I am trying to find CAUSATION for (non-vestibular non-pschycological)
episodic nausea that came on and then persisted after receiving CMF
(cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy for
breast cancer. It appears to have caused a rare injury to the
gastrointestinal (or autonomic nervous system) of the Lower Esophageal
Spchinter. To get assistance from medical insurer I must provide
"causation" that it was the treatment that I received that caused the
rare debilitating injury that caused symptoms to persist when
chemotherapy was discontinued early due to severe toxicity
experienced. My own clinicians provided a 'temporal' link as to the
time of onset of my persistent symptoms but temporal is not sufficient
for a claim to be succesful. Thank you Annie.

Hello annie,

I'm so sorry to hear of your insurance woes along with your health
problems.  These double whammies can send a person around the bend! 
Hopefully this information will bolster your clinician's temporal
tie-in with your chemotherapy regimen and satisfactorily settle the
claim with your insurance company.

I started my research with first locating the individual drugs in
question and their side effects:

cyclophosphamide (Cytoxan, Neosar)
http://www.nlm.nih.gov/medlineplus/druginfo/cyclophosphamidesystemic202174.html

methotrexate
http://www.nlm.nih.gov/medlineplus/druginfo/methotrexateforcancersystemic202355.html

fluorouracil (5-fu)
http://www.nlm.nih.gov/medlineplus/druginfo/fluorouracilsystemic202245.html

All of these medications list nausea in their side effect profile, but
my hunch was that methotrexate was the culprit in this drug
triumverate.

I searched Google for methotrexate+lower esophageal sphincter+nausea
and located the following article on Medscape.  You must register to
read the entire article, but this site is very user-friendly and login
is simple after that step.

-----------------

Drug-induced Gastrointestinal Disorders
Linda G. Tolstoi, RPh, MS, MEd
Medscape Pharmacotherapy 4(1), 2002. © 2002 Medscape
http://www.medscape.com/viewarticle/437034

Cytotoxic Effects

"Many chemotherapeutic drugs have cytotoxic effects on mucosal cells
of the small intestine because these cells have a high turnover
rate.[23]  Chemotherapeutic drugs such as actinomycin D, bleomycin,
cytosine, arabinoside, doxorubicin, 5-fluorouracil, methotrexate, and
vincristine can cause erosive enteritis. The clinical features include
pain, bleeding, vomiting, ileus, and diarrhea.[23]"

--and--

Malabsorption

"Drug-induced malabsorption interferes with the absorption of specific
nutrients. For example, tetracycline chelates calcium, cholestyramine
binds iron and vitamin B12, mineral oil reduces the absorption of
carotene and fat-soluble vitamins, thiazide diuretics impair ileal
transport of sodium, and aluminum/magnesium hydroxide precipitate
calcium and phosphate ions.[23] Colchicine, neomycin,
**methotrexate,** methyldopa, and allopurinol interfere with
absorption of nutrients by **causing mucosal damage.** Drug-induced
malabsorption may exacerbate the patient's poor nutritional
status.[23]"

---------------------

Further, this article from WebMd references the effect of chemotherapy
on the CTZ (chemoreceptor trigger zone) or the "vomiting center."

http://webcenter.health.webmd.netscape.com/content/dmk/dmk_article_57737

Currently, evidence indicates that acute emesis following chemotherapy
is initiated by the release of neurotransmitters from cells that are
susceptible to the presence of toxic substances in the blood or CSF.
Area postrema cells in the CTZ and enterochromaffin cells within the
intestinal mucosa are implicated in initiating and propagating
afferent stimuli that ultimately converge on central structures
corresponding to a "vomiting center." The relative contribution from
these multiple pathways culminating in nausea and vomiting symptoms is
complex and is postulated to account for the variable emetogenicity
(intrinsic emetogenicity and mitigating factors, i.e., dosage,
administration route, exposure duration) and emetogenic profile (i.e.,
time to onset, symptom severity, and duration) of agents."

----------------------

Additionally, here's a supporting article documenting methotrexate's
damage to the intestinal mucosa.
http://www.ijp-online.com/archives/1994/026/03/r0213-0217ra.pdf

"MTX induced severe damage of the intestinal mucosa.  The antitumor
drug administration induced malabsorption syndrome which led to change
in the chemical constituents of the intestine."

----------------------

This pdf document also cites drug-mediated (specifically Cytoxan and
methotrexate) mucosal injury and fungal esophagitis resulting from
their use.  Even though this paragraph deals with the lower GI tract,
the mucosal insult still seems relevant.   I would print this entire
document out as it refers to GI chemotherapy complications throughout.

http://216.239.33.100/search?q=cache:CWQAblEaszIC:www.cancer.org/downloads/PUB/DOCS/SECTION40/152.pdf+"chemotherapy-induced"+"fungal+esophagitis"&hl=en&ie=UTF-8

"Cancer patients receiving chemotherapy appear predisposed to C.
difficile-induced diarrhea even in the absence of antibiotics.  In a
study of such patients, methotrexate, doxorubicin, and
cyclosphosphamide were the drugs most frequently associated with C.
difficile infection.  It is speculated that anticancer drug-mediated
mucosal injury may produce the anaerobic environiment conducive to C.
difficile colonization."

