Stage III Colon Cancer Susquehanna Cancer Center Warren L Robinson, MD, FACP May 9, 2007

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1 Stage III Colon Cancer Susquehanna Cancer Center Warren L Robinson, MD, FACP May 9, 27 Stage III Colon Cancer Susquehanna Cancer Center

2 Colorectal cancer is the third most common cancer in the United States with an estimated life-time risk of 6%. 1 It affects males and females equally and is the second most common cause of cancer death. 2 Although highly curable when diagnosed in early stages, the 5 year overall survival is only 62%. One approach to improve survival has been the development of systemic adjuvant chemotherapy. As late as 1984 the Gastrointestinal Tumor Study Group reported no survival advantage with adjuvant chemotherapy or immunotherapy for patients with Dukes stage B2, C1 or C2 colon cancer. 3 However, in 1989 the North Central Cancer Treatment Group reversed this understanding with its seminal report of adjuvant Levamisole and Fluorouracil demonstrating a borderline improvement in survival for patients with stage C disease. 4 A statistically significant improvement in overall survival with adjuvant chemotherapy in node positive colon cancer emerged in a subsequent report 5 and has been confirmed by others. 6 Today systemic adjuvant chemotherapy is an established standard of care for patients with node positive colon cancer. The Commission on Cancer embarked on an assessment of the utilization of adjuvant chemotherapy in node positive colon cancer patients through its Cancer Program Practice Profile Reports (CP3R) as a measure of quality of cancer care at its approved programs. This report details an analysis of all analytic cases of stage III colon cancer seen at the Susquehanna Cancer Center between 1997 and 21. Results A total of 12 patients with Stage III colon cancer were observed during this time period averaging 2 new cases per year. Their demographics are displayed in Table 1. Male and female cases were Table 1 Demographics Total Cases 12 Average per Year 2 Male: Female 52: Caucasian: African-American 99:3 Age: Median (range) (yrs) 71(-88) Male 68(-87) Female 74(45-88) divided equally. The predominately Caucasian distribution likely reflects the population of this region. The median age at diagnosis was 71 years, 68 years for males and 74 years for females. 92% were over age years and 67% over 65 years. Table 2 displays the distribution of primary sites among these 12 Stage III patients. Overall, 46% patients presented with cecal or right colon lesions while % had left colon or distal lesions. However, % of male cases involved Table 2 Primary Location Total Male Female Cecum Ascending Hepatic Flex Transverse Splenic Flex Descending 3 3 Sigmoid NOS the distal colon compared to only 18% for females. Whereas the disease

3 involved the proximal colon in 76% of our female patients compared to only 36% for male patients. Involvement of the flexures and transverse colon were relatively consistent with 2% overall, 21% males and 18% females. Complete surgical resection was deemed to have been achieved in 96% of cases. The predominate surgical procedure was a limited colectomy in 94% of cases. Subtotal and total colectomies were each performed in 3% of patients. The lymph node evaluation is given in Table 3. Table 3 Lymph Node Analysis Total: Median (range) 8 (1-38) < 12 72% > 12 26% Not assessable 2% Positive: Median (range) 2 (1-21) leucovoran was employed in 99% of patients treated. Only one patient received 5-Fluorouracil plus levamisole during this period. Table 5 ChemoRx Contraindications Contraindication Number Perioperative death 2 Poor performance status 2 Dementia 2 Renal failure, dementia 1 Renal & heart failure 1 Heart failure 1 Heart Failure, COPD 1 Non-healing wound 1 Overall survival of this group of Stage III patients is depicted in Figure 1 comparing patients at this center with those reported to the State and National Registries. 76% of patients were symptomatic at the time of diagnosis. Abdominal pain, rectal bleeding, anemia, and change in bowel habit were the most frequent symptoms. 24 patients were identified through screening, 18 by stool hemoccult testing and 6 by colonoscopy. Table 4 displays the percentage of patients identified by screening by year. Figure 1 Overall Survival Five Ye a r Obse rve d Surviva l Ra te s State of PA National Cancer DataBase** ** 1999 is most recent data available from NCDB Table 4 Screened vs. Symptomatic (%) Year Screened Symptomatic Adjuvant chemotherapy was recommended to 89% of these Stage III patients and received by 81%. 8% of patients refused chemotherapy. 11% were deemed not to be suitable candidates for chemotherapy (Table 5). The regimen of 5-Fluorouracil and Figure 2 compares survival by sex. At all follow up intervals males in this group of patients achieved greater survival than females. Figure 2 Survival by Sex Susquehanna Hea lth Five Yea r Observe d Surviva l Female vs Male Female Male

