This document summarizes a presentation on the role of stereotactic body radiation therapy (SBRT) in treating upper gastrointestinal malignancies. It begins with an introduction to SBRT and its differences from conventional radiation therapy. It then discusses SBRT's role in treating metastatic liver lesions, primary liver malignancy, cholangiocarcinoma, and pancreatic malignancy. The document reviews the linear quadratic model for predicting SBRT effects and the risk of radiation-induced liver disease. It outlines the evolution of radiation therapy for liver malignancies including the emergence of SBRT, which allows higher ablative doses to be delivered to tumors while sparing more normal liver tissue.
1. Role of SBRT in upper GI malignancy
Dr . Supriya Sonaje
Junior Resident , Radiation oncology
department , Tata memorial hospital .
2. Flow of the presentation :
▪ Brief introduction to SBRT
▪ Role in metastatic liver lesions
▪ Role in primary liver malignancy
▪ Role in cholangiocarcinoma
▪ Role in pancreatic malignancy
▪ Recent advances
▪ Future perspectives
3. What is S.B.R.T. ?
▪ Stereotactic body radiation therapy is the term applied by
American society of the therapeutic radiology and
oncology (ASTRO) for the management and delivery of
image guided high dose radiation therapy with tumor
ablative intent within a course of treatment that does not
exceed 5 fractions .
▪ It’s a hypo-fractionated regimen .
4. How does it differ from the conventional 3DCRT/IMRT?
CHARECTERISTIC 3DCRT/IMRT SBRT
DOSE /FRACTION 1.8 -3.0 Gy 6-30 Gy
NO OF FRACTIONS 10-30 1-5
TARGET DEFINATION GTV/CTV/PTV GTV CTV / ITV /PTV
MARGIN centimeters Millimeters
REDUNDANCY IN GEOMETRIC
VARIATION
No yes
MAINTENANCE OF HIGH SPATIAL
TARGETINGACCURACY FORTHE
INTIRETREATMENT
Moderately enforced Strictly enforced
NEED FOR RESPIRATION MOTION
MANAGEMENT
Moderate Highest
STAFFTRAINING Highest Highest + special SBRT training .
Stereotactic body radiation therapy :report of AAPM task group 101, Benedict et al
5. How does it act ?
▪ In conventional fractionation radiotherapy , tumor volume is irradiated
along with margins to account for organ motion and set up errors , where
total dose is governed by the tolerance of the adjacent normal tissue
governed by the concept of linear quadratic model and 4 R’s of radiobiology
.
▪ By contrast , SBRT exploits the potent radiobiological effects of the large
dose /fraction which transcends the consideration of 4 Rs .
▪ Large dose per fraction high biologically effective dose ablative effect
.
6. Is linear quadratic model capable of predicting the
effect of SBRT ?
▪ SBRT falls past the shoulder in LQ model .
▪ LQ model likely overestimates the cell killing in
SBRT , making it’s use questionable .
▪ Another issue is , SBRT treatment time is
significantly longer due to high dose prescription ,
it has a significant impact on tumor control as
intrafractional repair takes place during this time.
7. We need a new model …
▪ This modified LQ model accounts
for ongoing intrafraction repair
process .
▪ Limitation – doesn’t explain the
mechanism of cell death( such as
antiangiogenic effect of endothelia
apoptotic cells ), beyond the DNA
damage based injury .
▪ Geurerro introduced the dose
protraction factor (G), repair rate
(λ) and delivery time (T) in the LQ
model .
8. In metastasis …
▪ The specific argument for the application of SBRT in the settings of
grossly evident metastasis can constructed in accordance with
some conceptual theories –
1. empiric/phenomenological concept - with locally aggresive
therapies like surgical resection and RFA – reports of 3-5 yr survival .
Then on one level , SBRT is a valid noninvasive substitute if it provides
similar efficacy with same or less toxicities .
2. Pattern of failure – tendency to recur at site initially involved by the
tumor . to target these sites .
9. In metastasis …
3. In settings of oligometastasis- the theory proposes oligometastasis
is the stage intermediate between completely absent and widely
metastatic , which might be cured if these limited numbers of sites of
metastasis are eradicated .
4. Norton simmon hypothesis – suggests the systemic burden of the
cancer cells increases from initially low to a lethal potential level
through a phase of exponential growth - local intervention before
this exponential growth starts .
10. In metastasis …
5. Immunomodulation – whereby effort is made to exploit the systemic
antitumoral immune response generated in certain conditions of
radiations induced cell deaths .
6. Possible use in reirradiation .
11. Evolution of radiotherapy in liver
malignancy
▪ The liver was first a target for radiation therapy as early as
1924 …..
