-
奥
曲
肽
治
疗
化
疗
相
关
性
腹
泻
最
终
版
< br>
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Octreotide in chemotherapy induced
diarrhoea in colorectal
cancer: a
review article
奥曲肽治疗直肠癌患者化疗
相
关性
诱发
腹泻：综述
Abstract
摘要
Background:
Chemotherapy-
induced diarrhea(CID)is well known in cancer
management. The risk is greater when
the primary cancer is colorectal. The article
aims towards assessing the role of
octreotide in CID through an extensive literature
search.
背景：
化疗相关性<
/p>
诱发
腹泻
(CID)
在癌症治疗中比较常见。
特别是原发灶位于
直
肠
的
癌
症则
风险更大。本文旨在通过全面的文献检索评价奥曲肽治疗
CID
的作
用。
Methods
：
After
searching through PUBMED,MEDLINE and the Cochrane
library, only those studies which were
published over the last 20
years in
English and where at least the majority of the
cohort were
colorectal patients, were
included. Two randomized trials, four
non-
randomized studies and two case-
series publications were thus
considered.
方法：
检索
PUBMED,MEDLIN
和循证医学图书馆，选出最近
20
年用英文发表的、
并且至少所选的主要
观察队列为结肠病人的研究论文。符合条件的共有两项随
机对照试验，四项非随机研究和
两篇系列案例研究文献。
Results:
It was seen in both the randomized
studies, that octreotide
had much
better outcome as compared to loperamide in
treating severe
CID. Among 88 patients
from the non-randomized studies with severe
CID, the primary cancer was colorectal
in 79 patients.61 patients had
drug-
resistant CID. Within a maximum of 96 hours,
octreotide reduced
CID by ≥ 2 grades in
91% of 88 pat
ients and in 88.52%
patients with
drug-resistant CID.
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结果：<
/p>
随机
对照试验
研究
结果
显示，奥曲肽治疗严重
CID
的
疗效比咯哌丁胺好
很多。非随机研究
结果显示，
88
例
严重
CID
病人中，原发是结肠癌的有
79
例
。
其中
61
例
病人有
CID
抗药性。
用奥曲
肽治疗最长时间为
96
个小时
后
，
88
例
严重
CID
病人中
，抗药性降低的患者为
91%
，抗药性患者中
88.52%
患者的
CID
评分至少
2
级。
Conclusion:
Octreotide is effecti
ve in treating
severe CID, resistant to other
modes of
treatment. It is associated with a few minor
adverse effects. Though
expensive,
octreotide could be considered as first line
medication in CID of grades 3
or above.
Its use in lower grades of CID would not be cost
effective.
结论：
奥曲肽对其他治疗方式无效的严
重
CID
患者有效，且不良反应较少。尽
管价格比较昂贵，奥曲肽仍可考虑作为
CID
评分３级以上患
者的一线药物。在
低级别的
CID
治疗
中，奥曲肽的作用并不是很大。
Key words:
octreotide, chemotherapy induced
diarrhoea, octreotide in diarrhoea.
关键词
：
奥曲肽，化疗导致的腹泻，奥曲肽治疗腹泻
Abbreviations
缩写
CID = Chemotherapy induced diarrhoea
化疗相关性
诱发
腹泻
5FU = 5
Fluorouracil5-
氟尿嘧啶
UFT=Uracil
优福定
NCI=National Cancer
Institute
国际肿瘤研究所
NICE=National Institute of Clinical
Excellence
国家临床优化研究所
Introduction
介绍
Colorectal cancer is the second
commonest cause for cancer related
mortality in England and Wales and the
third commonest cause in the
United
States(1). In the UK, there are 30000 new cases
each year, a
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quarter of which are Dukes C or Stage Ⅲ
at presentation
. (please
refer to (a) NICE Guidance on Cancer
Service: Improving Outcomes in
Colorectal Cancer, Manual Improving
Outcomes in Colorectal Cancers,
Manual
Update 2000 and (b) Cancer Stats monograph 2004
cancer
incidence survival and mortality
in the UK and EU. Bowel Cancer
Statistics. Cancer Research UK; 2004).
在英国和威尔士，结、直肠癌
的死亡率
是位居
所有
癌症死亡率的第二位，在美
国是
所有
癌症死亡率的第三位（
1
）。英国每年新增
30000
例结直肠癌患
者，其
中四分之一是
Dukes
Ｃ期或
肿瘤
III
期。（请参考（
a
）
NICE
癌症服务指导原
则：提高结直肠癌病愈率，提高结直肠癌病愈率手册，
2000
补充资料手册和
（
b
）英国和欧盟
2004
年癌症死亡率和生存率统计专题论文集。肠癌统计资<
/p>
料，癌症研究，英国；
2004
）
All Dukes C, high risk Dukes B
and metastatic colorectal cancers are
likely to be considered for either post
operative (Dukes B/C) or
palliative
chemotherapy (Dukes D/ metastatic disease)(2,3).