4 Figures 3-6 depict survival comparisons by various grouping. Those patients identified by screening had similar survival to those who were symptomatic. Patients with more than 12 nodes identified in the specimen and those with less than 4 positive nodes had superior survival. Those patients who received treatment lived longer than those who did not receive treatment. Figure 6 Survival by Treatment Five Year Observed Survival Rates Treatment vs Refused vs Contraindicated Discussion Contraindicated Refused Treatment Received Figure 3 Survival by Detection Method Five Year Obse rved Suriva l Rates Screening vs Symptomatic Screening Symptomatic 2 1 Figure 4 Survival by Total Nodes Five Year Observed Survival Rates Nodes Examined Nodes 12 Examined Nodes < 12 Examined 2 1 Figure 5 Survival by Positive Nodes Five Year Observed Survival Rates Positive Nodes Colon cancer is recognized to be a major health problem. Despite declining incidence and mortality rates in recent years, this disease remains the third most common malignancy among men and women and the second most frequent cause of cancer death. Patients presenting to this community cancer center have demographics similar to those reported to State and National registries. As expected the incidence was equal in males and females. 92% of our patients were over yrs and 67% greater than 65 yrs approximates Pennsylvania State data with 9% over yrs and 75% over 65 yrs. Our Stage III patients described in this review do demonstrate some differences from those patients reported in clinical trials. In general our patients were significantly older as shown in Table positive nodes 4 or more positive nodes Table 6 Age Distribution 2 1 Study Median(yrs) This report 71(-88) 92%> 67%>65 GITSG(3) 84%> 56%>61 NCCTG(5) 61(18-84) NSABP(6) 54%< 45%>

5 This age difference did not appear to adversely impact survival or the use of adjuvant chemotherapy in our patients. Among our patients overall 46% presented with right colon lesions compared to % distal and 2% at the flexures or transverse colon. Mortel 5 reported 33% proximal, 43% distal and 17% flexure or transverse sites. Wolmark 6 noted 42% right colon and 55% left colon or rectosigmoid tumors among his cases. This more proximal distribution of colon tumors among our patients is even more notable in our female patients who had 64% right sided, 18% flexure or transverse, and only 15% distal cancers. This pattern may have implications for screening strategies among patients in this area. The vast majority of our patients were symptomatic at the time of diagnosis. Although it is recognized that screening tests have limitations, this observation more like reflects the general consensus of under utilization of screening tests for colorectal cancer. 7 During the later years of this study the percent of patients identified by screening increased from a baseline of 18% to 42% in the final year. Interestingly, 21 was the first year of a concerted effort by the Lycoming County Colorectal Cancer Task Force to increase the use of screening through physician education programs and community awareness. Stage at diagnosis remains the single most important prognostic factor for colorectal cancer. 8 The survival of our unselected Stage III colon cancer patients compares favorably with State and National reference data. The number of lymph node metastases has been identified as affecting prognosis and in 26 is used to substage these patients. The 5 yr overall survival of our patients with less than 4 lymph node metastases was % compared to % for 4 or more lymph nodes involved. The number of lymph nodes recovered in the surgical specimen has also been demonstrated to have prognostic significance. 9 Among our cases the 5 year overall survival was 58% for 12 or greater nodes examined versus % for less than 12 nodes examined. These results are similar to those of Johnson et al 1 who observed a 5 year survival of 73% for Stage IIIB and 58% for Stage IIIC patients with more than 12 nodes examined as opposed to 55% and 35% respectively for three or fewer nodes examined. The Commission on Cancer has adopted the description of 12 or more nodes in the pathology report as the criteria for its next CP3R colorectal quality care project. Only 26% of our cases would have met this criterion. The median of 8 lymph nodes recovered in the specimens of our patients is not far below the reported U.S. average of Older studies reported the survival among women to be superior to men while later studies could not confirm an impact of sex on survival. 8 In our small group of patients males enjoyed greater survival at every interval. Nonetheless, sex is not generally recognized as a significant prognostic factor in this disease. Although surgery remains the principal modality with curative potential for colon cancer, adjuvant chemotherapy has been clearly demonstrated to improve survival of patients with node positive colon cancer. 12 The use of adjuvant chemotherapy is felt to be one

