Selective internal radiation therapies (SIRT) for treating ...
Role of SIRT Beyond First Line Therapy in Colorectal Cancer Cosimelli 50 §SIR-Spheres ... Grades...
Transcript of Role of SIRT Beyond First Line Therapy in Colorectal Cancer Cosimelli 50 §SIR-Spheres ... Grades...
Role of SIRT Beyond First Line Therapy in Colorectal Cancer
Dr Toh Han Chong
Division of Medical Oncology
National Cancer Centre Singapore
SIR-Spheres microspheres in 2nd-line Treatment of Colorectal Cancer Liver Metastases
Investigator n Treatment ORR TTP/§PFS Survival
Lim 30 SIR-Spheres† (+ 5FU/LV)70% 33% 5.3 mo nr
van Hazel 25 SIR-Spheres† + irinotecan 48% 6.0 mo§ 12.2 mo
9.2 mo§L
Cove-Smith 8/33‡ SIR-Spheres† + (FOLFIRI- or 38% 9.5 mo§ 17.0 mo FOLFOX-based chemo)
phase II/III studies
2nd-line irinotecan 4–13% 2.6–4.3 mo§ 6.4–10 mo
irinotecan + cetuximab 16–27% 3.2–4.0 mo§ 8.6–10.7 mo
3rd-line panitumumab 9–14% 1.9–3.2 mo§ 6.3–9.3 mo
† SIR-Spheres microspheres; nr: not reported; §PFS; §L PFS in the liver
Lim et al. BMC Cancer 2005;5:132. van Hazel et al. J Clin Oncol 2009;27:4089–95. Cove-Smith, Wilson. WCGIC 2011; Abs P-0150. Schoemaker et al. Brit J Cancer 2004;91:1434–41. Van Cutsem et al. Brit J Cancer 2005;92:1055–62. Seymour et al. Lancet 2007;370: 143–52. Fuchs et al. JCO 2007;21:807–14. Sobrero et al. J Clin Oncol 2008;26:2311–9. de Cerqueira Mathias et al. ECCO 2007;5: Abs P3055. Wilke et al. ECCO 2007;5: Abs P3025. Cunningham et al. N Engl J Med 2004;351:337–45. Hecht et al. Cancer 2007;110:980–8. Van Cutsem et al. J Clin Oncol 2007;25:1658–64. Van Cutsem et al. Ann Oncol 2008;19:92–8. Muro et al. Jpn J Clin Oncol 2009;39:321–6.
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SIR-Spheres microspheres in Salvage Therapy of Chemorefractory Colorectal Cancer Liver Metastases
Hendlisz et al. J Clin Oncol 2010;28:3687–94. Seidensticker et al. Cardiovasc Interv Radiol 2011; ePub. Cosimelli et al. Br J Cancer 2010; 103:324–31. Jakobs et al. J Vasc Interv Radiol 2008;19:1187–95. Cianni et al. Cardiovasc Interv Radiol 2009;32:1179–86. Nace et al. Int J Surg Oncol 2011; ePub. Cove-Smith, Wilson. WCGIC 2011; Abs. P-0150. Kennedy et al. Int J Radiat Oncol Biol Phys 2006;65:412–25.
Investigator n Treatment ORR SD TTP/§PFS Survival
Hendlisz 44 SIR-Spheres† + 5FU 10% 76% 5.5◊/4.5 mo 10.0 mo
5FU > salvage with 0% 35% 2.1 mo 7.3 mo SIR-Spheres† at PD
Seidensticker 29 SIR-Spheres† 41% 17% 5.5 mo§ 8.3 mo
29 best supportive care nr nr 2.1 mo§ 3.5 mo (matched-pairs)
Cosimelli 50 SIR-Spheres† 24% 24% 4 mo§ 12.6 mo
Jakobs 41‡ SIR-Spheres† 17% 61% 5.9 mo 10.5 mo
Cianni 41‡ SIR-Spheres† 46% 36% 9.3 mo§ 11.8 mo
Nace 51‡ SIR-Spheres† 13% 64% nr 10.2 mo
Cove-Smith 25/33‡ SIR-Spheres† + chemo 20% 36% 3.5–4.6 mo§ 13.2 mo
Kennedy 208‡ SIR-Spheres† 36% 55% responders 7.2 mo 10.5 mo non-responders/controls na na na 4.5 mo
P=0.0001 statistically significant data † SIR-Spheres microspheres; ◊ TTP liver; nr: not reported; ‡ retrospective data
HR 0.38◊/0.51; P=0.003◊/0.03 ns P=0.001
nr HR 0.26; P<0.001
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In patients with chemorefractory colorectal liver mets, SIR-Spheres microspheres significantly improves survival
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Bester et al. J Vasc Inter Rad, 2011;23: 96-105
Comparative Retrospective Study: Overall Survival (Bester et al)
Survival Distribution Function0.000.250.500.751.00 Years0.00.5 1.01.5 2.02.5 3.0STRATA:extrahep=No Censored extrahep=No
0
25
50
75
100
Overa
ll Surv
ival (%
)
0 6 12 18 24 30 36
Time from receiving or potentially eligible for SIR-Spheres microspheres (months)
Hazard Ratio 0.8 0.3 0.4 0.5 0.6 0.7
N Median Survival (95% CI) SIR-Spheres microspheres : 224 11.9 months (10.1 – 14.9) Standard Care: 29 6.6 months Hazard Ratio: 0.50 (0.30 – 0.77)
P=0.001
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Matched Pair Analysis: Study Design (Seidensticker et al)
• 1° end point: OS
• 2° end points: PFS, ORR, safety and tolerability
Matched mCRC
pairs by prior
treatment history
and
tumor burden +
liver involvement;
metastases;
ALP; CEA level
(N=29 per arm)
Seidensticker et al CVIR 2012; 35; 1066‒1073
ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen.
