OncoLink

Nausea

Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania

Introduction

Ever since the first chemotherapy was delivered to a lymphoma patient, nausea was, and has remained, a concerning side effect of cancer therapy. Nausea can be a debilitating symptom that may significantly interfere with the quality of a patients' life. Fortunately, we have learned a great deal about preventing and treating nausea and this has made a significant impact on improving cancer treatment.

What causes nausea?

Nausea can be caused by a great many contributing factors and needs be addressed individually in each patient. It may be caused by cancer treatments or by the tumor itself. Nausea is often the result of the medications that we instruct our patients to take -- separate from chemotherapy. For example, pain medications such as narcotics can evoke nausea. Some antibiotics, when taken alone may cause low-grade nausea, but in combination with the other medications, may cause severe nausea and vomiting. Radiation therapy may cause nausea if directed at the abdomen or head. The amount of nausea radiotherapy induces depends on the amount of radiation delivered, the fraction size, and the location of the body involved in the treatment. Metabolic abnormalities that result due to the cancer or the treatment may cause patients to be nauseated. For example, kidney failure and liver failure promote nausea. A high calcium level that often results from some squamous cell cancers can cause nausea. In fact, any electrolyte abnormality has the potential to cause nausea. Older patients, or those very sensitive to any body imbalances, may perceive nausea when constipated or even in pain. Finally, certainly anatomic problems would cause patients a great degree of nausea  problems such as a bowel obstruction. Some cancer patients may experience nausea if they have tumors in certain locations of the body such as the liver or the brain. These two locations tend to promote more nausea than cancer in other sites such as the lung for example.

Which chemotherapy agents are considered the worst offenders?

Chemotherapy is certainly one of the most well known causes of nausea in cancer patients. Although each person is different, and doses have much to do with the level of nausea, there are three chemotherapy drugs/classes that may cause a great deal of nausea. These are Platinums (Cisplatin in particular), Cyclophosphamide , and the Anthracyclin family ( Adriamycin). Cisplatin is used for a variety of cancers including lung cancer, head and neck cancer, testicular cancer, ovarian cancer, and some of the gastrointestinal cancers. Cyclophosphamide is often used both orally and intravenously for breast cancer, lymphoma, sarcoma, bladder cancers and leukemia. It is also used in very high doses in stem cell transplants where it causes some of the worst nausea. The Anthracyclines are a class of drugs that have a wide variety of applications. They are used for breast cancer, some gastric cancers, sarcomas, lymphomas, leukemia, and multiple myeloma. Not all patients who receive these chemotherapy drugs will get nauseated. Nausea is often a factor of the dose of drug given, the number of cycles administered, the route of administration (i.e. intravenous versus oral therapy), schedule of therapy (every week versus every three weeks) and, of course, the patient.

Patient factors that predispose to nausea

There are a few characteristics that doctors may use to predict whether or not a patient will experience nausea with the chemotherapy. Women tend to get more nauseated than men --especially those women who experienced much nausea with pregnancy. Younger patients usually are more nauseated than adults; however, older patients who are already taking many other medications for pre-existing conditions and have other diseases that compromise their performance status, are very likely to get nauseated. People prone to motion sickness are more likely to get sick. Surprisingly, it was noted that patients with a history of heavy alcohol use are less likely to experience nausea compared to those who do not drink alcohol. The mechanism for this is unclear.

How do we feel nauseated?

There is an area of the brainstem that has been identified to control nausea and vomiting. This " Vomiting Center" receives information from the rest of the body and coordinates the process. The nerves that signal the Vomiting Center come from a number of places: 1. From the vagal and splanchnic nerves (these nerves sense damage, obstruction, or damage to the bowel). This is why we sense nausea after radiation to the abdomen, constipation, severe diarrhea, infections, or abdominal pain. 2. Some information comes from the brain itself which senses smell and taste and from the inner ear transmitting information about movement and balance. This is why we often get nauseated when we smell or taste something unpleasant or when we sense motion. 3. The pharynx (back of the throat) also sends information to the Vomiting Center when it senses obstruction or damage. This is why we sense gag when we get a throat culture. In addition, the Vomiting Center also gets input from another part of the brain called the Chemoreceptor Trigger Zone, (CTZ). The CTZ sits in an area of the brain called the Postrema. Its sole function is to sense emetogenic or nausea causing chemicals in the blood. The CTZ is able to do so because the Postrema sits in the back part of the brainstem that is weakly protected by the blood brain barrier and therefore allows it to sense blood born toxins.

