Role of SIRT Beyond First Line Therapy in Colorectal Cancer Dr Toh Han Chong Division of Medical Oncology National Cancer Centre Singapore
MILESTONES IN THE TREATMENT OF COLON CANCER
SIR-Spheres microspheres in 2 nd -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 2 nd -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 3 rd -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. 419-EA-1011
SIR-Spheres microspheres in Salvage Therapy of Chemorefractory Colorectal Cancer Liver Metastases 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 P=0.001 HR 0.38 /0.51; P=0.003 /0.03 ns 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) nr HR 0.26; P<0.001 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 statistically significant data SIR-Spheres microspheres; TTP liver; nr: not reported; retrospective data 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. P=0.0001 419-EA-1011
In patients with chemorefractory colorectal liver mets, SIR- Spheres microspheres significantly improves survival 5
n uf n oi bi rt vi vr us oit cn tu sid la 1.00 0.75 0.50 0.25 0.00 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years STRATA: extrahep=no Censored extrahep=no Overall Survival (%) Comparative Retrospective Study: Overall Survival (Bester et al) 100 N Median Survival (95% CI) SIR-Spheres microspheres : 224 11.9 months (10.1 14.9) Standard Care: 29 6.6 months P=0.001 75 Hazard Ratio: 0.50 (0.30 0.77) 50 0.3 0.4 0.5 0.6 0.7 Hazard Ratio 0.8 25 0 0 6 12 18 24 30 36 Time from receiving or potentially eligible for SIR-Spheres microspheres (months) Bester et al. J Vasc Inter Rad, 2011;23: 96-105 6
Matched Pair Analysis: Study Design (Seidensticker et al) Matched mcrc pairs by prior treatment history and tumor burden + liver involvement; metastases; ALP; CEA level (N=29 per arm) 1 end point: OS Patients who received SIR-Spheres* compared to those on BSC alone 2 end points: PFS, ORR, safety and tolerability ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen. * SIR-Spheres microspheres Seidensticker et al CVIR 2012; 35; 1066 1073 7
Overall Survival (%) n uf n oi bi rt vi vr us oit cn tu sid la 1.00 0.75 0.50 0.25 0.00 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years STRATA: extrahep=no Censored extrahep=no Matched Pair Analysis: Overall Survival (Seidensticker et al) 100 75 n Median Survival, months SIR-Spheres microspheres 29 8.3 mo (6.6 10.2) P<0.001 Best Supportive Care 29 3.5 mo (1.9 5.7) Hazard Ratio 0.26 (95% CI 0.15 0.48) 50 25 0 Seidensticker et al CVIR 2012; 35; 1066 1073]. 0 2.5 5 7.5 10 12.5 15 17.5 Time (months) 8
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 lifethreatening Seidensticker et al CVIR 2012; 35; 1066 1073 9
Randomized Controlled Trial in Refractory Patients: Study Design (Hendlisz et al) Eligible Patients Liver-only mcrc, PS 0 2, refractory to chemotherapy Stratification Institution Interval to progression on chemotherapy Random Assignment 5FU protracted IV infusion (300 mg/m 2 D1 14 q3w) Arm A: Arm B: SIR-Spheres microspheres on Day 1 (D1) Cycle 1 (C1) + 5FU protracted IV infusion (225 mg/m 2 D1 14 C1 and 300 mg/m 2 D1 14 q3w thereafter) Eligible Patients Crossover Liver-dominant mcrc, PS 0 2 Hendlisz, et al. J Clin Oncol. 2010;28:3687 3694. until progression SIR-Spheres microspheres until progression 10
In patients with chemorefractory colorectal liver mets, SIR- Spheres microspheres significantly prolongs time to liver progression 11
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 - ascites; 1 with thrombocytopenia, 1 with stomach ulcer, ascites Hendlisz A, et al. J Clin Oncol. 2010;28:3687 3694. 12
Safety of SIR-Spheres microspheres in mcrc patients Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities 1,2 Side Effect Constitutional Total Incidence Grade Clinical Presentation Prevention/Treatment 2 3 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 GI Total 25% 5% Nausea 9% 1% Days 0-3 post treatment Emesis 6% 1% Days 0-3 post treatment Pan-cultures not necessary. Acetaminophen in low doses safe for 3-7 days *Antiemetics, low-dose steroids for 7 days *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. 13
Safety of SIR-Spheres microspheres in mcrc patients Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities 1,2 Side Effect GI Total (cont.) Incidence Grade 2 3 25% 5% Clinical Presentation Prevention/ Treatment Radiation Cholecystitis <1% Persistent abdominal pain Avoid cystic artery Hepatic Abscess <1% Abdominal pain, septic symptoms Biochemical 16% 2% Radiation Pancreatitis Radiation Induced Liver Disease (RILD) Radiation Pneumonitis <1% <1% (median) (0-4%) <1% Steady rise first 6 weeks post treatment, return to baseline by 12 weeks post treatment Abdominal pain, elevated enzymes typical for pancreatitis Progressive ascites and elevation of Alkaline Phosphatase, AST, ALT and +/- total bilirubin, ammonia levels Can be asymptomatic, but serious cases present with pleural effusion and can progress to ARDS 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. Prophylactic antibiotics in patients with violated ampulla or prior Whipple Appropriate radiation dose selection 14 Supportive care Steroids, supportive care Steroids, supportive care
Median survival after Yttrium 90 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: Yttrium 90 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
J Cancer Res Clin Oncol 2013 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 %).
European Society Medical Oncology: m-crc guidelines September 2014. Statement: In patients with liver-limited metastases failing the available chemotherapeutic options, radioembolisation with Yttrium 90 resin microspheres can also prolong the time to progression. ( Level II - small randomised trials). 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.
Integrating SIRT into the mcrc treatment paradigm Potentially curative surgery or ablation Resectable 10 20% Liver-only or liverpredominant mcrc Decrease RR > Radioembolisation > Radioembolisation <20% 1 st -line chemotherapy +/- Biologics 2 nd -line chemotherapy +/- Biologics VEGF n th -line chemotherapy +/- Biologics EGFR Chemorefractory? Radioembolisation Radioembolisation K-ras and Raf Mutants Radioembolisation Clinical Trials SIRT
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