Chemotherapy induced diarrhea(CID) is
common and could be as high as
82%.Nearly a third of these patients
have severe grade 3-4
diarrhoea(Fig.1),
which is frequently responsible for
hospitalization,
chemotherapy dose
modification and early termination of treatment.
Chemotherapy regimens used in
adjuvant(4,5) and metastatic(6,7)
colorectal disease and respective
incidences of CID are summarized in
the
charts(Fig.2.3).
所有的杜克斯
C
期，高危的杜克斯
B
期和转移的结直肠癌似乎都
可考虑手术后
化疗（
(Dukes B/C
期
)
或姑息性化疗（杜克斯
D
期
/
癌转移）
(2
,3)
。化疗相关性
诱发
腹泻（
CID
）非常普遍，可能高达
82%
。其中大约三分之一患有比较严重
的
3-4
级腹泻（见表
1
），这往往是由于住院治疗
、化疗剂量改变和治疗较早结
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束引起的
。辅助化疗方案
(4,5)
和转移性结直肠癌疾病（
6,7
）及其
CID
发病
率请
见图表（表
2,3
）中的汇总。<
/p>
Capecitabine, irinotecan,
cetuximab and 5FU bolus regimens are often
associated with higher incidences of
diarrhea(8-12). Primary
colorectal
cancer is an independent risk factor for CID.
Other
independent risk factors reported
in the literature are diarrhea with
chemotherapy in earlier cycles,
chemotherapy in summer months(13),
older age group females(14,15),
dihydropyrimidine dehydrogenase (DPD)
deficiency, uridine diphosphate
glucoronyl transferase (UGT)
deficiency(16-20) and adjuvant
chemotherapy as compared to palliative
therapy(16). Diarrhoea can cause
dehydration, electrolyte imbalance,
renal impairment ,nutritional
deficiency and can have negative impact
on the management of cancer itself.
Severe diarrhea decreases
patient
’
s
tolerance towards chemotherapy often resulting in
dose
reduction or early termination of
the treatment. Increased morbidity
increases the cost of care and leads to
poorer clinical outcomes.
Diarrhoea can
be associated with chemotherapy induced
neutropenia,
which can be serious or
even fatal. The severity of the CID is
assessed by the National Cancer
Institute(NCI)
criteria(16).Dranitsaris
and colleagues reported an incidence of
54.2% diarrhoea after the first cycle
of chemotherapy in a
retrospective
study and this resulted in a median dose reduction
by
20% and median delay in treatment by
7 days. 32.3% cases in this
study
needed hospitalization and their median length of
hospital stay
was 8 days (21).
< br>卡培他滨，伊立替康，西妥昔单抗和
5-
氟尿嘧啶推注方
案通常导致高腹泻率
(8-
12)
。原
发性结直肠癌是
CID
的独立的危险因素。文献报道的其他的独
立的危险
因素有化疗早期疗程导致的腹泻、夏季化疗相关性
诱发
腹泻以及老年组女性
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（
14,15
）、双氢嘧啶脱氢酶（
DPD
）缺乏，尿苷二磷酸葡萄糖醛酸基转移酶缺
乏（
UGT
）
(16-20)
以及与姑
息性治疗相比较的辅助化疗（
16
）。腹泻会导致脱
水、电解质失衡、肾损害、营养缺乏，并且对癌症治疗本身有负面影响。严重
的腹泻降低患者对于化疗的耐受能力，从而导致剂量的减少和治疗结束过早。
发病率增
加提高了治疗成本，并且导致不良的治疗结果。腹泻可能与化疗诱发
的嗜中性白血球减少
症有关，可能非常严重甚至致命。
NCI
划分了
CID
的严重
性等级。
Dra
nitsaris
及其同事在一项回溯性研究中报道，第一个
疗
程
后腹泻发生
率为
54.2%
，这导致治疗剂量平均降低
20%
，治疗时间平
均延长
7
天。此项研
究中
32.3%
的患者需要住院治疗，并且平均住院期为
8
天。
Fig.1.
