Chemotherapy adverse effect

By : Somayyeh Nasiripour,Pharm.DBaord of clinical pharmacy

Enterotoxicity of chemotherapeutic agents

GI) toxicity due to chemotherapeutic drugs is a common problem in cancer patien

include diarrhea, constipation, colitis (neutropenic, C. difficile-induced, and immune-mediated), and intestinal perforation

DIARRHEA

most commonly described with fluoropyrimidines (particularly 5-fluorouracil [5-FU] and capecitabine ) and irinotecan

dose-limiting and major toxicity of regimens containing a fluoropyrimidine with or without irinotecan.

Both 5-FU and irinotecan cause acute damage to the intestinal mucosa, leading to loss of epithelium

With irinotecan , early onset diarrhea occurs during or within several hours of drug infusion in 45 to 50 percent of patients and is cholinergically mediated

This effect is thought to be due to structural similarity of the drug with acetylcholine

In contrast, late irinotecan-associated diarrhea is not cholinergically mediated. The pathophysiology of late diarrhea appears to be multifactorial with contributions from dysmotility and secretory factors as well as a direct toxic effect on the intestinal mucosa

These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa

SN-38 is glucuronidated in the liver and is then excreted in the bile

A direct correlation has been noted between mucosal damage and either low glucuronidation rates or increased intestinal beta-glucuronidase activity

Severe toxicity has been described with irinotecan in patients with Gilbert's syndrome who have defective hepatic glucuronidation

experimental studies have shown that inhibition of intestinal beta-glucuronidase activity with antibiotics protects against mucosal injury and ameliorates the diarrhea

Clinical manifestations

can be debilitating and in some cases, life-threatening.

Findings in such patients include volume depletion, renal insufficiency, and electrolyte disorders such as hypokalemia, metabolic acidosis, and depending upon water intake, hyponatremia (increased water intake that cannot be excreted because of the hypovolemic stimulus to the release of antidiuretic hormone) or hypernatremia (insufficient water intake to replace losses).

CID can also lead to treatment delays, increased cost of care, reduced quality of life, and diminished compliance with treatment regimens.

5-Fluorouracil 5-FU (and its oral derivatives capecitabine , cause diarrhea

Both the therapeutic efficacy and frequency of diarrhea associated with 5-FU are increased when given with leucovorin (LV).

The highest frequency of diarrhea occurs with bolus rather than continuous 24-hour infusion of 5-FU/LV for up to five days, particularly with weekly

administration,

but it occurs with all schedules

In multiple reports of weekly 5-FU/LV, diarrhea has been seen in up to 50 percent of patients, one-half of whom required hospitalization for

intravenous fluids

treatment is routinely withheld for > grade 2 diarrhea, an approach that has led to a significant reduction in severe enterotoxicity with these regimens

risk factor

the presence of an unresected primary tumor,

shortened bowel resulting from pervious surgery,

previous episodes of CID

, treatment during the summer season

bolus 5-FU and LV are combined with oxaliplatin

Women

Predictive markers• Because early detection of patients who are at risk of developing life-threatening

toxicity to 5-FU might allow dose reduction or selection of an alternative treatment regimen, various genotypic and phenotypic approaches have been undertaken to predict toxicity.

• None has proven to be sufficiently reliable to be adopted in routine clinical care.• Dihydropyrimidine dehydrogenase (DPD), the first of three enzymes in the

fluoropyrimidine metabolic pathway, is the rate limiting enzyme in 5-FU catabolism

• Patients who are partially or totally deficient in DPD activity cannot adequately degrade fluoropyrimidines, leading to an increased risk of severe, sometimes fatal toxicity.

• In patients with even partial DPD deficiency, administration of a fluoropyrimidine can lead to life-threatening complications, including severe diarrhea, mucositis, and pancytopenia

Capecitabine

oral fluoropyrimidine that is converted to 5-FU in three sequential enzymatic reactions.

The dose-limiting toxicities are diarrhea, palmar-plantar erythrodysesthesia, and neutropenia.

Like 5-FU, capecitabine is contraindicated in patients with known DPD deficiency.

