High risk stage II colon cancer

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1 High risk stage II colon cancer Joel Gingerich, MD, FRCPC Assistant Professor Medical Oncologist University of Manitoba CancerCare Manitoba Disclaimer No conflict of interests 16 October 2010 Overview Review the natural history and benefit of adjuvant chemotherapy in stage II colon cancer Identify high risk prognostic factors in stage II colon cancer Review the role of microsatellite instability in patients with stage II colon cancer Colon cancer 2010 Incidence 22,500 4 rd leading cause of cancer in Canada 2010 Death 9,100 2 nd leading cause of death in Canada Canadian Cancer Society s Steering Committee: Canadian Cancer Statistics Toronto: Canadian Cancer Society, 2010 Gunderson L et al: J Clin Oncol 28: Non-metastatic colon cancer: SEER data Adjuvant chemotherapy in stage II colon cancer Intergroup Meta-analysis: N = 3302, 7 studies, stage II = 1440 Outcome No Chemo FU-based chemo P value 5-year DFS year OS QUASAR: N = 3239, stage II = 2963, FU-based chemo Outcome HR (95% CI) P value Recurrence 0.78 ( ) Death 0.84 ( ) Translates to 5 year OS benefit = 3.6% FU = fluorouracil Canadian Cancer Society s Steering Committee: Canadian Cancer Statistics Toronto: Canadian Cancer Society, 2010 Gunderson L et al: J Clin Oncol 28: Gill S et al: J Clin Oncol 22: Quasar collaborative group et a: Lancet. 2007;370:

2 Adjuvant FOLFOX in stage II colon cancer: MOSAIC trial Outcome FU-based chemo (%) FOLFOX (%) P value 5-year DFS year OS N = 2,246, Stage II = 898 There was a trend to improved DFS and OS in stage II patients that had high risk features 5-year DFS = 7.7% 6-year OS = 1.8% *FOLFOX was associated with increased toxicity compared to fluorouracil ASCO guidelines for stage II colon cancer The routine use of adjuvant chemo is not recommended Certain high risk stage II patients could be considered for adjuvant chemotherapy: T4/perforation Number of analyzed lymph nodes LVI Obstruction* High grade The risks and benefits of treatment need to be discussed Andre T et al: J Clin Oncol 27: Benson III AB et al: J ClinOncol. 2004;22: High risk factors in colon cancer Tumor Stage 1. Local tumor extent* 2. Number of examined lymph nodes* 3. Lympho-vascular invasion* 4. Tumor obstruction* 5. Tumor grade* 6. Mesenteric nodules 7. Residual tumor Compton CC et al: Arch Pathol Lab Med (7): Nodal micrometastases 2. Serum CEA 3. Circumferential margin 4. Histology type 5. 18q deletion 6. DNA content 7. Microsatellite stability 8. Gene profiling Tumor in colon wall T4a = Through serosa T4b = Into adjacent organ Stage II IIA = T3 N0 IIB = T4a N0 IIC = T4b N0 AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th ed, Edge, SB, Byrd, DR, Compton, CC, et al (Eds), Springer, New York p C19DE1F94871&GDL_Disease_ID=DB2F8EAC DD-B04E-684AFEF2AD94 5-year survival by T stage: SEER data (N = 74,690) 5-year survival by number of examined lymph nodes: Stage II colon ca Study N No. of LN Relative Survival (%) P-value Le Voyer et al (prospective) Swanson et al (retrospective) 648 < > 20 35, > Swanson et al: at least 13 lymph nodes need to be removed to reliably predict N0 disease < Gunderson LL et al: J Clin Oncol 28: Abdelrazeq AS et al: Colorectal Dis. 2008;10(8): Le Voyer TE et al : J Clin Oncol 2003;21: Swanson RS et al: Ann Surg Oncol. 2003;10(1):65 71 Chang GJ et al: J Natl Cancer Inst. 2007;99(6):

