gi tumour
DESCRIPTION
Gi tumourTRANSCRIPT
Radiosurgery in cancer managementwith special attention to GI tumours
Debnarayan Dutta, MDConsultant Radiation Oncologist
Apollo Speciality Hospital, Chennai
INDIA
Cyberknife
PUBMED Indexed publications (320 +)
Till September 2010: 30 Full length paper
Significant research & academic work on ‘Cyberknife’
------------------------ GI malignancies ?
Common Gastro-intestinal tumours-Carcinoma Oesophagus
-Carcinoma stomach
- Liver tumours
- HCC
- Cholangiocarcinoma
- Klaskin tumour
- Liver metastasis
- Multiple
- Solitary / oligo
- Carcinoma pancreas
- GIST / carcinoid
-Colon cancer
- Carcinoma rectum
- Carcinoma anal canal
- Recurrent disease
- Surgery / Conv CT-RT
-Surgery / Conv CT-RT
- Resection / transplant
- Sys CT/ TACE
- Rad-Immuno therapy
- Conv RT
- SRS
Surgery/ CT / Conv RT / SRS-Surgery / CT / SRS
- Surgery / CT-RT / Hypo RT
- CT-RT / Hypo RT / Surgery
- Surgery / Pall CT or RT / SRS
Fundamental Principles: GI malignancies
• Surgery: primary curative treatment for Cancer
• Systemic therapy is essential component in the multimodality
management of cancer
• Radiation therapy: loco-regional treatment
• Local treatment:
- Radiotherapy
- Radiosurgery
- Radioimmunotherapy
- TACE / RFA
• Systemic treatment:
- Chemotherapy
- Immunotherapy / targeted therapy
Outcome: Local control
Outcome: Survival Functions
3-D Conformal RT
IMRT
Radiosurgery
Stereotactic Radiosurgery Systems
• Gamma- Knife
• Linear Accelerator Based Systems
- Novalis
- Trilogy
• Proton Beam Therapy
• Robotic radiosurgery: CyberKnife
Conventional extra-cranial
Linac. Radiosurgery
Modern SBRT Systems
Defining Accuracy
Tumor motion
Patient setup
Patient
movement
Imaging (CT, MRI, etc.)
Treatment planning
Beam delivery
Total
Clinical
Accuracy
SynchronyTM
Modern SBRT Accuracy
• Mechanical Accuracy = 0.2 mm
• Total Clinical Accuracy
– Stationary lesions: 0.95 mm
– Moving lesions: 1.5 mm
Total
Clinical
Accuracy
CyberKnifeTotal Clinical Accuracy
Chang et al.Neurosurgery, 2003
Murphy MJ et al. Int J Radiat Oncol Biol Phys. 2003
Robotic Radiosurgery
Highly precise RT delivery system
- Respiratory tracking
- Fiducial tracking
- Intra-fraction motion correction
- Incomparable dose distribution
Hypofractionated RT
- High dose short course RT
- Higher BED delivered to target
Ideal for moving targets
PUBMED search
‘CyberKnife’ ‘CyberKnife’ AND ‘Liver’
Number of papers per year
Stereotactic Radiosurgery
for Liver TumorsHepatocellular Carcinoma
- Primary management
- Recurrent / residual disease
- ‘Bridge’ management in pts waiting for Transplant
Metastatic liver disease
- Solitary/ Oligo with primary controlled
- Multiple
- Recurrent / residual disease
Others
- Cholangiocarcinoma
- Klaskin tumour
Worldwide Incidence of Hepatocellular Carcinoma
High (> 30:100,000)
Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)
