GI tract toxicities

associated chemotherapy

Sun Yang, BsPharm, Ph.D, BCPPS, APh.Department of Pharmacy Practice

Chapman University School of Pharmacy

Complications of the GI tract

• Nausea and vomiting• Cisplatin and many others

• Xerostomia/dry mouth• Radiation

• Stomatitis/mucositis/esophagitis• Methotrexate, 5-FU• High-dose regimen

• Diarrhea• 5-FU• Irinotecan

• Constipation• vincristine

Xerostomia (dry mouth)

• Neil is a 55-year-old man with newly diagnosed, locally advanced head and neck cancer. His planned therapy includes cisplatin and fluorouracil given with concurrent radiation for a total of 6 weeks after surgical resection.

• PMH: poor mouth hygiene, and a decision is made to consult the dental department before initiating radiation and chemotherapy.

Question:• Is he at risk for developing oral complications?

Xerostomia

• Radiation therapy for Head/neck cancer• One of the most frequent side effects• Occurs secondary to radiation-induced changes/damage to the salivary glands

• Dose-dependent• <6000 rad, reversible within 6-12 mo after end of therapy• As little as two to three radiation doses of 200 rad.

• Dose-limiting toxicity• Loss of salivary buffering capacity, lower salivary pH, reduced secretion of IgA,

reduction of saliva production• Alter the sense of taste

• N/V, poor nutrition• Cause caries

• Caries and decalcification may become sufficiently severe to compromise tooth integrity• Increase oral bacteria increase infection risk

• Fungi/Bacteria/Virus

Xerostomia management

• Prevention• Amifostine (Ethyol)

• Prodrug to free thiol: free radical scavenger• ASCO guideline:

• both acute and late xerostomia in H&N cancer pts.

• MOA: Organic thiophosphate• Approved to reduce the incidence of

moderate to severe xerostomia in pts having RT for H&N cancer

• Dose: 200 mg/m2 or 500mg IV prior to RT• Reduce incidence ~30%• 3-mins IV infusion 15-30 mins before each

fraction of radiation• Limitations

• Expensive/adverse effect profile/not 100%• IV: N/V and hypotension• SubQ: less N/V and hypotension but

increase infusion site reactions.

• Treatment• Pilocarpine

• 5-10mg PO TID• Cholinergic effect increase salivary

flow

• Artificial saliva substitutes (spray, rinse, chewing gums)

• Oral comfort agents• Sucrose-free hard candy/chewing gum

• Prevention of radiation-induced caries

• Aggressively using fluorides (acidulated fluorides)

• Rinse daily for 1 min with 5-10 ml of a fluoride rinse.

• Oral hygiene with regular dental checkups and avoidance of sucrose

Mucositis/Stomatitis

• Neil successfully completed his first two weeks of combined chemotherapy and radiation therapy; however, 3 days into his third week, he complains of generalized burning, discomfort, and pain on the ventral surface of his tongue.

• On clinical observation, both the ventral surface of his tongue and the floor of his mouth appear erythematous and several discrete lesions are present in both areas.

Therapy-related stomatitis or oral mucositis.

Mucositis/stomatitis

• Non-specific effect of chemoTx and RT on basal epithelium of mouth• Non-keratinized mucosa

• Symptoms• Lesions are discrete initiallymay progress to ulceration; • May extend to esophagus, entire GI tract.• Occurs ~5-7 days after chemoTx or at almost any point during radiation therapy• Regress and resolve completely in ~1-3 weeks depending on severity.

