1 RTOG 0315:A randomized, double blind, placebo-controlled phase III study to determine the efficacy of Octreotide acetate in preventing or reducing the severity of chemo radiation-induced diarrhea in patients with anal or rectal cancer. B. Zachariah, J. James, C.K. Gwede, J. Ajani, L. Chin, D. Donath, B. L. Kane, M. Rotman, L. Berk. (Abstract #4032)

2 INTRODUCTION Diarrhea is a common side effect of pelvic radiotherapy.Diarrhea is a common side effect of pelvic radiotherapy. Addition of chemotherapy increase the severity of diarrhea.Addition of chemotherapy increase the severity of diarrhea. In a multi-institutional study for rectal cancer,35% of patients treated with pelvic RT with concurrent chemotherapy( 5 F- Fluorouracil) experienced> grade 2 diarrhea(1).In a multi-institutional study for rectal cancer,35% of patients treated with pelvic RT with concurrent chemotherapy( 5 F- Fluorouracil) experienced> grade 2 diarrhea(1). Sandostatin has shown to control grade 3-4 diarrhea in >90% of patients treated with 5 FU containing chemotherapy.(2,3,4)Sandostatin has shown to control grade 3-4 diarrhea in >90% of patients treated with 5 FU containing chemotherapy.(2,3,4) To date there are no prophylactic measures effective in preventing the incidence of enteritis during chemo-radiationTo date there are no prophylactic measures effective in preventing the incidence of enteritis during chemo-radiation

3 OBJECTIVES To determine the efficacy of long acting Octreotide in preventing the onset of grade 2-4 diarrhea in patients receiving concurrent chemo-radiation therapy for anal or rectal cancer.To determine the efficacy of long acting Octreotide in preventing the onset of grade 2-4 diarrhea in patients receiving concurrent chemo-radiation therapy for anal or rectal cancer. To assess the impact of diarrhea on chemo-radiation delivery and medical resource utilization.To assess the impact of diarrhea on chemo-radiation delivery and medical resource utilization.

4 Eligibility Histologic proof of anal or rectal cancer without metastasis beyond pelvic regional nodes.Histologic proof of anal or rectal cancer without metastasis beyond pelvic regional nodes. Planned to receive full course radiotherapy with concurrent chemotherapy.Planned to receive full course radiotherapy with concurrent chemotherapy. No h/o prior pelvic or abdominal radiotherapy.No h/o prior pelvic or abdominal radiotherapy. Patients with a history of chronic or acute regional enteritis, malabsorption syndrome(s) or other inflammatory bowel disease were excluded.Patients with a history of chronic or acute regional enteritis, malabsorption syndrome(s) or other inflammatory bowel disease were excluded. Patients with uncontrolled diabetes or history of cholecystits or gallstones(unless cholecystectomy was performed) are excluded.Patients with uncontrolled diabetes or history of cholecystits or gallstones(unless cholecystectomy was performed) are excluded. Patients with a history of hepatic disease are excluded (patients with LFTs <3x the upper limit of normal are eligible)Patients with a history of hepatic disease are excluded (patients with LFTs <3x the upper limit of normal are eligible)

5 Eligibility…continued No glucocorticoid therapy, insulin sensitizers, or exogenous growth hormone with 6 months of study entry.No glucocorticoid therapy, insulin sensitizers, or exogenous growth hormone with 6 months of study entry. Hyper fractionated split course radiotherapy, and/or planned brachytherapy prior to completion of external beam radiation therapy is not allowedHyper fractionated split course radiotherapy, and/or planned brachytherapy prior to completion of external beam radiation therapy is not allowed

6 Study schema STRATIFY RANDOMISESTRATIFY RANDOMISE RT Dose Arm.1:Sandostatin LAR DepotRT Dose Arm.1:Sandostatin LAR Depot 1. <50Gy Pre-RT (between day-7and day-41. <50Gy Pre-RT (between day-7and day-4 2. >50Gy of RT) and day 22(+3days) 2. >50Gy of RT) and day 22(+3days) Chemotherapy Arm. 2:PlaceboChemotherapy Arm. 2:Placebo 1. Bolus Pre-RT (between day-7 and day-41. Bolus Pre-RT (between day-7 and day-4 2. Continuous of RT) and day22(+3days) 2. Continuous of RT) and day22(+3days) GenderGender 1.Male1.Male 2.Female 2.Female