▪ But …The use of conventional external beam radiation
therapy (RT) as a curative technique, was hampered by
early evidence of radiation induced liver injury (RILD)– in
1965 Ingold et al. published the first report of dose-limiting
toxicity after whole-liver RT, demonstrating a 44% risk of
RILD among patients treated with 35 Gy.
12. Evolution of radiotherapy in liver malignancy
▪ RTOG 84 05 (1993) -Phase I/II Dose-EscalatingTrial of Accelerated
Fractionation in the Palliative Irradiation of Hepatic Metastases
from Primary Cancer of the GITract.
▪ Objectives-1. to determine whether progressively higher total doses
of hepatic irradiation can prolong survival . 2. to refine existing
concepts of liver tolerance for fractionated external radiation
employing a fraction size which might be appropriate in clinical
protocols evaluating elective or adjuvant radiation of the liver.
▪ Enrolled -173 patients with liver metastasis from known GI malignancy
.
▪ Method- whole liver irradiation to the doses 1.5 Gy/fx BID in the
groups of 27 Gy ,30 Gy and 33 Gy .
13. Evolution of radiotherapy in liver
malignancy
RTOG 84 05 continues..
▪ Results - progressively larger total doses of radiation did not prolong
median survival or decrease the frequency with which liver metastases
were the cause of death. rates of late liver injury among patients treated
with 27–30 Gy and 33 Gy (1.5 Gy/fraction) of 0% and 10%, respectively.
▪ Concluded - whole-liver RT was deemed unsafe at relatively low doses (i.e.,
33 Gy in fractions of 1.5 Gy), far below doses needed for adequate tumor
control.
14. What exactly is this RILD ??
▪ RILD can be seen in two different scenarios :
▪ Classic RILD : the syndrome is composed of -fatigue, weight gain, increased
abdominal girth, hepatomegaly, anicteric ascites, and an isolated elevation in
alkaline phosphatase out of proportion to other liver enzymes.
▪ typically within 4 months following hepatic radiation therapy.
▪ Pathophysiology –VOD( veno -occlusive disease ) - radiation injury to
sinusoidal endothelial cells and central vein endothelium --> activation of the
coagulation cascade, accumulation of fibrin and formation of clots in the
central veins and hepatic sinusoids deposition of reticulin and collagen
occludes the vessel vascular congestion and decreased oxygen delivery to
the central zone death of centrilobular hepatocytes and atrophy of the inner
hepatic plate hepatic dysfunction observed clinically in RILD.
15. What exactly is this RILD ??
▪ Non classic RILD – seen in the settings of the cirrhosis and viral hepatitis .
▪ Characterized by - jaundice and/or markedly elevated serum transaminases (> 5
times the upper limit of normal) within 3 months of completion of hepatic RT.
▪ Pathophysiology – in addition to the endothelial damage seen in classic RILD ,
direct hepatocyte damage also operates . hepatocellular loss and dysfunction
along with hepatic sinusoidal endothelial death and stellate cell activation ,
secondary to radiation-induced mitotic catastrophe of regenerating
hepatocytes in cirrhotic livers and reactivation of Hepatitis B virus in patients
with chronic viral hepatitis.
▪ Chou et al. demonstrated that the HBV reactivation due to a bystander effect,
whereby IL-6 is released from endothelial cells after irradiation
16.
17. Evolution of radiotherapy in liver malignancy
▪ Use of 3D-CRT –The ability to conform RT
to pre-specified targets led many to revisit
the idea of delivering higher, tumoricidal
doses of radiation while sparing normal
hepatic tissue.- era of partial liver
irradiation .
In 1991 , Emami et al outlined projected
tolerance doses for partial liver irradiation.
▪ But , this data is for normal tissue
tolerance and used for estimating normal
tissue complication probability ….
Volume of the
irradiated liver
TD (5/5)
(tolerated dose
associated with
5%complication at 5
yrs)
TD(50/
5)(Tolerate
d dose asso.
With 50 %
complication
s at 5 yrs)
1/3rd liver
volume
50 Gy 55 Gy
2/3rd liver
volume
35 Gy 45 Gy
Whole liver
volume
30 Gy 40 Gy
18. Further challenges in the liver irradiation
especially in settings of primary liver malignancy ….
HCC is a complex disease in the background of pre-neoplastic cirrhotic
process where liver function is already deranged .
The disease is heterogeneous around the world reflecting the different
underlying epidemiological background and risk factors.
Need for the tolerance doses for the individualized cases……
19.
20. Evolution of radiotherapy in liver malignancy
▪ Analysis of radiation-induced liver disease using the Lyman
NTCP model-Laura Dawson , et , university of Michigan .
▪ Objective -To describe the dose-volume tolerance for radiation-induced liver
disease (RILD) using the Lyman-Kutcher-Burman (LKB) normal tissue
complication probability (NTCP) model.