---------------------
 
The correlation of chemotoxicity on intestinal membranes is made in
this study article involving rats:

http://216.239.51.100/search?q=cache:BcLCPsMz3vAC:www.accc-cancer.org/publications/Dietsup.pdf+%22vitamin+e+protects+intestinal++basolateral%22&hl=en&ie=UTF-8

"An oral preparation of vitamin E was given concurrently with
intravenous CMF in rats and protected their intestinal membranes
against chemotherapy-induced toxicity."

 
=========================
ADDITIONAL REFERENCES
=========================

Morrow G, Laughner J, Bennett J: Prevalence of nausea and vomiting and
other side effects in patients receiving cytoxan, methotrexate,
fluorouracil (CMF) therapy with and without prednisone. Proc Am Soc
Clin
Oncol 3:105, 1984 (abstr C-408) 

http://www.nci.nih.gov/cancerinfo/pdq/supportivecare/nausea/healthprofessional/

http://www.nci.nih.gov/cancer_information/pdq/doc_cit.aspx?citationid=MEDL_87238537

Good explanatory information and photos here {beware the pop-up}:
http://members.tripod.com/danil_hammoudi/gipathology/id17.htm

The Longitudinal Muscle in Esophageal Disease:
http://mailbag.com/users/oesophagus/webdoc1.htm

Sequential use of Antibiotics and Adjuvant Chemotherapy Leading to a
Fatal Pseudomembranous Colitis:
http://216.239.51.100/search?q=cache:7hoAyNZOdGUC:www.mjm.mcgill.ca/issues/v03n02/v03p102/v03p102.pdf+%22CMF%22+%22mucosal+damage%22+&hl=en&ie=UTF-8

Further Studies:
http://www.asco.org/asco/ascoMainConstructor/0,1003,_18%7C0010772%7C00_20%7C006%7C00_19%7C0012022%7C00_12%7C002032,00.asp?state=

==================
CONCLUSION
==================

From a layperson's perspective, methotrexate along with the additive
effects of Cytoxan and 5-fu could contribute to your lower esophageal
sphincter (LES) problem.  Mucosal erosion around the sphincter itself,
which resulted in incomplete closure of valve, might be causing the
persistent nausea you're having.  I wish I could 100% guarantee this
connection but it might lie in the interpretation.  It doesn't seem
like that much of a leap -- especially with the high doses a person
receives while undergoing chemotherapy.
 
I trust these articles will be beneficial to your case.  Google
Answers has been fortunate to have several doctors shadowing us in the
comment section and I do hope they'll feel free to offer their
expertise.  Again, Google Answers is no substitute for expert medical
advice.  We do, however, appreciate the opportunity to locate
necessary information for patients.

Thank you for using our service and if any of the above information is
unclear, please don't hesitate to ask for a clarification before
rating my answer.  I hope that you make a complete recovery and that
your claims are paid in full with this supporting information.

Best of luck and please let me know if I can assist you further,
V

---

Request for Answer Clarification by tomc-ga on 10 Nov 2002 01:02 PST

Dear Dr Voila-ga, thank you for your speedy and rapid reply. You
provided me with heaps of study material that will take me some time
to understand. With a quick read I have not yet found causation and
note that you are 'not 100% sure'. I hope and pray that you will give
it more thought and if you discover more please pass it on to me. Can
you please tell me if clinicians across the world will also read my
question and your reply and in what format? I am not very e-literate
yet and may just miss an important reply.

In my case the heartburn/reflux and nausea came on 7 years ago during
CMF chemo for breast cancer and persisted when treatment was abandoned
early due to severe toxicity with sores in the mouth, nausea, sight
and more. For more than 5.5 years the GI symptoms did not react to
conventional treatment/investigations until reflux surgery was
performed. But the episodic N remained.Thank you Annie.

---

Clarification of Answer by voila-ga on 10 Nov 2002 08:13 PST

Hello again annie,

I actually went to bed and woke up thinking about this question so,
yes indeed, I plan on giving it quite a bit more thought.  Also I ran
across several studies involving the use of metoclopramide (Reglan), a
drug used to combat nausea in chemotherapy patients.  Do you know if
you were given this medication or something similar?

http://www.nlm.nih.gov/medlineplus/druginfo/metoclopramidesystemic202364.html

Metoclopramide (met-oh-kloe-PRA-mide) is a medicine that increases the
movements or contractions of the stomach and intestines. When given by
injection, it is used to help diagnose certain problems of the stomach
and/or intestines. It is also used by injection to prevent the nausea
and vomiting that may occur after treatment with anticancer medicines.
Another medicine may be used with metoclopramide to prevent side
effects that may occur when metoclopramide is used with anticancer
medicines.

