Download 2007_files/Babu Octreotide ASCO2007

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)
www.rtog.org
1
INTRODUCTION
• Diarrhea is a common side effect of pelvic radiotherapy.
• 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 FFluorouracil) 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)
• To date there are no prophylactic measures effective in
preventing the incidence of enteritis during chemo-radiation
www.rtog.org
2
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 assess the impact of diarrhea on chemo-radiation delivery
and medical resource utilization.
www.rtog.org
3
Eligibility
• Histologic proof of anal or rectal cancer without metastasis
beyond pelvic regional nodes.
• Planned to receive full course radiotherapy with concurrent
chemotherapy.
• 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 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)
www.rtog.org
4
Eligibility…continued
• 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 allowed
www.rtog.org
5
Study schema
•
•
•
•
•
•
•
•
•
•
STRATIFY
RT Dose
1. <50Gy
2. >50Gy
Chemotherapy
1. Bolus
2. Continuous
Gender
1.Male
2.Female
RANDOMISE
Arm .1:Sandostatin LAR Depot
Pre-RT (between day-7and day-4
of RT) and day 22(+3days)
Arm. 2:Placebo
Pre-RT (between day-7 and day-4
of RT) and day22(+3days)
www.rtog.org
6
MATERIALS AND METHODS
•
•
•
•
•
•
•
Patients over age 18 were included in the study.
Required sample size was 226.
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.
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.
Patients are followed up at 3,6,9 and 15 months from the start of
radiotherapy.
www.rtog.org
7
Patient Characteristics
–
•
•
Pretreatment Characteristics
Placebo
(n=107)
Sandostatin
(n=111)
•
•
Age Median
Range
61
37-85
•
•
•
Gender Male
Female
n
69
38
•
•
•
Planned RT Dose
<50 Gy
> 50 Gy
20
87
19
81
18
93
16
84
•
•
•
Planned Chemo
Bolus
Continuous infusion
19
88
18
82
20
91
18
82
•
•
•
•
Disease Site
Not Reported
Anal
Rectal
1
19
87
1
18
81
1
20
90
1
18
81
•
•
•
•
Baseline Diarrhea
None
Grade 1
Grade 2
89
15
3
83
14
3
91
17
3
82
15
3
61
27-83
%
64
36
n
%
69 62
42 38
www.rtog.org
8
PATIENT ACCRUAL
The study accrued 233 patients from December 2003 to
February 2006.
• 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.
www.rtog.org
9
RESULTS-1
Table II. Incidence of Diarrhea ,GI symptoms and Other
Toxicities by Study Arm
Placebo
Sandostatin
Grade
Grade
1 2 3 4
1 2 3 4
Gastrointestinal
N
22 32 29 12 21 31 31 0
%
21 30 27 11
19 28 28
Worst Diarrhea
N
24
23 29 0
25 23 25 0
%
22 27
23 21 23
23
www.rtog.org
10
RESULTS-2
• Incidence of Diarrhea, Gi symptoms and Other Toxicities
Placebo
Sandostatin
Grade
Grade
1 2 3 4
1 2
3
4
Blood/B.Marrow
6 10 3 4
5 8
9
3
%
6 9 3 4
5 7
8
3
Skin
16 28 9 0
14 22 9 0
%
15 26 8 13 20 8 Pain
7 25 4 0
11 14 6 1
%
7 24 4 10 13 6 1
www.rtog.org
11
RESULTS
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Treatment Compliance, RT and chemotherapy.
Placebo
sandostatin
%
%
Hospitalization
None
76
83
1
15
9
2
5
4
>3
3
1
Unknown
2
3
Chemotherapy dose
Modification
No
70
60
Yes
28
37
Unknown
2
3
Radiotherapy
Dose modification
no
62
60
yes,adverse event
18
20
yes,other reason
18
17
Unknown
2
3
Use of other antidiarrheal agents
no
35
39
yes
63
58
unknown
2
3
www.rtog.org
12
RESULTS
• Seventy seven percent of patients completed the study drug
regimen.
• 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.
www.rtog.org
13
DISCUSSION
•
Octreotide has been shown to control chemotherapy induced diarrhea
resistant to loperamide therapy(2-4). Rosenoff et al has reported the use of 2040mg 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.
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.
•
•
www.rtog.org
14
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.
www.rtog.org
15
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.
www.rtog.org
16
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) 593-598,1998.
• 2.Cascinu S et al. Octreotide versus loperamide in the
treatment of fluorouracil induced diarrhea. A randomized trial. J
Clin Onc 11(1):148-51,1993.
• 3.Zidan et al. Octreotide in the treatment of severe
chemotherapy induced diarrhea. Ann Oncol,2001,12:227-229.
• 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 chemotherapyinduced diarrhea: Results of the STOP trial. Supportive
oncology 2006: 4:289-294
www.rtog.org
17
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,2006:8506
www.rtog.org
18