—
NCI grading of
diarrhea
National Cancer Institute
Criteria for assessing the severity of
chemotherapy-induced diarrhoea
Grades
of CID
1
2
3
4
Frequency of Diarrhoea
＜
4 times/day
4-6
times/day
≥
7
times/day
Stoma output
Mild
Moderate
severe
Need for intravenous fluid
resuscitation
None
＜
2
4 hrs
＞
2
4 hrs
None
None
Yes
Interfering with daily
Activities
Diarrhoea
resulting into life threatening consequences like
haemodynamic collapse or shock.
5
Death due to consequences of diarrhoea
表
1.
—<
/p>
美国国立癌症研究所（
NCI
）
腹泻分级
美国国立癌症研究所评价化疗相关性腹泻严重性的标准
CID
等级
腹泻频率
造瘘病人排泄
量
需要静脉输液
复苏
无
＜
2
4
小时
＞
2
4
小时
日常活动干扰
1
2
3
4
＜
4
次
/
天<
/p>
轻
中度
严重
无
无
有
4-6
次
/
天
≥
7
次
/
天
腹泻导致生命危险，例如血液动力学衰竭或休克
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5
腹泻导致死亡
Fig.2.
—
Chemotherapy-induced diarrhea
in colorectal cancer in adjuvant setting
Chemotherapy-induced
diarrhea in colorectal cancer in adjuvant setting
No
Chemotherapy/Regimens
Incidence
of CID
NCI
grade
≤
3
1
2
FOLFOX 4
FLOX
11%
38%
MOSAIC trial, AndreT., et
al. .,2004
NSABP
trial,Kuebler J.P., et
al,..,2007
Reference-(5)
3
CapO/OxCap
11%
X-ACT s C.,et
ctal
Cancer,2006 Reference-(9)
4
5
6
Capecitabine+Oxaliplatin(XELOXA)
Mayo Clinic Regimen(FU/LV)
Roswell Park Regimen(FU/LV)
19%
16%
29%
Schmoll et l of
Clinical of
Oncology,y;25(1)
Reference-(10)
表
2.
—
采用辅助疗法的结直肠癌患者的
化疗相关性腹泻
编号
采用辅助疗法的结直肠癌患者的化疗相关性腹泻
化疗
/
方案
CID
发生率
NCI
等级≤
3
1
奥沙利铂、氟尿嘧啶和甲酰
四氢叶
酸钙方案
2
FLOX
38%
11%
MOSAIC
trial, AndreT., et al.
.,2004
NSABP trial,Kuebler J.P., et
al,..,2007
Reference-(5)
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Reference/Trial/Citation
参考文
献
/
试验
/
引
文
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3
CapO/OxCap
11%
X-ACT s C.,et
ctal
Cancer,2006 Reference-(9)
4
卡培他滨
+
奥沙利铂
< br>(XELOXA)
19%
Schmoll et l
of
Clinical of
Oncology,y;25(1)
Reference-(10)
5
6
Mayo Clinic
Regimen(FU/LV)
Roswell Park
Regimen(FU/LV)
16%
29%
Fig.3.
–
Chemotherapy-induced
diarrhea in advanced/metastatic colorectal cancer
Chemotherapy-induced
diarrhea in advanced/metastatic colorectal cancer
No.
Chemotherapy/Regimens
Incidence of CID
NIC
grade
≤
3
1
2
3
4
5
6
7
8
Capecitabine/Oxaliplatin
5-FU+Oxaliplatin
OxMdG
Fegimen
OxMdG+Cetuximab
XELOX
XELOX+ Cetuximab
FOLFIRI
FOLFOX 6
16%
12.5%
6%
13%
15%
25%
14%
11%
Cao Y.,et
al. Journal of
Colouectal Disease, 2009
Reference-(11)
Adams R.A.,et
h
Journal of Cancer (2009)
100,251-8
Reference-(12)
Tournigand C., et al.
GERCOR
study. Journal
of Clinical Oncology,
Jan
2004,24(2)
Reference-(6)
9
FOLFOX 4+Bevacizumab
7.8%
Emmanouilides C.,et al.
BMC Cancer,2007,7(91)
Reference-(7)
表
3.
晚期
/
转移性结直肠癌患者的化疗相关
性腹泻
晚期
/
转移性结直肠癌患者化疗相关性腹泻
编号
化疗
/
方案
CID
发生率
参考文献
/
试验
/
< br>引文
Reference/Trial/Citation
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NCI
等级≤
3
1
2
3
4
5
6
7
卡培他滨
/
奥沙利铂
5-
氟尿嘧啶
+
奥沙利铂
OxMdG
Fegimen
OxMdG+
西妥昔单抗
XELOX
XELOX+
西妥昔单抗
氟尿嘧啶、亚叶酸和伊
立替康联合用药
8
奥沙利铂、氟尿嘧啶和
甲酰四氢叶
酸钙方案
（
FOLFOX
6
）
9
氟
尿嘧啶、亚叶酸和伊
立替康联合用药
（
FOLFOX 4
）
+
贝伐单
抗
Aim of
the study
研究目的
Octreotide has often been used to treat
CID. In the absence of a fixed protocol,
treatment has been purely empirical.