Patients who received
SIR-Spheres*
compared to those on
BSC alone
* SIR-Spheres microspheres
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Seidensticker et al CVIR 2012; 35; 1066‒1073].
0 2.5 5 7.5 10 12.5 15 17.5
Survival Distribution Function0.000.250.500.751.00 Years0.0 0.51.01.52.0 2.53.0STRATA: extrahep=NoCensored extrahep=No
0
25
50
75
100
Overa
ll Surv
ival (%
)
Time (months)
Best Supportive Care 29 3.5 mo (1.9–5.7)
SIR-Spheres microspheres 29 8.3 mo (6.6 –10.2)
n Median Survival, months
P<0.001
Hazard Ratio 0.26 (95% CI 0.15–0.48)
Matched Pair Analysis: Overall Survival (Seidensticker et al)
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Matched Pair Analysis: Safety (Seidensticker et al)
• Adverse events following SIRT were predominately transient and self-limiting, including:
– grade 1–2 fatigue (69%)
– grade 1 abdominal pain/nausea (48%)
– 3 patients developed grade 2 gastrointestinal ulcer, which were managed medically
– 3 cases of grade 3 radiation-induced liver disease (RILD) were medically managed and not life-threatening
Seidensticker et al CVIR 2012; 35; 1066‒1073 9
Stratification
•Institution
•Interval to progression on chemotherapy
Random Assignment
5FU protracted IV infusion (300
mg/m2 D1–14 q3w) 5FU protracted IV infusion (225
mg/m2 D1–14 C1
and 300 mg/m2 D1–14
q3w thereafter)
until progression
SIR-Spheres microspheres
on Day 1 (D1) Cycle 1 (C1)
until progression
Eligible Patients
Liver-only mCRC,
PS 0–2, refractory to
chemotherapy
Arm A: Arm B:
Eligible Patients Crossover
Liver-dominant mCRC,
PS 0–2 SIR-Spheres microspheres
Randomized Controlled Trial in Refractory
Patients: Study Design
(Hendlisz et al)
+
Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 10
In patients with chemorefractory colorectal liver mets, SIR-Spheres microspheres significantly prolongs time to liver
progression
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Randomized Controlled Trial in Refractory Patients: Adverse Events (Hendlisz et al)
Parameter 5FU Alone 5FU + SIR-Spheres microspheres
n = 23 n = 21
Grades 1–2 Grades 3–4 Grades 1–2 Grade 3–4
Gastrointestinal
Stomatitis 1 1 2 -
Nausea - - 5 -
Constipation 3 - - -
Anorexia 6 1 5 -
Pain
Abdominal pain 3 - 4 -
Myalgia 1 - 2 -
Constitutional Fatigue 6 5 8 - Dermatological/Skin 2 - - - Hand-foot syndrome 2 - - 1 Pulmonary 1 2 - - Other Toxicity 1† - 2‡ -
Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.
† ascites; ‡ 1 with thrombocytopenia, 1 with stomach ulcer, ascites 12
Safety of SIR-Spheres microspheres in mCRC patients
Side Effect Incidence
Grade Clinical Presentation Prevention/Treatment 2 3
Constitutional Total
43% 1%
Weight loss 3% 0% Days 0-7 post treatment *Antiemetics, † low-dose steroids for 7
days
Fatigue 37% 1% Days 0-14 post treatment †Low-dose steroids for 7 days
Fever 2% 0% Days 0-3 post treatment Pan-cultures not necessary.
