Role of Radiotherapy in Primary and Metastatic Liver Tumors

1. ROLE OF RT IN PRIMARY
AND METASTATIC LIVER
TUMORS
Presenter Dr Anil Gupta
AIIMS, New Delhi

2. LIVER TUMORS
Benign lesions>>>Mets>> Primary liver tumors
Rapid development of highly sensitive clinical imaging has led to the detection of
focal lesions of the liver more frequently
Malignant tumors of liver
May present as epigastric fullness/discomfort or jaundice or be detected by routine
physical examination or radiographic studies for other indications
Among mets- liver is mc site (~25%)
Primary site for liver mets- colorectal, breast, lung, GI malignancies
Primary liver malignancy- Hepatocellular carcinoma> intrahepatic
cholangiocarcinoma

3. HOW TO
APPROAC
H LIVER
MASSES

4. PRIMARY LIVER TUMOR
The mc primary liver cancer hepatocellular
carcinoma (HCC)
It arises from underlying end stage liver
disease secondary to viral hepatitis or non-
viral chronic liver diseases
The leading viral causes of HCC are hepatitis B
virus and hepatitis C virus
MC non-viral etiologies - alcohol use and non-
alcoholic fatty liver disease/non-alcoholic
steatohepatitis

5. Its incidence has continuously risen in the last few decades
Only potential curative treatment is Liver transplant / surgical resection
Only 10-30% are suitable for upfront surgical resection

6. For Non Surgical Candidate

7. CHILD PUGH SCORE

8. Barcelona-Clinic Liver-Cancer (BCLC) Staging
System
Median
Survival-
20m
Range 14
to 45 m
Median
Survival-
11m
Range 6
to 14 m
Median
Survival
- 3 m
5 Yr
Survival
70-80%
5 Yr
Survival ~
70%
AASLD/EASL/AAPSL do not incorporate Radiotherapy in treatment
NCCN- as an alternative option to ablation or arterially directed therapies
Can we ignore Radiotherapy treatment in

9. Radiofrequency Ablation (RFA) And
Microwave Ablation (MWA)-
DRAWBACKS1. They have heat sink effect
2. Not suitable for tumor more than 3 cm
3. Dosimetry issues
4. Not suitable for patients with
-with bleeding diathesis
-tumors close to the diaphragm, GI tract, pancreas, hepatic hilum
and major bile ducts or vessels
In Radiotherapy no heat sink effect is there, highly accurate dosimetry with steep
dose gradient, can be used in lesions near blood vessels. Although should be
avoided lesion near diaphragm and intestine.

10. Trans-arterial Chemoembolization
(TACE)- DRAWBACKS
Not suitable for
1. Impaired portal-vein blood flow due to portal-vein thrombus
2. Malignant portal vein thrombosis
3. Untreatable arteriovenous fistula
4. Impaired renal function
Radiotherapy is the only modality which can recanalize portal vein in malignant
portal vein thrombosis.

11. Radiotherapy
“Classic” RILD
1. typically occurs within 4
months
2. present with fatigue, anicteric
ascites, and hepatomegaly
with relatively normal liver
function tests and normal
bilirubin
“Non-classic” RILD
1. Patients with underlying liver
disease
2. Within 3 months
3. associated jaundice and/or
significant elevation of serum
transaminases
Historically
EBRT has had a limited role in HCC due to risk of radiation-induced
liver disease (RILD)

12. Historically
The whole liver could be safely treated to 2100 cGy in seven fractions
(RTOG 76-09) or 3000 cGy in twenty fractions b.i.d (RTOG 84-05 )
With these lower radiation dose regimens, EBRT only offered
palliation
Newer Models
Doses as high as 7260 cGy were safe, if delivered to less than a third of the
liver volume
3200 cGy to the whole liver -5% risk of RILD
No cases of RILD observed when the mean dose less than 3100 cGy
The liver radiation tolerance was lower with patients with HCC Vs those with
liver metastases
NORMAL TOLERANCE OF LIVER

13. 3DCRT VS IMRT
Technique 3DCRT IMRT
Dose 3600– 6000 cGy at
180–500 cGy per
fraction
4000– 6600 cGy in
250–400 cGy per
fraction
Local control were 43% at 1 year
and 28% at 3 years
70% at 1 year and 47%
at 3 years
Overall survival 36% at 1 year and
14% at 3 years
59% at 1 year and 33%
at 3 years
Toxicity rates- RILD 5% or less in 5% or less
(Bae et al 2017)

