# Radiation Oncology/Gall bladder

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Please see the Bile Duct section for more information. Some papers report jointly on bile duct and gall bladder cancers.

## Overview

* Incidence: 1.1 per 100,000 in U.S. with 5,000 annual cases reported via SEER
* Surgery primary treatment, but only minority resectable
* Reports generally limited to single institution experience
* SEER 1973-03 ASTRO Abstract Conditional Survival of Gallbladder Adenocarcinoma Treated with Radiotherapy: Analysis from the SEER Database (2005 Fuller CD, 2005 ASTRO, Abstract #2074)
** 850 histologically confirmed GB cases, who received RT as part of treatment. 128 local disease, 469 regional disease, 237 distant disease
** 5-year OS: 6%; conditional survival at 5-years 60-70%
** Conclusion: "This is the first attempt, in the absence of well-designed clinical trials, to define population survival rates for patients with gallbladder carcinomas who have received radiation therapy as a component of their management. This dataset represents the largest pooled data for gallbladder carcinoma, and is markedly larger than any given institutional series. Consequently, while imperfect, this data represents a useful estimate for patients with considerable post-diagnosis survival. Although the disease-free survival outcomes for patients with gallbladder adenocarcinoma treated with radiotherapy remain low, for those patient surviving even 1 year post-diagnosis, conditional survival estimates increase rapidly."

## Staging

AJCC 7th Edition (2009)
Primary Tumor:
* Tis - carcinoma in situ
* T1
** T1a - invades lamina propria
** T1b - invades muscular layer
* T2 - invades perimuscular connective tissue; no extension beyond serosa or into liver
* T3 - perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure (such as stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts)
* T4 - invades main portal vein or hepatic artery; or invades two or more extrahepatic organs or structures
Regional Lymph Nodes:
* N0 - none
* N1 - metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein
* N2 - metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes
Distant Metastases:
* M0 - none
* M1 - yes
Stage Grouping:
* I - T1 N0
* II - T2 N0
* IIIA - T3 N0
* IIIB - T1-3 N1
* IVA - T4 N0-1
* IVB - N2 or M1
Changes from 6th Edition:
* N divided into N1 and N2
* Stage groupings have shifted: Stage I is now T1N0 (was T1-2N0), T2N0 moved from Stage IB to II, T3N0 from IIA to IIIA, T4 is now Stage IVA, N+ moved to Stage IIIB or IV (depending on N1 or N2)

### Previous staging editions

AJCC 6th Edition (2002)
Primary Tumor:
* Tis - carcinoma in situ
* T1
** T1a - invades lamina propria
** T1b - invades muscular layer
* T2 - invades perimuscular connective tissue; no extension beyond serosa or into liver
* T3 - perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure (such as stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts)
* T4 - invades main portal vein or hepatic artery; or invades two or more extrahepatic organs or structures
Regional Lymph Nodes:
* N0 - none
* N1 - yes
Distant Metastases:
* M0 - none
* M1 - yes
Stage Grouping:
* IA - T1 N0
* IB - T2 N0
* IIA - T3 N0
* IIB - T1-3 N1
* III - T4
* IV - M1

## Surgery

* MSKCC 1990-2001 PMID 14534886 -- Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. (Jarnagin WR, Cancer. 2003 Oct 15;98(8):1689-700.)
** Retrospective. 80 GB and 76 hilar CCA reviewed
** Recurrence: 66% GB vs. 68% CCA at 2 years; median time to recurrence GB 11.5 months vs. CCA 20.3 months (p=0.007)
** Site of recurrence: isolated locoregional GB 15% vs. 59% CCA; distant (with or without concomitant locoregional) GB 85% vs. 41% CCA. Site of recurrence no apparent impact on survival
** Conclusion: "After resection, recurrent GBCA is much more likely than recurrent HCCA to involve a distant site. GBCA is also associated with a much shorter time to recurrence and a shorter survival period after recurrence. The results demonstrated significant differences in the clinical behavior of these tumors and suggested that an adjuvant therapeutic strategy targeting locoregional disease, such as radiotherapy, is unlikely to have a significant impact in the overall management of GBCA. Conversely, there is at least some rationale for such an approach in patients with HCCA based on the pattern of initial recurrence."