3 Mesenteric tumor nodules Tumor nodules without any evidence of lymph node tissue or lymph node architecture Seen in 14.8% of colorectal specimens Stage II (N = 19) 5-year OS = 60% Lower than expected (SEER data = 82.5%) Similar to stage III disease 7 th edition TNM staging Tumor nodules = N1c Stage IIIa disease Gunderson L et al: J Clin Oncol 28: Lo DS et al: Cancer Jan 1;112(1):50-4 AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th ed, Edge, SB, Byrd, DR, Compton, CC, et al (Eds), Springer, New York p 143 Lymphovascular invasion in Stage II + III colorectal cancer (N = 461) Outcome + LVI (%) No LVI (%) P value 5-year OS (colon) Local recurrence 16 7 <0.05 Abdominal recurrence 33 9 <0.05 Distant recurrence 13 8 <0.05 LVI seen in 13.2% of examined specimens Similar findings in most, but not all studies Minsky BD et al: Int J Radiat Oncol Biol Phys. 1989;17(2): Colonic obstruction/ perforation Tumor Grade Stage II + III disease (N = 1492) Colonic obstruction seen in 20.5% of cases Most were distal colon (83%) Well differentiated Moderately differentiated Low grade (>50% gland formation) Outcome (stage II) Obstruction No obstruction P value 5-year DFS Multivariate analysis: HR = 1.89 ( ), P = Obstruction was not a associated with a worse outcome in stage III disease Colonic perforation = colonic obstruction for outcome Chin CC et al: Int J Colorectal Dis (2010) 25: Bionde S et al: Am J Surg. 2008;195(4): Poorly differentiated undifferentiated Compton CC et al: Arch Pathol Lab Med (7): Newland RC et al: Cancer 1994; 73(8): High grade (< 50% gland formation) Prospective trial, stage III (N = 579), High grade 32% High tumor grade was an independent factor affecting overall survival: HR = 1.48, P < year survival = 46% vs. 26% Prognostic factors in Stage II colon cancer Well characterized prognostic factors have been identified that affect outcome in stage II colon cancer Mismatch repair genes Single base-pair mismatch Short insertion/deletion loop 5-year relative survival may range from as low as 60% to has high as 90% DNA Exonuclease complex Repairs the damaged DNA i.e. MutSα: MSH2 + MSH6 DNA mismatches occur commonly in normal cells 1 x

4 Defects in mismatch repair (MMR) genes Microsatellite Instability DNA Mutation methylation HNPCC = 2-3% of all colon cancers Sporadic = 15% of all colon cancer cases MMR genes MSH2 MSH6 PSM2 DNA Repetitive nucleotide sequences (microsatellites) inactive mismatch repair genes (both alleles) Accumulation of DNA errors Microsatellite instability PCR and IHC staining for MMR abnormalities MSI-High = >30% panels abnormal Sensitivity = 93% (misses MSH6) Specificity = 100% Testing 5 known microsatellite regions for MSI by PCR A: gel electrophoresis B: fluorescent primers Hampel H et al: N Engl J Med 2005;352: Suraweera N et al: Gastroenterology. 2002: 123: MSH2 - Sensitivity = 93% Specificity = 100% + MSH6 + PSM2 - IHC testing - - Differences between genetic and sporadic colorectal cancer Genetic (HNPCC): Younger patients Normal BRAF MSH % of cases Sporadic: Older patients Mutated BRAF 95% of cases Identifying colon cancer patients to be screened for HNPCC Amsterdam criteria 3 affected family members 2 generations 1 under age 50 Low sensitivity Low specificity Bethesda guidelines Colon cancer diagnosed < 50 2 HNPCC associated cancers MSI-H like tumor histology High sensitivity 1 st degree relative with Low specificity HNPCC cancer (pt or relative <50) 2 or more 1 st degree relative with HNPCC cancer Microsatellite unstable colon cancer Proximal colon Poorly differentiated Increased mucinous/signet-ring component Medullary growth pattern Lymphocytic infiltration Crohn s like lymphocytic reaction Umar A et al. J Natl Cancer Inst 2004; 96(4): Gastroenterology Jul;121(1):195-7 Hampel H et al: N Engl J Med 2005;352: Umar A et al. J Natl Cancer Inst 2004; 96(4):