7 MATERIALS AND METHODS Patients over age 18 were included in the study.Patients over age 18 were included in the study. Required sample size was 226.Required sample size was 226. Eligible patients will have a H&P 2 weeks prior to randomization.Eligible patients will have a H&P 2 weeks prior to randomization. After a test dose with Sandostatin s.c patients are randomized and given the study drug or placebo as outlined in the schema along with concurrent chemo-radiation.After a test dose with Sandostatin s.c patients are randomized and given the study drug or placebo as outlined in the schema along with concurrent chemo-radiation. All acute and late adverse events were reported and scored for severity using the NCI Common Terminology Criteria for Adverse Events (CTCAE v3)All acute and late adverse events were reported and scored for severity using the NCI Common Terminology Criteria for Adverse Events (CTCAE v3) Patient kept a diary to document the incidence of diarrhea and use of anti-diarrheal medications,which was monitored and documented weekly by the data manager and the physician.Patient kept a diary to document the incidence of diarrhea and use of anti-diarrheal medications,which was monitored and documented weekly by the data manager and the physician. Patients are followed up at 3,6,9 and 15 months from the start of radiotherapy.Patients are followed up at 3,6,9 and 15 months from the start of radiotherapy.

8 Patient Characteristics – Pretreatment Characteristics Placebo Sandostatin (n=107) (n=111) Age Median Range n % n % Gender Male Female Planned RT Dose <50 Gy > 50 Gy Planned Chemo Bolus Continuous infusion Disease Site Not Reported Anal Rectal Baseline Diarrhea None Grade Grade

9 PATIENT ACCRUAL The study accrued 233 patients from December 2003 to February The study accrued 233 patients from December 2003 to February Two hundred and nineteen patients were included in the analysis. Fourteen patients did not meet the eligibility criteria for inclusion or withdrew their consent for participation in the study. Patient demographic and stratification variables were well balanced between the placebo and Sandostatin arm.Two hundred and nineteen patients were included in the analysis. Fourteen patients did not meet the eligibility criteria for inclusion or withdrew their consent for participation in the study. Patient demographic and stratification variables were well balanced between the placebo and Sandostatin arm. Median follow up for these patients was 9.69 months.Median follow up for these patients was 9.69 months.

10 RESULTS-1 Table II. Incidence of Diarrhea,GI symptoms and Other Toxicities by Study Arm Placebo Sandostatin Grade Grade Gastrointestinal N % Worst Diarrhea N %

11 RESULTS-2 Incidence of Diarrhea, Gi symptoms and Other ToxicitiesIncidence of Diarrhea, Gi symptoms and Other Toxicities Placebo Sandostatin Placebo Sandostatin Grade Grade Grade Grade Blood/B.Marrow Blood/B.Marrow % % Skin Skin % % Pain Pain % %

12 RESULTS Treatment Compliance, RT and chemotherapy. Placebo sandostatin % % Hospitalization None >3 3 1 Unknown 2 3 Chemotherapy dose Modification No Yes Unknown 2 3 Radiotherapy Dose modification no yes,adverse event yes,other reason Unknown 2 3 Use of other anti- diarrheal agents no yes unknown 2 3

13 RESULTS Seventy seven percent of patients completed the study drug regimen.Seventy seven percent of patients completed the study drug regimen. Thirteen percent of patients experienced adverse events or complications.Thirteen percent of patients experienced adverse events or complications. There was no statistically significant difference between the treatment arms in the number of hospitalizations required, use of additional antidiarrheal agents, and whether radiotherapy or chemotherapy modifications, delays or interruptions were required.There was no statistically significant difference between the treatment arms in the number of hospitalizations required, use of additional antidiarrheal agents, and whether radiotherapy or chemotherapy modifications, delays or interruptions were required.

