Molecular epidemiology of colorectal cancer

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I. J. Radiation Oncology

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● Biology ● Physics

Volume 51, Number 3, Supplement 1, 2001

Radiosensitization with Capecitabine in Gastrointestinal Malignancies

E. Ben-Josef1,2,4, U.N. Vaishampayan3,4, V. Vaitkevicius3,4, K. Levin1,4, P. Philip3,4, S. Han2,1, B. Allen2, A.F. Shields3,4 1 Department of Radiation Oncology, Wayne State University, Detroit, MI, 2VA Medical Center, Detroit, MI, 3Division of Hematology Oncology, Wayne State University, Detroit, MI, 4Karmanos Cancer Institute, Detroit, MI Purpose: Capecitabine is an oral 5-FU prodrug with pharmacodynamics mimicking continuos infusion 5-FU. Capecitabine is far more tumor-selective and has been shown to be superior to 5-FU in radisensitizing breast and colon cancer xenografts. Clinical data is scarce. We report here our experience in gastrointestinal malignancies. Materials and Methods: A retrospective review of medical records was conducted. Thirty patient (20 males and 10 females) were treated for rectal (11), colon (6), pancreatic (5), gall bladder (2), esophageal (2), GE junction (2), gastric (1), and ampullary (1) cancer. Median age was 63 years (range 35-85). Performance status was 0-2 and all had adequate renal, hepatic and bone marrow function. Histology was adenocarcinoma in all except 2 patients with squamous cell carcinoma of the esophagus. Therapy was given post-operatively [adjuvant (15), positive margins (3)], neoadjuvant pre-operatively (4), as the only therapy with curative (2) or palliative intent (6). Median radiotherapy dose was 50.4 Gy (range 29.9-64.8) at 1.8 Gy (range 1.15-2.5) per fraction. Three previously irradiated patients received twice daily therapy (1.15 or 1.2 Gy) to a total of 29.9Gy to 46 Gy. Capecitabine was administered at 1350-2500mg/m2/day (median 1600), in two divided doses orally, five days per week for the duration of radiation therapy. Toxicity was evaluated weekly and scored using the NCI Common Toxicity Criteria. Results: Toxicities included G1 hand-foot syndrome (30%), nausea [G1 (23%), G2 (7%)], diarrhea [G1 (30%), G2 (20%), G3 (3%)], anemia [G1 (10%), G2 (3%)], neutropenia [G1 (7%), G3 (10%)], thrombocytopenia [G1 (13%), G2 (3%)], G3 asthenia (3%), and G4 cardiac ischemia (3%). Capecitabine dose was reduced in 10% of patients and radiotherapy was completed in all patients as planned. Weight loss (median 5 lbs; range 1-17) occurred in only 19 patients (63%). Most adverse effects occurred after three weeks of therapy. There was one hospitalization and no treatment related deaths. Response data was available for 8 patients with evaluable disease in the radiation field. Of these, there were 2 who did not respond, 4 with partial response and 2 with complete response. Conclusion: Concurrent Capecitabine with radiation is very well tolerated. Acute GI toxicity appears to be particularly low. This regimen is convenient to patients, and avoids the risks, inconvenience, and cost of ports and pumps. Further evaluation is warranted.

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Intratumoral 166 Hollmium-CHICO Therapy in Locally Recurrent Pelvic Malignancies