All the signals are transmitted to the Vomiting Center by way of neurotransmitters. Neurotransmitters, function much like hormones in that they are small molecules excreted by one place and act on another far away location with in the body. The type of neurotransmitters involved in relaying the messages of nausea and vomiting have been fairly well studied and those that have been implicated include: serotonin, dopamine, acetylcholine, and histamine. The Vomiting Center also has GABA and opioid receptors on its surface and can gather information via these signaling pathways as well.

Nausea Syndromes

Oncologists tend to divide nausea in three separate syndromes: anticipatory, acute, and delayed.

Some people, who have experienced much nausea with previous treatments, can begin to feel nauseous up to 24 hours before actually getting the next dose of chemotherapy. This is conditioned response that developed after multiple treatments. This is called "Anticipatory Nausea". It does not happen to everyone. Those who do experience this type of nausea often claim that they feel queasy when they set foot in the Oncologists office. Others report feeling sick when they "smell" the chemo suite.

"Acute Nausea" is a clear reaction to chemotherapy and occurs anytime from the minute of infusion up to 24 hours after treatment. The usual peak time is 2-6 hours after infusion. Time of onset may vary somewhat  for example, some people receiving a nitrogen mustard may note nausea as soon as the needle is inserted into the vein. Other patients receiving Carboplatinum or Cyclophosphamide may have Acute Nausea peak at 8-10 hours post infusion.

"Delayed Nausea" is typically seen 24-96 hours after treatments. This type of nausea is not thought to be serotonin mediated and the severity and duration clearly correlated with the drug and the dose used. If a patient has Acute Nausea, they are more likely to experience Delayed Nausea.

Treatment

The treatment of nausea in the field of Oncology is a necessary and integral part of cancer therapy. The standard of care is to pre-medicate the patient with anti-nausea medications prior to chemotherapy, give continuous coverage for a minimum of three days following chemotherapy infusion, and provide "breakthrough" coverage for the days immediately following treatment. Oncologists use medications that block the pathways of the involved neurotransmitters. For example, the most widely used class of antiemetics (anti-nausea) is the serotonin antagonists. These drugs include agents such as ondansetron (zofran), granisetron (kytril), and now palonosetron (aloxi). These agents are given in the office prior to therapy and are usually prescribed for continuous coverage for three days following treatment.

Steroids seem to increase the results of the serotonin antagonists and are often given in combination prior to treatment. Although a variety of steroids have been used in clinical trials, Dexamethasone has the most use. Although the best dose has not yet been worked out, it has great activity against acute nausea and should not be omitted.

The dompaine antagonists such as compazine and inapsine have great activity in delayed nausea. These agents are usually prescribed as "breakthrough" antiemetics to be taken after chemotherapy. They are not as effective as the serotonin antagonists and may cause sedation and movement side effects. In addition, in a few elderly patients, this class of drugs, may cause low blood pressure so they must be administered with caution.

A drug called metoclopramide (Reglan) has two mechanisms of action and is often used to fight nausea. It acts centrally on the CTZ to decrease the noxious stimuli sensed by the center, and acts peripherally by stimulating gastric and small bowel motility. This is a great drug to use in combination with other anti-nausea drugs although by itself it is a rather weak agent.

Benzodiazapimes are wonderful medications to use for patients suffering from anticipatory nausea. They have an amnesia and anti-anxiety effect that helps in this condition. These medications are metabolized by the liver and often have interactions with other medications so they must be administered with care.

Other possible nausea fighting medications include antihistamines such as Phenergan, Dramamine, Antivert, or even Benadryl. These interfere with the histamine neurotransmitters known to be involved in causing nausea. Antacids may sometimes be helpful as they block other histamine receptors. A scopolamine patch may be helpful for patients who have increased secretions and have their nausea mediated by the acetylcholine neurotransmitters.

The new drug on the block is a drug called aprepitant, (Emend). It has a unique mechanism of action in that it blocks substance P from transmitting nausea signals via the receptor called NK-1. This new agent was discovered quite serendipitously. It was initially intended to be a pain fighting medication when it was noted that substance P induces vomiting in animals. This medication is an oral drug that is indicated for Delayed Nausea.

Finally, a variety of complementary therapy methods also have a role to play in the fight against nausea. They are extremely effective when combined with conventional medication. These methods include guided imagery, relaxation training, and biofeedback.