1. C. ENG 1, G. J. CHANG 2, P. DAS 3, M. RODRIGUEZ-BIGAS 2, J. M. SKIBBER 2, W. QIAO 4, G. L. ROSNER 4, L. T. UKEGBU 1, R. A. WOLFF 1, C.H. CRANE 3 DEPARTMENT OF GASTROINTESTINAL MEDICAL ONCOLOGY 1, DEPARTMENT OF SURGICAL ONCOLOGY 2, DEPARTMENT OF RADIATION ONCOLOGY 3, DEPARTMENT OF BIOSTATISTICS 4 A Phase II Study of Capecitabine and Oxaliplatin with Concurrent Radiation Therapy (XELOX-XRT) in Squamous Cell Carcinoma Of The Anal Canal The University of Texas M.D. Anderson Cancer Center, Houston, TX

2. BACKGROUND Anal cancer accounts for 1.5% of all digestive system malignancies in the United States. 1 Squamous cell carcinoma (SCC) represents approximately 80% of all anal cancers. 2 Greater than 90% of patients will present with locoregional disease that is treated with concurrent chemoradiation therapy with curative intent reserving abdominal perineal resection (APR) for salvage surgery. Risk factors for anal carcinoma include HPV infection and chronic immunosuppression. The treatment paradigm of anal carcinoma has remained unchanged for the past three decades.

3. BACKGROUND(cont’d.) Traditionally, 5-FU based combinations with mitomycin C (MMC) are provided with concurrent radiation therapy but may result in significant and dose-limiting hematologic toxicities 3. 5-FU with cisplatin has also been investigated. The use of capecitabine rather than continuous infusion 5-FU may allow increased convenience without compromising synergy with radiation therapy. Oxaliplatin has radiosensitization properties, and a favorable toxicity profile relative to MMC or cisplatin. 3 To date, the role of oxaliplatin and capecitabine in squamous cell carcinoma of the anal canal has not been reported.

4. Rationale The use of oral capecitabine rather than infusional intravenous 5-FU allows increased convenience. The radiosensitizing properties of oxaliplatin, its improved toxicity profile relative to cisplatin, and its synergism with 5-FU validates further analysis as a radiation sensitizer. The combination of capecitabine and oxaliplatin (XELOX) has been determined to be feasible in the palliative treatment of metastatic colorectal cancer but also in combined modality therapy with radiation in the treatment of rectal cancer. Hence, XELOX-XRT, may result in equivalent or decreased toxicities to that of the traditional regimen of IV 5-FU with mitomycin C or cisplatin without compromising efficacy.

5. Objectives Primary Objectives: Determine time to treatment failure: Defined as:  Disease persistence or progression  Disease recurrence  Treatment-related mortality Determine treatment-related toxicities: Defined as:  > Grade 3 gastrointestinal symptoms  Grade 4 radiation-induced dermatitis  > Grade 3 hematologic or nonhematologic toxicity (excluding radiation dermatitis)  Toxicities resulting in treatment delays > 7 days Secondary Objectives: Rate of complete response (CR) Rate of locoregional control (LCR) Two-year rates of: Colostomy-free survival Overall survival Progression-free survival

6. Study Design Single institution Phase II study to evaluate the efficacy and safety of capecitabine and oxaliplatin with concomitant radiation therapy (XELOX- XRT) in patients with previously untreated locally advanced squamous cell carcinoma of the anal canal. Interim safety analysis using Bayesian stopping rules: Toxicity and failure- free survival was evaluated after every 10 patients and was initiated three months after the 10 th patient enrolled. Further study will be pursued if 4-yr failure-free survival is not worse than 73% and risk of acute toxicity is < 45%. Early stopping rule: > 80% probability that the risk of acute toxicity is > 35%

7. Eligibility Criteria Histologically proven SCCA of the anal canal AJCC stage II-IIIB (T 1-4 N x M 0 or T x N 1-3 M 0 ) ECOG PS 0-1 Informed consent No prior radiation to the pelvis No prior surgery for anal carcinoma excluding biopsy No peripheral neuropathy > CTC Grade 2 (Ver 3.0) Treatment naïve to oxaliplatin or 5-FU-based therapy No need for anticoagulation with coumadin HIV (+) patients were ineligible

8. Treatment Regimen(Chemotherapy) DrugRouteDoseSchedule* OxaliplatinCentral Line, IV 50 mg/m 2, weekly Days 1, 8, 22, and 29 during radiation therapy only. CapecitabineOral825 mg/m 2, twice daily Given Monday to Fridays only, on days of radiation therapy only. Weeks 1-2 and 4-5 only. Chemotherapy initially consisted of capecitabine (825 mg/m 2 BID, M-F) and weekly oxaliplatin (50 mg/m 2 ) (Group 1) subsequently modified due to treatment-related diarrhea to omission of chemotherapy during weeks 3 and 6 (Group 2).