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M. Chun , S. Kang1, C. Park2, J. Won3, K. Park4, Y. Oh1, H. Kil1, C. Joh2, S. Yoon2 1 Radiation Oncology, Ajou University Hospital, Suwon, South Korea, 2Nuclear Medicine, Ajou University Hospital, Suwon, South Korea, 3Radiology, Ajou University Hospital, Suwon, South Korea, 4Atomic Energy Research Institute, Taejeon, South Korea Purpose: Local recurrence after the primary treatment in pelvic malignancies is rarely controlled with external radiotherapy (EBRT). Brachytherapy in addition to EBRT is useful to increase the tumor dose for better local control. Intratumoral injection with P32 had been attempted in patients with locally advanced pancreatic cancer for higher dose of radiation to the tumor. 166Hollmium has been used in oncology practice last 5 years either for treatment of hepatoma or for skin cancer in Korea. This is the first report of 166Hollmium therapy experience with injection into the recurrent tumors. Materials and Methods: From November 1997 to October 2000, total 6 patients underwent 166Hollmium-CHICO treatment 1 to 4 months after completion of planned EBRT. 166Hollmium-CHICO therapy was considered as either boost or re-treatment after evaluation of response from EBRT. Patients were selected with following criteria 1) localized recurrent tumor in the pelvis, 2) tumor size ⱕ 5, 3) ECOG performance status ⱖ 2. 166Hollmium-CHICO was injected through CT scan guided needle. We checked the presence of isotope leakage into normal tissue using Gamma camera. Patients were regularly followed in the clinic. For response evaluation, CT scan and/or FDG PET scan were performed 3-6 months later. Results: All patients except one were free from local symptoms with local control during follow-up period and maintained the good quality of life. All complained some discomfort at the injected site and dexamethasone (3-4 mg per day) could relieve the ache. Two patients are alive with stable disease more than 1 year (15 and 38 months, respectively). Complete remission was achieved in another one for more than a year. The patient with CR was benefited with isotope treatment since her bone marrow could not tolerate the high dose of radiation due to her known condition of aplastic anemia. Conclusion: This study showed the feasibility of intratumoral 166Hollmium-CHICO therapy as an active treatment in locally recurrent pelvic malignancies with good local control and minimum side effect.

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Molecular Epidemiology of Colorectal Cancer 1,2

H. Elsaleh , F. Grieu1, D.J. Joseph1, B. Iacopetta2 1 Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia, 2Surgery, University Of Western Australia, Nedlands, Australia Background: Environmental influences appear to have a greater impact on the incidence of colorectal cancer (CRC) then hereditary factors, with changing dietary habits and an ageing population potentially influencing the pattern of presentation over time. Aims: To determine whether the presentation of CRC over the past two decades has changed with respect to patient age, primary tumor site, gender and frequency of the common molecular alterations. Accurate documentation of these changes

Proceedings of the 43rd Annual ASTRO Meeting

should assist in understanding the process of carcinogenesis and therefore in helping to direct future environmental and therapeutic interventions. Methods: Establish a tumor bank database of Stage II-III CRC spanning the years 1986-1990, evaluate the molecular alterations (Ki-ras, TP53 and MSI a marker associated with DNA methylation) and correlate with clinicopathological factors. Results: 1203 patients from a single institute were identified from histopathology records. The proportion of female CRC patients and of proximally located tumors has increased in recent years (P⫽0.008). A significant difference in mean age between males and females with proximal tumors was observed (64 years vs 74 years, respectively, P⬍0.0001) but no difference was seen in patients with distal tumors (67 years for both). MSI was more common in proximal tumors from older females whereas TP53 mutations were more common in distal tumors from males. The female to male incidence of MSI was 2:1 (P⬍0.0001) No sex or site differences were observed for the frequency of Ki-ras mutation. Over time MSI become more common and TP53 mutation less common (P⫽0.003), correlating with the increase in incidence of proximal tumors in females. Interpretation: Longitudinal patterns of CRC presentation together with correlative molecular factors reveal influences underlying the biology of this disease. The increasing frequency of proximal tumors in older female patients may due to increased DNA methylation in the colonic mucosa, a factor with known links to age, sex and dietary factors. The mechanism of carcinogenesis in the proximal colon of females is likely to differ significantly to that occurring in the distal colon of males and females are likely to be more responsive to preventative dietary interventions.