--------------

To answer your question, yes, anyone can access any question from
Google Answers if they have internet access.  They would log on and go
to http://www.answers.google.com.  From the search box on the main
page, they could type in your user name, "tomc" or "cyclophosphamide,"
{no quotation marks} click enter, and your question will come up. 
Also they could access it through this URL: 
https://answers.google.com/answers/main?cmd=threadview&id=104203

The reason I said I couldn't guarantee the insurance company would
rule in your favor is that I don't have knowledge of your other
medical history.   If there were *any* other contributing factors,
i.e., GERD, hiatal hernia, peptic ulcer disease, being overweight,
sedentary lifestyle, chronic stress, your carrier could say your
symptoms were attributable to those factors and not the CMF.  
However, if your clinicians can link the onset of your symptoms
temporally, these studies should verify them causally.  I do
understand your dilemma in proving causation but your clinicians will
need to advise if these studies meet that burden of proof.

In the meantime, researcher7 is one of the 'good guys' I mentioned in
your answer.  If you wouldn't mind answering the question posed,
he/she may know a mechanism of action in how these drugs were
administered.  Any advice from someone with firsthand knowledge of
this subject is most appreciated.

I will continue to look today for additional studies, confer with my
colleagues, and report any new findings.  Thanks for your patience.

Will be in touch this evening,
V

---

Clarification of Answer by voila-ga on 10 Nov 2002 22:59 PST

Hi annie,

Here are a couple more studies that look interesting.  These were
taken from TOXNET http://toxnet.nlm.nih.gov as suggested by
researcher7.  I also plan on checking out the neurotoxic effects of
this methotrexate tomorrow.

"Barrett esophagus after chemotherapy with cyclophosphamide,
methotrexate, and 5-fluorouracil (CMF): an iatrogenic injury?" [see
comments]
Authors:  Sartori S, Nielsen I, Indelli M, Trevisani L, Pazzi P,
Grandi E Author Address: St. Anna General Hospital, Ferrara, Italy
Source: Ann Intern Med 1991 Feb 1;114(3):210-1

Comments: 
Comment in: Ann Intern Med 1991 Feb 1;114(3):243-4
Comment in: Ann Intern Med 1991 May 15;114(10):913

Substance (CAS Registry Number): 
CMF regimen (NO CAS RN) 

Cyclophosphamide (50-18-0) 
Fluorouracil (51-21-8) 
Methotrexate (59-05-2) 

Language: English
International Standard Serial Number: 0003-4819
Publication Types:  JOURNAL ARTICLE
Entry Month: April, 1991
Journal Title Code: 5A6
Title Abbreviation: Ann Intern Med
Year of Publication: 1991
Secondary Source ID: DART/MED/91083231
Last Revision Date: August 5, 1991

--------------------

"Cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen 
Authors:  Waddell JA, Holder NA, Solimando DA
Author Address: Dept. of Pharm., Brooke Army Med. Ctr., Bldg. 3600,
3851 Roger Brooke Dr., San Antonio, TX 78234, USA Internet:
aubrey.waddell@cen.amedd.army.mil

Source: Hosp. Pharm.; VOL 34 ISS Nov 1999, P1268-1269, 1273-1274,
1276-1277, (REF 41)

Abstract: 

IPA COPYRIGHT: ASHP The dosage schedules, preparation, administration,
precautions, and adverse effects of combined treatment with
cyclophosphamide, methotrexate, and fluorouracil for the treatment of
breast neoplasms are discussed.

CAS Registry Numbers: 
6055-19-2 
6055-19-2 
59-05-2 
51-21-8 

Language: English
International Standard Serial Number: 0018-5787 
Coden: HOPHA 
Entry Month: April, 2000
Classification Code: 6/9 
Year of Publication: 1999 
Secondary Source ID: IPA/00/1190144

------------------------

GI toxcicity from chemotherapy:
http://www.uic.edu/classes/pmpr/pmpr652/Final/bressler/gitoxi.html 


Annie, thanks so much for your very generous bonus on this question.  
 It's most appreciated.   If after your clinicians review these
studies and you need further assistance, just post a clarification on
this same question and I'll be glad to run down any leads for you.

Search words:
CMF+LES incompetence
CMF+adverse effects+side effects
CMF+achalasia
CMF+mucosal erosion
CMF+esophagitis+gastritis
CMF+loosening of lower esophageal sphincter
CMF+chronic nausea+persistent
chemotherapy+LES incompetence
CMF+esophageal dysmotility
CMF+aperistalsis
CMF-induced+nausea+delayed gastic emptying
CMF+GE sphincter

---

Request for Answer Clarification by tomc-ga on 11 Nov 2002 09:13 PST

voila did you get my 'post request' of minutes ago as it disappeared
whilst Tom and myself typing and editing a reply to you? We are not
very e-literate and type very slow. I find this type of correspondence
very stressfull. Annie.

---

Clarification of Answer by voila-ga on 11 Nov 2002 11:32 PST

No, Annie, this is the first message I'm seeing.  This
e-correspondence is not the best avenue for communication but it's the
only method Google Answers allows for at the moment.  You can add as
many clarification notices or comments as you wish.  Whatever you see
on the screen in the clarification and comment sections is what I and
anyone logging on to Google Answers can see.  I do understand your
hesitancy about disclosing your medical history in such a public
forum, so feel free to ignore any questions you don't feel comfortable
answering.

Please know that none of the researchers at Google Answers are medical
doctors; rather we're "doctors" of research and help people locate
hard-to-find information.  While I've done medical research for a
while now and have worked in the medical field for over 20 years, in
no way would I hold out my opinion as expert.

