Post-Resection CA 19-9 Predicts Overall Survival in Patients Treated with Adjuvant Chemoradiation; RTOG 9704 A. Berger, K. Winter, J. Hoffman, W. Regine, R. Abrams, H. Safran, A. Konski, A Benson III, J. MacDonald, and C. Willet

CA 19-9 Most important tumor marker for pancreatic adenocarcinoma. Serum levels are an important predictor of recurrence and survival after resection. It is also related to Lewis blood group determinants. Pancreatic cancer patients with a Lewis negative (a-, b-) phenotype will have undetectable CA 19-9 levels. This phenotype is thought to occur in 10-15% of the population.

Impact of Post-operative CA 19-9 Levels In a study of 40 patients from FCCC, Montgomery et al determined that using a serum CA 19-9 cutoff value of 180 U/ml in the 1 to 3 month post-operative period was one of the most important determinants of survival and recurrence. They demonstrated that patients with a value >180 U/ml had a median survival of 13 months compared to 34 months for those with CA 19-9 ≤180 U/ml. This study eliminated those patients (n=8) with an undetectable CA 19-9 level. In a study by Berger et al, the median survival of 7 resected patients with undetectable CA 19-9 levels was 32 months. Montgomery AnnSurgOnc, 1997. Berger AnnSurgOnc, 2004.

RTOG 9704 538 patients entered over 4 year period with 451 analyzable. Largest adjuvant chemoradiation trial ever performed in pancreatic cancer. Primary endpoint was overall survival. Results presented at ASCO and ASTRO 2006 (manuscript submitted). Patients with pancreatic head tumors experienced improved survival. Secondary endpoints included an analysis of the prognostic significance post-operative CA 19-9 levels.

SCHEMA RANDO STRAT M I I Z FY E ARM 1: Pre-CRT 5-FU ARM 2: Pre-CRT GEM + Chemoradiation Post CRT 5-FU Nodal Status Neg. vs. Pos Tumor Diameter <3cm vs. ≥3cm Surgical Margins Pos. vs. Neg. vs. Unknown ARM 2: Pre-CRT GEM + Chemoradiation Post CRT GEM

TREATMENT Pre-CRT Chemotherapy: Starting 3-8 weeks after definitive tumor-related surgery: Arm 1: 3 weeks of continuous infusion (CI) 5-FU at 250 mg/m2/day. Arm 2: Gemcitabine at 1000 mg/m2, weekly x 3. Chemoradiation (CRT): Starting 1-2 weeks after completion of pre-CRT chemotherapy: Arms 1 & 2: 50.4 Gy @ 1.8 Gy/fx for 5.5 weeks and CI 5-FU, 250 mg/m2/day, during XRT. Post-CRT Chemotherapy: Starting 3-5 weeks after CRT: Arm 1: 3 months of CI 5-FU [(4 wks on + 2 wks off) x 2]. Arm 2: 3 months of Gemcitabine [(3 wks on + 1 wk off) x 3].

CA 19-9 Testing Red cell phenotyping for Lewis Ag a and b were performed—if both were negative, the patient was considered Lewis Ag negative and assigned a CA 19-9 level of zero. All other patients had serum sent to central laboratory for CA 19-9 determination. 385 patients had analyzable CA 19-9 levels that met protocol eligibility; 66 patients had levels which could not be determined. Analysis was performed for all patients (n=385), patients with pancreatic head tumors (n=335), and for patients with non-head tumors (n=50).

Table 1—Baseline Demographics Gender n % Male 225 58 Female 160 42 Primary Tumor Location Head 335 87 Everything Else 50 13 N-Stage N0 127 33 N1 258 67 AJCC Stage (5th Edition) Stage I 47 12 Stage II 71 18 Stage III 233 61 Stage IV A 34 9 Surgical Margins R0 154 40 R1 133 35 Unknown 98 25 Race White 339 88 African American 23 6 Other CA 19-9 (U/ml) ≤180 220 57 >180 Lewis Antigen Negative 132

RESULTS There were no significant differences in baseline characteristics by CA 19-9 level except that CA 19-9 levels >180 were associated with larger tumors (p=0.048). There were no significant differences in overall survival between ≤ 180 and undetectable groups. 97% of patients with CA 19-9 >180 were dead at last follow-up while 74% were dead in the <180 group. Median survival in >180 group was ~9 months, while in ≤ 180 group, it was ~21 months. 3-year survival by CA 19-9 group— Undetectable=24% ≤ 180=30% >180=≤9%

Table 2—Multivariate Analysis Overall Survival Adjustment Variables Adjusted HR p-value Treatment (Gem vs. 5-FU) 1.23 (0.97, 1.54) 0.08 CA19-9 <180 vs. ≥ 180 <180 vs. Lewis Antigen Negative 3.58 (2.40, 5.34) 1.12 (0.87, 1.44) <0.0001 0.37 Nodal Involvement (No vs. Yes) 1.46 (1.13, 1.89) 0.004 Tumor Diameter (<3 vs. ≥ 3cm) 1.07 (0.83, 1.37) 0.60 Surgical Margin Status Negative vs. Positive Negative vs. Unknown 1.24 (0.94, 1.63) 0.96 (0.71, 1.30) 0.13 0.78

Figure 1—Survival Curve for all patients by CA 19-9 grouping Lewis Antigen Negative CA19-9 ≥ 180 Lewis Antigen Negative p = 0.25 CA19-9 ≥ 180 p = < 0.0001 Patients at Risk CA19-9 < 180 Lewis Antigen Neg. CA19-9 ≥ 180 220 132 33 164 94 10 93 46 3 56 29 39 21 22 10

SUMMARY A post-resection CA 19-9 level ≤ 180 U/ml corresponds to a 72% reduction in death in all patients treated with adjuvant chemoradiation for pancreatic cancer compared to patients with CA 19-9 > 180 U/ml. This is independent of treatment, margin status, size of primary tumor, and nodal involvement. Post-resection CA 19-9 was a prognostic factor in all patient groups (all, head only, non-head lesions) with HR of 3.58, 3.52, and 4.61, respectively. The incidence of Lewis Antigen negative patients (34%) may be higher than previously thought; these patients have survival which is comparable to patients with CA 19-9 levels ≤180 U/ml.

CONCLUSIONS Post-resection CA 19-9 is an important prognostic factor in patients undergoing adjuvant chemoradiation for pancreatic adenocarcinoma. Patients with post-resection CA 19-9 levels >180 U/ml have a very poor survival (median=9 months). These patients should be considered for additional/prolonged chemotherapy.