▪ Duration of the study -1987 to 1999
▪ Patient characteristics – total 203 patients with mixed population (HCC,
Cholangiocarcinoma and metastatic lesions)
21. ▪ Treatment protocol – –radiation - whole liver irradiation(n-41 ), whole
liver irradiation followed by partial liver boost (n-20) and partial liver
irradiation (n-142).Twice daily in 11 fractions/wk, 1.5–1.65 Gy/fraction,
with a minimal interfraction interval of 4–6 h.The median dose -52.5 Gy
(range 24–90) (with 3DCRT technique)
▪ Concurrent chemotherapy - infusion hepatic artery fluorodeoxyuridine
(FUdR) (n 169) or bromodeoxyuridine (BUdR) (n 34) first 4 weeks of RT.
With 2-week break in RT after 2 weeks to minimize risk of complications
related to the hepatic artery catheterised for chemotherapy delivery.
▪ Patient followed up to 4 months after completion of treatment ,
complication was defined as RTOG Grade 3 or higher RILD < or =4
months after completion of radiotherapy.
22. ▪ Methodology - Normal liver (liver minus gross tumor) DVHs obtained for all
203 patients.
▪ The physical dose values in 3D dose distribution for each treatment course
were converted to normalized isobiologic effective doses at 1.5 Gy/fraction
using the LQ model (alpha/beta-2Gy) before computation of the
composite dose distributions from which the DVHs were computed.
▪ the Kutcher and BurmanVeff DVH reduction scheme was used to convert
the nonuniform complex dose distributions into “equivalent” uniform dose
distributions. (Veff -the normal liver volume, which, if irradiated uniformly
to the reference dose, would be associated with the same NTCP as the
nonuniform dose distribution actually delivered)
▪ Mean dose of each patient was calculated .
23. ▪ Indivisualization of NTCP –
▪ The NTCP model parameters TD50(1), m (steepness of the
dose-response at TD50), and n (volume effect)were adjusted
to maximize the probability of predicting complications for
those patients who experienced complications and
maximize the probability of predicting no complications for
those patients who were complication free.
24. ▪ Results -Of 203 patients treated with focal liver irradiation, 19 developed
RILD.
▪ strong volume effect for RILD and a correlation of NTCP with the mean
liver dose.
▪ No cases of RILD were observed when the mean liver dose was <31 Gy.
▪ in addition to NTCP and the mean liver dose, a primary hepatobiliary
cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery
chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender
were associated with RILD.
▪ Conclusion -liver exhibits a large volume effect for RILD, suggesting that
the mean liver dose may be useful in ranking radiation plans.
25. Further step in evolution of RT in liver
…
1.Phase IITrial of High-Dose conformal RT
With Concurrent Hepatic Artery Floxuridine
for Unresectable Intrahepatic Malignancies, L.
Dawson et al , UM .
▪ Duration – 1996-2003
▪ Patients -128 (mixed population)
▪ RT dose – median 60.75 Gy (1.5-
Gy fractions bid).
▪ BED-
▪ Median survival-15.8 months
▪ 3yr survival- 17%
2.A multicenter retrospective cohort study of
practice patterns and clinical outcome on
radiotherapy for hepatocellular carcinoma in Korea
▪ Duration –2004-2005
▪ Patients – 398 from 10 different institute ,
advanced HCC.
▪ total dose of ≥45 Gy
▪ BED –
▪ Median survival-12 months
▪ 2 yr OS- 27.9 %
26. ▪ Both the studies concluded - doses >/=75 Gy were
associated with higher overall survival (23.9months
vs.14.9months).(Laura et al)
▪ BED >53.1 Gy were shown by multivariate analysis to be
significant factors for a better prognosis(Korean group)
▪ Also observed -primary hepatobiliary tumors recurred
primarily locally, illustrating the importance of intensified
local therapy for these tumors.
27. Emergence of SBRT….
▪ Liver is parallel organ , reflecting much larger doses are
tolerated well if only a small particular volume is irradiated
…
▪ advances in accounting for tumor motion, target
localization, and treatment delivery systems have allowed
SBRT to create highly conformal, dose escalated, and
ablative treatment for primary hepatic malignancies. In this
way, SBRT has offered a new and promising form of
noninvasive and definitive treatment in this setting.