The initially approved dose for treatment of metastatic breast and colorectal cancer was 2500 mg/m 2 per day for 14 of every 21 days, but later studies suggest that this

dose is too high, particularly in American patients.

Lower doses (beginning at 2000 mg/m 2 per day for 14 of every 21 days) may improve the therapeutic index without compromising efficacy.

Irinotecan

•often accompanied by other symptoms of cholinergic excess, including abdominal cramping, rhinitis, lacrimation, and salivation.

•The mean duration of symptoms is 30 minutes;• it is usually well controlled by subcutaneous or IV atropine Early-

onset • unpredictable, noncumulative, and occurs at all dose leve•late diarrhea and neutropenia were the main dose-limiting toxicities Late

diarrheaDiarrhea of any grade was seen in 50 to 88 percent of patients and it was severe in 9 to 31 percent.Diarrhea has been less common in later studies because of the stricter adherence to management guidelines (including routine early institution of high-dose loperamide

• The median time to onset is about six days with the 350 mg/m 2 every three weeks schedule

• 11 days with the weekly schedule (125 mg/m 2 )

• Late diarrhea is less common with the every three week schedul

Treatment

• nonpharmacologic and pharmacologic interventions• Initial nonpharmacologic measures include avoidance of foods

that would aggravate the diarrhea and aggressive oral rehydration with fluids that contain water, salt, and sugar (since glucose promotes intestinal sodium absorption)

• The mainstay of the drug therapy of CID is the opiates. Loperamide (Imodium) and diphenoxylate (Lomotil) are the most commonly used, and both are FDA-approved for this indication.

• Both give a rapid onset of action. • Loperamide appears to be more effective and has been

recommended in treatment guidelines

• The standard dose of loperamide is an initial 4 mg dose followed by 2 mg every four hours or after every loose stool. This regimen is only moderately effective in CID

• more aggressive regimen (4 mg initially, then 2 mg every two hours or 4 mg every four hours until diarrhea-free for 12 hours) is often required, particularly for irinotecan -induced diarrhea

Octreotide: a synthetic long-acting somatostatin analog, acts via several mechanisms

decreased secretion of a number of hormones, such as vasoactive intestinal peptide (VIP);

prolongation of intestinal transit time’

reduced secretion

increased absorption of fluid and electrolytes

It is approved by the Food and Drug Administration for the treatment of diarrhea related to VIP-secreting tumors and symptoms due to carcinoid syndrome.

Octreotide is also beneficial in patients with CID from fluoropyrimidines, irinotecan , and 5-FU-based chemoradiotherapy

although the optimal dose has not been determined

Although one randomized trial in 41 5-FU-treated patients showed that octreotide was more effective than standard-dose loperamide (90 versus 15 percent resolution of diarrhea by day 3)

octreotide is generally reserved as a second-line therapy for patients who do not respond to high dose loperamide because of its high cost and the general effectiveness of loperamide,

The recommended starting dose of octreotide is 100 to 150 microg subcutaneously, three times a day

However, several reports suggest that higher doses (500 microg) may be more effective

The available data support upward titration of the dose (up to 2500 microg three times daily) in nonresponders

The side effects of octreotide are generally mild, including bloating, cramping, flatulence and fat malabsorption. Hypersensitivity-like reactions and hypoglycemia can occur at higher doses.

Other antidiarrheal agents

Anticholinergic drugs are not commonly used because of side

effects. However, they can be helpful when diarrhea is associated

with significant cramping.

Absorbents (eg, pectin, aluminum hydroxide ) and adsorbents (eg,

kaolin, charcoal) bind osmotically active substances and can be

effective adjunctive therapy in patients with mild diarrhea.

Prevention and treatment of chemotherapy-induced nausea and

vomiting

Three distinct types of CINV have been defined

Acute emesis, which most commonly begins within one to two hours of chemotherapy and

usually peaks in the first four to six hours

Delayed emesis, occurring more than 24 hours after chemotherapy

Anticipatory emesis, occurring prior to treatment as a conditioned response in patients

who have developed significant nausea and vomiting during previous cycles of chemotherapy

CHEMOTHERAPY DRUG EMETOGENICITY

Highly emetic — >90 percent risk of emesis

Moderately emetic — >30 to 90 percent risk of emesis

Low emetogenicity— 10 to 30 percent risk of emesis

Minimally emetic — <10 percent risk of emesis

For combination regimens, the emetic level is determined by identifying the most emetic agent in the combination and then assessing the relative contribution of the other agents.