## RT alone / Palliation

* Duke, 2005 - PMID 15990005 — "Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience." Willett CG et al. Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):1030-4.
** 22 pts treated with surgery + RT + concurrent 5-FU (in 18).
** Median f/u 1.7 yrs. The 5-year OS, DFS, metastases-free survival, and LRC were 37%, 33%, 36%, and 59%, respectively. Median survival was 1.9 years.
* PMID 2472186 Houry S, Br J Surg. 1989 May;76(5):448-50.
** Conclusion: "This experience is the largest published and suggests that radiotherapy may increase survival after no resection or palliative resection of gallbladder carcinoma."
* PMID 5268194 Vaittinen E, Ann Chir Gynaecol Fenn Suppl. 1970;168:1-81.
** No abstract
** Palliative resection, survival improved with EBRT 13 months vs. surgery only 8 months (p<0.1)

## Adjuvant RT

* SEER database; 2007 (1992-2002) PMID 17516546 -- "Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease." (Mojica P, J Surg Oncol. 2007 Jul 1;96(1):8-13.)
** SEER review. 3,187 cases (35% Stage I, 36% Stage II, 6% Stage III, 21% Stage IV). Adjuvant RT given in 17%
** Outcome: median OS RT 14 months vs. no RT 8 months (SS); survival benefit only if regional spread or liver infiltration
** Conclusion: adjuvant RT improves survival with locally advanced GB cancer
* Santiago Chile; 2005 (1991-02) ASTRO Abstract "Post-Operative Adjuvant Radiochemotherapy in the Treatment of Gallbladder Cancer." (Baeza MR, ASTRO 2005, Abstract 2094)
** Retrospective. 49 patients with completely resected GB, treated adjuvantly with RT (WA + boost or boost only) + chemotherapy (5-FU or Gemcitabine)
** 5-year OS: 52%; treatment well tolerated
** Conclusion: "Adjuvant radiochemotherapy is a safe and useful treatment for gallbladder cancer after a macroscopically complete resection. The results achieved of 52% survival at 5 years in patients who have had a complete macroscopic resection, compares favorably with the survival reported after surgery alone for those patients."
* 1994 PMID 7536333 Mahe M, Radiother Oncol. 1994 Dec;33(3):204-8.
** Conclusion: "From this experience it appears that ERT in gall-bladder carcinoma is well tolerated, can obtain local control and prolonged survival after complete resection and good palliation in non-resectable tumors."
Prediction Model for ChemoRT Benefit
* Oregon; 2011 PMID 22067404 -- "A Nomogram for Predicting the Benefit of Adjuvant Chemoradiotherapy for Resected Gallbladder Cancer." (Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, Kim JS, Thomas CR. A Nomogram for Predicting the Benefit of Adjuvant Chemoradiotherapy for Resected Gallbladder Cancer. J Clin Onc, 2011, 29(35):4627-4632, http://dx.doi.org/10.1200/JCO.2010.33.8020)
** Nomogram
** SEER database 4180 patients from 1988-2003. Multivariate Cox proportional hazards model developed. Concordance index from boostrap modeling 0.71
** Conclusion: In absence of large randomized data, regression model can be used for individualized predictions of survival benefit from adjuvant RT

## Adjuvant Chemo

* Japan (1986-1992)
** Randomized. 508 patients (pancreas n=173, cholangio n=139, gallbladder n=140, ampulla n=56), s/p surgery. Stage II-IV. Arm 1) adjuvant chemo with mitomycin C + 5-FU 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 chemo 26% vs. observation 14% (SS); DSS 20% vs. 12% (SS)
*** Conclusion: There may be benefit for systemic chemotherapy

## Stage IV

* Tsukuba Japan 1976-90 PMID 1853615 -- Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder carcinoma. (1991 Todoroki T, World J Surg. 1991 May-Jun;15(3):357-66.)
** 86 pts with Stage IV. 30% resection, 50% palliative surgery, 20% no surgery
** 27 resected pts: 9 surgery alone, 17 IORT (20-30 Gy) +/- PORT (mean 36.4 Gy), 1 PORT
** 3-year OS: 10% resection + IORT, 0% surgery alone

## Review

* PMID 10430298 Houry S, Hepatogastroenterology. 1999 May-Jun;46(27):1578-84.
** Conclusion: "The results published encourage further trials in well defined populations. Radiotherapy seems to be a safe procedure, morbidity is minimal, and a slight effect on survival is observed after curative or palliative surgical procedures."