28. First liver SBRT- Bloomgren et al , Karolinska
University … Acta Oncologica Vol. 34, No. 6, pp. 861-870, 1995
▪ Total patients(n)-31 , total patients with liver lesion -9
▪ treated with 16–66 Gy in 1–3 fractions
▪ Objective response rate – 70%
30. AUTHOR
ANDTRIAL
DESIGN
(N) TYPE OF METS TUMOR
VOLUME
RT
DOSE(Gy)
BED(Gy
)
TOXICITY OUTCOME
Herfarth2004,
phaseI/II
35 Not reported 1–132 mL
(median,
10 mL)
Dose
escalation,
14–26 Gy (1
frx)
33.6-
93.6
No
significant
toxicity
1–yr LC, 71%
18–mo LC, 67%
1–yr OS, 72%
MendezRome
ro, 2006, I/II
(HCC+METS )
17 CRC (14),Lung (1)
Breast(1),Carcinoi
d (1)
1.1–322
mL
(median,
22.2 mL)
30–37.5 Gy
(3 frx)
60-84.37 2 Grade 3
liver
toxicities
2-yr LC, 86%
2-yr OS, 62%
Hoyer, 2006,II 44 CRC (44) 1–8.8 cm
(median,
3.5 cm)
45 Gy (3
frx)
112.5 1 liver
failure
2 severe
late GI
toxicities
2-yr LC, 79%
(by tumor) and 64%
(by patient)
Rusthoven ,
2009,I/II
47 CRC (15),Lung (10)
Breast (4),Ovarian
(3),Esophageal (3)
HCC (2),Other (10
0.75–97.98
mL
(median,
14.93 mL)
Dose
escalation,
36–60 Gy (3
frx)
79.2-180 No RILD
Late Grade
3/4
<2%
1-yr LC, 95%
2-yr LC, 92%
Median survival,
20.5 mo
31. AUTHOR
AND
TRIAL
DESIGN
(N) TYPE OF METS TUMOR
VOLUME
RT
DOSE(Gy)
BED(
Gy)
TOXICITY OUTCOME
Lee ,
2009I/II
68 CRC (40),Breast (12)
Gallbladder (4),Lung
(2),Anal canal (2)
Melanoma (2),Other
(6)
1.2–3,090
mL
(median,
75.9 mL)
Individualiz
ed dose,
27.7–60 Gy
(6 frx)
40.4-
120
No RILD
10% Grade
3/4
acute toxicity
No Grade 3/4
late
toxicity
1-yr LC, 71%
Median survival,
17.6 months
Ambrosino ,
2009,
prospective
cohart
27 CRC (11)
Other (16)
20–165 mL
(median, 69
mL)
25–60 Gy (3
frx)
33-180 No serious
toxicity
Crude LC rate 74%
Goodman ,
2010,I.
19 CRC (6),Pancreatic (3)
Gastric (2),Ovarian (2)
Other (6)
0.8–146.6
mL
(median,
32.6 mL)
Dose
escalation,
18–30 Gy (1
frx)
50.4-
120
No dose–
limiting
toxicity
1-yr local failure, 23%
2-yr OS, 49%
32. Dose individualization in study by Lee et al for
radiation dose escalation
▪ Patients were stratified according to the effective volume to be irradiated
33. What exactly is this Veff (effective volume)?
▪ According to definition -the liver volume minus all GTVs, which, if irradiated
uniformly to the treatment dose, would be associated with the same risk of
toxicity as the non uniform dose distribution delivered.
▪ To simplify it , consider we are prescribing the dose of 60 Gy to the liver and if
2/5 liver got 60 Gy, 1/5 got 30 Gy, 1/5 got 20 Gy, 1/5 got 0 Gy.
▪ TheVeff at reference dose 60 Gy = 2/5*60/60 + 1/5*30/60 + 1/5*20/60 +
1/5*0/60 = 0.567
34. N- 79 patients with metastatic liver lesion
▪ Patients were stratified according to the effective volume of the liver
(Veff) irradiated . -lowVeff 0.22, midVeff 0.22 to 0.51, and highVeff 0.51
to 0.8).
▪ RILD risk probability was estimated using the NTCP curves individualized
by U.M. A correction for the dose fractionation of the liver dose volume
histograms was made assuming alpha/beta - 2.5 Gy.
▪ isotoxic” dose levels were specified, with estimated RILD risks of 5%, 10%,
and 20% for low mid and highVeff respectively .
37. ▪ Which tumors and patients should be considered candidates for SBRT?
▪ Among the reviewed studies of SBRT for liver metastases, there is significant
heterogeneity concerning patient selection (CRC vs. other primary subtypes),
tumor volumes, total dose, dose per fraction, and dosimetric planning
criteria.
▪ ideal candidates for liver metastasis SBRT have a good performance status
ECOG - 0–1), possess adequate hepatic function, have noextrahepatic
disease, and have an uninvolved liver volume of 700 mL or greater
38. ▪ Does intensification of radiation dose improve the treatment in SBRT ?
▪ A dose response for local control exists, although there is uncertainty in the
optimal threshold dose beyond which local control is improved. A total
prescription dose of 48 Gy or higher in 3 fractions is recommended when
possible.
▪ What toxicity can be expected after SBRT?.
▪ Grade 1 or 2 toxicity is common after SBRT, but severe toxicity (Grade $3) is
uncommon.Toxicity is more likely in patients receiving a high dose to the
bowel or to large volumes of the liver.