This review article aims towards assessing the
role of octreotide in CID through an
extensive literature search.
奥曲肽经常被用来治疗
CID
。由于没有固定的方案，完全是凭经验来进行治
疗。本综述的目的在于通过全面的文献研究来评估奥曲肽治疗
CID
的作用。
Methods and
materials
方法和材料
We
have searched PUBMED, MEDLINE and Cochrane library
for relevant published
articles over
the last 25years from 1984 to phrases like
“
octreotide
CID
”
,
“
colorectal cancer CID and
octreotide
”
and
“
chemotherapy induced
diarrhea in
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16%
12.5%
6%
13%
15%
25%
14%
Cao Y.,et al. Journal of
Colouectal Disease, 2009
Reference-(11)
Adams R.A.,et
h
Journal of Cancer (2009)
100,251-8
Reference-(12)
Tournigand C., et al.
GERCOR
study. Journal
of Clinical Oncology,
Jan
2004,24(2)
Reference-(6)
11%
7.8%
Emmanouilides C.,et al.
BMC
Cancer,2007,7(91)
Reference-(7)
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colorectal cancer and
octreotide
”
were used to
search for relevant articles . We
included those studies, which were
published in English and where the whole cohort
or at least a major proportion of it
were colorectal cancer patients. We have included
two randomized trials, four non-
randomized controlled studies and two case series
publications in our review.
我们检索了从
1984
到
2009<
/p>
年
25
年间
Pu
bMed
，
MEDLINE
和循证医学
图书馆
中的有关文献。检索用词有
“
o
ctreotide
CID
”
以及“
colorectal
cancer CID and
octreotide
”、
“
chemotherapy induced
diarrhea in colorectal cancer and octreotide
（结
直肠癌患者化疗相关性腹泻和奥曲肽）”。入选文献均用英文撰写而且样
本人群
中至少大部分是结直肠癌患者。综述包括了两组随机对照临床试验、四组非随
机对照研究和两篇系列病例报道。
The
articles related to patients having chemotherapy
solely for cancers other than
colorectal carcinoma and solitary case
reports regarding use of octretide or other
modes of medications to control CID
were excluded. We have also looked at the
pharmaco-economic aspects relating to
octreotide, its recommended safe dose and its
adverse effects in the treatment of CID
only.
排除了仅使用化疗治疗癌症的非结直肠癌患者、使用奥曲肽治疗的单个病例
报
告以及其他控制
CID
的用药方案。
本文也从药物经济学的角度审视了单独使用
奥曲肽治疗
CID<
/p>
时的推荐安全剂量和副作用。
Results
结果
1)
Octreotide
VS
other medications in CID<
/p>
奥曲肽和其他药物治疗
CID
的对比
A randomized trial (22)
established the effectiveness of octreotide ,
against loperamide in
controlling
severe CID (NIC grades 2 and above) in a cohort of
41patients(68.3% colorectal
cancer)(P
＜
0.005
)
.
在
41
个患
者的队列研究（
68.3%
的结直肠癌患者）
< br>(P
＜
0.005
)
的随机临床试验
（
22
）
中，证明了奥曲肽相对比洛哌丁胺在控制严重
CID
（
NIC
级别
2
级和以上
）的效
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果。
Gebbia et al.
performed a similar randomized trial(23), where
the group of patients receiving
octreotide had much better results,
compared to those receiving loperamide (Fig.4). <
/p>
Gebbia
等进行了类似的随机试验（
23
），证明患者使用奥曲肽比使用洛哌丁胺效
果更好（见表<
/p>
4
）。
A
prospective study (26) reporting the effects of
octreotide in a cohort with opioid-resistant
CID, demonstrated 94% success rate with
no serious side effects. Cascinu et al.(27) has
reported a better success rate (96.3%
complete response within 72hours of onset of
treatment) with octreotide in a cohort
of 27 patients (21 patients with advanced
colorectal
cancer and rest with
advanced pancreatic cancer). When we combined the
results of all these
non-randomized
studies, in a cohort of 88 patients (colorectal
cancer in 79 out of 88 cases)
with
severe CID (NCI grades 3 and above), 61 patients
(69.32%) with opioids or loperamide
resistant CID were treated with
octreotide, which was effective in controlling
diarrhea in
54(88.52%) patients within
a maximum of 4 days.