Acetaminophen in low doses safe for 3-7 days
GI Total
25% 5%
Nausea 9% 1% Days 0-3 post treatment *Antiemetics, †low-dose steroids for 7
days
Emesis 6% 1% Days 0-3 post treatment *Antiemetics, † low-dose steroids for 7
days
Pain 11% 2% Days 0-14 post treatment Analgesics prn
Ulceration 5%
(median) (0-20%)
Nausea, pain beyond day #14 post treatment
Prophylactic embolisation of GDA, Gastric arteries
1. Kennedy AS, McNeillie P, Dezarn WA et al. International Journal of Radiation Oncology, Biology and Physics 2009; 74: 1494-1500. 2. Sangro B, Carpanese L, Cianni R et al. Hepatology 2011; 54: 868-878.
Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities1,2
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Safety of SIR-Spheres microspheres in mCRC patients
Side Effect Incidence
Grade Clinical Presentation Prevention/ Treatment
2 3 GI
Total (cont.) 25% 5%
Radiation Cholecystitis <1% Persistent abdominal pain Avoid cystic artery
Hepatic Abscess <1% Abdominal pain, septic symptoms Prophylactic antibiotics in patients
with violated ampulla or prior Whipple
Biochemical 16% 2% Steady rise first 6 weeks post
treatment, return to baseline by 12 weeks post treatment
Appropriate radiation dose selection
Radiation Pancreatitis
<1% Abdominal pain, elevated
enzymes typical for pancreatitis Supportive care
Radiation Induced Liver Disease (RILD)
<1% (median) (0-4%)
Progressive ascites and elevation of Alkaline Phosphatase, AST, ALT and +/- total bilirubin, ammonia
levels
Steroids, supportive care
Radiation Pneumonitis
<1%
Can be asymptomatic, but serious cases present with pleural
effusion and can progress to ARDS
Steroids, supportive care
1. Kennedy AS, McNeillie P, Dezarn WA et al. International Journal of Radiation Oncology, Biology and Physics 2009; 74: 1494-1500. 2. Sangro B, Carpanese L, Cianni R et al. Hepatology 2011; 54: 868-878.
Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities1,2
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• Median survival after Yttrium90 Radioembolization was 10.5 months with 21% survival at 24 months.
• ORR: 72%
• Four factors were associated with poor prognosis:
1. Extensive tumour volume
2. Number of previous lines of chemotherapy
3. Poor radiological response to treatment
4. Low pre-op Haemoglobin.
• Clinical toxicity after treatment were minor (grade I/II) and resolved without active intervention.
• Conclusion: Yttrium90 Radioembolization is a safe and effective treatment for unresectable, chemorefractory m-CRC.
• Treatment at an earlier stage before chemoresistance develop and before extensive infiltration is present should be considered.
Saxena, Bester et al Annals of Surgical Oncology. 2014
• Review 20 papers ( 979 Patients) between 2004 – 2012.
• All patients failed 3 lines of chemotherapy.
• Median survival 12 months.
• Most cases of acute toxicity were mild (Grade I or II) resolved without intervention.
• Grade 4 less than 3%.
• The most common acute toxicities were fatigue (38.5 %), abdominal pain (16 %) and nausea/vomiting (19 %).
• Prognostic factors identified with a poor outcome:
– The presence of extra-hepatic disease
– Extensive pre-treatment chemotherapy (≥ 3 lines) -
– Extensive liver disease (≥ 26 %).
J Cancer Res Clin Oncol 2013
European Society Medical Oncology: m-CRC guidelines September 2014.
Van Cutsem E et al on behalf of the ESMO Guidelines Working Group for m-CRC.
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol 2014; 25 (Suppl 3): iii1-iii9.
Statement: “In patients with liver-limited metastases failing
the available chemotherapeutic options, radioembolisation
with Yttrium90 resin microspheres can also prolong the time to
progression.” ( Level II - small randomised trials).
Integrating SIRT into the mCRC treatment paradigm
SIRT Clinical Trials
Radioembolisation K-ras and Raf Mutants
Radioembolisation
Radioembolisation
> Radioembolisation
> Radioembolisation
Liver-only or liver-
predominant mCRC
Resectable Potentially curative
surgery or ablation
1st-line chemotherapy
2nd-line chemotherapy
nth-line chemotherapy
Chemorefractory?
10–20%
<20%
Decre
ase R
R
+/- Biologics
+/- Biologics VEGF
+/- Biologics EGFR