GI Toxicity From Chemotherapy
L. Bressler
November, 1997
I. Explanation
of terms
II.
Vomiting mechanisms
III. Consequences of inadequately treated nausea and
vomiting
IV. Emetic Mechanisms of chemotherapeutic agents
V.
Antiemetics
VI.
Conclusions/Guidelines
VII. Suggestions
VIII.
Stomatitis
IX. Other GI toxicities: Diarrhea
OBJECTIVES
1. Discuss the (potential) mechanisms of chemotherapy-induced nausea and vomiting.
2. Discuss the mechanism(s) of antiemetic drugs.
3. Discuss the phenomena of anticipatory nausea and vomiting.
4. Select an antiemetic regimen, noting patient specific concerns (eg. type of chemotherapy, patient preferences).
5. Discuss the side effects of antiemetic treatments, and be able to prevent or minimize them.
6. Discuss the mechanism of chemotherapy-induced stomatitis.
7. Suggest, in writing, a rational treatment for chemotherapy-induced stomatitis.
8. List those chemotherapeutic agents commonly associated with diarrhea.
9. Suggest, in writing, a rational treatment for chemotherapy-induced diarrhea.
REQUIRED READING
NONE
SUGGESTED READING
NONE
A. NAUSEA - a psychic experience of human beings which may or may not be associated with vomiting. It is a subjective phenomenon difficult to identify in experimental animals.
B. VOMITING - EMESIS; the forceful expulsion of the gastro-intestinal contents through the mouth.
C. RETCHING - the labored rhythmic activity of respiratory musculature which usually precedes or accompanies vomiting. Retching is not ordinarily accompanied by opening of the mouth.
A. VOMITING CENTER (VC) - The VC coordinates the act of vomiting. It is located in the reticular formation in the medulla. The VC is anatomically close to other loci in the medulla, specifically, those concerned with salivation, spasmodic respiratory movements (eg. retching), the inspiratory and expiratory centers, and the vasomotor center. Activities of all of these centers are involved in the motor expression of vomiting. Drugs don't usually stimulate the VC directly. Instead, the VC receives input from the chemoreceptor trigger zone (CTZ), from the so-called "periphery", from higher brain centers and from the vestibular apparatus.
B. CTZ - The CTZ is located in the floor of the fourth ventricle in the medullary surface. It is more superficially located than the VC. It is exposed to both blood and CSF, and it is sensitive, as the name implies, to emetic chemicals. Many drugs that cause nausea and vomiting, but by no means all, do so via stimulation of the CTZ. The prototype for studying CTZ stimulation (eg. in animals) is apomorphine.
C. "PERIPHERY" - "Peripheral" input to the VC is through vagal and sympathetic afferents, originating primarily in the pharynx and GI tract. Note that parenterally administered drugs can cause nausea and vomiting by this mechanism. The prototype for studying peripheral stimulation of the VC (eg. in animals) is intragastric copper sulfate.
D. HIGHER BRAIN CENTERS - Higher brain centers can also provide input to the VC. This may be in response to such stimuli as taste and smell. Higher brain centers probably are involved in NAUSEA, as well as in the development of ANTICIPATORY NAUSEA and VOMITING.
E. VESTIBULAR APPARATUS - The vestibular apparatus provides input to the VC, probably by way of the CTZ. It is important in motion sickness, but is thought not to have a major role in chemotherapy-induced nausea and vomiting.
A multitude of neurotransmitters and receptors may be involved in the transmission of impulses to the VC. Of recent interest is the role of SEROTONIN in chemotherapy-induced nausea and vomiting.
NAUSEA and VOMITING are SEPARATE phenomena. It may be that an emetic stimulus divides, producing vomiting, as described above, and nausea, a central phenomenon.
III. Consequences of inadequately treated nausea and vomiting
A. NONCOMPLIANCE with chemotherapy
1. Noncompliance due to nausea and vomiting has been estimated to occur in as many as 25-50% of patients.
2. Noncompliance is of particular concern in patients with potentially curable diseases (eg. Hodgkins, testicular cancer).
