SUMMARISES THE ROLE OF RADIATION IN THE LIVER , GALL BLADDER AND PANCREAS

1. INDICATIONS , EVIDENCES AND
TECHNIQUES OF RT IN PANCREAS, LIVER
AND GALL BLADDER
DR.AMRITA RAKESH
DNB RESIDENT
BHAGWAN MAHAVEER CANCER HOSPITAL AND RESEARCH CENTRE
,JAIPUR

2. PANCREAS – CLINICAL AND RADIOLOGICAL
ANATOMY
• Pancreas - retro peritoneal structure
lying within the four parts of the
duodenum.
• Head of pancreas – anterior to IVC ,
opposite L1-L3.
• Body passes obliquely to the left
overlying the aorta, the left psoas
muscle and the splenic artery and
vein.
• Tail extends in front of the left kidney
to the hilum of the spleen.

5. CARCINOMA PANCREAS

7. OVERVIEW OF TREATMENT
1. Resection is the only chance for cure, and resectable patients should
undergo surgery without delay followed by adjuvant therapy.
2. Borderline resectable patients may benefit from neoadjuvant and then
surgery.
3. Unresectable may benefit from chemotherapy and chemoradiation.
4. Metastatic disease from chemotherapy or other palliative treatments.

8. • Surgical resection is prerequisite for long term control but is only
feasible in about 20% of patients, of whom only 30% will actually
have an adequate R0 resection margin of >1mm.
• Also – no evidence of metastatic disease, no obstruction or minimum
portal vein involvement ( <180 deg involvement over <1 cm).

9. Whipple Procedure
• Radical pancreaticoduodenectomy
• Used for cancer of the pancreas head only
• Removal of:
• Pancreas head
• Duodenum
• Stomach
• Portion of jejunum
• Gallbladder
• Spleen
• Duct anastomoses: pancreatic, common bile to jejunum

10. Where does RT fit?
• Adjuvant RT +/- CT
• Neo-adjuvant RT +/- CT
• Palliative RT

11. NEOADJUVANT THERAPY

12. SEER database
3,885 Resectable Pancreas Cancer
TREATMENT NUMBER MEDIAN SURVIVAL
NEOADJUVANT XRT 70 23 MONTHS
POST-OP XRT 1478 17 MONTHS
SURGERY ONLY 2337 12 MONTHS

13. ADJUVANT AND PALLIATIVE SETTING

15. Arch Surg. 1985 Aug;120(8):899-903.
Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative
resection (GITSG TRIAL)
Kalser MH, Ellenberg SS.
• N = 46 (completely resected with microscopically negative margins).
• Observation vs FU-based CT-RT.
• RT was given in split course (20 Gy/10#  2 week gap 20
Gy/10#).
• Interim analysis itself showed striking survival advantage for adjuvant
CT-RT.
• Median survival for observation vs adjuvant were 10.9 months vs 21
months. (p=0.03)

16. ESPAC – 1
Lancet 2001;358(9293):1576-1585
• N = 289 (completely resected)
• 4 arms: 1) observation 2)chemotherapy(5FU/FA) alone
3)CT-RT 4)CT-RT followed by chemotherapy alone.
• No statistically significant difference between the 4 arms.
• Chemo vs no chemo statistically significant median survival advantage
(20.6 months vs 15.5 months).
• Chemoradiation vs no chemoradiation  statistically significant median
survival disadvantage (15.9 months vs 17.9 months, p=0.05).

18. Eur J Surg Oncol. 2017 Apr
Clinical results of stereotactic body radiotherapy (SBRT) in the treatment
of isolated local recurrence of pancreatic cancer after R0 surgery: A
retrospective study.
Comito T1 et al.
• Retrospective analysis on patients treated with SBRT for isolated local
recurrence from resected pancreatic adenocarcinoma.
• prescription dose was 45 Gy in 6 fractions for all patients.
• Primary end-point -- freedom from local progression (FFLP).
• Secondary end-points -- overall survival (OS), progression free survival
(PFS) and toxicity.