40. • 5th most common cancer worldwide and 2nd most common cause of cancer deaths after
lung cancer .
• 5 year survival rate being less than 10% in untreated cases .
41. AJCC 7th edition : primary liver cancer
T1- Solitary tumor without vascular
invasion
T2-solitary tumor with vascular invasion or
multiple tumors not more than 5 cm
T3 –T3a -multiple tumors more than 5 cm
T3b-single tumor or multiple
tumors of any size involving a major branch
of the portal vein or hepatic vein
T4 – tumor(s) with direct invasion of
adjacent organs other than gallbladder or
perforation of visceral peritoneum
▪ N0- no regional metastasis
▪ N1- regional lymph node metastasis
(Regional LNs include – hilar ,
hepatoduodenal ligament lymph nodes,
inferior phrenic, and caval lymph nodes)
M0- no distant metastasis
▪ M1- distant metastasis
42. Is AJCC TNM staging capable of deciding the
management and prediction of prognosis in
the liver cancer patients ?
▪ Answer :NO
▪ WHY?
TNM staging contains variables only related to the tumor stage and has a poor
prognostic value .
▪ Need for a valid cancer staging that should serve to select the appropriate
primary and adjuvant therapy, to estimate the prognosis, and also to assist in
the evaluation of the results of treatment, and to exchange information
without ambiguity .
45. EASL & EORTC guidelines for the management of HCC
46.
47.
48.
49. AUTHOR INSTITUTE N CP
CLAS
S
TUMOR
VOLUME
RT DOSE MEDIAN
(RANGE)
BED 1YR
OS
1YR
LC
TOXICITI
ES>/=
GRADE3
Tse
et
al.2008
Princess
Margaret
Hospital,
Canada,
phase I
31 A 9–1,913
mL
36
(24–54) Gy /6
fractions
33.6-
102.6
48% 65% 28%
M´ende
z
Romero
et
al.2006
Erasmus
MC,
Netherland
s phase I/II
8 A, B 0.5–7.2
cm
25–37.5GY/3-5
fractions
46-
65.62
75% 75% 12.5%
C´arden
es
et
al.2010
Indiana
University,
USA ,phase
I
17 A,B #6 cm
(cumulativ
e)
36–48 Gy 3-4
fractions
79.2-
105.6
75% 100% 18%
50. AUTHOR INSTITUTE N CP
CLASS
TUMOR
VOLUME
RT DOSE BED Media
n OS
1YR
LC
TOXICITI
ES>/=
GRADE3
Kang
et
al.2012
KIRMS, Korea
phase II
47 A,B 1.3–8 cm 57
(42–60)/3
fractions
100.8-
180
69%
at
2
year
s
95%
at
2
year
s
26%
Ibarra
et
al.2012
Multi-
institutional ,
pooled analysis
21 A,B 9.5–
1,493.8
mL
30
(18–50)/I-10
fractions
50.4-
75
87% 64% 8%
RILD
only
Bujold
et al
2013
Princess
Margaret
Hospital,
Canada, phase
I/II
102 A 1.4–23.1
cm
36
(24–
54)/6fractio
ns
33.6-
102.6
55% 87% 36%
51. SBRT Vs other radical treatment alone
▪ There are no prospective randomized studies to date comparing the
relative efficacy of SBRT with other treatments for HCC such as surgery
orTACE.
▪ In a retrospective series from Tianjin Medical University in China, 26
patients who underwent microscopic gross total resection (R0)were
compared with 22 patients treated with Cyber Knife SBRT for stage I
HCC.
▪ This series showed no significant difference in 3-year survival rates with
surgery versus SBRT (69.2% vs. 57.1%, p5.49), although this study was
nonrandomized and included a small number of patients.
52. SBRT in cases with tumor vascular thrombosis
▪ TVT, involving the portal or hepatic veins, represents a subset of patients with
advanced HCC with a particularly poor prognosis.
▪ Unfortunately, patients withTVT are ineligible for many standard treatments
such as surgery, PEI, and RFA, particularly when the thrombus affects hilar or
major portal veins.
▪ untreated patients withTVT have median survival of only 2–4 months.
▪ Radiation to portal venous tumor thrombus was first reported byTakagi et al.
in 1989 and achieved a histologic and/or angiographic response in 2 of 7
patients (29%).
▪ Despite limited numbers, these data have presented SBRTas a potential
therapy with or withoutTACE for patients with advanced HCC andTVT.
53. RT in TVT . . .
Author INSTITUTE N TECHNIQ
UE
TUMOR
VOLUME
RT DOSE BED 1YR
OS
MS TOXICI
TIES>/=
GRADE
3
Lin et al.