• Cause• Antimetabolites (MTX, 5-FU, cytarabine)• Antitumor antibiotics• High dose chemotherapy• Allogeneic BMT (GVHD)

Mucositis/Stomatitis

• Prevention• Avoid mouthwashes or rinses that contain alcohol because they may be

painful and cause drying of the mucosa.• Active rinse with mouthwashes• Sodium bicarbonate rinse, saline rinse, before eating and drinking

• Cryotherapy (chew on ice before high dose melphalan)• Marginal effect• Reduce blood flow to the mouth

• Paliformin• Kapivance, keratinocyte growth factor• Approved for autologous BMT patients to reduce the incidence and duration of

severe oral mucositis.• 60mg/kg/day IV starting -3+2 of transplant

Mucositis/Stomatitis-Treatment

• Palliative care (=control symptoms)• Topical/local anesthetics for localized pain control

• Opioid: control pain associated with severe mucositis• Acetaminophen: AVOID!! As it may mask the fevers in neutropenic patients• Ibuprofen: AVOID!! As it may cause more bleeding in pts with thrombocytopenia

• Kaolin, Benadryl, antiacids, antihistamine• Mouthwashes

• Biotene oral rinse• Chlorhexidine: reduce infection; pain• “Swish & Spit” or “Swish & swallow”

• Gelclair, sucralfate-adherent barrier over mucosa• Caphosol (Supersaturated Ca phosphate)• TPN if enteral nutrition is severely compromised

MTX and mucositis• When MTX >500 mg

• Severe BM suppression and mucositis unless rescued by leucovorin

• Calcium leucovorin is a reduced folate which can• Replenish the folate pool depleted by MTX; DNA synthesis restart even in

presence of MTX• Rescue after high-dose MTX

• Begin 24-36hrs after initiation of MTX• May stop when [MTX] < 5x 10-8 M (0.05 µM) @ 72 hrs (or 0.01 µM)• Starting dose: 10-15 mg/m2 IV and titrated according to MTX levels

• Precaution: if pt presents ascites or third space fluid collection• Prolonged excretion and increased toxicity of MTX• May increase leucovorin dose and prolong leucovorin treatment

MTX levels: Why and When?

• Predict toxicity and helps to adjust the rescue dose of leucovorin• MTX levels at 24hr, 48 hr, and 72 hr after MTX started

• If [MTX]48 1. < 1x10-6 M (1µM), then continue leucovorin 10-15mg/m2 q6h x 8 doses, IV2. > 1x10-6 M (1µM), then increase leucovorin to 50-100mg/m2 q6h x 8 doses

IV until it falls below 1x10-6 M (1µM), then follow option #1

• Concurrent urinary alkalinization and hydration• Increase elimination from kidney• Nephrotoxicity

µM=5x 10-8M

• Depending on the time of sampling• 24 hr; 48 hr; 72 hr

Lower GI tract complications

• Mal-absorption, diarrhea, and constipation• Related to structural changes after the therapy

• Diarrhea• Irinotecan• High dose of cytarabine• Fluorouracil

• Constipation• Vinca alkaloids

• Autonomic nerve dysfunction constipation• Should be treated prophylactically with stool softeners and mild stimulants.

ChemoTx-induced diarrhea patient case

Jessy, a 60-year-old woman with recurrent colon cancer refractory to FOLFOX regimen, is beginning her first course of cetuximab and irinotecan in the morning.At night, you were called by the resident for medication to manage her diarrhea and abdominal cramping.

Irinotecan (Camptosar)

• Indication• First line treatment of metastatic colorectal cancer in combination with 5-

FU/LV +/- bevacizumab• Single agent second line treatment after failure of 5-FU based chemotherapy

• Topoisomerase I inhibitor- irreversible DNA double strand breakage • ChemoTx regimen

• FOLFIRI (for colorectal cancer)• Irinotecan 180mg/m2 IV day 1• LV 400mg/m2 IV day 1• 5-FU 400mg/m2 IVP, then 2400 mg/m2 cont. IV infusion over 46 hours• Cycle repeat every 2 weeks

• Plus bevacizumab 5mg/kg IV day 1

Irinotecan Side effects

• General• Myelosuppression (dose-limiting)

• Neutropenia (risk increase in pts with prior history of radiation to abdomen or pelvic)• Monitor CBC w/differential, plt, ANC

• N&V• ? Emetogenic risk

• Monitor liver function test• If absence of liver metastases, dose adjustment in liver impairment