14. SBRT
SBRT is an EBRT technique whereby very high, potentially ablative
doses are delivered to tumors in shorter durations than for
conventional EBRT
SBRT may offer higher local control rates but also require advanced
tumor tracking, image guidance, and respiratory management to
minimize the risk of morbidity
For HCC not eligible for transplant, SBRT can offer high rates of local
control with radiographic freedom from progression of 80% with 3
year overall survival of 21%. Grade 3 toxicity in 8% of the patients.
SBRT used as a bridge to transplantation in early stage inoperable
HCC, with doses ranging from 3000– 5400 cGy using a median
fractional dose of 600 cGy Qiu et al

15. RADIOBIOLOGY-SBRT
 Vascular damage
 No/minimal repair
 Shorter treatment time-minimal repopulation
 Unlikely reoxygenation
 Kills in all phases of cell-no redistribution phenomenon
 Imunogenesis (Due to release of massive antigens)
 Abscopal effect by cytokines

16. RESULTS

17. SBRT IN PORTAL VEIN TUMOR THROMBOSIS
No other treatment can recanalize portal vein
3 DCRT SIRT SBRT
Pooled response
rates
51.3% 33.3% 70.7%
OS 43.8% 46.5% 48.5%
Thirty-seven studies comprising 2513 patients- metanalysis and systemic review
by Chai Hong Rim et al 2017

19. Stereotactic Body Radiation Therapy as an
Alternative to Transarterial
Chemoembolization for Hepatocellular
Carcinoma
Issue 100,
Jan 2018
Sapir, E., Tao, Y., Schipper, M. J.,
Bazzi, L., Novelli, P. M., Devlin, P.,
... Feng, M. (2018). Stereotactic
Body Radiation Therapy as an
Alternative to Transarterial
Chemoembolization for
Hepatocellular
Carcinoma. International Journal
of Radiation Oncology Biology
Physics, 100(1), 122-130.
DOI: 10.1016/j.ijrobp.2017.09.00
1
An Institute experience

20. RESULTS
P<0.01
Overall Survival
Freedom from
in-liver
progression
(FFLP)
grade III events TACE SBRT
13% 8%

21.  BCLC A, Child-Pugh score ≤7, had a single HCC from 4-7 cm, no evidence of
macrovascular invasion, no evidence of metastatic disease, ECOG 0, and were not
suitable for resection or liver transplantation
 Median time to CR was 3 months (range 1-17). 1- and 2-year OS was 80% and 67%,
respectively. 1- and 2-year PFS was 67% and 52%

22. RADIOTHERAPY IN POST LIVER
TRANSPLANT
For curative resectable or transplantable cases, recurrence rates
can be as high as 30%.48–51
Cause- Microvascular invasion
Solution- ??Adjuvant radiotherapy
Can be tried in certain scenario
- Close resection margins
- Tumors close to major vessels
adjuvant
radiation
adjuvant
TACE
conservativ
e
manageme
nt
3 year
relapse-
free
survival
45% 27% 11%
3 year
overall
survival
73% 44% 28%

24. ONGOING TRIAL
Transarterial Chemoembolization Versus Stereotactic Body Radiation Therapy for
Hepatocellular Carcinoma (TRENDY)
NCT02470533
Randomized Phase III Study of Sorafenib versus Stereotactic Body Radiation
Therapy followed by Sorafenib in Hepatocellular Carcinoma RTOG01112
NCT01730937
Stereotactic Body Radiation versus Trans-arterial Chemoembolization as bridge to
Liver Transplant
NCT02182687

25. ELIGIBILITY CRITERIA FOR LIVER
SBRT
 Sufficient functioning liver volume (>700 cc)
 Lesion should be away from bowel
 Child Pugh score ≤ 7
 BCLC ≤ C
 ECOG Performance ≤ 3
 maximum lesion size of ≤ 5cm /≤ 6cm ≤ 10cm
 Maximum number 1-3 nodules
 Should be treated by Radiotherapy before
 Low Viral Count

