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.