Also, I meant to add that your clinicians could sign on to Google
Answers after locating your question and add any information or
follow-up remarks in the comments section if they wish.  I have a
full-time position during the week and only research for GA on the
weekends, but I will answer your posts as quickly as possible.

Could you give your message another try please?

---

Clarification of Answer by voila-ga on 12 Nov 2002 10:46 PST

Hi Annie and Tom,

If you've seen the Sartori et al. study, you've maybe seen this one as
well but I would be remiss in not including it in my research.  This
is a very small sampling {15} of patients receiving chemotherapy but
note is made that there is no *increased* prevalence of Barrett's;
however it doesn't say it won't occur.  It would be necessary to read
the full article for completeness sake.

Barrett's esophagus: lack of association with adjuvant chemotherapy
for localized breast carcinoma.
Authors: Herrera JL, Uzel C, Martino R, Cooke C, DiPalma JA
Author Address: Division of Gastroenterology, University of South
Alabama College of Medicine, Mobile.

Source: Gastrointest Endosc 1992 Sep-Oct;38(5):551-3
Abstract: 

This study was designed to prospectively, endoscopically, and
histologically determine the prevalence of Barrett's esophagus in
patients who had received adjuvant chemotherapy for localized breast
carcinoma. Fifteen white women who received cyclophosphamide,
methotrexate, and 5-fluorouracil (N = 8) or cyclophosphamide,
adriamycin, and 5-fluorouracil (N = 7) chemotherapy underwent
esophagogastroduodenoscopy and esophageal biopsy a mean 31.1 months
(median, 11 months) after completion of full-course chemotherapy.
Twelve of 15 patients had experienced oral ulcerations, diarrhea, or
odynophagia during chemotherapy. In no patient was Barrett's esophagus
identified endoscopically or histologically. This study fails to
demonstrate an increased prevalence of Barrett's esophagus in breast
carcinoma patients who had received adjuvant chemotherapy.

-----------------

Please know I'm still working your question and will post anything of
interest.  I have also run your dilemma by several other researchers
in case I've missed something.

Keep the faith,
V
 
p.s.  Thanks researcher7 for your input.  I realize you're doing this
out of the goodness of your heart and your comments are most
appreciated.  The more mind power we have on this one, the better.

---

Clarification of Answer by voila-ga on 20 Nov 2002 12:15 PST

Hi Annie and Tom,

Sorry I've been away but my system crashed and I had to buy a whole
new one.  I haven't forgotten about you.  I'm still trying to learn
this new equipment, so I feel your pain about computers.  Before my
system crashed I'd found this article that alludes to CMF as a cause
of duodenal ulcers.  I'll be checking further this weekend and I'm
sorry for the delay.

http://www.emedicine.com/MED/topic591.htm

---

Clarification of Answer by voila-ga on 24 Nov 2002 20:43 PST

From the Beth Israel House Staff Manual
http://home-dev.caregroup.org/UG_manual/Chemotherapy.htm

Delayed Toxicity for 5-fu:
Oral and GI ulcers, bone marrow depression, neuro defects (esp.
cerebellar), cardiac arrhythmias, angina, alopecia, conjunctivitis,
CHF, hyperpigmentation.

-----------

From the Oncology Nursing Forum, "Risk Factors and Antiemetic
Management of Chemotherapy-Induced Nausea and Vomiting"
http://www.ons.org/xp6/ONS/Library.xml/ONS_Publications.xml/ONF.xml/ONF1997.xml/August_Supplement.xml/Members_Only/Article_4.xml

"Anticipatory nausea and vomiting occur most commonly in
women--especially those who receive cyclophosphamide, methotrexate, or
5-fluorouracil--and in patients experiencing inadequate emetic control
(Jacobsen, Bovbjerg, & Redd, 1993; Morrow, Lindke, & Black, 1991;
Wilcox, Fetting, Nettesheim, & Abeloff, 1982). Other risk factors for
anticipatory nausea appear to be nausea and vomiting after the first
chemotherapy treatment, moderate or severe nausea or vomiting after
treatment, age less than 50 years, susceptibility to motion sickness,
feeling warm or hot after treatment, sweating after last chemotherapy
treatment, and generalized weakness after last chemotherapy
treatment."

------------

This indication/risk document lists "GI toxicity" for 5-fu and "GI
ulcers" for methotrexate:
http://216.239.51.100/search?q=cache:nZ1G26lLTJwC:www.angelfire.com/tx5/scribe2004/scribes1/F090709.doc+%225-fu%22+%22GI+ulcers%22&hl=en&ie=UTF-8

-------------

From CancerNet and "Cancer Management: A Multidisciplinary Approach"
Fifth Edition (2001)

Common Toxicities of Chemotherapy:

The oral mucosa is very sensitive to chemotherapeutic drugs because
the tissue is subject to rapid turnover. Stomatitis (mucositis)
usually begins within days of the initiation of chemotherapy, and
symptoms of mucositis often parallel hematologic toxicity. Painful
ulcerations can occur throughout the GI tract, from the lips to the
anus.