B. PATIENT DISCOMFORT
1. Time off from work or school, with resultant financial consequences.
2. Disruption of personal life.
C. MEDICAL COMPLICATIONS
1. ESOPHAGEAL TEAR (Mallory-Weiss syndrome) or pathologic BONE FRACTURE from violent or repeated retching or vomiting.
2. DEHYDRATION
3. Prolonged ANOREXIA and MALNUTRITION may compromise the patient's ability to tolerate normal dosages of chemotherapy.
4. METABOLIC ABNORMALITIES from vomiting: metabolic alkalosis, hypokalemia, hypochloremia
5. ANTICIPATORY NAUSEA and/or VOMITING
a. Anticipatory nausea and/or vomiting are nausea or vomiting that occur before administration of, and in anticipation of, chemotherapy.
b. Anticipatory symptoms have been reported in as many as one-third of patients receiving chemotherapy.
c. Anticipatory symptoms are a conditioned response. The best treatment for anticipatory nausea/vomiting is prevention, by minimizing post chemotherapy nausea and vomiting in the first place.
IV. EMETIC MECHANISMS of chemotherapeutic agents
A. Emetic mechanisms (from those mechanisms and neurotransmitters discussed above) are known for only a few drugs.
1. NITROGEN MUSTARD emesis in dogs is mediated through the CTZ, and in cats, through the periphery and higher brain centers.
2. CISPLATIN emesis is mediated through the periphery and appears to be related to serotonin.
3. For most other drugs, the mechanism of emetic effect is unknown. In some cases, emetic mechanism is inferred indirectly from results of antiemetic use.
B. It is likely that there are several mechanisms for chemotherapy-induced nausea and vomiting, perhaps even more than one mechanism for the same drug. This makes it unlikely that any one antiemetic will be successful against all chemotherapy-induced nausea and vomiting, and also supplies a rationale for combination antiemetic therapy.
A. PHENOTHIAZINES
1. Proposed antiemetic mechanism: blockade of dopamine receptors in the CTZ.
2. Piperazines (PROCHLORPERAZINE, THIETHYLPERAZINE, PERPHENAZINE) are the most potent antiemetics (among the phenothiazines) but also have the greatest tendency to cause extrapyramidal side effects (EPS).
3. Piperidines (THIORIDAZINE) are poor antiemetics.
4. Aliphatics (CHLORPROMAZINE) are less potent than piperazines, but are associated with less EPS. Chlorpromazine is often preferred in children for this reason (less EPS).
5. GUIDELINES for use
a. Phenothiazines are often successful in minimizing nausea and vomiting from drugs with LOW to MODERATE EMETOGENIC POTENTIAL (eg. METHOTREXATE, 5-FLUOROURACIL).
b. Use a variety of dosage forms: parenteral, oral, rectal suppositories (eg. in case patients can't keep down oral medications).
c. Duration of antiemetic effect is three to four hours, less than the usual recommended dosing intervals. Antiemetics can often be given at these more frequent dosing intervals.
d. Occasionally, doses higher than those usually recommended may be administered, and may be more effective (eg. prochlorperazine 30-40mg as a short IV infusion).
e. SIDE EFFECTS accompanying short-term use
i. EPS - ACUTE DYSTONIC REACTIONS (spasms of the neck or back, with torticollis or opisthotonos in severe cases; difficulty swallowing, trismus, protrusion of the tongue or oculogyric crisis).
ii. EPS - AKATHISIA - motor restlessness ranging from a feeling of inner disquiet to inability to sit or lie quietly (agitation, jitteriness) or to sleep.
iii. EPS - TREATMENT - DIPHENHYDRAMINE 25-50mg PO or parenterally (ie. if swallowing is difficult) or BENZTROPINE 2mg PO or parenterally. BENZODIAZEPINES may also be useful for akathisia.
iv. autonomic effects - hypotension, dry mouth, urinary retention
v. SEDATION
B. BUTYROPHENONES - DROPERIDOL and HALOPERIDOL
1. Proposed antiemetic mechanism: blockade of dopamine receptors in the CTZ.
2. Clinically, butyrophenones are used as more "potent" antiemetics than phenothiazines. This is somewhat empiric. Higher doses of phenothiazines may be just as "potent". (see above)
3. SIDE EFFECTS are qualitatively similar to phenothiazines. The doses are less well defined.
4. Suggested STARTING DOSES: DROPERIDOL 1.25mg IV push or IM; HALOPERIDOL 2.5mg IV push or IM (these are not necessarily equipotent and are somewhat empirically derived; IV doses may also be given as short infusions). Doses may repeated at four hour intervals and increased or decreased based on efficacy and side effects. Oral haloperidol might be used by patients at home, following parenteral dosing.
C. METOCLOPRAMIDE
1. High doses are more effective than low (standard, eg. 10mg QID) doses for chemotherapy-induced nausea and vomiting. High doses block serotonin receptors as well as dopamine receptors.