2006
Taipei,
Taiwan,
Prospective
study
9
7
SBRT
3D-CRT
6.5 cm
(median
)
13.8 cm
(median
)
45 GY/15
fractions
45Gy/25fra
ctions
58.5
53.1
6mont
hs
6.7mo
nths
Bujold
et
al.2013
Princess
Margaret
Hospital,
Canada,prosp
ective study
56 SBRT 1.8–23.1
cm
36
(24–
54)Gy/6
fractions
33.6-
102.6
44% 10.6
month
s
36%
54. SBRT as Bridge to Liver Transplantation
▪ OLT is a potentially curative treatment option for some patients with
advanced HCC, particularly those within the Milan criteria.
▪ Given the limited availability of donor organs, up to 20%of patients
with advanced HCC experience progressive disease while on a
waitlist for OLT, thus become ineligible .
▪ Local therapies like RFA andTACE may be used to ‘bridge’ the patient
until the donor organ is available .
▪ Liver directed RT has emerged as a new option .
55. Radiotherapy as a bridge to liver transplantation
for hepatocellular carcinoma,Laura Dawson et al , PMH ,
Canada Transpl Int 2010;23:299–306.
▪ Duration – 2006-2008
▪ N-10 -median age was 55 (range 36–64)
▪ Tumor charecteristics -tumor diameters ranging from 25 to 108 mm, 8/10-
beyond Milan criteria.
▪ Radiation details –a median dose of 33 Gy (range: 8.5–54 Gy) over 1–6
fractions with 3DCRT .
▪ Results -100% local control and tumor , volume regression of 10%–50%.all
transplanted patients were without recurrence at a median follow-up of 14
months.
56. Facciuto ME, et al. Stereotactic body radiation therapy in
hepatocellular carcinoma and cirrhosis: Evaluation of radiological
and pathological response. J Surg Oncol 2012; 105:692–698.
▪ N-27 patients
▪ RT details-26–36 Gy in 2–4 fractions
▪ Technique –SBRT
▪ Results - complete response in 14%, partial response in 23%, and
stable disease in 63%
57. Response assessment in liver post SBRT :EASL-EORTC
clinical guidelines for management of HCC
58. Dawson LA. Overview: Where does radiation therapy fit in the
spectrum of liver cancer local-regional therapies? Semin Radiat
Oncol2011;21:241-246.
59. ONGOING STUDIES…
▪ RTOG 1112 –randomized phase III study of sorafenibVs SBRT followed by sorafenib in
HCC. (Laura Dawson)
▪ Primary objective -To determine if SBRT improves overall survival in HCC patients
treated with Sorafenib.
▪ Patient population -Unsuitable for resection or transplant or radiofrequency ablation
(RFA); Unsuitable forTACE or refractory toTACE; BarcelonaClinic Liver Cancer Stage
(BCLC) Intermediate (B) orAdvanced (C)
▪ Status- currently accruing (target -398)
▪ Randomization –arm1- daily sorafenib . Arm 2-SBRT alone (27.5 Gy – 50 Gy in 5 fractions)
Followed by Sorafenib alone daily.
60. ONGOING STUDIES…
▪ Integrated Phase II/III Randomized ControlTrial ofTransarterial
Chemoembolisation Alone or in Combination With Stereotactic Body
Radiation in Patients With Unresectable Hepatocellular Cancer( Dr .
Supriya Chopra et al ,Tata Memorial Hospital )
▪ Primary objective - to assess a benefit in in-field progression free survival.
▪ Estimated enrollment-386.
▪ Duration – 2014-2022
▪ Arms- arm 1 –TACE . arm 2-sorafenibTACE SBRT sorafenib .
62. ▪ Cholangiocarcinoma accounts for 15-20 % primary liver cancers
worldwide .
▪ At present , surgical resection is the only curative treatment , but
unfortunately 50-90% patients present with unresectable disease .
▪ 5 yr survival -5-10 %
63.
64.
65. SBRT in intrahepatic cholangioca
AUTHOR INSTITUTE N TREA
TMEN
T
TYPE
TUMOR
VOLUME
RT DOSE
MEDIAN (RANGE)
1YR
OS
1YR
LC
TOXICITIES>/=
GRADE3
Barney
et al 2012
MayoClinic,
USA ,
retrospective
10 SBRT 16–412.4
mL
6 3 Gy /3 fr 73% 100% 20% (1 grade 5
liver failure,1
grade 3 biliary
stenosis)
Dewas
et al.2012
Lille, France ,
retrospective
6 SBRT 0.5–11.2
cm
39–45 Gy /3-4 fr 100% 100% NS
Goyal et
al.2010
Case
WesternReserve
University,
USA,
retrospective
3 SBRT 80–818 mL 24–45 Gy / 1–3 fr 0 % 67% 0%
66. SBRT in intrahepatic cholangioca
AUTHOR INSTITUTE N TREATMEN
TTYPE
TUMOR
VOLUME
RT DOSE
MEDIAN
(RANGE)
1YR OS 1YR LC TOXIC
ITIES>
/=
GRAD
E3
Tse et
al.2008
PrincessMargaret
Hospital,Canada,
phase I
10 SBRT 10–465
mL
32.5
(28.2–48)Gy
/6fractions
58% 65% 20%
Goodman
et al.2010
Stanford
University,USA
phaseI
5 SBRT <5 cm 18-30Gy
single
fraction
71% 23% 1-
year
local
failurec
none
Ibarra et
al.2012
Multi-institutional
pooled analysis
11 SBRT 30.6–
818.5
mL
30
(22–50) Gy /1-
10 fractions
45% 50% 7%
RILD
only
69. ▪ Surgery as a part of multimodality treatment in resectable pancreatic
cancer is the only potentially curable strategy .