在一个
前瞻性研究中（
26
），报道了奥曲肽在治疗一个对阿片样物质
有抗药性的
CID
患者队列的有效性为
94%
，且没有严重的副作用。
Cascinu et al.
(27)
在一个
27
名患者
(
其
中
21
名患者有晚期直肠癌，其余的是晚期胰腺癌
)
的队列
中报道了更高的有效率（在开
始治疗
72
小时完全有效率达到了
96.3%
）。当我们将所有的随机研
究的结果综合起
来，发现在一个
88
名
严重
CID
（
NCI
< br>级别为三家或者以上）患者（
79
名为结直肠癌患
者）的队列中，
61
名患者（
69.32%
）为阿片样物质或者洛哌丁胺抵抗性
CI
D
患者使用
奥曲肽，在至少
4
天之内有
54
名患者（
88.52%
）有效控制腹泻。
In
a prospective non-randomized study(24), colorectal
cancer patients with grade 3-4,
loperamide resistant CID were treated
with octreotide. In this cohort, nearly 16% of
patients
had complete resolution of
diarrhea and about 29% experienced reduction of
diarrhea by at
least two grades. In the
remaining 25% of cases, diarrhea ,was reduced by
one grade.
在一个前瞻性非随机研究中（
24
），
3-4
级、对洛哌丁胺有抗药性的结直
肠癌患
者，使用奥曲肽来治疗
CID
。
在这个队列中，大约
16%
的患者的腹泻症状完全消退，
大约
29%
的患者症状减轻了至少两个级别。
剩下的
25%
的病例中，腹泻减轻了
1
个级
别。
A
similar prospective multicentre trial by Zidan et
al.(25) in a cohort of patients, (the
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majority of which were colorectal
cancer patients) with severe loperamide resistant
CID,
octreotide was used as a failsafe
and complete resolution of diarrhea was noted in
94%
cases without any major adverse
effects. This study did not specify the exact
percentage of
colorectal cancer
patients who were among this complete resolution
group.
Zidan
等
(25)
以对洛哌丁胺有严重抗药性的
CID
患
者群（大多数为结直肠癌患者）
为研究对象，进行了一个类似的前瞻性多中心试验，将奥
曲肽作为一种特效药，发现
94%
的患者腹泻痊愈且没有任何严
重副作用。该研究没有给出痊愈患者中直结肠癌患
者的确切百分比。
A prospective study (26) reporting
the effects of octreotide in a cohort with opioid-
resistant
CID, demonstrated 94% success
rate with no serious side effects. Cascinu et
al.(27) has
reported a better success
rate (96.3% complete response within 72hours of
onset of
treatment) with octreotide in
a cohort of 27 patients (21 patients with advanced
colorectal
cancer and rest with
advanced pancreatic cancer). When we combined the
results of all these
non-randomized
studies, in a cohort of 88 patients (colorectal
cancer in 79 out of 88 cases)
with
severe CID (NCI grades 3 and above), 61 patients
(69.32%) with opioids or loperamide
resistant CID were treated with
octreotide, which was effective in controlling
diarrhea in
54(88.52%) patients within
a maximum of 4 days.
一项前瞻性研
究报道了奥曲肽对具有阿片样物质抗药性的
CID
患者群的作用
（
26
）证实了其治愈率为
94%
，且没有严重副作用。
Cascinu
等
(27)
对
27
名患者（
21
名患者为比较严重的结直
肠癌，其余为比较严重的胰腺癌患者）用奥曲肽治疗，获得
了更高的治愈率（在
72
小时的治疗时间内
96.3%
完全有效）。综合所有这些非随机研
究的结果，在
8
8
名患有严重
CID
（
NCI
评级为
3
以上）的患者
（其中结直肠癌患者为
79
例）中，
6
1
名具有鸦片样物质或洛哌丁胺抗药性的
CID
患者（
69.32%
）使用奥曲肽
治疗，
54
名患者（
88.52%
）在
4
天内腹泻得到有效控制。
Two case series publications
by Rosenoff (28,29) reported successful treatment
of severe
CID (NCI grades 3 and
above), refractory to loperamide and/or
diphenoxylate atropine, by
octreotide
LAR(long acting release preparation). Both these
publications demonstrated
improvement
in patient
’
s quality of life
and tolerance towards chemotherapy. No serious
adverse effects were reported in either
of them.
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