2. A commonly reported dose/schedule is 2mg/kg in 50ml D5W or 0.9% NaCl infused over 15-30 minutes. This dose is repeated at approximately two hour intervals for a total of five times.
a. Oral metoclopramide is less convenient to use, being only available in 10mg tablets.
b. Lower and higher doses of IV metoclopramide (eg. 1-3mg/kg) have also been used. Higher doses might be used for outpatients who can only receive one or two (as opposed to five) doses.
3. EPS, similar to those seen with phenothiazines and butyrophenones, also occur with metoclopramide, as metoclopramide also blocks dopamine receptors in the CTZ.
4. In addition, metoclopramide has a PERIPHERAL EFFECT, enhancing forward motility of the GI tract (ie. the "opposite" of vomiting). This may also result in DIARRHEA.
5. SEDATION is also reported with metoclopramide.
D. STEROIDS
1. Steroids have been reported to have an antiemetic effect, although the mechanism remains speculative. In addition, most literature supports the use of dexamethasone in combination with other agents for highly emetogenic chemotherapy.
2. Much of the literature documenting a beneficial effect of steroids describes patients who received chemotherapy that was not clearly highly emetogenic (eg. CYCLOPHOSPHAMIDE, METHOTREXATE, 5-FLUOROURACIL).
3. The steroids most commonly used are DEXAMETHASONE and METHYLPREDNISOLONE (one suggested dose of dexamethasone: 20mg IV then 10mg PO every six hours for 24 hours).
4. Short term use of steroids in this setting isn't accompanied by many side effects. PERINEAL BURNING has been reported with IV injection of steroids. This can be minimized by prolonging the rate of injection.
E. CANNABINOIDS
1. THC (DRONABINOL) is marketed for chemotherapy-induced nausea and vomiting unresponsive to more "standard" treatment. It is also recommended for delayed or prolonged nausea and vomiting (symptoms lasting longer than 24 hours, usually following treatment with cisplatin). This latter use probably requires better documentation before it can be accepted as "standard".
2. The antiemetic mechanism is unclear; THC may act at higher brain centers that transmit impulses to the vomiting center.
3. Usual dose of THC is 5-10mg/m2 PO every three to four hours. Doses for delayed or prolonged nausea or vomiting are generally lower (eg. 2.5-5mg twice a day).
4. The most common SIDE EFFECTS are DROWSINESS and a "HIGH". Dizziness and reddening of the eyes are also seen.
5. The cost of THC can be prohibitive - thus, it remains a useful second or third choice antiemetic.
F. BENZODIAZEPINES
1. Benzodiazepines are frequently used in combination, or sometimes alone, to treat chemotherapy-induced nausea and vomiting.
a. Benzodiazepines provide an ANTIANXIETY effect, quite useful in nervous patients.
b. Benzodiazepines produce ANTEROGRADE AMNESIA, leaving the patient with a "fuzzy" recollection of the time of chemotherapy and shortly thereafter. This may help to PREVENT ANTICIPATORY NAUSEA and VOMITING.
c. Benzodiazepines have been reported to have a separate ANTIEMETIC effect. The mechanism of such an effect is unclear. Perhaps it is an antinausea effect, acting on the psychic component.
2. LORAZEPAM has been used in various doses and by various routes of administration (eg. 0.05mg/kg IM, 3mg PO, 4mg IV).
3. ALPRAZOLAM has been reported to be useful in patients with anticipatory symptoms, when given beginning the night before chemotherapy.
G. SEROTONIN ANTAGONISTS
1. Recent literature has focused on serotonin as a mediator in chemotherapy-induced nausea and vomiting.
2. Selective antagonists of serotonin at the S3 (serotonin3) receptor (ondansetron, granisetron) have become among the most widely used antiemetics. Dolasetron was very recently marketed.
a. Results with serotonin receptor antagonists are quite positive for nausea and vomiting due to cisplatin as well as other chemotherapeutic agents, although they are very expensive to use.
b. Serotonin receptor antagonists have no antidopaminergic activity and therefore do not cause EPS. They also ar not sedating. They are very well tolerated; the most common SIDE EFFECT reported is HEADACHE.
c. The recommended dose of ondansetron is 32mg IV as a single dose or 0.15mg/kg IV as a short infusion before chemotherapy and 4 and 8 hours after chemotherapy. Other, widely used, lower doses may be similarly effective although there is less literature support for them. Oral tablets are marketed for cyclophosphamide-containing chemotherapy regimens. The oral dosage form is also likely to be used for "follow-up" after IV dosing in patients receiving other chemotherapeutic agents (eg. cisplatin).