19. RESULTS:
Median local recurrence disease free interval (DFI) was 14 months.
FFLP was 91% and 82% at 1 and 2-years, respectively.
Median PFS was 9 months.
Median OS was 18 months.
CONCLUSIONS:
SBRT seems to be an effective and safe therapeutic option for isolated local recurrence
of pancreatic cancer after surgery.

20. RTOG contouring guidelines for adjuvant RT for
pancreas
• Treatment Volumes: GTV
• By definition there is no GTV (tumor has been resected)
• Location of pancreatic tumor prior to resection must be reviewed and
contoured based on preoperative axial imaging/simulation
• Pre-operative diagnostic or simulation scans can be fused with post-
operative CT to facilitate localization of tumor bed
• Surgical and pathological information must be reviewed at time of
treatment planning

22. Treatment Volumes: CTV
• The post operative CTV is that area where there is likely to be the highest
concentration of residual sub-clinical tumor that can be treated with
radiotherapy without resulting in a treatment volume that encompasses an
excessive amount of normal organs and normal tissue.
1. Post-operative bed
• Based on location of initial tumor from pre-operative imaging and
pathology reports pathology reports
2. Anastomoses
• Pancreaticojejunostomy(PJ)
• Choledochal or hepaticojejunostomy

23. 3. Abdominal nodal regions
• Peripancreatic
• Celiac
• Superior mesenteric
• Porta hepatis
• Para-aortic

24. ROI Delineation: CA and SMA
• The most proximal 1.0 -1.5 cm of the celiac artery (CA)
• The most proximal 2.5 to 3.0 cm of the superior mesenteric artery
(SMA)

25. ROI Delineation: PV
• Contour from the bifurcation of the PV . The PV bifurcation can be
extrahepatic or almost intrahepatic.

26. PROTAL VEIN
TUMOR BED
PANCREATICOJEJUNOSTOMY
CELIAC ARTERY
AORTA
IVC

27. SUPERIOR MESENTERIC ARTERY

28. ROI Delineation: Post -op Bed
• preoperative imaging or simulation
• Surgical clips placed for purposes of delineating areas of concern
intraoperatively

29. ROI Delineation: PJ and Aorta
• The pancreaticojejunostomy (PJ) is identified by following the
pancreatic remnant medially and anteriorly until the junction with
the jejunal loop is noted.
• The aorta (Ao) from the most cephalad contour of either the celiac
axis PV or PJ to the bottom of the L2 vertebral body. If the GTV
contour extends to or below the bottom of L2 then contour the aorta
towards the bottom of the L3.

30. ROI EXPANSIONS
• Expansion 1 – 1.0 cm expansion on PV, PJ, CA, and SMA
• Expansion 2 – 2.5 to 3.0 cm to the right,1.0 cm to the left, 2.0 to 2.5
cm anteriorly, 0.2 cm posteriorly on Aorta
• CTV – Boolean addition (merging) of Expansion 1 and 2 – Confirm that
CTV encompasses tumor bed and contoured clips
• PTV – 0.5 cm expansion on CTV

32. PALLIATIVE
• AP/PA beams or an anterior and two lateral wedged beams may be
used.
COMPLEX
Using 6-10 MV photons , CT forward planning with volumes shaped
with MLC may be used to minimize dose to kidneys , liver , spinal cord
and small bowel in 3D-CRT.
Full inverse planning using dose constraints to OAR and IMRT with
three anterior and 2 lateral or seven beam plan ,may be optional to
reduce dose to the small bowel.

33. DOSE FRACTIONATION
• Radical (in combination with chemo with GEM or 5-FU).
45-50.4 Gy in 25-28 fractions of 1.8 Gy given in 5-5 ½ week.
Surgical resection may be followed 8 weeks post RT.
• Adjuvant (resected)
45-46 Gy in 1.8-2.0 Gy/# to tumor bed, surgical anastomoses and
adjacent lymph node basins, followed by additional 5-9 Gy to the
tumor bed and anastomoses if clinically appropriate. Escalation above
54 Gy should ideally be avoided.