Worldwide Incidence of Hepatocellular Carcinoma
HCC Epidemiology
El-Serag HB,
Gastroenterology
2004
A. Surgical resection
B. Ablation
Cryotherapy
Radiofrequency ablation
Laser interstitial thermal therapy (LITT)
Microwave coagulation therapy
C. Chemotherapy
Neoadjuvant
Intra-arterial
Systemic
Chemoembolisation
D. Radiotherapy
Stereotactic body radiation
Selective interstitial radiation therapy
E. Liver transplantation
Treatment Options
RFA
Study Pt No. Tumour size
(cm)
Mean FU (Mo) Complete
necrosis (%)
Rec Rate
(%)
Survival
Rossi (1996) 39 <3 22.6 95 41 1-yr: 94%
3-yr: 68%
5-yr: 40%
Rossi (1998) 23 <3.5 10 100 28 -
Aligaier (1999) 12 - 5 100 0 -
Francica (1999) 15 1-4.3 15 90 33 -
Curley (1999) 48 - 15 100 2.1 -
Niccli (2000) 47 1-6 11.8 100 - 2-yr: 83%
Curley (2000) 110 3.4 19 95 49 -
Poggi (2001) 15 1.5-6.2 9.2 88 20 -
Buscarini (2001) 88 <3.5 34 93 39 1-yr: 89%
3-yr: 62%
5-yr: 33%
Highly selected group; no long term / randomized data
TACE
Survival
Study Therapy n 1-Yr (%) 2-Yr (%) p-value
Retrospective / nonrandomized study with control
Vetter (1991) Dox+ Lipidol+ gelatin 30 59 0 <0.001
Conservative Rx 30 30 0
Bronowicki (1994) Dox,Cis or Epi + Lipidol+ gelatin 127 64 38 <0.001
Conservative Rx 127 58 6
Stefarini (1995) Dox+ Lipidol+ gelatin 69 73 44 <0.001
Conservative Rx 64 16 8
Prospective / randomized study
Peletier (1990) Dox + gelatin 21 24 - NS
Conservative Rx 21 31 -
French Group (1995) Cis + Lipidol+ gelatin 50 62 38 NS
Conservative Rx 46 43.5 26
Peletier (1998) Cis + Lipidol+ gelatin + Tam 37 51 24 NS
Tamoxifen 36 55 26
Randomized studies did not show survival benefit.
Issues with portal vein thrombosis
TACE Meta-analysis
Marginal benefit with TACELlovert JM, Hepatology 2003
Radio-immunothrerapy
Study Isotope Results
Kumar (2007) Rhe188 MS: 980 days
Goin (2005) Y90 (150 Gy) Well tolerated
Ho S (1998) I131 1-Yr OS: 31%
2-Yr OS: 23%
MS: 6 mo
Wang (2008) Ph32 2-Yr OS: 79.5%
3-Yr OS: 65.5%
Need perfusion scan. <20% shunting required.
Require repeat treatment.
Costly treatment.
Targeted therapies: Sorafinib
Study Type N Result
Llovet JM*
(2008)
Multi-centric
Ph III
602 Median OS: 10.7 vs 7.9 mo (P<0.001).
Symptomatic progression : 4.1 vs. 4.9 mo, (P=0.77).
Radiologic progression: 5.5 vs 2.8 mo (P<0.001).
3 month survival benefit
Abou-Alfa GK^
(2006)
Ph II 137 Median TTP: 4.2 mo & OS: 9.2 mo.
Grade 3/4 toxicities: Fatigue (9.5%), diarrhea (8.0%), & hand-
foot skin reaction (5.1%).
Muszbek N#
(2008)
Ph III
Economic
analysis
- LYG was longer for sorafenib.
(1.52 vs. 1.03 LYG/pt for sorafenib & BSC).
Lifetime total costs: $47,51 for sorafenib & $10,376 for BSC
ICER: $75,821/LYG.
Cheng AL^^
(2009)
Multi-centric
Ph III
271 Median OS: 6.5 vs 4.2 mo(p=0.014).
Median TTP :2.8 vs1.4 mo (p=0.0005).
*N Engl J Med. 2008 ;359(4):378-90. ^J Clin Oncol. 2006 ;24(26):4293-300.