d. The recommended dose of granisetron is 10mcg/kg over 5 minutes, as a single IV dose before chemotherapy. Oral granisetron is also recommended instead of a parenteral serotonin antagonist. Whether such use is, indeed, as effective and less costly than parenteral agents is still being debated.
e. Ondansetron and granisetron appear to be equivalent in efficacy.(Dolasetron is probably of similar effectiveness.) There is however, little comparative data using 10mcg/kg of granisetron and 32mg of ondansetron. Most of the supportive literature for granisetron describes higher doses (3mg or 40mcg/kg). Cost to individual institutions or buying groups may be the ultimate determinant in the choice of serotonin receptor antagonist. I would not recommend either of these drugs for most mildly or moderately emetogenic chemotherapy regimens, specific patient concerns notwithstanding.
A.
CISPLATIN is the most highly emetogenic drug, causing nausea and vomiting in 90% or more (but not 100%) of patients.
B.
Other HIGHLY EMETOGENIC drugs include DTIC, DOXORUBICIN, NITROGEN MUSTARD, and IFOSFAMIDE.
C.
DTIC is often given daily for five days. Nausea and vomiting commonly decrease over the five day period.
D.
BLEOMYCIN and VINCRISTINE cause almost no nausea or vomiting
E.
Nausea/vomiting that are not anticipatory do not occur immediately. The shortest "lag time" is about 30-60 minutes, and "lag time" may be six hours or longer (eg. after CYCLOPHOSPHAMIDE). It should be remembered, however, that anticipatory nausea and vomiting still cause much discomfort for patients and may still require treatment.
F.
Nausea/vomiting, when they do occur, commonly IMPROVE WITHIN 24 HOURS.
G.
The EXCEPTION to this is CISPLATIN, following which nausea, vomiting, or anorexia may last for a week or more.
H.
Nausea/vomiting from CISPLATIN are DECREASED by giving the drug as a PROLONGED INFUSION (eg. 24 hours).
I.
Antiemetics should be started BEFORE chemotherapy administration - well before nausea and vomiting might be expected to be seen.
J.
Many of the antiemetics discussed above are used acutely, before chemotherapy. Attention should be paid to follow-up with oral or rectal medications, lower doses, or even continued dosing with the same drug. This assures treatment throughout the expected duration of nausea and vomiting, or in the event of delayed or prolonged symptoms. Having said that, it is commonly believed that most antiemetics display decreased effectiveness when given over multiple days (eg. with daily x five cisplatin). Consistent follow-up with appropriate adjustments is important.
K.
The choice of antiemetic is OFTEN EMPIRIC. The literature supports the use of any of a number of drugs, even if a pharmacologic rationale (ie. based on mechanism of nausea and vomiting of the particular chemotherapeutic agent[s]) is absent.
L.
The subjective nature of nausea and the degree of patient discomfort often seen may justify this empiric approach.
M.
Nausea and vomiting are DISTINCT ENTITIES. They may occur together or separately. The presence of (and disappearance of) nausea must be evaluated separately from vomiting.
N.
ANTICIPATORY NAUSEA and VOMITING are very real phenomena. The way to prevent them would appear to be to prevent post chemotherapy nausea and vomiting from occurring in the first place.
O.
SIDE EFFECTS play an important role in the patient's overall assessment of antiemetic effectiveness. Patients may prefer a drug that, objectively, has not helped that much, over a drug with side effects that they find intolerable.
P.
Consider the patient's needs - do they want to be awake or asleep? Do they have a companion if they are at home, or with whom they can travel to and from an outpatient facility? Are they at risk of aspiration? Make sure sleeping patients lift their heads so as not to aspirate if they vomit.
Q.
DEXAMETHASONE/METOCLOPRAMIDE is the most widely used combination for DELAYED nausea and vomiting. Low doses of metoclopramide are used in this setting.
VII. SUGGESTIONS (see K above)
A. The following regimens can be used for highly emetogenic chemotherapy. Some of these regimens (ie. haloperidol and lorazepam) can be very sedating. This may be beneficial, but certainly needs to be considered in view of the patients' desires, responsibilities, etc.:
- metoclopramide
- haloperidol/lorazepam
- high dose prochlorperazine
- ondansetron or granisetron or dolasetron
- chlorpromazine/secobarbital*
*secobarbital can provide effects qualitatively like those of lorazepam
B. For less highly emetogenic chemotherapy:
- droperidol
- prochlorperazine
- dexamethasone
C. THC as second line treatment for either of the above categories
D. DIPHENHYDRAMINE prophylactically with any of the above to prevent EPS and/or increase sedation.
E. Dexamethasone in combination with those regimens listed in A above
As is the case with myelosuppression and alopecia, stomatitis (oral mucositis) results from the effects of chemotherapy on rapidly proliferating tissues - in this case, epithelium in the mouth. Although mucositis can involve the esophagus, ileum or colon, stomatitis is the most common.