5 Determining the positive predictive value for MSI N = 326 Stage II and III colon cancer Sporadic MSI TIL 2-4+ = Tumor-infiltrating lymphocytes (>2 per high powered field) MSI is associated with improved prognosis: Metaanalysis of stage II and III colorectal cancer pts with MSI Overall survival 13 studies N = 2935 MSI = 508 (17%) MSI better No MSI better HR 0.67 ( ) P < 0.05 Sinicrope F et al: Cancer 2010;116: Popat S et al: J Clin Oncol 2005;23: Adjuvant Fluorouracil in stage II and III colorectal cancers with MSI Relapse free survival (N = 454) 7 studies, N = % had colon cancer 810 had stage II disease MSI found in 454 (14%) Defective MMR as a predictive marker in Stage II colon cancer Pooled analysis from 5 randomized controlled trials Adjuvant fluorouracil vs. placebo N = 1027 Defective MMR = 165 Chemotherapy better Chemotherapy worse Dess Guetz G et al: Eur J Cancer. 2009;45(10): Ribic CM et al: N Engl J Med. 2003;349: Defective MMR and outcome in stage II and III colon cancer Defective MMR: Stage II HR = 2.30 ( ) P = % of stage II patients had dmmr Surgery Chemotherapy Defective MMR: Stage III HR = 1.01 ( ) P 0.98 Defective MMR conclusions Defective MMR colon cancers: do not benefit from fluorouracil based adjuvant chemotherapy MMR status should be assessed prior to considering treatment in stage II colon cancer patients normal MMR: Stage II HR = 0.84 ( ) P = 0.38 Normal MMR: Stage III HR 0.64 ( ) P = 0.01) 5

6 Why would adjuvant fluorouracil not be effective in defective MMR colon cancer? Anti-tumor immune response seen in dmmr tumors may be inhibited by the immunosuppressive effects of chemotherapy dmmr tumors associated with lymphocytic infiltration MMR genes required to identify DNA damage caused by fluorouracil apoptosis dmmr tumors don t undergo FU induced apoptosis Are FOLFOX and FOLFIRI effective in MSI tumors? FOLFOX: N = 233, retrospective, FOLFOX vs. FU in adjuvant colon ca -MSI-H pts did better if they received FOLFOX compared to FU -HR = 0.17 ( ), P = 0.01 Irinotecan: N = 723, prospective, IFL vs FU in adjuvant colon ca -5-year DFS improved in pts with MSI who received IFL -76% vs. 59%, P = 0.03 Schwitalle Y et al: Gastroenterology Apr;134(4): Kim ST et al: Cancer Chemother Pharmacol. 2010;66(4): Zaanan A et al: Annals of Oncology. 2010;21: Bertagnolli MM et al: J Clin Oncol. 2009;27: Genomic profiling 2010 treatment 3-year Recurrence risk QUASAR prospective study: N = 1, genes (including MSI) Could significantly predict DFS, OS Could not predict FU response Stage II High risk features: T4 12 LN (+) LVI High No grade = No Obstruction/perforation adjuvant chemotherapy dmmr Check for microsatellite instability Bethesda /Amsterdam criteria *Proximal tumor Yes = No *Poor histology adjuvant *Tumor infiltrating chemotherapy lymphocytes Treatment Shared decision process Weigh risks and benefits Absolute benefit in overall survival < 5% Online decision tool = Adjuvantonline.com Barrier A et al: J Clin Oncol. 2006;24(29): Kerr D et al: [abstract 4000] J Clin Oncol. 2009;25(15 suppl):169s Conclusions Thank-you Stage II colon cancers have a good prognosis High risk prognostic factors have been identified which increase risk of relapse The benefit of adjuvant chemotherapy in stage II colon cancer is small MSI predicts lack of response to FU chemotherapy 6