Agents that are commonly associated with stomatitis include bleomycin,
doxorubicin, 5-FU, and methotrexate. The dose and schedule of these
drugs influence the severity of toxicity. Continuous infusions of 5-FU
and doxorubicin can cause severe stomatitis; therefore, at the
earliest signs of mouth soreness, infusions of these drugs should be
discontinued.

--------------

Mallory-Weiss lesion following cancer chemotherapy  

Authors: 
Enck RE 

Author Address: Dept. of Med., Hematology-Oncology Service, William
Beaumont Army Med. Cntr., El Paso, TX 79920

Source: Lancet; VOL 2 ISS Oct 29 1977, P927-928, (REF 3) 


Abstract: 

IPA COPYRIGHT: ASHP A Mallory-Weiss tear was observed in a 53-yr-old
male following IV fluorouracil (I) and oral semustine (II)
chemotherapy. I (1.5 g, 4 times weekly) was given. The patient
tolerated this well having only slight nausea and vomiting. Three
months afterwards, II, 300 mg (150 mg/sq m) orally every 6 weeks, was
given and I reduced to 800 mg 4 times weekly, the drugs being taken on
the same day. Moderate nausea and vomiting lasting less than a day
followed the first dose of II, but 12 hr after the second dose 6 weeks
later, there was nausea and vomiting, persisting to the point of
violent retching with severe midepigastric pain which progressively
worsened throughout the day. This case emphasizes that nausea and
vomiting, a common toxicity with many chemotherapeutic agents, may
have serious clinical sequelae. Fortunately for this patient, the tear
was self-limiting and was managed without blood transfusions. Because
giving I and II on the same day may have potentiated the
gastrointestinal toxicity, it was suggested that they be given on
separate days, with the early administration of antiemetics, if
needed.

---------------

Merck Manual:
http://www.merck.com/pubs/mm_geriatrics/sec13/ch106.htm

Specific (distinctive) gastritis: Specific gastritis may be caused by
infections, Crohn's disease, eosinophilia, systemic disorders (eg,
sarcoidosis), or physical agents (immunosuppressants, some
chemotherapeutic agents [eg, 5-fluorouracil], radiotherapy).
Distinctive histologic and sometimes endoscopic features allow a
diagnosis or markedly narrow the differential diagnosis.

---

Clarification of Answer by voila-ga on 01 Dec 2002 17:29 PST

Dear Annie and Tom,

Is there any way your docs can assist you in contacting Dr. Sartori? 
He seems to be one of the few in the world to be doing any serious
investigation on this particular issue.  Here are a couple more
articles he co-authored which should be helpful to your case.  I
accessed these through the BioMedNet research engine.


Randomized trial of omeprazole or ranitidine versus placebo in the
prevention of chemotherapy-induced gastroduodenal injury.
Sartori S, Trevisani L, Nielsen I, Tassinari D, Panzini I, Abbasciano
V
J Clin Oncol 2000 Feb 18:463-7
J Clin Oncol • Volume 18 • Issue 3 


Abstract
PURPOSE: Anticancer drugs may induce acute mucosal injury to stomach
and duodenum. This study was planned to evaluate the efficacy of
omeprazole or ranitidine in preventing such an injury. PATIENTS AND
METHODS: Two hundred twenty-eight cancer patients with normal stomach
and duodenum or with less than three erosions, who were selected to be
treated with cyclophosphamide, methotrexate, and fluorouracil (90
breast carcinoma patients) or fluorouracil alone (138 colon carcinoma
patients), were randomly assigned to treatment with omeprazole 20 mg,
ranitidine 300 mg, or one placebo tablet a day. Seven days after the
second course of chemotherapy (CT), the patients underwent a further
esophagogastroduodenoscopy to evaluate the mucosal injury. Endoscopic
findings were quantified on the basis of an arbitrary score, and the
occurrence of epigastric pain or heartburn was assessed weekly.
RESULTS: A significant difference was found among the three groups (P
=.0032), as well as between pre- and postCT endoscopic findings (P
=.00001). Endoscopic scores after CT were significantly higher than
pretreatment scores in the placebo (P =.003) and ranitidine (P =.003)
groups but not in the omeprazole group (P =.354). Acute ulcers were
significantly less frequent in patients receiving omeprazole or
ranitidine than in those receiving placebo (P =.0001 and P =.0315,
respectively). Epigastric pain and/or heartburn were significantly
less frequent in patients receiving omeprazole (P =.00124) or
ranitidine (P =.038) than in those receiving placebo. CONCLUSION:
Omeprazole is effective in preventing chemotherapy-induced
gastroduodenal injury. Ranitidine is effective in reducing the
frequency of ulcers and upper gastrointestinal symptoms but is not
effective in preventing the global endoscopic worsening caused by
chemotherapy. The different efficacy of omeprazole and ranitidine can
be explained by their different pharmacodynamics.