▪ Unfortunately , appr. 85 % patients present with an advanced disease
which is not amenable to surgery .
▪ R0 resection is the goal in surgery .
72. ▪ Resectable tumors , even after surgical resection ,has local
recurrence of 50-80 % and distant recurrence 40-90 % .
▪ Calls for the need for adjuvant treatment .
79. For an unresectable pancreatic tumor , this dose of radiation is inadequate , as
demonstrated by high rates of local tumor progression and poor survival .
And also the GI toxicities in the range above grade 3 noted .
Attempts were made to evaluate if increasing dose of radiation may improve
outcomes by sparing organs at risk to minimize the toxicities .
80. AUTHOR N SBRT DOSES BED GR 3 GI
TOXICITIES
L.C. AT 1YR MEDIAN
OS
Chang et al
Stanford
university
77 25 Gy /SF 87.5 0% acute
toxicity
9% -late
Freedom from
local progression
at 6 months – 94%
and at 12 months
84%
10-11.9
months
Rwigema et al 71 18–25 Gy, in a
single-fraction
SBRT (n 67)
Fractionated SBRT
(n-4)
50.4-
87.5
4% grade 3
acute
toxicities
overall
FFLP rate - 64.8%
10.3
Didolkar et al 85 15-30Gy/3 fractions 22.5-
60
22.7 % 91.7 % 8.6
Mahadevan et
al
36 8, 10, or 12 Gy × 3
followed by
Adj gemcitabine
43.2,
60,
72,
14% 78% 14.3
81. AUTHOR N SBRT DOSES BED GR 3 GI
TOXICITIES
L.C. AT 1YR MEDIA
N OS
Mahad
evan
et al.
39 8–12 Gy × 3 after induction
gemcitabine
4.2-79.2 0 acute 3 (9%)
late
85 20
Hoyer
et al.
22 15Gy × 3 fraction 112.5 79% acute
grade 2+
57% 5.4
mont
hs
Koong
et al.
15 15, 20, or 25 Gy × 1 37.5,
60,87.5
0 100% 11
mont
hs
Schelle
nberg
et al.
16 25 Gy × 1 after induction
gemcitabine + post-SBRT
gemcitabine
87.5 1 (6%) acute 2
(13%) late
100% 11.4
mont
hs
Herma
n et al.
49 6.6 Gy × 5 after induction
gemcitabine
54.78 1 (2%) acute 3
(6%) late
78% 13.9
82. SBRT in pancreas
▪ It was recently suggested that locoregional treatment with CRT can improve local
control which could translate into a better quality of life.
▪ SBRT s particularly appealing for LAPC, as it may deliver a potentially more effective,
focally ablative therapy over a short period; versus 5–6 weeks of conventional RT .
▪ This innovative therapy has potential to improve quality of life in patients with poor
outcome, by controlling their disease locally. however distant metastases still account
for the vast majority of disease-related mortality.
▪ To date, there is no established standard for the SBRT dose and fractionation schedule
for LAPC.
83. ONGOING STUDIES…
▪ A Randomized Phase III Study Evaluating Modified FOLFIRINOX
(mFFX) With or Without Stereotactic Body Radiotherapy (SBRT)
in theTreatment of Locally Advanced Pancreatic Cancer
,Stanford University.
▪ Primary Outcome Measures: difference in progression-free survival
between mFOLFIRINOX alone vs. mFOLFIRINOX and SBRT
▪ N- 172
▪ Duration -2013-2018.
▪ Status – currently accruing .
87. Upfront resection patients (n=241) underwent resection without neoadjuvant treatment for
resectable disease were compared to BRPC or LAPC patients (n=61) who underwent resection
afterchemotherapy and 5 fraction SBRT.(treatment protocols – chemo for BRPC –gem-doce –
capecitabine – 21 days cycle, for LAPC- folfirinox , SBRT doses – 50 Gy in 5 fractions to PTV )
significantly higher T classification, N classification, and vascular resection/repair rate. Surgical
positive margin rate was lower after neoadjuvant therapy (3.3% vs. 16.2%, P=0.006). Post-
operative morbidities (39.3% vs. 31.1%, P=0.226) was similar between the groups. Median OS
was 33.5 months in the neoadjuvant therapy group compared to 23.1 months in upfront
resection patients who received adjuvant treatment (P=0.057).4.9 % patients ha dgrade 3
toxicities attributable to SBRT , 42.6% had grade 3 toxicity attributable to chemo.