#Curr Med Res Opin. 2008 ;24(12):3559-69. ^^Lancet Oncol. 2009 Jan;10(1):25-34
Study Type n Dose Median
FU (Mo)
LC (%) OS Toxicity
Mendez (2006) Ph I/II 8 25Gy/%#
30Gy/3#
13 82 1-Yr: 75%
2-Yr: 40%
Gr-3/4: 1 pt
Choi (2006) Ph II 20 50Gy/5-10# 23 NR 1-Yr: 70% Gr-3: Nil
Tse (2008) Ph I 31 36Gy/6# 17.6 65 Median OS: 11.6 mo
1-Yr: 48%
Gr-3: 8 pt
Choi (2008) Ph II 31 30-36Gy/3# 10.5 72 At 11 mo: 72% Gr-3: Nil
Yang (2009) Ph II 40 50Gy/10# 35 65 1-Yr: 73% Gr-3: Nil
Cardenes (2010) Ph I 6 12-16 Gy/2-3# 24 100 1 Yr: 75%
2-Yr: 60%
Gr-3: 3 pt
Louis (2010) Ph II 25 45Gy/3# 12.7 95% 1-Yr OS: 79% Gr-3: 2 pt
Initial results of SBRT for HCC
All recurrent / resistant HCCs
Local control / survival function: impressive
TACE+ SBRT in unresectable HCC
Study n RT Dose Results
Yoshikawa (1990) 31 48 Gy 5-Yr: 35%
Guo (2003) 107 55 Gy 3-Yr: 28.4%
5-Yr: 15.8%
Wu (2004) - - 1-Yr: 93.6%
2-Yr: 53.8%
3-Yr: 25.9%
MS: 25 mo
Marelli (2006) Meta-analysis
7 RCT
- Improves survival with
TACE+SRT
Zhou 50 - 1-Yr: 60%
2-Yr: 38%
3-Yr: 28%
MS: 17 mo
TACE + SRT is a safe an effective palliation treatment in unresectable HCC
SBRT planning: Normal tissue constraints
Organ/ Critical structure Dose Constraints
Liver V21<33%
Spinal cord Dmax 22 Gy
Kidney V15< 33%
Stomach V21< 5 cm3
Intestine V16<5 cm3; Dmax < 27 Gy
Duodenum D15 < 5cm3; Dmax < 24 Gy
SBRT planning: 1
Tumour volume is not critical
Volume of normal tissue spared / tolerance is critical
SBRT planning: 2
Multiple tumours also can be treated simultanously
Total size treated <10 cm
SBRT planning: 3
Sub-diaphragmatic location tumours better treated with SBRT
RFA / resection difficult
Even small tumours in the left lobe is difficult to treat without reducing the dose as
duodenal toxicities are high
SBRT planning: 4
SBRT planning: 5
Multi-centric disease is difficult to treat, but possible
Results of SBRT for HCC
Smaller tumours (<3 cm): Better local control
Acceptable LC even in larger tumour
Child Pugh A: Better Survival
Higher RT dose: Better LC (45Gy/3# better than 25Gy/5#)
Lower dose to normal liver: less toxicity (RILD)
Combination treatment may improve survival.
Llovet. J of Hepatology 2008
Treatment is based on low level of evidence
Proposed clinical studies on HCC with SBRT
Mirabel EPDC 2010
Need answers: SBRT for Liver Tumors
• Tumor control is good for small tumors
– Is it as good as RFA?
• RFA control rates are poor for intermediate (3-7cm) and large( >7cm)
lesions
– Can combination Therapy (RFA+CK) work ?
• Targeted therapies (Sorafinib) & SBRT will improve both local
control/Survival ?
• TACE is poor for Large and multiple lesions
– Can addition of SBRT help ?
Liver Metastasis
• INCIDENCE
• Metastasis is the most common neoplasm in an adult liver.
• Liver is the second most common site for metastatic spread, after the
lymph nodes.
• The primary sites most commonly metastasizing to the liver are -
Colon (65%)
Pancreas (63%),
Breast (60.6%),
Gallbladder and extra hepatic bile ducts
(60.5%),
Ovary (52%)
Rectum (47%)
Stomach (45%)
Lung (36%),
Kidney (26%)
Colorectal Liver Metastasis
• Nearly 2/3rd of pts with colorectal cancer will develop hepatic metastasis.
• 25% - 50% of pts dying of cancer have hepatic metastasis.
• Metachronous - Metastases appearing much latter than treatment of
primary eg. melanoma of chord.
• Synchronous - Primary & metastasis detected at the same time. eg-
carcinoma stomach.
• Precocious - Metastases appearing before primary is suspected. eg-
carcinoid, rectal carcinoma.