Irinotecan Tx associated diarrhea- Early onset

• Para sympathetic stimulation:• Cholinergic reaction

• Occurs within 24 hours of Tx• Presentation: flushing, diaphoresis, abdominal cramping/pain,

diarrhea• Treatment

• Atropine 0.25mg to 1 mg IV bolus (30 mins before chemoTx); pre-emptive Tx• Monitoring HR/ADRs

Irinotecan Tx associated diarrhea- Late onset• Dose-limiting toxicity• Caused by direct irritation of GI mucosa by active metabolite SN-38

• Occurs about 24 hours following treatment (typically 3-10 days)

• Can be severe and prolonged• Can lead to dehydration/malnutrition/electrolytes imbalance

• Lab monitoring• Renal function• K+/Mg2+/Na+/Cl-

Irinotecan Tx associated diarrhea- Late onset diarrhea• Loperamide

• 4 mg PO loading dose, followed by 2mg PO every 2 hours around the clock

OR• 4mg PO every 4 hours around the clock• Continue until diarrhea-free for 12 hours• If persists >24 hours and no improvement

with medication treatmentER or call the oncologist STAT• Pharmacist:

• Education: diet/fluids• Prepare the medication• OTC max dosing=16mg

• Octreotide• Somatostatin analog:

• antisecretory activity in the gut• promotes the absorption of sodium,

chloride and water from luminal content.• SubQ injection:

• 100-2000 mcg SubQ TID• 20-40 mg long-acting octreotide

Based on current evidence, should be limited to second-line therapy for chemoTx-associated diarrhea.

Irinotecan Tx associated diarrhea- PharmGx

• Pharmacogenetic studies• Increased neutropenia risk in patients with reduced activity in the drug-

metabolizing enzyme UGT1A1• Responsible for metabolism of bilirubin and SN-38 to inactive metabolites

• PharmGKB: UGT1A1*28/*28 allele• Decrease in SN-38 inactivation higher concentration in serum increase toxicity• High risk of developing severe neutropenia when receiving irinotecan

Neurotoxicity associated with Chemotherapy

Sun Yang, BsPharm, Ph.D, BCPPS, Aph.Department of Pharmacy Practice

Chapman University School of Pharmacy

Neurologic toxicities• Radiation to brain

• Tumor invaded to brain

• Intrathecal, direct instillation into CNS• Small dose methotrexate or cytarabine• Liposomal cytarabine• Cause chemical arachnoid itis

• High dose diffuse from BBB into CNS• Methotrexate• Cytarabine: cerebellar toxicity• Ifosfamide: encephalopathy• Busulfan-induced seizure in bone marrow transplant

MTX-associated neurotoxicities

Ifosfamide-associated neuro-toxicities

Vincristine- and Platinum-associated peripheral neuropathy

MTX-neurotoxicities

• The manifestations of MTX neurotoxicity are largely determined by its dose and route of administration

1. Cause little or no neurotoxicity when administered orally or IV in doses < 1000 mg/m2

2. High dose of IV MTX (≥ 1000 mg/m2): • Diffuse through BBB• Acute, sub-acute, or chronic neurotoxicity

• Transient and reversible• Renal function, hydration, alkalinization of urine• Leucovorin rescue• Co-administration of other antineoplastic agents

MTX-neurotoxicities

3. IT MTX: Aseptic meningitis: • Most commonly neurotoxic effect of IT MTX• 10-50%• Headache, back pain, N/V, fever and lethargy.• Usually, 2-4 hrs after the drug injected, then may last for 12-72 hrs. • CSF analysis:

• Pleocytosis with elevated protein content• Culture negative

• Symptoms are self-limited and treatment is NOT required. But if the headache and stiff neck are severe, a short course of corticosteroids may be helpful.

• Co-administering MTX with IT hydrocortisone or oral corticosteroids may prevent

MTX-neurotoxicities

4. Leukoencephalopathy• Delayed complication, after 6 months of MTX Tx and when

cumulative IT dose>140mg, concurrent whole-brain radiotherapy• MOA: Cranial irradiation either potentiates the toxic effects of MTX or

disrupts the BBB, allowing high-concentration of MTX to reach the brain.• Clinical feature

• A gradual impairment of cognitive function months to years following treatment with MTX

• Ranging from mild learning disability to severe progressive dementia accompanied by somnolence, seizures, ataxia, and hemiparesis.

