Trial Information

Evaluation of the Efficacy of Esomeprazole in Suppressing Nausea and Vomiting in Patients Undergoing Chemotherapy for Breast Cancer

1. Breast Cancer

The American Cancer Society estimates that there will be approximately 215,990 new
cases of breast cancer diagnosed in women during 2004 in the United States. Breast
cancer is the most common malignancy in women in the United States and the second
leading cause of cancer death in women.

Treatment options for breast cancer have evolved from extensive surgical approaches to
breast-conserving techniques and the use of adjuvant and neo-adjuvant chemotherapy,
radiation, and endocrine therapy to reduce the risk of recurrence.

2. Chemotherapy in Breast Cancer

The use of adjuvant chemotherapy is a well established and routine part of care for
breast cancer. Chemotherapy can reduce a woman's risk of recurrence by 25-30%. The
amount of risk reduction depends on the patient's age, nodal status, and hormone
receptor status.

Anthracycline-based chemotherapy is standard in the treatment of breast cancer with
doxorubicin being the most frequently used agent in this group. Currently the most
commonly used chemotherapy regimens for breast cancer include: *
doxorubicin/cyclophosphamide (AC) * fluorouracil/doxorubicin/cyclophosphamide (FAC) *
cyclophosphamide/methotrexate/fluorouracil (CMF) *
docetaxel/doxorubicin/cyclophosphamide (TAC) * fluorouracil/epirubicin/cyclophosphamide
(FEC) * single agent taxanes (paclitaxel and docetaxel) Except for the taxanes, these
agents are known to cause significant nausea and vomiting after administration.

Cancer drugs differ both quantitatively and qualitatively in their emetogenic
potential. Emetogenic potential can be influenced by chemotherapy-related
characteristics and patient characteristics.

3. Gastrointestinal Side Effects of Chemotherapy

Nausea and vomiting following administration of chemotherapy for cancer are among the most
significant and feared side effects of patients undergoing treatment. Despite continued
advances in pharmacology, the ability to prevent or control nausea, vomiting, or retching
remains a problem for patients. Research has confirmed that chemotherapy related nausea and
vomiting negatively affects quality of life. Among patients, the same level of nausea and
vomiting varies in effect on quality of life. It is difficult to substantiate the degree of
this effect, but it has been shown that even with serotonin antagonists, patients still rank
nausea as their most bothersome chemotherapy side effect, while vomiting is ranked as third
to fifth most bothersome.

The risk for chemotherapy induced nausea and vomiting is related to the anti-neoplastic
agents administered and to patient related factors. Emetogenic potential is affected by the
intrinsic emetogenicity of the chemotherapy drugs, the combination of agents, the doses
administered and the rate of administration. Patient related factors include: 1.
gender-increased risk in females 2. age-increased risk in younger, premenopausal patients 3.
history of alcohol intake-low chronic intake decreases risk 4. history of motion
sickness-increases risk 5. hyperemesis during pregnancy-increases risk.

Emesis is a complex phenomenon characterized by three components: nausea, vomiting, and
retching. Nausea is a subjective phenomenon of an unpleasant sensation in the epigastrium
and in the back of the throat that may or may not culminate in vomiting; it is also
described as feeling "sick at the stomach." Nausea exists only insofar as it is defined by
the patient. Vomiting is the forceful expulsion of the contents of the stomach, duodenum and
jejunum through the oral cavity as a result of changes in intrathoracic positive pressure.
It is also described as "throwing up." Retching, also called "dry heaves," is the attempt to
vomit without expelling any material.

Drugs used to improve the control of nausea and vomiting include serotonin antagonists,
dopamine antagonist (metoclopramide, prochlorperazine), corticosteroids, benzodiazepines,
and phenothiazines. The American Society of Clinical Oncology (ASCO) has developed clinical
practice guidelines for the management of chemotherapy-induced nausea and vomiting based on
the emetogenic potential of the agents being administered. For combinations with moderate
emetogenic potential, acute emesis is managed with a corticosteroid and serotonin receptor
antagonists. Serotonin receptor antagonists currently available include ondansetron,
granisetron, and dolasetron. Studies indicate they are equally effective in the management
of chemotherapy-related nausea/vomiting/retching. Delayed emesis (greater than 24 hours
post-chemotherapy) can be controlled with a number of agents including steroids, serotonin
receptor antagonists or metoclopramide. Recommended combinations include dexamethasone, 8 mg
for 2-3 days, then 4 mg for 1-2 days and metoclopramide, 20-40 mg twice daily to four times
daily for 3-4 days, or Zofran 8 mg twice daily for 3 days. With combination chemotherapy,
patients should receive the antiemetic regimens appropriate for the chemotherapy agent with
the highest emetic risk.

Drugs used to improve the control of nausea and vomiting include serotonin antagonists,
dopamine antagonist (metoclopramide, prochlorperazine), corticosteroids, benzodiazepines,
and phenothiazines. The American Society of Clinical Oncology (ASCO) has developed clinical
practice guidelines for the management of chemotherapy-induced nausea and vomiting based on
the emetogenic potential of the agents being administered. For combinations with moderate
emetogenic potential, acute emesis is managed with a corticosteroid and serotonin receptor
antagonists. Serotonin receptor antagonists currently available include ondansetron,
granisetron, and dolasetron. Studies indicate they are equally effective in the management
of chemotherapy-related nausea/vomiting/retching. Delayed emesis (greater than 24 hours
post-chemotherapy) can be controlled with a number of agents including steroids, serotonin
receptor antagonists or metoclopramide. Recommended combinations include dexamethasone, 8 mg
for 2-3 days, then 4 mg for 1-2 days and metoclopramide, 20-40 mg twice daily to four times
daily for 3-4 days, or Zofran 8 mg twice daily for 3 days. With combination chemotherapy,
patients should receive the antiemetic regimens appropriate for the chemotherapy agent with
the highest emetic risk.