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Patterns of Local Failure after Esophagectomy: Role of Adjuvant Radiotherapy 1

D. Khuntia , C.A. Reddy1, T.W. Rice2, D.J. Adelstein3, J.P. Saxton1, M.A. Chidel1 1 Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, 2Thoracic Surgery, Cleveland Clinic Foundation, Cleveland, OH, 3Hematology and Oncology, Cleveland Clinic Foundation, Cleveland, OH Purpose: To evaluate the patterns of locoregional failure for patients undergoing esophagectomy alone for carcinoma of the esophagus. Materials and Methods: The authors conducted a single-institution retrospective analysis of 170 ultrasound-staged patients who underwent esophagectomy alone between January 3, 1991 to July 5, 2000 for invasive esophageal carcinoma. KaplanMeier, logrank test, and Cox proportional hazards regression were used to evaluate the significance of age, sex, histology, differentiation, TNM pathologic stage, location of primary, invasion of G-E junction, length of primary, presence of Barrett’s esophagus, presence of signet cell histology, nearest surgical margin, and type of surgical anastomosis in predicting local failure. Location of local failure for each patient was also noted. Results: One hundred seventy patients (138 men and 32 women) were evaluated. The 5-year overall survival was 35.6%. Local regional failure was identified in 39 patients (23%) resulting in a 5-year local control rate of 61.0%. Using univariable analysis, factors predictive of local failure were higher grade (p⫽0.005), pathologic stage T2-4 N0 vs. T1 N0 (p⫽0.034), pathologic stage N1 or M1a (p⬍0.0001), tumor length ⬎3 cm (p⫽0.0007), absence of Barrett’s esophagus (p⬍0.011), presence of signet cells (p⫽0.049), and abdominal or thoracic anastomosis (p⫽0.006). Age, sex, histology, location of primary, invasion of G-E junction, and nearest surgical margin were not predictive of local failure. Multivariable analysis reveals the only factor independently predictive of local failure was pathologic TNM stage, with N1 or M1a predictive for local failure. Of the patients that failed locally, 57% had failures at the middle mediastinum, 50% at the distal mediastinum, 47% at the site of anastomosis, 27% at the celiac nodes, and 7% at the upper mediastinum. Also regarding local failures, 83% of patients with abdominal anastomosis had failures at the anastomosis, 50% with thoracic anastomosis had anastomotic failures, and 13% with cervical anastomosis had failures at the anastomosis. Three-year and 5-year actuarial survival was 16% and 0%, respectively, for patients with local failure and 67% and 58%, respectively, for patients without local failure. In regards to distant failure, node positivity was a predictor for distant failure, but T stage was not (p⫽0.001). Conclusion: The current study identifies definite predictors of local failure for patients with invasive esophageal carcinomas following esophagectomy alone. Based on the failure analysis, adjuvant therapy is not necessary for T1 N0 lesions. Patients with T2-4 N0 may require adjuvant therapy. Node positivity is strongly predictive of local (and distant) failure suggesting adjuvant therapy should be included in the management. For patients with lower esophageal primaries and negative margins of resection, it is unnecessary to include a cervical anastomosis, but intrathoracic and abdominal anastomoses should be included in a radiotherapy portal. The anastomosis should be treated in all patients with upper and middle esophageal primaries regardless of the location of the anastomosis. Celiac node coverage is indicated only for lower esophageal primaries.

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A Phase II Study of Preoperative Chemotherapy and Radiation Therapy followed by Esophagectomy in Localized Esophageal Carcinoma

A.K. Chan1, A.O. Wong2, G.A. Gelfand3, P.C. Mitchell4, S. McFadden3 1 Radiation Oncology, Tom Baker Cancer Center, Calgary, AB, Canada, 2Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada, 3Surgery, Foothills Hospital, Calgary, AB, Canada, 4Surgery, Calgary General Hospital, Calgary, AB, Canada Purpose: Because of the poor locoregional control after esophagectomy in our previous retrospective review, we conducted a phase II study to evaluate the efficacy of combining preoperative chemotherapy and regional radiation with surgical resection in the local control of localized (M0) esophageal carcinoma. Materials and Methods: Since 1996, fifty patients have been enrolled in this study. There were 39 males and 11 females. The median age was 60 years. There were 38 adenocarcinomas and 12 squamous cell carcinomas. All 50 patients presented with a localized (M0) esophageal carcinoma. Majority (92%) of the tumors was located in the lower esophagus and the GE junction. 31 patients (62%) presented with a circumferential tumor, and 34 patients (68%) had a tumor longer than 5 cm. Using the 1983

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