Stomatitis is PAINFUL, which may IMPAIR NUTRITIONAL INTAKE. In addition, mucosal breaks predispose to secondary INFECTIONS.
Among the chemotherapeutic agents most likely to cause stomatitis are 5-FLUOROURACIL, METHOTREXATE, BLEOMYCIN and DOXORUBICIN.
SYMPTOMS of stomatitis generally begin 3-4 days after chemotherapy. They include tingling, dryness, pain, burning, sensitivity of teeth and gums, dysphagia and impaired taste. Symptoms progress, becoming the most severe within a week. Lesions appear as an ULCERATION with ERYTHEMATOUS BORDERS. The lips, tongue, gums, buccal mucosa, palate or floor of the mouth may be involved. The lesions slowly HEAL (barring infection) in 7-10 days.
TREATMENT of stomatitis is SYMPTOMATIC - PAIN RELIEF and HYGIENE. Various agents, alone or in combination, have been used. None have been studied in a comparative fashion so superiority of one treatment over another cannot be stated.
VISCOUS LIDOCAINE and DICLONINE 0.5% are used for LOCAL ANESTHESIA. A common combination is DIPHENHYDRAMINE/KAOLIN-PECTIN in equal parts. Although diphenhydramine is reported to have local anesthetic properties, documentation of this effect with the concentrations used clinically is scanty. Kaolin-pectin "soothes" or "coats", and prolongs the contact time of other agents with the oral mucosa.
Sometimes combinations may mask the unpleasant taste of viscous lidocaine. For example: VISCOUS LIDOCAINE/MAALOX/MOUTHWASH (alcohol free if possible). MAALOX probably works as the kaolin-pectin above, and MOUTHWASH provides an ANTISEPTIC as well as a FLAVOR. Alcohol in mouthwashes may intensify burning or drying.
Extemporaneously prepared suspensions of SUCRALFATE have been described for use in stomatitis. It is suggested that sucralfate may help heal oral lesions. This is similar to its effects in peptic ulcer disease.
A suspension of ALLOPURINOL has been used to minimize stomatitis due to 5-fluorouracil (5-FU). This is based on the premise that allopurinol results in inhibition of one of the activation pathways of 5-FU (ie. a form of biochemical modulation).
CHLORHEXIDINE GLUCONATE (Peridex?) may be used to decrease secondary infections in stomatitis. It has been reported to decrease plaque and gingivitis as well as decreasing mucositis and bacteria. The dose is 15cc three times a day (swish & spit).
TANNIC ACID (Zilactin?) is available without a prescription and may provide relief for painful stomatitis. After an initial burning sensation, it forms a thin protective film that can often withstand eating and drinking.
Patient acceptability is obviously an important consideration in choosing a treatment for symptomatic relief of stomatitis. Patients must also be cautioned so as not to aspirate food, bite their tongue, etc., following the use of local anesthetics. It may be necessary to swallow the anesthetic (eg. lidocaine) in order to reach some painful lesions, requiring a greater volume than that which can be dabbed on a more easily accessible lesion. Systemic side effects (eg. seizures) have been reported following the use of viscous lidocaine. Patients should use the minimum amount necessary to provide relief.
IX. OTHER GI TOXICITIES: DIARRHEA
Several chemotherapeutic agents are associated with the development of diarrhea. Although alterations in colonic mucosa are a likely mechanism for such, there may be other contributing factors as well. Diarrhea can be severe, with resultant fluid and electrolyte disturbances, and even fatality. Two of the most common causes of diarrhea include 5-FLUOROURACIL and IRINOTECAN.
Management of 5-FU-induced diarrhea is usually nonspecific and includes opioids (loperamide, diphenoxylate), kaolin-pectin, or, occasionally, octreotide.
IRINOTECAN is associated with acute diarrhea (eg. during or shortly after drug administration) that is thought to be cholinergic mediated. It is recommended that such diarrhea be treated with atropine. "High dose" loperamide is recommended for late irinotecan-induced diarrhea (eg. 4mg at the onset of diarrhea, then 2mg every 2 hours until diarrhea-free for 12 hours).
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