26. NORMAL DOSE CONSTRAINTS TO
MAINTAIN

27. LIMITATIONS OF RADIOTHERAPY
 SBRT Planning and Delivering is Challenging
 It becomes especially more challenging for HCC due to -
Adjoining healthy liver is radiosensitive
CT density is similar to that of the adjoining healthy liver
Tumor motion is nonlinear and has hysteresis
 Hepatitis virus B reactivation may occur after local treatment for
HCC
HYSTERESIS IN
LIVER
Can the limitations be overcome?? If yes---
How???
Changes in GI organ luminal filling

28. INTERSTITIAL BRACHYTHERAPY

29. 4D CT Simulation With Synchronized
Intravenous Contrast Injection

30. (a)
Clinical Examples-How To Distinguish HCC from other
structures
HCC Lesion
Tumoral thrombosis in Portal
vein
THAD
(b) (c)
(d)
(e)

31. Pre Treatment Verification-Image
Guidance

32. Motion Management
Gating Active breath
Coordinator

33. CHANGES IN GI ORGAN
LUMINAL FILLING
Real-time Magnetic Resonance-guided Liver Stereotactic Body
Radiation Therapy

34. RADIOTHERAPY FOR LIVER
METASTASIS
 Liver metastases are frequently seen in colorectal, breast, lung,
neuroendocrine, and gastrointestinal malignancies
 Approximately 50% of patients with colorectal cancer eventually develop
metastatic disease to the liver
 The leading cause of death from colorectal cancer is liver failure (Park, J.
et al)
 Liver metastases can cause significant pain from hepatic capsular
involvement, thus negatively affecting health related quality of life for
patients with metastatic disease

35. More extensive liver disease can cause liver
dysfunction that can limit the administration
of systemic chemotherapy

36. STANDARD TREATMENT OPTION FOR
OLIGOMETASTASES
 Surgical resection is the standard treatment option for oligometastases
 “oligometastases,” referring to an intermediate stage of metastases where
the number and site of metastatic disease is limited and therefore may be
amenable to local forms of treatment (Hellman, 1998)
 The potentially curative treatment of liver metastasis with surgical
resection has been reported for many years, with 5-year survival rates now
of 50%-60%
 Moreover, if patients are well selected, up to 20% can achieve long-term
disease-free survival after hepatectomy
 Unfortunately, the majority of patients (up to 80%–90%) are not resectable at
diagnosis

37. ALTERNATIVE TREATMENT
OPTIONS
RFA is most effective when reserved for treating three or fewer
lesions, <3.5 cm in diameter, which are not in close proximity to
large blood vessels
RFA is the most established local therapy, a recent meta-analysis
reporting a wide range of 5 year survival (14-55%) and local control
(3-60%) (Lo SS et al)
High conformal dosimetry, together with a steep dose gradient
allowing relative sparing of normal liver tissue, makes SBRT a
particularly attractive technique for liver irradiation

38. CLINICAL EXAMPLE
CECT abdomen showing
liver metastatsis in
colorectal cancer patient,
measuring 2.4 cm in SAD
Delineation of GTC,
PTV and OARs
Dose color wash. Dose
prescribed – 36 Gy/3#
After 3 months of SBRT same lesion now measuring 1.3 cm in SAD
Kumar S et al

39. Most studies have reported rates of <1% of RILD after SBRT for liver
metastases.

40. Retrospective analysis of 29 patients delivered 8 Gy single fraction dose to Liver

41. 33 patients not suitable for RFA treated with single 24 – 26 compared
with RFA.
Observational Study
14 Feb 2013
Acta Oncologica
SBRT RFA
1 yr LC 85% 65%
2 yr LC 80% 61%
local DFS 34.4 m 6 m (p<0.001)
freedom from distant
recurrence
11.4 m 7.1 m (p=0.25)

42. Presently SBRT used for patients ineligible for surgery and unsuitable for
RFA/alternative ablative techniques on the basis of either lesion size (3.5 cm) or
location.
Randomized clinical phase III trial testing the efficacy of RFA and SBRT in the treatment of
colorectal carcinoma liver metastases for metastases <4cm
Primary end point is local progression free survival.

43. CONCLUSION
 Radiotherapy is less used treatment in malignant liver tumors due to
- low tolerance of liver to radiation
- no available phase III data
- no consensus on the optimal dose fractionation
- requirement of advanced technology to deliver safer treatment
 But SBRT is particularly an attractive option due to
- high conformal dosimetry
- steep dose gradient allowing relative sparing of normal liver tissue
 Needs further refinement in technology and robust Randomized phase II/III trials

44. FURTHER READING