34. Unresectable or locally advanced-
45-50.4 Gy in 1.8-2.0 Gy/# in chemoradiation
SBRT doses of three fractions (total 30-45 Gy) or 5 fractions (25-45 Gy).
Palliative
30 Gy in 10 daily fractions of 3 Gy given in 2 weeks.
This dose may be used to palliate pain or in association with more intensive
chemotherapy.

36. LIVER

37. Parameters 1 2 3
ENCEPHALOPATHY none 1-2 3-4
ASCITES absent slight moderate
ALBUMIN (g/dl) >3.5 2.8-3.5 <2.8
PROTHROMBIN TIME
SECONDS OVER CONTROL
INR
<4
<1.7
4-6
1.7-2.3
>6
>2.3
BILIRUBIN (mg/dl)
*FOR PRIMARY BILIARY
CIRRHOSIS
<2
<4
2-3
4-10
>3
>10
CHILD-PUGH SCORE

38. CLASS A GOOD OPERATIVE
RISK
5-6
CLASS B MODERATE
OPERATIVE RISK
7-9
CLASS C POOR OPERATIVE RISK 10-15

39. TREATMENT OPTIONS
• SURGICAL RESECTION –
remove gross tumor with a margin of 1 to 2 cm of normal liver.
5-yr survival after resection exceeds 50%.
The main limiting factor for resection – LIVER FUNCTION.
• LIVER TRANSPLANTATION –
Selection criteria-
solitary tumor upto 5cm or up to 3 nodules with tumor size <3cm
[UNOS criteria].

40. PRINCIPLES OF SURGERY
• Adequate liver function  child pugh class A , without portal
hypertension
• Solitary mass without major vascular invasion.
• Adequate future liver remnant (FLR) (atleast 20%without cirrhosis
and at least 30-40% with child pugh class A cirrhosis: adequate
vascular and biliary inflow and outflow.
• For patients with chronic liver disease being considered for major
resection , preoperative portal vein embolization should be
considered.

41. PRINCIPLES OF LOCOREGIONAL THERAPY
• PERCUTANEOUS ABLATION-
Early stage HCC pt not suitable for resection or transplantation.
Ethanol injection – necrosis rate 90% to 100% of the HCC <2cm
HCC >3cm,necrosis rate reduced to 50%.
RFA – best results with a single tumor <4cm diameter.
• TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION –
Intra-arterial embolization of tumor artery with lipiodol.
Also as a palliative measure for unresectable HCC.
• Drug eluting beads-TACE

42. • Radioembolisation(RE) with yttrium-90 microspheres.
• Relatively contraindicated in patients with bilirubin >3 mg/dl.
• RE with yttrium-90 has increased risk of radiation induced liver
disease in patients with bilirubin over 2 mg/dl.
• Also contraindicated in main portal vein thrombosis and child-pugh
class C.

43. RADIOTHERAPY
• HCC is a radiosensitive tumor.
• Major drawback
* poor radiation tolerance of adjacent normal liver
* the difficulty of tumor localization.
• EBRT is treatment option (category 2B) for patients with unresectable
disease, or those who are medically inoperable due to comorbidity.

44. • Options- 3D conformal , IMRT , SBRT.
• SBRT (1-5 fractions) is often used for patients with 1-3 tumors. Could
also be considered for larger lesions or more extensive disease,if there
is sufficient uninvolved liver and liver radiation tolerance can be
respected.
• No extrahepatic disease.
• Palliative EBRT for symptoms control.

49. J Clin Oncol. 2013 May
Sequential phase I and II trials of stereotactic body radiotherapy
for locally advancedhepatocellular carcinoma.
Bujold A1 et al.
• N = 102
• Two trials of SBRT
• 2004 to 2010.
• All patients had Child-Turcotte-Pugh class A disease, with at least 700
mL of non-HCC liver.