----------------------

Misoprostol and omeprazole in the prevention of chemotherapy-induced
acute gastroduodenal mucosal injury. A randomized, placebo-controlled
pilot study.
Sartori S, Trevisani L, Nielsen I, Tassinari D, Abbasciano V
Cancer 1996 Oct 78:1477-82
Cancer • Volume 78 • Issue 7 


Abstract
BACKGROUND: Chemotherapy (CT) may induce acute mucosal injury to the
stomach and duodenum, but its prevention has been scarcely
investigated. METHODS: One hundred and eighty-two cancer patients with
normal stomach and duodenum or having fewer than 3 erosions, selected
to be treated with cyclophosphamide, methotrexate, and 5-fluorouracil
(CMF) (77 breast carcinoma patients) or 5-fluorouracil (5-FU) (105
colon carcinoma patients), were randomly assigned to prophylactic
treatment with misoprostol, 400 micrograms twice a day; omeprazole, 20
mg once a day; or placebo, 1 tablet twice a day. Seven days after the
end of the second source of CT, all patients underwent control
esophagogastroduodenoscopy. Endoscopic findings were quantified on the
basis of an arbitrary score: 0 = normal; 1 = less than 3 erosions; 2 =
3-15 erosions; 3 = more than 15 erosions or ulcer; 4 = giant ulcer
(greatest dimension of more than 2 cm) or multiple ulcers with
cumulative greatest dimension exceeding 2 cm. RESULTS: Mean score
increased significantly in the placebo and misoprostol groups, either
after CMF (P < 0.001 and P < 0.05, respectively) or after 5-FU (P <
0.001 for both), whereas it did not in the omeprazole group. Gastric
and duodenal ulcers were significantly less frequent in patients
receiving omeprazole than in those receiving placebo (P < 0.05 after
both CMF and 5-FU). No significant difference was observed between
placebo and misoprostol. Omeprazole was significantly more effective
than placebo and misoprostol in reducing the frequency and degree of
the endoscopic worsening, either after CMF or after 5-FU (P < 0.05 for
both CT regimens). Epigastric pain and/or heartburn were significantly
less frequent in patients receiving omeprazole than in those receiving
placebo (P < 0.01) or misoprostol (P < 0.001). CONCLUSIONS: The strong
and prolonged inhibition of gastric acid production induced by
omeprazole seems to be effective in preventing chemotherapy-induced
gastroduodenal mucosal injury. Further trials are necessary to verify
whether such a prevention of endoscopically observed injury can
translate into prevention of clinically significant injury.

----------------------

Annie, if I'm understanding you, your insurer is saying you're
predisposed to nausea because you experienced morning sickness while
pregnant?  This seems absolutely ludicrous!  If an insured male had
breast cancer and experienced nausea or later had a fundoplication,
*his* claims would be valid because he had no such predisposition?

Also,  am I'm reading that you were H. pylori positive?  Ask your docs
if the chemotherapy could so change the intestinal flora which, in
turn, would create an optimal environment for the growth of
Helicobacter bacteria.

You also asked if one day you just *woke up* with Barrett's.  Without
the above risk factors (heavy NSAID/aspirin use, obesity, smoking,
chronic constipation, etc.), I don't think this is likely but ask this
of your gastroenterologist.  Yes, I suppose one *could* wake up with a
horse's head in your bed, but it's not bloody likely ... as long as
you stay away from the Corleone family!

I'm slowkly running of search words to come up with for anything else.
 My other advice would be to enlist the support of your state's
insurance commissioner.  You need as many people in your corner as
possible and, as a taxpayer, these folks are at your disposal.  As a
last resort if you still can't get satisfaction, you could pursue this
situation through the courts.

Annie, I'll be here if you need me but after discussing this case with
other researchers and healthcare professionals, my avenues of research
are dwindling.  All of the literature tends to support the fact that
CMF *may* induce injury to the GI tract which, coupled with the
temporal link and the above supporting data, ought to cinch the
causation claim.


Best of luck,
V

---

Request for Answer Clarification by tomc-ga on 03 Dec 2002 03:13 PST

Dear Voila, Annie is ill and asked me to reply. The pregnancy
'predisposition' of nausea and heartburn was not the main issue. It
was mentioned to try and lend weight to the report of the consultants
used by our insurer. The main reason of turning us down is simply that
we cannot find reported cases of long-term persistent symptoms of
GERD/nausea after CMF chemo. We were told that breast cancer patients
recover from persistent nausea and GERD when treatment is completed.
We were hoping that you with your vastly superior skills can find
something. I cannot understand that Annie was GERD free prechemo and
during CMF develop GERD that persisted for so many years.
Funduplication last year did help. But now it looks like it is back
but without heartburn ie only reflux as if the esophagus is tending
towards Barrett's. We requested our GP to research the local Gastro's 
to see who has experience in Barretts'before I take her in for
gastroscopy. It looks to me with early morning defecation that some
gut straining brings on an a dry type reflux (almost regurgerate)that
sets of her feeling funny in the head and nauseas the whole day. At
night when she lies down, our bed is elevated, she coughs (never
smoked)and feels like something in the esophagus. During the day she
feels and tastes an almost bad type food sensation taste in her mouth.
Thank you Tom.

---

Clarification of Answer by voila-ga on 03 Dec 2002 08:04 PST

Good morning Tom,

Sorry Annie isn't feeling well.  I'm very familiar with the symptoms
you describe and it's not pleasant.  All this insurance wrangling
can't be helpful to the situation either.