As an example, cyclophosphamide and doxorubicin are both moderately emetogenic agents, but when given together, the regimen is highly emetic

5-HT3 receptor antagonists A key advance in the prevention of CINV was the development of selective type three 5-hydroxytryptamine (5-HT3) receptor antagonists, a drug class

that has a high therapeutic index for prevention of CINV

single-agent 5-HT3 receptor antagonists are more effective than less specific agents such as high-dose metoclopramide

and as effective as the combination of high-dose metoclopramide and dexamethasone .

When 5-HT3 antagonists are used in combination with dexamethasone, they are more effective than high-dose metoclopramide plus dexamethasone

In addition to increased efficacy, these agents are easier to administer and are associated with significantly fewer serious side effects than the less

specific serotonin inhibitor metoclopramide

• dolasetron , granisetron , ondansetron , and tropisetron first-generation

• palonosetron second-generation

First generation agents

The first-generation 5-HT3 receptor antagonists all appear equally effective at preventing CINV at the recommended doses. At least two meta-analyses have shown no clear advantage for either ondansetron or granisetron in the prophylaxis of acute or delayed emesis

There is a plateau in therapeutic efficacy at a definable dose level for each drug, and further dose escalation does not improve outcome [ 14 ].

A single dose of a 5-HT3 receptor antagonist prior to chemotherapy is therapeutically equivalent to a multiple dose schedule [ 15-19 ].

The efficacy of 5-HT3 receptor antagonists is significantly improved when they are combined with glucocorticoids.

Oral formulations of these agents are as effective as intravenous formulations

EKG interval changes and cardiac arrhythmias

EKG interval changes are a class effect of the first-generation 5-HT3 antagonists, including ondansetron , granisetron and dolasetron ,

although they have not been reported with transdermal granisetron

EKG interval changes appear to be most prominent one to two hours after a dose of these agents, are mostly small and clinically insignificant, and return

to baseline within 24 hours

However, potentially fatal cardiac arrhythmias, including torsade to pointes, have been reported in association with QTc prolongation [ 23,25-27 ]. The

following sections describe the warnings/precautions regarding cardiotoxicity of these agents from the US FDA.

Ondansetron FDA has issued a warning about QTc prolongation and potentially fatal

cardiac arrhythmias

QT prolongation occurs in a dose-dependent manner and specifically at a single IV dose of 32 mg.

Revised labeling includes a recommendation to limit single IV doses to no more than 16 mg,

avoid use of ondansetron in patients with congenital long-QT syndrome, and to use ECG monitoring in certain patients, including those with

hypokalemia or hypomagnesemia, heart failure, bradyarrhythmias, and in patients taking other medications that increase the risk of QTc

prolongation

Neurokinin-1 receptor antagonists

The introduction of the NK1 receptor (NK1R) antagonists aprepitant and fosaprepitant (a parenteral water-soluble prodrug of aprepitant that is effective as a one-day treatmen

have significantly improved the ability to prevent both acute and delayed CINV in patients receiving highly and moderately emetic chemotherapy

he benefit of combining an NK1R antagonist ( aprepitant , fosaprepitant , or casopitant) with an 5-HT3 receptor antagonist plus a glucocorticoid for the prevention of acute CINV was addressed in a meta-analysis of 17 trials, totaling 8740 patients who were receiving

highly or moderately emetogenic chemotherapy

Need for a 5-HT3 agent

Aprepitant and fosaprepitant improve control of CINV when combined with a 5-HT3 receptor antagonist and dexamethasone .

Aprepitant plus dexamethasone alone is not as effective as the three-drug combination regimen.

A 5-HT3 receptor antagonist remains necessary, at least in patients receiving cisplatin -based chemotherapy.

One versus three-day administration

In the United States, both aprepitant and fosaprepitant are approved for use in three-

day schedules.

