June 11, 2013 at 2:24 am #67795EliParticipant2000miler wrote: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.
Bruce, I read it the same way you did.June 11, 2013 at 1:53 am #67794
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.
BruceJune 11, 2013 at 1:00 am #67793EliParticipant
Take a look at this article.
Definition section says:Quote:Periampullary carcinoma is a widely used term to define a heterogeneous group of neoplasms arising from the head of the pancreas, the distal common bile duct and the duodenum. This term should be distinguished from ampullary carcinoma as a tumor topographically centered in the region of the ampulla of Vater…
The next section (“Epidemiology, clinical characteristics and diagnosis”) enumerates cancers included in the periampullary carcinoma group:
Adenocarcinoma of the duodenum
Carcinoma of the distal bile duct (extrahepatic CC)
Carcinoma of the pancreasJune 11, 2013 at 12:28 am #67792
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:
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,
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?
BruceJune 6, 2013 at 4:21 pm #67791
Bruce….you are addressing the law of medicine, so to say. Surgery removes an abnormal growth of tissue (in our case malignant and life threating) interfering with the pathological function of the patient. Results can be curatative or life extending.
MarionJune 6, 2013 at 1:28 pm #67790
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?
BruceJune 6, 2013 at 5:11 am #67789
Bruce…phase II studies need to be followed up by large, phase III studies in order to validate the findings. They generally are randomized and compare the investigational drug to another or, to a standard of treatment, if applicable.
Biliary tract cancers include, gallbladder, ampulla of Vater, and pancreatic cancer, but the reality is that these are four different diseases. We know for sure that gallbladder has a completely, different cell structure; the others have similarities but they are not the same.
I believe that Phase II clinical studies lumping together these disease simply cannot present with accurate data. Stratification helps but the true meaning of a study can only derive from a large amount of patients presenting with the same disease, in Phase III studies.
Having said that, there still is uncertainty re: extrahepatic vs. intrahepatic bile duct cancer. Is it the same cancer?
In an ideal setting we would like to see large scale, Phase III clinical trials, extrahepatic and intrahepatic, separated. The later is unlikely to happen, as recruitment is not feasible due to low volume of available patients.
But it could happen if more international clinical trials were conducted. That again has been hindered by the recent decision that virtually no global clinical trials will be supported by the government – we lack the necessary funding. This in turn will lead us to the pharma industry. Not a question of money here, but a question of return on the investments. Oh my, I better stop here.
MarionJune 6, 2013 at 2:22 am #67788
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.
BruceJune 5, 2013 at 9:54 pm #67787
Bruce….thanks for pointing out my error, it is much appreciated. Having said that, dear Bruce, at present there is no data reflecting survival benefit derived from post resection based adjuvant therapy. I believe that we are close, but at this point, physicians determine such therapy individually.
It would be interesting to see the results from your data collection based on the postings of this site re: adjuvant therapy.
Thanks so much for providing information to the patient community at large.
MarionJune 5, 2013 at 8:12 pm #67786
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 BairdJune 5, 2013 at 6:04 pm #67785
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.
BruceJune 5, 2013 at 1:20 pm #67784pcl1029Member
Thanks for your insight, you may be correct, we may miss to account for the time element for the efficacy, but i agree of using the HR for survival studies;for the toxicity study, we may need the time element and the degree too.In the mean time I will just use all of available statistic tools to compare the studies.
I think what the presenter’s comment is just a simple answer due to the fact that some people were also there to ask specific questions and he just want to answer them all while the time is short.
But I will look into the statistic or going to a seminar for a day to refresh my memory.
thanks again, Bruce.
God bless.June 5, 2013 at 5:44 am #67783gavinModerator
From 2011, AMMF’s meeting with Cancer Research UK re BILCAP trial –
BILCAP ASCO poster from ASCO 2011 –
Thanks to Helen at AMMF for this.
Just thought I’d post this for those interested in BILCAP who may not have heard of it.
GavinJune 5, 2013 at 2:45 am #67782
Bruce….you won’t find any data re: adjuvant therapy for cc – it has not been collected. What will be of most interest is the data collected from the Bilcap trial presently undergoing in the UK. This trial will prove the efficacy of Gemcitabine (Gemzar) in adjuvant settings. Data will be released in 2014.
MarionJune 5, 2013 at 12:22 am #67781
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.
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