years survivor.  She is not included in the analysis since there was no lymph node data for her.

Bruce

This post was first postesd on 6/1/13 and edited on 6/4/13 to correct for the inclusion of Klatskin and other tumor data that was contained in the SEER Bile Duct - Intrahepatic file, but was not intrahepatic cholangiocarcinoma.  This data has been eliminated in this revised analysis.  Also, some surgery cases where the surgery could not be specifically identified as a resection were included in the previous analysis.  These were mostly pre-1998 data where surgical codes were not included in SEER.  These were also eliminated in this analysis.


This is my first analysis using SEER (Surveillance Epidemiology and End Results) data.  I requested a CDROM when I submitted my application to SEER, but just received a username and password to their online data, so I just used that in this analysis.

SEER has several databases and sites containing cholangiocarcinoma data, some of which is duplication, and some of which is not.  I used the database "Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2012 Sub (1973-2010 varying)" and the Site and Morphology "CS Schema v0204"  The SEER 18 database has the latest data which goes through 12/31/2010.  I found Intrahepatic CC patients in three ofther Site and Morphology sections, but the CS Schema v0204 had the most, a total of 11,789.

The survival curves below show that a single postive node substantially reduces survival for patients who have resected intrahepatic cholangiocarcinoma.

In the analysis, I eliminated those patients with mutiple cancers, patients who had non-resection surgery, and patients who died from causes other than intrahepatic cc or its complications.  A total of 355 patients were used in the analysis.  These patients were diagnosed with intrahepatic cc from 1998 - 2010, median 2006.  Their ages ranged from 17 - 84, median 59 years.

Median survival is 3.42 years for 0 positive LNs and 1.33 years for 1 positive LN.   Statistical parameters for the analysis are Chsq = 33.9, 1 degree of freedom, p = 5.78 e-09.  I wanted to do this analyis from the start using the posted Cholangiocarcinoma Foundation data, but never could find sufficient data to get a statistically significant comparison.  However,  I will add those to the plot in a later post to show comparison between those from the boards and SEER's.

Bruce Baird


https://sites.google.com/site/bbairdsr/seer3.png

I just ordered a DVD with the SEER (Surveillance, Epidemiology, and End Results) data for 1973-2010.  They didn't ask for any money, so I guess it's free.  The DVD has the SEER Stat software, SEER binary data for use with the SEER Stat software, and ASCII data which I can use in the R statistical program.

The SEER data contains data for all types of cancer including intrahepatic, perihilar, and extrahepatic cc.  The paper by Olivier Farges, et al, which reported research done to develop the AJCC 7th edition TNM staging of patients with resectable intrahepatic cholangiocarcinoma used an earlier version of the SEER data.  That version contained data for 598 patients who had undergone cancer-directed surgery for IHCC.  Because of the large size of the database, survival statistics developed using this data should be very statistically significant.

Bruce Baird

24

(4 replies, posted in General Discussion)

Thanks Marion.  The link below shows diagrams of various surgical procedures envolving the GI tract. Six of them have Roux-en-Y reconstruction.  No mention of Roux Y Lis, but it must be one of these.

http://www.nature.com/ajg/journal/v103/ … 178f1.html

The following link has a better diagram of the Roux-en-Y Hepaticojejunostomy procedure used for a Klatskins tumor.  You need to scan down to Figure 4b.  It shows the removed bile duct & gall bladder.  It probably should also show the section of removed liver as this is usually the case.

http://www.cpmc.org/advanced/liver/pati … ofile.html

Bruce

25

(4 replies, posted in General Discussion)

What is a Roux Y Lis?  All of my Google results ended up in a foreign language.  I know a Roux en Y is normally used for a Klatskin tumor.  Is a Roux Y Lis used in a Whipple procedure?

Bruce