I do hope your docs can review some of these studies through the
Medline website to see what they contain.  Since I only have access to
the abstract and not the full article, I'm flying somewhat blind.  I
do hope you'll speak to them about contacting Dr. Sartori as he seems
to be an expert in this area of study.  Usually docs will speak
franckly with other docs and I'm sorry the man is so far away in
Italy.  Why U.S. physicians aren't pursuing this link somethat baffles
me.

If you could also ask your docs about the Helicobacter factor in my
previous question and confirm that she received an antiemetic pre and
post chemotherapy.  Also, I think the temporal link is the key issue
with all of these studies documenting mucosal injury.  None will ever
be as black-and-white as to say "CMF = Barrett's" though.

I'm continuing to work this question and still have a couple calls to
make, so I haven't thrown in the towel.  I very much want to help you
both but I'm seeing those dreaded words at the end of the abstracts
"more studies are required."

Will be in touch when I have something further.  Hope Annie feels
better soon.

Best,
V

---

Clarification of Answer by voila-ga on 09 Dec 2002 07:47 PST

Hello Annie and Tom,

I think this is about as close to a "smoking gun" theory as we'll get.

http://daccx.bsd.uchicago.edu/drug/Bulletins/N0498.html

"The three consecutive phases of emesis include nausea, retching and 
vomiting.1 Nausea is a subjective, unpleasant feeling that may or may 
not be associated with vomiting. Nausea is mediated by the autonomic 
nervous system and is accompanied by diminished gastric tone, reduced 
peristalsis, retrograde duodenal peristalsis and subsequent reflux of 
intestinal contents into the stomach.1,2 Retching may occur before or 
after vomiting and is defined as a synchronized movement of the 
diaphragm, chest wall and abdominal muscles.3 Vomiting is the forceful 
emptying of the gastric contents through the sustained action of 
abdominal muscles and the opening of the gastric cardia.2,3 Unlike 
nausea, retching and vomiting are mediated through the somatic nervous 
system.


"Chemotherapy is postulated to stimulate the release of various 
neurotransmitters from the CTZ. These neurotransmitters transmit 
impulses to the VC and vomiting ensues. In addition, chemotherapy 
stimulates the release of peripheral neurotransmitters from the 
pharynx and upper gastrointestinal (GI) tract. Peripheral 
neurotransmitters are not released by a direct chemotherapy-receptor 
interaction, but rather as a result of chemotherapy-induced local gut 
irritation or damage.6 Recent findings suggest that the primary 
initiation of CINV is via serotonin (5-HT3) receptors located on vagal 
afferent neurons in the proximal small bowel.6,7,

-------------

It would also probably be helpful to speak to the editors of this book:
http://www.meb.uni-bonn.de/cancernet/304466.html
Berger, AM, Clark-Snow, RA:  Nausea and vomiting. In: DeVita VT Jr, 
Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of 
Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997,
2705-2712.

Please let me know if your clinicians have had a chance to review all 
the literature presented thus far.  I do hope Annie's feeling much 
better today.


Best regards,
V

You render an exceptional service for which I am very grateful.

Although this question has been answered, perhaps you could tell me,
which drugs of those listed above, you took orally and which you took
by IV. I have been involved with cancer research as an investigator at
a major cancer center  and perhaps, I might be able to add some
information to your request.

Thank you

One other point of clarification:

Were those 3 drugs the only ones, administered to you during your chemo treatment?

Were these 3 drugs given to you individually or in a form of a "cocktail"?

Thank you.

I have just reviewed the side-effects of the three drugs, which you
took during your chemo treatments.  The book, which I have used is The
Cancer Chemotherapy Handbook published by Year Book Medical
Publishers, Inc.

What may be of interest in your case are the neurological side-effects
observed on  occasion with methotrexate. These are:
headache,paraplegia, brain atropy, and mental impairment, after
intrathecal methotrexate administration.

Other excellent links:

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAA8taGuO:2

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAAKZaikP:1

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAAncaOwP:1


I'll keep searching and post when I have more information.

I'm wondering if by any chance, cisplatin ( Platinol ) was given as
part of the chemotherapy protocol.  Cisplatin is commonly used for
breast cancer and is one of the most emetogenic agents used in cancer
chemotherapy; nausea and vomiting occur in 67% to 100% of patients and
is dose related.  Prophylatic antiemetics should always be prescribed;
nausea and vomiting may last up to 1 week after therapy.

Neurotoxicity:
Peripheral neurotoxicity is dose and duration dependent.  The
mechanism is through axonal degeneration with susequent damage to the
long sensory nerves.  Toxicity can first be noted at doses at 200
mg/m2, with measurable toxicity at doses greater than 350 mg/m2.  This
process is irreveresible and progressive with continued therapy.