Issues related to inhibition of CYP3A4

NK1 receptor antagonists such as aprepitant and fosaprepitant are moderate inhibitors of the cytochrome P450 enzyme CYP3A4, which

is particularly important in drug metabolism

CYP3A4 is responsible for the metabolism of glucocorticoids, and thus the dose of dexamethasone was reduced in clinical trials from 20 mg to 12 mg on day 1 and from 8 mg twice daily to 8 mg daily on

days 2 and 3 when given concurrently with aprepitant

This dose reduction applies only when glucocorticoids are used as antiemetics in conjunction with NK1 receptor antagonists, not when

given as an antitumor component of a chemotherapy regimen

Glucocorticoids

Short courses of glucocorticoids are widely used both as single agents for regimens with low risk of causing

CINV

and in combination with 5-HT3 receptor inhibitors and/or NK1 receptor antagonists for more emetic

chemotherapy regimens.

. Although the various glucocorticoids are probably equally effective when used at an appropriate dose,

dexamethasone has been the most extensively evaluated and is the most widely used.

Combination with a 5-HT3 antagonist

• Glucocorticoids alone represent insufficient first-line therapy for patients receiving either moderate or highly emetic chemotherapy agents. However, the antiemetic efficacy of the 5-HT3 receptor antagonists is significantly enhanced by the addition of a glucocorticoid

DoseThe optimal dose of dexamethasone for highly to moderately emetic chemotherapy not containing cisplatin was evaluated by the Italian

Group for Antiemetic Research [ 52 ]. In this trial, all patients received IV ondansetron and were randomized to one of three schedules of

dexamethasone following chemotherapy (either 8 or 24 mg IV prior to chemotherapy, or 8 mg IV before treatment followed by 4 mg every six

hours). Rates of complete protection from acute or delayed emesis were similar among the groups, and the authors concluded that a

single 8 mg IV dose prior to chemotherapy represented the appropriate dexamethasone regimen.

the dose of dexamethasone is reduced when it is in combination with an NK1 receptor antagonist

Alopecia• Is usually temporary, and the degree of hair loss varies widely.

• Loss of hair is not limited to the scalp; any area of the body may be affected.

• Patients receiving a Taxane as part of their chemotherapy regimen are especially prone to total body alopecia.

• Hair loss usually begins 1 to 2 weeks after chemotherapy, and regrowth may begin before the chemotherapy courses are completed

Single Agents Associated With AlopeciaFrequent Occasional

Cyclophosphamide MechlorethamineIfosfamide Thiotepa

Fluorouracil Methotrexate

Dactinomycin Vinblastine

Daunorubicin Vincristine

Doxorubicin Etoposide

Bleomycin Carmustine

Vindesine Hydroxyurea

Paclitaxel Cytarabine

Irinotecan Topotecan

Epirubicin Gemcitabine

Docetaxel Erlotinib

Etoposide Sorafenib

Mitoxantrone

Nail Changes

• A reduction or a cessation of mitotic activity in the nail matrix causes a horizontal depression of the nail plate.

• Within weeks, these pale horizontal lines (“Beau's lines”) begin to appear in the nail beds.

• They are most commonly seen in patients receiving chemotherapy for >6 months.

Nail changes• Nail changes including Hemorrhagic onycholysis,

Discoloration, and Acute exudative paronychia are seen in ~40% of patients receiving Paclitaxel and Docetaxel

• Brown or blue lines deposit as horizontal or vertical bands in the nails.

• These lines are seen more commonly in dark-skinned patients.

• As with Beau's lines, these pigmentation lines generally grow out with the nail

Beau's lines

Acral Erythema

Hand-foot Syndrome Mechanism:

Direct toxic effect, accumulating in acral sites• Clinical:

• Prodrome of dysesthesia• 2-4 days later: pain, edema, well-demarcated erythema

beginning on lateral borders• Significant desquamation

• Hands > feet• Bullous variant (cytarabine, methotrexate)

Acral Erythema

• Agents reported to cause this reaction include:

• Cytarabine, Fluorouracil, Doxorubicin,

Lipsomal Doxorubicin, Methotrexate, Capecitabine, And Hydroxyurea

Acral Erythema