9. Treatment Regimen(Radiotherapy) Radiation (IMRT was optional) T x -T 1 Lesions 45 Gy in 25 fractions Initial fields30.6 Gy in 17 fractions T 2 Lesions 55 Gy in 30 fractions Second Phase14.4 Gy in 8 fractions Boost 10 Gy in 5 fractions for T 1-2 tumors T 3-4 lesions 59 Gy in 32 fractions 14 Gy in 7 fractions for T 3-4 tumors Inguinal boost 55 Gy if > 1-3 cm 59 Gy if > 3 cm

10. Evaluation BaselineDuring Treatment 6-12 weeks post treatment CXR, CT of the chest/abdomen/pelvis Proctosigmoidoscopy U/S guided FNA for palpable inguinal lymph nodes Weekly physical exam for treatment toxicity CXR, CT of the chest/abdomen/pelvis Proctosigmoidoscopy Physical Exam U/S guided FNA for palpable inguinal lymph nodes if clinically indicated

11. Results  20 patients were enrolled. All patients were evaluable for toxicity; 19 for response.  Five of the first 11 patients (Group 1) developed grade 3 treatment-related diarrhea (Table 2). The regimen was then modified for the subsequent 9 patients (Group 2), of whom only one patient developed diarrhea. Number of patients Group 1 (N=11)Group 2 (N=9) Grade 3/4 Toxicity of interest 7 (78%)2 (22%) Table 1

12. Toxicities of Interest Number of Events Group 1Group 2 ADVERSE EVENT N%N% DEHYDRATION 18.300 DIARRHEA 541.7150 FATIGUE 18.300 HEMOGLOBIN 18.300 NAUSEA 00150 PAIN (ABDOMEN NOS) 18.300 PAIN (NOS) 216.700 PAIN (PERINEUM) 18.300 Table 2

13. Adverse Events by Maximum Grade Maximum Grade Group 1: N (%) Group 2: N (%) Total: N(%) 37 (64%)2 (22%)9 (45%) 24 (36%)6 (67%)10 (50%) 10 (0%)1 (11%)1 (5%) Total Treated 11920

14. Response Rates  Complete response rates of the primary tumor were 100% in Group 1 and 100% in Group 2, respectively.  One patient in Group 1 developed distant disease to the liver 10 months after the completion of chemoradiation therapy.  One patient developed a second microscopic primary SCCA of the anal canal (<1mm focus), 3.5 yrs after completing initial therapy. He was treated with chemoradiation therapy and remains disease-free.  Based on the log-rank test (p=0.4), there was no significant difference between the two treatment groups regarding time to treatment failure. (Graph1)

15. Kaplan Meier Failure Free Survival  Based on the log-rank test (p=0.4), there was no significant difference between the two treatment groups regarding time to treatment failure

16. Conclusions Capecitabine and oxaliplatin with concurrent radiation therapy is an effective approach in the treatment of locally advanced squamous cell carcinoma of the anal canal. Weekly chemotherapy administration resulted in increased toxicity (predominately grade 3 diarrhea). Omission of chemotherapy weeks 3 and 6 decreased toxicity without compromising efficacy of therapy. After a median follow up of 2 years, no patient has developed a local recurrence or required salvage resection with colostomy for a colostomy-free survival rate of 100%. XELOX-XRT is feasible and an apparently effective approach for locally advanced squamous cell carcinoma of the anal canal and warrants further investigation.

17. References 1.Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5-26. 2.Bendell JC, Ryan DP. Current perspectives on anal cancer. Oncology (Huntingt) 2003; 17:492-7, 502-3; discussion 503, 507-9. 3.Ajani et al. A phase III randomized study of 5-fluorouracil (5-FU), mitomycin, and radiotherapy versus 5-fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal.. JAMA, April 23; 299(16), 1914-21, 2008