6 of the main reasons the 5 yr survival has improved from % in the 19 s to 62% in the 199 s and has become a well recognized standard of care. 11% of our patients were deemed to be poor candidates for adjuvant chemotherapy due to comorbid conditions. All other patients at our center determined to be suitable for adjuvant chemotherapy were offered chemotherapy. 91% of that group of patients received treatment. This degree of adjuvant chemotherapy utilization significantly exceeds the report of Potosky for the SEER program 13 in which 9% of patients under 55 yrs, 65% of patients yrs and % of patients over 75 yrs received adjuvant chemotherapy. The % 5 year survival observed in our treated patients matches that of reported trials of adjuvant chemotherapy. Patients with Stage III colon cancer managed at the Susquehanna Cancer Center are generally older and more often present with proximal lesions than typically reported in clinical trials. They receive surgical and adjuvant therapy which rivals best practices. Their 5 year survival matches State and National reference standards. As we move forward an effort should be made to increase the number of lymph nodes examined in the surgical specimen. Refinements in adjuvant therapy may further enhance survival, but diagnosis at an earlier stage with better prognosis through screening remains a major public health priority.

7 1. Bromer MQ & Weinberg DS: Screening for Colorectal Cancer-Now and the Near Future. Semin Oncol 32:3-1, Jemal A et al: Cancer Statistics 27. CA Cancer J Clin 57:43-66, Gastrointestinal Tumor Study Group: Adjuvant Therapy of Colon Cancer Results of a Prospectively Randomized Trial. NEJM 31: , Laurie JA, Moertel CG, Fleming TR, et al: Surgical Adjuvant Therapy of Large-Bowel Carcinoma: An Evaluation of Levamisole and the Combination of Levamisole and Fluorouracil. JCO 7: , Moertel CG et al: Levamisole and Fluorouracil For Adjuvant Therapy of Resected Colon Carcinoma. NEJM 322: , Wolmark N et al: The Benefit of Leucovorin-modulated Fluorouracil as Postoperative Adjuvant Therapy for Primary Colon Cancer: Results From National Surgical Adjuvant Breast and Bowel Project Protocol C-3. JCO 11: , Lymphadenectomy: Results of a Secondary Analysis of a Large Scale Adjuvant Trial. Ann Surg 235: , Johnson PM et al: Increasing Negative Lymph Node Count Is Independently Associated With Improved Long-Term Survival in Stage IIIB and IIIC Colon Cancer. J Clin Oncol 24; , Schrag D et al: Adjuvant Chemotherapy Use for Medicare Beneficiaries with Stage II Colon Cancer. J Clin Oncol 2:3999-5, Sun W, Haller DG: Adjuvant Therapy of Colon Cancer. Semin Oncol 32:95-12, Potosky AL et al: Age, Sex and Racial Differences in the Use of Standard Adjuvant Therapy for Colorectal Cancer. J Clin Oncol 2: , Etzioni DA et al: A Population- Based Study of Colorectal Cancer Test Use. Cancer 11; , Skibber JM, Minsky BD, Hoff PM: Cancer of the Colon, Chapter 33.7 in Devita Cancer: Principles and Practice of Oncology, 6 th edition, 21, pp Prandi M et al: Prognostic Evaluation of Stage B Colon Cancer Patients is Improved by an Adequate