14 DISCUSSION Octreotide has been shown to control chemotherapy induced diarrhea resistant to loperamide therapy(2-4). Rosenoff et al has reported the use of mg of octreotide LAR in patients with chemotherapy induced diarrhea refractory to conventional anti-diarrheal agents. In their reports majority of patients treated experienced resolution to grade 0-1 diarrhea and were able to continue chemotherapy at full dose with minimal symptomatology(5).Octreotide has been shown to control chemotherapy induced diarrhea resistant to loperamide therapy(2-4). Rosenoff et al has reported the use of mg of octreotide LAR in patients with chemotherapy induced diarrhea refractory to conventional anti-diarrheal agents. In their reports majority of patients treated experienced resolution to grade 0-1 diarrhea and were able to continue chemotherapy at full dose with minimal symptomatology(5). Our study addresses the role of prophylactic use of octreotide LAR ® in reducing the incidence of severe diarrhea in patients receiving concurrent chemo- radiotherapy for patients with anal or rectal cancer confined to the pelvis.Our study addresses the role of prophylactic use of octreotide LAR ® in reducing the incidence of severe diarrhea in patients receiving concurrent chemo- radiotherapy for patients with anal or rectal cancer confined to the pelvis. There was no statistically significant difference in the incidence of grade 2+diarrhea(p=0.21)with 49% and 44% in the placebo and octreotide acetate treatment arms respectively.There was no statistically significant difference in the incidence of grade 2+diarrhea(p=0.21)with 49% and 44% in the placebo and octreotide acetate treatment arms respectively. Martenson et al (6) has conducted a similar study using octreotide LAR (20mg) prophylactically in patients receiving pelvic radiotherapy with or without 5 FU. Martenson et al (6) has conducted a similar study using octreotide LAR (20mg) prophylactically in patients receiving pelvic radiotherapy with or without 5 FU.

15 DISCUSSION Octreotide did not reduce the severity or incidence of diarrhea during pelvic radiotherapy. Grade 2-3 diarrhea was 52% and 48% in the octreotide and placebo arm respectively (p=0.86). Some measures of bowel functions were worse in the octreotide arm.Octreotide did not reduce the severity or incidence of diarrhea during pelvic radiotherapy. Grade 2-3 diarrhea was 52% and 48% in the octreotide and placebo arm respectively (p=0.86). Some measures of bowel functions were worse in the octreotide arm.

16 CONCLUSIONS Prophylactic use of octreotide acetate has not shown to significantly reduce the incidence of mild, moderate or severe diarrhea and utilization of medical resources in patients receiving concurrent chemo-radiation for anal or rectal cancer.Prophylactic use of octreotide acetate has not shown to significantly reduce the incidence of mild, moderate or severe diarrhea and utilization of medical resources in patients receiving concurrent chemo-radiation for anal or rectal cancer.

17 REFERENCES 1.Miller RC et al. Acute treatment related diarrhea during postoperative adjuvant therapy for high risk rectal carcinoma. Int J Radiat Oncol Biol Phys 41(3) , Miller RC et al. Acute treatment related diarrhea during postoperative adjuvant therapy for high risk rectal carcinoma. Int J Radiat Oncol Biol Phys 41(3) , Cascinu S et al. Octreotide versus loperamide in the treatment of fluorouracil induced diarrhea. A randomized trial. J Clin Onc 11(1):148-51, Cascinu S et al. Octreotide versus loperamide in the treatment of fluorouracil induced diarrhea. A randomized trial. J Clin Onc 11(1):148-51, Zidan et al. Octreotide in the treatment of severe chemotherapy induced diarrhea. Ann Oncol,2001,12: Zidan et al. Octreotide in the treatment of severe chemotherapy induced diarrhea. Ann Oncol,2001,12: Barbounis V et al. Control of Irinotecan induced diarrhea by octreotide after loperamide failure.4.Barbounis V et al. Control of Irinotecan induced diarrhea by octreotide after loperamide failure. 5.Rosenoff SH et al. A multicenter,randomised trial of long acting octreotide for the optimum prevention of chemotherapy- induced diarrhea: Results of the STOP trial. Supportive oncology 2006: 4: Rosenoff SH et al. A multicenter,randomised trial of long acting octreotide for the optimum prevention of chemotherapy- induced diarrhea: Results of the STOP trial. Supportive oncology 2006: 4:

18 REFERENCES 6.Martenson JA. Phase III double blind study of depot octreotide versus placebo in the prevention of acute diarrhea during pelvic radiotherapy. Results of North Central Treatment Group Protocol N00CA. JCO 2006 ASCO Annual Meeting Proceedings part I vol.24 N0 18S,June 20 suppliment,2006:85066.Martenson JA. Phase III double blind study of depot octreotide versus placebo in the prevention of acute diarrhea during pelvic radiotherapy. Results of North Central Treatment Group Protocol N00CA. JCO 2006 ASCO Annual Meeting Proceedings part I vol.24 N0 18S,June 20 suppliment,2006:8506