Studies done with standard antiemetics in women undergoing treatment with
anthracycline-based chemotherapy for breast cancer show a success rate for emetic control in
the range of 60-65%. 4. Measurement of Nausea, Vomiting, and Retching

It remains difficult to compare clinical studies of nausea and vomiting because of the
variety of measurement tools utilized and the variable time periods that were monitored
following chemotherapy. The ideal tool would include assessment of: 1. duration and severity
of nausea 2. frequency, duration, and severity of vomiting/retching 3. number of antiemetics
utilized 4. impact of nausea and vomiting on quality of life 5. adverse effects experienced

5. Proton Pump Inhibitors

Despite utilization of the antiemetics recommended by ASCO, approximately one-third of
patients undergoing anthracycline-based chemotherapy still develop nausea and vomiting. A
current therapeutic challenge is to find and prove methods to control nausea and vomiting
after chemotherapy.

Although the pathophysiology of nausea and vomiting is not well understood, we know that
chemotherapy causes damage to the gastrointestinal (GI) mucosa. The pathobiology of the
mucosal damage has been reviewed by Blijlevens and can be divided into four phases: the
inflammatory phase, the epithelial phase, the ulcerative/bacteriological phase and the
healing phase. This mucosal injury is usually self-limiting with a complete cycle of injury
to healing lasting approximately 2-3 weeks. The mucosal damage can be increased in patients
receiving chemotherapy and corticosteroids which breast cancer patients require as
pre-medications. Since cytotoxic chemotherapy damages the mucosal lining, it leaves the GI
mucosa exposed to the normal acid-producing gastric parietal cells. The resultant damage has
been seen endoscopically in patients receiving chemotherapy with cytosine arabinoside.
Hence, suppression of acid secretion from the gastric parietal cells should reduce mucosal
injury and related symptoms.

Historical therapies for gastrointestinal distress have included anticholinergics, as well
as H-2 receptor antagonists, to help reduce acid secretion. H-2 receptor blockers were
effective by blocking the histamine driven acid secretion, but despite its targeted action,
acid production continues through alternative pathways. Recently a group of new agents known
as proton pump inhibitors have been developed which target the final common pathway of acid
secretion. These agents are known to act directly on the H+/K+-ATPase in the gastric
parietal cell. Since these agents act directly on the final stimulatory pathway, they
provide rapid symptom resolution and reliable healing in gastroesophageal reflux disease and
peptic ulcer disease.

To date, two large clinical trials have been performed to evaluate the effectiveness of
proton pump inhibitors in preventing mucosal injury. The first trial selected 182 patients
with breast cancer (77 pts) or colon cancer (105 pts) who were receiving cyclophosphamide,
methotrexate and 5-FU (CMF), or 5-FU, respectively. These patients were randomized to
receive either omeprazole (20 mg daily), misoprostol (a prostaglandin analogue) (400 mg
twice daily), or placebo (once daily) for two full courses of chemotherapy (56 days).
Endoscopic evaluation (EGD) was performed one week prior to initiation of chemotherapy and
one week after the end of the second cycle of chemotherapy comparing the number of
erosions/ulcers in the stomach and duodenum. The omeprazole group had a lower frequency and
degree of erosions compared to placebo and misoprostol. Symptoms of epigastric pain and
heartburn were also significantly less in the omeprazole patients. A second study performed
by the same group evaluated patients with breast or colon cancer (n=228) receiving either
CMF or 5-FU. These patients were randomized to receive omeprazole 20 mg daily, ranitidine
300 mg daily (a H2 blocker), or placebo once daily for 56 days. EGD was performed as above,
before cycle 1 and after cycle 2 of chemotherapy. The omeprazole group experienced the
lowest frequency of ulcers (n=2), followed by the ranitidine group (n=8), and the placebo
group (n=18). Symptoms of epigastric pain or heartburn were also significantly less in the
omeprazole arm (n=11) compared to the ranitidine (n=13) or placebo (n=24) arms. Chemotherapy
was delayed in the placebo and ranitidine group, but not in the patients receiving
omeprazole. These two trials demonstrate the ability of a proton pump inhibitor (omeprazole)
to limit the mucosal injury induced by chemotherapy. Protecting the mucosa from damage also
appeared to significantly decrease the frequency of upper GI symptoms. It should be noted
that nausea or vomiting was not assessed in either trial since various antiemetics were
given during chemotherapy.

Esomeprazole magnesium is the latest proton pump inhibitor that has been developed. It is
unique in that it is the S- isomer of omeprazole, and as such, has better bioavailability
and elevated levels compared to the racemic omeprazole. Since the proton pump is the last
step in acid production, blockade of this pump causes reduction in gastric acidity. This
effect is dose related up to a dose of 20-40mg daily. Esomeprazole is currently clinically
indicated for the treatment of erosive esophagitis and symptomatic gastroesophageal reflux
disease. In addition, it is approved to treat Helicobacter pylori in patients with duodenal
ulcer disease in conjunction with either amoxicillin or clarithromycin and amoxicillin.