50. • The SBRT dose range was 24 to 54 Gy in six fractions.
Median dose = 36 Gy/6 #
• Primary end points were toxicity and local control at 1 year (LC1y),
defined as no progressive disease (PD) of irradiated HCC by RECIST
(Response Evaluation Criteria in Solid Tumors).
• LC1y was 87% (95% CI, 78% to 93%)
• Median overall survival was 17.0 months (95% CI, 10.4 to 21.3
months)

52. Rep Pract Oncol Radiother. 2017 Jul-Aug
Validation of the liver mean dose in terms of the biological effective dose
for the prevention of radiation-induced liver damage.
Doi H et al.
• AIM:
determine the optimal mean liver biologically effective dose (BED) to
prevent radiation-induced liver disease (RILD) in stereotactic body
radiation therapy (SBRT).
• N = 50

53. • All distributions of the physical doses were transformed to BED2 using
the linear-quadratic model.
• CONCLUSION:
A mean BED2 of 73 and 16 Gy for the whole liver appeared appropriate
to prevent RILD in patients with Child-Pugh classes A and B,
respectively. The mean BED2 for the liver correlated well with the PTV.

54. Int J Radiat Oncol Biol Phys. 2017 Apr
Role of Stereotactic Body Radiation Therapy Before Orthotopic Liver
Transplantation: Retrospective Evaluation of Pathologic Response and
Outcomes.
Mannina EM et al.
• PURPOSE:
To analyze the results of stereotactic body radiation therapy (SBRT) in
patients with early-stage, localized hepatocellularcarcinoma who
underwent definitive orthotopic liver transplantation (OLT).
• N = 38

55. • Median follow up = 4.8 yrs from OLT.
• 9 of 38 patients (24%) recurred
• 10 of 38 patients (26%) died
• Kaplan-Meier estimates of 3-year overall survival and disease-free
survival are 77% and 74%, respectively
• Pathologic response rate (complete plus partial response) was 68%.
• CONCLUSIONS:
Stereotactic body radiation therapy before to OLT is a well-tolerated
treatment providing 68% pathologic response, though 74% of explants
ultimately contained viable tumor.

56. J Hepatol. 2017 Feb
Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant
in patients with hepatocellular carcinoma. An intention-to-treat analysis.
Sapisochin Get al.
• N = 379, treated with either SBRT (n=36, SBRT group), TACE (n=99,
TACE group) or RFA (n=244, RFA group).
• July 2004 to December 2014

57. From the time
of listing
1 yr survival 3 yr survival 5 yr survival
SBRT 83% 61% 61%
TACE 86% 61% 56%
RFA 86% 72% 61%

58. From the time
of transplant
1 yr survival 3 yr survival 5 yr survival
SBRT 83% 75% 75%
TACE 96% 75% 69%
RFA 95% 81% 73%
In conclusion, SBRT can be safely utilized as a bridge to LT in patients
with HCC, as an alternative to conventional bridging therapies.

60. Onco Targets Ther. 2016; 9: 7169–7175.
Effect of CyberKnife stereotactic body radiation therapy for
hepatocellular carcinoma on hepatic toxicity
Ping Liang,1,* Cheng Huang,2,* Shi-Xiong Liang,2,3 Ye-Fei Li,3 Shang-Xiao Huang,2 Zu-Ping Lian,1 Jian-Min
Liu,1 Yang Tang,1 and Hai-Jie Lu4
• N = 104
• August 2009 to December 2012.
• Average dose = 42.81±4.78 Gy (28–55 Gy)
• Average fraction size = 8–16 Gy to the planning target volume
• Average fractions = 3.31±0.81 (2–6 fractions)

61. • Radiation-induced hepatic toxicity (RIHT), defined as an increase of at least
two points of bilirubin within three months following CyberKnife SBRT,
occurred in 13 of the 104 patients (13/104, 12.5%).
• Conclusion
CyberKnife SBRT is a feasible and safe treatment for HCC with regard to
hepatic toxicity, while V25 and normal liver volume may be an independent
factor of grade 2–3 hepatic toxicity and RIHT, respectively.