▪ Conclusions: Patients with BRPC or LAPC and sufficient response to neoadjuvant multi-agent
chemotherapy and SBRT have similar or improved peri-operative and long-term survival
outcomes compared to upfront resection patients.
88. N-12
received neoadjuvant chemotherapy, and gemcitabine/capecitabine . Most were treated
with fractionated SBRT to 36 Gy/3 fractions (n = 7) and the remainder with single fraction
to 24 Gy (n = 5).
▪ No grade 3+ acute toxicities attributable to SBRT were found.
▪ Two patients developed post-surgicalvascular complications and one died secondary to
this.The mean time to surgery after SBRT was 3.3 months. An R0 resection was
performed in 92% of patients (n = 11/12). In 25%(n = 3/12) of patients, a complete
pathologic response was achieved, and an additional 16.7% (n = 2/12)demonstrated <10%
viable tumor cells.
▪ median progression free survival is 27.4 months.
▪ Overall survival is 92%, 64% and 51 % at 1-, 2-, and 3-years.
90. Charged particles for SBRT…
▪ Proton beam therapy for hepatocellular carcinoma:The University ofTsukuba
experience.
▪ N-318
▪ Duration -2001-2007
▪ solitary hepatocellular carcinoma or multiple tumor foci totaling <3 in number or any
number of lesions provided all could be covered in the same irradiation field.
▪ Three schemes were used, depending on tumor location. A total dose of 77.0 GyE in
35 fractions - tumors within 2 cm of the digestive organ, 72.6 GyE in 22 fractions-
tumors within 2 cm of the porta hepatis, and 66.0 GyE in 10 fractions -peripheral
tumors >2 cm from both the gastrointestinal tract and the porta hepatis.
▪ ( gray equivalents (GyE), defined as the proton dose corrected by its relative
biological effectiveness)
91. Charged particles for SBRT…
▪ Proton beam therapy for hepatocellular carcinoma:The
University ofTsukuba experience.
▪ Results -The 5-year overall survival rate was 44.6%, with only 5
patients developing grade 3 toxicities (1 gastrointestinal, 4 skin)
▪ Authors concluded -proton beam therapy to be both safe and
effective for the treatment of patients with hepatocellular
carcinoma
92. Charged particles for SBRT…
▪ The Safety and Efficacy of High-Dose Proton Beam Radiotherapy for
Hepatocellular Carcinoma: A Phase 2 Prospective Trial – Bush et al
▪ 76 patients treated with proton RT for HCC with cirrhosis, with 63GyE in 15
fractions over 3 weeks .
▪ study included a significant number of patients with advanced stage and
decompensated liver disease, with 54% outside of the Milan criteria, 24%
with CP class C, Despite otherwise poor prognosis for this cohort of
patients, Bush et al. reported median progression-free survival of 3 years
and a local failure rate of 20% occurring at an average of 18 months (range:
2–60 months). Furthermore, this treatment was very well tolerated, with no
reported grade3 toxicities.
93. Charged particles for SBRT…
▪ These limited data have suggested a potential role for charged particle
therapy in the treatment of primary hepatic malignancies. Nonetheless,
the relative efficacy of these therapies versus conventional photon SBRT
is unknown, and future prospective clinical studies and cost-effective
analyses will be necessary before widespread use of these treatment
modalities.
94. Limitations of SBRT
▪ Despite these encouraging data, there are several potential limitations of liver-
directed SBRT.
▪ In the absence of long-term follow-up and multi-institutional prospective data,
the curative potential and the durability of this treatment remain unknown.
▪ Second, because SBRT uses dose-fractionation schemes based on normal liver
tolerance, an inverse relationship exists between tumor size and allowable dose.
This inherent dose-volume relationship may theoretically limit the efficacy of
this treatment for larger tumors.
▪ Further more , the impact of SBRT on future treatment and dosing strategies for
regional recurrences, new primary tumors, and locally recurrent tumors remains
largely unstudied and investigational.
95. FUTURE PERSPECTIVES
▪ Ideal dose and fractionation schema –all the studies reflect the
heterogeneous practice of SBRT .
▪ Need for proper selection criteria – most of the studies have excluded
patients with CP class B and C – role of RT remains unclear in this group .
▪ advances in metabolic and functional imaging may further enable SBRT to
overcome tumor resistance while sparing normal liver.
▪ No randomized trials, no level 1 evidence .