Liver Metastasis- Colorectal cancer
n 5-Yr OS (%)
Nordlinger (1994) 144 25
Adam (1997) 64 41
Tuttle (1997) 23 32
Yamamoto (1999) 90 31
Sugarbaker (1999) 170 32
Surgical resection
Favorable Prognostic Factors
Progression from AJCC stage I/II without intervening stage III
DFS prior to diagnosis of metastasis: >36 months
Anticipated survival without surgery >3 mo
Good GC/ functional status
<2 metastatic sites involved
Complete resection
SBRT for Liver TumorsToxicity (%)
Study No. of
lmets
Tumour
Vol (ml)
Dose
(Gy)
No. of
Fr
Pres Isodose
(%)
Crude local
control (%)
FU
(Mo)
Gr 1-2 Gr 3-4
Blongen (1998) 21 46 20-45 1-5 Periphery
Of PTV
95 9.6 12 0
Sato (1998) 5 8 50-60 5-10 80 100 10 5 5
Harfarth (2001) 56 10 14-26 1 80 78 5.7 NR 0
Wrif (2001) 23 50 28-30 3-4 65 83 9 29 0
Wate (2004) 5 6 45 3 90-100 86 19.3 0 0
Schefter (2005) 22 18 35-60 3 Periphery
Of PTV
NR 7.1 27 0
- 174 9.9 30-55 7-20 80 88 14.5 28 0
Colorado (2009) 100 - 60 3 - 93% - 3 0
Hoyer (2006) 141 - 15 3 - 2-Yr: 79 4.3 - -
Milano (2008) 293 - 50 10 - 2-Yr: 67 41 - -
Mendez-
Romero (2006)
45 - 12.5 3 - 2-Yr: 82 13 - -
Rusthoven
(1999)
49 - 20 3 - 2-Yr: 92 16 - -
Local control rate: 78-100% at 1.5-2 yr FU
No Gr 3-4 acute toxicity
Present status of SBRT for Liver metastasis
- Usually SBRT done for small primary metastasis not suitable for surgery
- Post Chemotherapy residual disease
- Not responding to chemotherapy
- Few multiple liver metastasis with good PS, local disease controlled, no other metastasis
- Need multi-centric, randomized studies
Cholangiocarcinoma
Park JS, Gut & Liver 2010
Dutta D, HOPE 2010
Cholangiocarcinoma
Stereotactic radiosurgery
in pancreas Cancer
Local Control after Whipple+ChemoRT
+ve margin (%) Local Failure (%)
GITSG 0 47
EORTC 19 51
ESPAC 28 63
CONKO 19 37
RTOG 34 25
Rout C Pancreas 2009
Resection status & Survival
R1 resection = Poor Survival
Post OP R1 Resection
• Fiducials placed at surgery
• One planning CT with oral and IV contrast
• 1000cGy to +ve margins 3-4 weeks post OP
• 5040cGy 5-6 field IMRT6-8 weeks postOP
• Concurrent Xeloda
• Adjuvant Gemcitabine
BIDMC
R1(Pos. Margin)- Survival by Treatment
Locally Advanced Pancreas Cancer
RT vs. ChemoRT
Chemo vs. ChemoRT
SBRT in pancreas cancer: Results
SBRT in pancreas cancer: Toxicity
Inoperable pancreatic cancer: CK followed by CT
PET-CT Scan
LFT / Biopsy
If non-metastatic,
inoperable carcinoma
pancreas
Patients with
locally
advanced
inoperable
pancreatic
carcinoma
Treatment with Robotic radiosurgery:
•30 Gy/5 fraction to CTV (6Gy/Fr)
•GTV is PET uptake
•CTV includes GTV and 1 cm margin
•CTV to PTV margin: 0-1 mm
•Treatment to start within 6 wks of diagnosis
•PET scan based planning
Follow up at 2/4 wk post RT, 2 wk after completion of
last cycle CT & then 3 mothly x 2 yrs. Every 6 monthly
assessments thereafter.
Assessment of-
•Response (with PET scan). 2) Resectability.
•Toxicity 4) Overall and PFS 5) QOL.
Chemotherapy start 2-4 weeks after completion
of RT.
Gemcitabine / Carboplatin based chemotherapy
Gemcitabine 1 gm/m2 D1, 8
Carboplatin AUC 2 D1, 8 Repeat 3 weekly x 4
cycles
Review after 4 cycle for response / operability
If inoperable, 2 more cycle of CT
If operable, consider 2 cycle CT after Surgery
Eligibility Criteria: 1.Inoperable advanced or partially resected pancreatic cancer.
2.Biopsy proven malignancy (adenocarcinoma / squamous carcinoma).
3.KPS >= 70; age 18-65 years
4.Medically fit for chemotherapy
5.No prior history of treatment with radiation or chemotherapy.
(For ethical committee clearance)
Potential role of SBRT
1. GIST with primary disease , nodal disease or metastasis
2. Neuroendocrine tumour in intestine, pancreas, nodal involvement
3. Low grade lymphomas with post-chemotherapy residual disease
4. Para-aortic nodal disease metastasis
SBRT in GI tumours
Summary
- SBRT has potential role in HCC, liver mets, cholangiocarcinoma,
pancreas, Klaskin tumour, GIST…
- Initial results are impressive with low toxicity, high response rate
- Short course, high dose radiation therapy will improve local control
and may improve survival function
- Need multi-centric prospective studies.