Patient AB

AB is a 35-years old male newly diagnosed non-Hodgkin’s lymphoma (NHL). CSF positive for malignant cells indicating metastasis in CNS.Sig: MTX 12 mg + Hydrocortisone 25 mg, IT q week

How to prepare the medication?MTX/Hydrocortisone:

Preservative FreeDilutionFilter through 0.22um filterIT labelSyringe

Management of accidental overdose of IT MTX

• Significant overdosing of IT MTX, particularly a dose > 500 mg compared with the usual dose of 10 to 12 mg, must be treated vigorously since it can lead to acute myelopathy, encephalopathy, seizures, and death.

• Combination therapy• IT glucarpidase (carboxypeptidase G2) to metabolize the MTX• Rapid CSF drainage by lumbar puncture, CSF exchange, ventriculolumbar

perfusion to reduce the amount of MTX in the CSF• Systemic leucovorin rescue• Alkaline diuresis• Dexamethasone (4mg q6hrs x 4 doses)

MTX-associated neurotoxicities

Ifosfamide-associated neurotoxicities

Vincristine- and Platinum-associated peripheral neuropathy

Ifosfamide-induced encephalopathy

• MOA• Metabolite: Chloroacetaldehyde, CYP3A4• Depletion of glutathione in CNS

• Incidence: 10-20%, within 12 hrs, up to 6 days after start• Risk factors

• History of ifosfamide-induced encephalopathy• High dose, bolus IV dose• Renal dysfunction• Low serum albumin• Bulky abdominal disease (especially bulky pelvic disease)

• Presents hours to days after initiation of treatment with confusion and disorientation

Ifosfamide-induced encephalopathy

• Albumin: hypertonic solution• Chloroacetaldehyde is highly protein

bound; • Lower albumin increased free

chloroacetalde hyde cross into CNS

• Thiamine• Anticonvulsant activity

• Thiamine deficiency cause inhibition of ATP synthesis and abnormal carbohydrate metabolism, which can cause altered cerebral energy metabolism and altered nerve conduction.

• Methylene blue• Use as treatment and prophylaxis• MOA:

• Acts as an electron acceptor, which decreases flavoprotein inhibition caused by chlorethylamine, thereby corrects mitochondrial respiration.

• Inhibit the formation of chloracetaldehyde by inhibit extrahepatic monoamine oxidases.

• 50 mg IV TID• SEs: Blue-green discoloration of skin, urine,

stool, N/V, headache, hemolysis• DDIs: SSRIs, SNRIs, MAOs.

MTX-associated neuro-toxicities

Ifosfamide-associated neuro-toxicities

Vincristine- and Platinum-associated peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN)• Agents

• Platinum, taxanes, vincas, anti-myeloma agents (thalidomide, lenalidomide)• MOA

• Peripheral, motor and sensory neuron damage• Neurotoxins inactivate the components required to maintain the metabolic needs of

axons• An extension of anti-tumor effects

• Platinum-DNA adduct formation in dorsal root ganglia

• Risk factors• Cumulative dose• Old age• Female• Diabetic neuropathy• Vitamin B deficiency

Glove-and-Stocking neuropathy

Peripheral Neuropathy-Vincristine

• Vinca alkaloids; Principal toxicities• Vincristine: constipation and neurotoxicity• Vinblastine/Vinorelbine: neutropenia

• Vincristine-associated neurotoxicity• Cranial nerve damage

• Trigeminal nerve palsy• Eyelid lag, jaw pain, hoarseness

• Peripheral neuropathy• Autonomic (30-50%)

• Constipation, urinary retention, orthostatic hypotension• Few days post vincristine Tx• Routine prevention with laxatives

Peripheral Neuropathy-Vincristine• Presentation

• Paresthesia (numbness and tingling) is an early subjective symptom of Vincristine/Vinblastine neurotoxicity

• involving the feet and hands (or both)• happens within the first days to weeks of therapy

• Loss of deep tendon reflexes w continued tx• Symptoms usually bilateral and symmetric

• Paresthesia: • Pain and temperature sensory loss >> vibration and proprioception sensory loss

• Loss of ankle jerks• Depression of deep tendon reflexes• Areflexia (absent reflexes): 50-70% of patients treated with a cumulative dose > 6-8mg• Motor weakness with a foot drop or muscle atrophy

• Elder more susceptible• Exacerbated by COLD exposure• Either partially or completely reversible, but recovery often takes several months.