62. Radiother Oncol.
Transcatheter arterial chemoembolization in combination
with radiotherapy for unresectable hepatocellular carcinoma: a
systematic review and meta-analysis.
Meng MB1, Cui YL, Lu Y, She B, Chen Y, Guan YS, Zhang RM.
• 17 trials
• 1476 patients
• Therapy I  TACE + RT & Therapy II  TACE alone
• 5 of total were Randomized Controlled Trials (RCTs) and 12 were Non-
randomized Controlled Clinical Trials (CCTs).
• Our results showed that Therapy I, compared with Therapy II, significantly
improved the survival and the tumor response of patients, and was thus more
therapeutically beneficial. Serious adverse events were not increased exception
for total bilirubin (TB) level.

63. RADIATION DOSES
Series Number of
patients
Radiation dose
(Gy)
Chemotherapy Response
rate(%)
Stillwagon et.
al (RTOG)
135 21, 3 qd Concurrent
ADR, 5-FU
22
Order et al.
(RTOG)
105 21, 3 qd + I-131
10-12 x 2
courses
Concurrent
ADR & 5-FU
48
Seong et al. 27 51.8(mean), 1.8
qd
none 67
Dawson et al. 25 58.5 (median) ,
1.5 bid
Concurrent HAI
Fluorodeoxy-
uridine
68

64. Design of treatment field
• Aruga et al. studied organ motion using CT-images during static
exhalation and static inhalation phases. The variation ranged from 2.6
to 23.7 mm: from 0.4 to 5.9 mm in lateral direction , 2.2 to 24.5 mm
in longitudinal direction , and 0.2 to 11.7 mm in the vertical
direction.
• Breath-gating or breath holding irradiation may help.
• In general, margin in lateral direction = 6 to 9 mm.
• Vertical direction = 9 to 12 mm
• Superior direction = 10 mm
• Inferior direction = 19 to 21 mm.

67. Potential RT toxicities
Clinical
• Radiation induced liver disease (RILD)
1. CLASSIC – anicteric hepatomegaly , ascites,
elevated liver enzymes (ALP > AST/ALT).
2. NON-CLASSIC – Elevation of transaminases.
1 week-3 months
• Biliary obstruction ,stricture.
• GI – stomach , intestinal bleeding , obstruction
, fistula.
Pathological
• Hyperemia
• Veno-occlusive disease
• Central venous congestion
• Atrophy to adjacent hepatocytes.

68. EBRT for Gallbladder Cancer
• ADJUVANT
Postoperative EBRT using conventional 3D conformal RT or IMRT is an
option for resected Extrahepatic chlangiocarcinoma and gallbladder
cancer.
Target volume should cover the draining regional lymphnodes to 45
Gy @ 1.8Gy/# and 50.4 to 59.4 Gy @ 1.8 Gy/# to the tumor bed
depending on margin positivity.

69. • UNRESECTABLE
Conventionally fractionated radiotherapy with concurrent 5-FU based
chemotherapy to standard or high dose is acceptable for intrahepatic
and extrahepatic tumors.
SBRT (1-5 fractions) is an acceptable option for intrahepatic tumors.

70. CONCLUSION
• RT may be a treatment option in patients who are unsuitable for other
established local therapies
• RT is safe and effective in patients with normal underlying liver
function.
• Good local control = survival benefit ?

72. RT in portal vein thrombosis
• PVT is poor prognostic factor. Precludes surgery and arterial-directed
therapies.
• RT has been used with PVT – sometimes in combination with TACE.
• Recanalization occurs in 30-80% post RT.
• However, it is a slow process – median time to maximum response is 6
months.
• Median survival 4 to 13 months.