REFERENCE:
Drug Information Handbook
Lexi-Comp's Clinical Reference  Library

Hi viola I do not have any fear of my problem being out in the public
arena. Perhaps it may be of help for somebody else that was injured
like myself. In answer to resaercher7 I did not receive cisplatin. It
was an oral protocol CMF with MTX and 5-FU single push injections on
days 1 and 8 with cyclophosphamide tablets from day 1 to 14 daily with
a recovery period from day 15 to 28. My LES and GI persistent symptoms
started early in treatment cycle and the heartburn became refractory
for 5.5 years up to a loose partial funduplication proceedure.
Aggravated by radiation but is predated by CMF toxicity. Sartori et al
only researched while treatment was ongoing and not followed up. I
wrote to him but got noe reply. Thus I still do not have a causal
report.Thanks Annie.

Hello voila, the citation by Herrera is the only one of many examaning
Barrett esophagus who found no sign of this after a mean of 2,5 years.
All the others report the development of Barretts. He concedes 12 of
the 15 had oral ulcerations but he is silent (in the abstract) on
heartburn/reflux suffered during this period. My question is do you
assume no esophageal injury and no reflux persisting after CMF and
then one day you have Barretts?. For me to find causation I need to
find patients who suffered persistent heartburn/reflux after CMF
treatment. The lucky patients can find relief with conventional reflux
treatment. I am one of the rare 'unlucky' who eventually found relief
with funduplication surgery. Thus please help to find patients who
developed heartburn/reflux during CMF treatment and who for the rest
of their life require ongoing treatment be it drugs or surgery. Annie

Clarification:

Annie:  You mentioned "single push injection".  This is an IV
procedure.  Are you saying that all 3 meds were given by this "single
push injection?

The area of your brain that is involved with nausea/vomiting is called
the CTZ area.  When drug interactions are reviewed online for cancer
chemotherapy/nausea interaction, it might be a good idea to put in the
word "CTZ" in the search.

Drugs given by IV can cause stomach/GI upsets.  Good example of this
is the case of erythromycin.  The question in my mind, right now, is
how an IV administered medication can cause an ulcer of the esophagus.

Clarification:

I think I see the picture now.  The drugs used for chemotherapy were
administered IV.  After administration, one side-effect observed was
the nausea,vomiting,and an acid stomach.  Acid reflux then resulted,
either directly or indirectly from the administered drugs.  The acid
reflux then caused the ulceration.

So, to zero in on the specific issue, we'd have to know whether the 3
drugs administered together by IV-push may have resulted in
acid-reflux  to the extent that an ulcer of the esophagus resulted.

Reading all of this, brings to my mind another question.  This
question concerns the dosage of the 3 drugs which you received. Have
you checked your medical charts to confirm the levels of the meds
given? Are these the doses, one usually observes in similar chemo
treatments of breast cancer with these 3 drugs?

I'll try to get back to this question on Thursday 11/14.  

Good luck in your searches.  I believe we'll find the answer.

Clarification:

I misread the statement concerning the protocol.

Oral:  cyclophosphamide; MTX

IV Push:  5-FU

Clarification:

Prior to chemotherapy, was there any evidence suggestive of a
pre-dispostion to an esophogeal ulcer?

Thank you.

Dear researcher7, on day 1 and 8 injections of MTX and 5-FU plus from
day 1 to 14 tablets of cyclophosphamide. Then a 'rest recovery' period
of no treatment from day 15 to 28. Six of these cycles were planned
over a 6-month period. But I could only complete an oftened delayed,
due to toxicity, 3.5 courses over a period of 6 months. Nausea,
heartburn/reflux, sight body shakes poor memory hyperventilation are
some of the symptoms that I can recall at the moment came on and
persisted when treatment was eventually discontinued. The heartburn
did not respond to drug treatment but 5.5 years later a partial loose
funduplication backed up with ranatidine resolved this system (cannot
tolerate proton pump inhibutors). The only previous heartburn ever was
nearly 40 years previously with 3 pregnancies with morning sickness.
My medical insurer is using this as a 'precondition' I also had
episodes with motion sickness( particularly in the old days with Yank
tanks-I still have a sence of humour.) I have records of some of the
gastroscopies and biopsies taken at about 3 months after treatment
stopped and another 3 taken over the course of time. The 1st one
reported 'mild diffuse gastritis ' and helico bacter pylori all of
which I received treatment for later followed by a gall bladder
removeal and other tetst which included the inevital counselling all
of which was fruitless and so was hypnosis acupuncture until
eventually ablation of the area postrema was stongly recommended. My
GI symptoms were vastly improved with reflux surgery and currently my
episodic nausea is reasonably controlled with a mix of amitriptilyne,
domperidone .ranitidine and sumatriptan. The sigth was restored by
cataract syurgery and now daily eye drop lubrication. I am sending
this instalment as I am scared the time will elapse as I type very
slow and do not know how to reply off-line. Thank you for your
assustance. Annie and Tom.

Thank you voila and researcher 7. I will follow up in more detail. The
Beth Israel manual describes the infection of cmf toxicity but it is
silent on persistent symptoms when the chemo is discontinued. This is
my problem area. The Oncology Nursing forum discuss anticipatory N.
This is classed as psycological and not an injury. I have actually
been in contact with Dr Gary Morrow. He postulates that patients that
are sussecptible to motion sickness is more susceptible to chemo N. My
insurer consider this as a precondition of N. The CancerNet site 5th
edition looks promising and I will try to get into it or try and get
the publication. Thank you Annie.