Sensory Peripheral neuropathy-platinums

• Cisplatin > Oxaliplatin > Carboplatin• 50-100% patients• Acute, reversible, occurring within hours or 1-2 days, resolve within

14 days and recurrence with further dosing• 50% seen in 300-600 mg/m2 cumulative dose (cisplatin)

• Persistent (> 14 days)• Stocking-and-glove distribution

• Burning pain in toes/fingers, progress to ankles and arms• Often reversible, may take months or years to recover.

Patient Case

AB is a 24-years old male with diabetes and testicular cancer receiving ifosfamide, mesna, etoposide, and cisplatin (VIP).He has Hx of ALL when he was 10 years old, received intensive chemotherapy with prophylactic cranial irradiation.

• Etoposide IV 75 mg/m2/day days 1-5• Ifosfamide IV 1200 mg/m2/day days 1-5• Cisplatin IV 20 mg/m2/day days 1-5• Mesna IV 120 mg/m2 prior to ifosfamide day 1

Today’s lab: ANC=450, Scr=1.8, albumin=2.7

Which risk factors most likely put AB at risk of ifosfamide-induced neurotoxicity?

Peripheral Neuropathy Management

• Proposed protectants• Vincristine:

• Max 2 mg/course;• Limit <6-8 mg cumulative

• Amifostine, vitamin E, Ca/Mg infusion pre oxaliplatin, N-acetylcysteine, gabapentin

• No standard, evidence-based Tx available• Provide personal safety measures to prevent burns, falls• Avoid cold food/beverages; keep warm

• Busulfan-induced seizure• Alkylator toxic to stem cells and

myeloid cells• High dose in bone marrow ablation

prior to transplant• Extensive liver metabolism

• Good CNS penetration induce seizure

• Phenytoin or Keppra prophylaxis required!!!

Other neuro-toxicities

• Neurotoxicity from high-dose cytarabine

• Cerebral: generalized encephalopathy, seizures

• Cerebellar toxicity: problem with balance

• With dose> 3000mg/m2, multiple doses

• Finger-to-nose, tremor, shin-scrape prior to each dose administration

• If abnormal, hold dose and call MD• Chemical conjunctivitis

• Tearing, burning, pruritis• Methylprednisolone 1% eye gtt OU qid

Patient Case

AB, a 39-year-old woman with acute lymphocytic leukemia, has been admitted to the hospital for induction chemotherapy.

• Methotrexate 3 g/m2 IV once on day 1• Cytarabine 2g/m2 IV every 12 hours on days 2 and 3 for four doses• Dexamethasone 20 mg orally daily for 5 days

Laboratory data obtained on admission include a WBC count of 120,000 cells/µl, with 9% neutrophils, 11% lymphocytes, and 80% blasts. On day 2, she complains of numbness in her hands and feet during morning ward round.

Patient Case

AB, a 39-year old woman with acute lymphocytic leukemia, has been admitted to the hospital for induction chemotherapy.

• Methotraxate 3g/m2 IV once on day 1• Cytarabine 2g/m2 IV every 12 hours on days 2 and 3 for four doses• Dexamethasone 20 mg orally daily for 5 days

Laboratory data obtained on admission include a WBC count of 120,000 cells/µl, with 9% neutrophils, 11% lymphocytes, and 80% blasts. On day 3, she complains of numbness in her hands and feet. On day 10, during the ward round, you noticed that AB was confused and had difficult performing a finger-to-nose neurologic examination. In addition, oncologist also noted an eyelid lag and ataxia. AB also complains of severe constipation over the past 48 hours.