Chapter 9: Colorectal Cancer

Epidemiology

Five-Year Survival

Work-up

Pathology

World Health Organization Classification

1. Adenocarcinoma (>90%)

2. Mucinous adenocarcinoma

3. Adenosquamous carcinoma

4. Small cell carcinoma

5. Medullary carcinoma

6. Signet ring adenocarcinoma

7. Squamous cell carcinoma

8. Undifferentiated

Skibber JM et al. Cancer of the colon. In: Devita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2001:1216–1270

Staging

Adjuvant and Advanced Regimen: Bolus Fluorouracil + Leucovorin (Roswell Park Regimen)

Petrelli N et al. J Clin Oncol 1989;7:1419–1426

Wolmark N et al. J Clin Oncol 1999;17:3553–3559

Adjuvant therapy:

Leucovorin calcium 500 mg/m²; administer intravenously in 250 mL 0.9% sodium chloride injection (0.9% NS) over 2 hours once per week for 6 consecutive weeks (weeks 1–6), every 8 weeks (total dosage/cycle = 3000 mg/m²)

Fluorouracil 500 mg/m²; administer by intravenous injection over 1–2 minutes, starting 1 hour after leucovorin once per week for 6 consecutive weeks (weeks 1–6), every 8 weeks (total dosage/cycle = 3000 mg/m²)

Advanced colorectal cancer:

Leucovorin calcium 500 mg/m²; administer intravenously in 250 mL 0.9% NS over 2 hours once per week for 6 consecutive weeks (weeks 1–6), every 8 weeks (total dosage/cycle = 3000 mg/m²)

Fluorouracil 600 mg/m²; administer by intravenous injection over 1–2 minutes, starting 1 hour after leucovorin once per week for 6 consecutive weeks (weeks 1–6), every 8 weeks (total dosage/cycle = 3600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Treatment Modifications

Patient Population Studied

Patients with stage II (Dukes B) or III (Dukes C) colorectal cancer after potentially curative resection (duration of therapy was 4 cycles). Now, the standard regimen as adjuvant therapy is FOLFOX-4, 6 months For advanced disease this regimen has to be considered for special cases (old patients . . .)

Wolmark N et al. J Clin Oncol 1999;17:3553–3559

Efficacy (N = 691)

Toxicity (N = 691)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA, serum electrolytes, creatinine, BUN, and LFTs

2. Every 2–3 months: CT scans to assess cancer status in patients presenting with advanced colorectal cancer

Adjuvant and Advanced Regimen: Bolus Fluorouracil

Francini G et al. Gastroenterology 1994;106:899–906

Poon MA et al. J Clin Oncol 1989;7:1407–1418

Van Cutsem E et al. J Clin Oncol 2001;19:4097–4106

Leucovorin calcium 20 mg/m² per day; administer by intravenous injection over 30 seconds on 5 consecutive days, given on days 1–5, every 4 weeks, for 6 cycles (total dosage/cycle = 100 mg/m²)

Fluorouracil 425 mg/m² per day; administer by intravenous injection over 1–2 minutes after leucovorin on 5 consecutive days, given on days 1–5, every 4 weeks, for 6 cycles (total dosage/cycle = 2125 mg/m²)

or

Leucovorin calcium 200 mg/m² per day; administer by intravenous injection at a rate <160 mg/minute on 5 consecutive days, given on days 1–5, every 4 weeks, for 6 cycles (total dosage/cycle = 1000 mg/m²)

Fluorouracil 400 mg/m² per day; administer by intravenous injection over 1–2 minutes after leucovorin on 5 consecutive days, given on days 1–5, every 4 weeks, for 6 cycles (total dosage/cycle = 2000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

• Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Treatment Modifications

Patient Population Studied

Patients with stage II or III colorectal cancer after potentially curative resection, or with advanced colorectal cancer.

Efficacy (N = 301)

Toxicity (N = 299)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA, serum electrolytes, creatinine, BUN, and LFTs

2. Every 2-3 months: CT scans to assess cancer status

Adjuvant and Advanced Regimen: Capecitabine

Twelves C et al. N Engl J Med 2005;352:2696–2704

Van Cutsem E et al. J Clin Oncol 2001;19:4097–4106

Capecitabine 1250 mg/m² per dose; administer orally with water within 30 minutes after a meal twice daily for 28 doses on days 1–14, every 3 weeks (total dosage/cycle = 35,000 mg/m²)

Notes:

• Capecitabine is given for 2 consecutive weeks followed by 1 week without treatment

• Doses are rounded down to approximate a calculated dose using combinations of 500-mg and 150-mg tablets

• In practice, treatment often is begun with capecitabine 1000 mg/m² per dose twice daily for 28 doses on days 1–14 (total dosage/cycle = 28,000 mg/m²). Dosage may be increased during subsequent cycles if initial treatment at a lesser dosage is tolerated

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Treatment Modifications

Patient Population Studied

Patients receiving first-line treatment for metastatic colorectal cancer and adjuvant therapy for early stage colorectal cancer. Equivalent to bolus fluorouracil 1 leucovorin. At present, the standard regimen for adjuvant therapy is FOLFOX-4 for six months

For advanced disease, this regimen should be considered for special cases; eg, elderly patients

Efficacy (N = 301)

Toxicity (N = 297)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA, serum electrolytes, creatinine, BUN, and LFTs

2. Every 2-3 months: CT scans to assess cancer status in patients presenting with advanced colorectal cancer

Metastatic Disease Regimen: Infusional Fluorouracil

Hansen RM et al. J Natl Cancer Inst 1996;88:668–674

Fluorouracil 300 mg/m² per day; administer by continuous intravenous infusion in 50–1000 mL 0.9% sodium chloride injection or 5% dextrose injection (total dosage/week = 2100 mg/m²). Treatment is continued indefinitely until toxicity/disease progression

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Patient Population Studied

A study of 159 patients with previously untreated metastatic adenocarcinoma of the colon or rectum

Toxicity (N = 159)

Treatment Modifications

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA serum electrolytes, and LFTs

2. Weekly: CBC with differential count

3. Every 2-3 months: CT scans to assess response

Efficacy (N = 159)

Metastatic Disease Regimen: Single-Agent Irinotecan (CPT-11)

Cunningham D et al. Lancet 1998;352:1413–1418

Irinotecan 350 mg/m²; administer intravenously over 90 minutes in 250 mL 5% dextrose injection (D5W) or 0.9% sodium Chloride injection (0.9% NS), on day 1, every 3 weeks (total dosage/cycle = 350 mg/m²)

Note: Reduce dosage to 300 mg/m² for patients ≥70 years of age or whose WHO performance status = 2 (total dosage/4-week cycle = 300 mg/m²)

Alternative

Pitot HC. Oncology 1998;12(8 Suppl 6):48–53

Irinotecan 100–125 mg/m²; administer intravenously over 90 minutes in 250 mL 0.9% NS or D5W every week for 4 consecutive weeks every 6 weeks (total dosage/cycle = 400–500 mg/m²)

Note: Four weeks of treatment followed by 2 weeks without treatment

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25 – 1 mg administer subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

• If symptoms are severe, add as primary prophylaxis at least 30 min before irinotecan during subsequent cycles

• For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Treatment Modifications

Toxicity (N = 183)

Patient Population Studied

A study of 189 patients with metastatic colorectal cancer with documented disease progression within 6 months of fluorouracil-based treatment

Efficacy (N = 189)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA, serum electrolytes, and LFTs

2. Weekly: CBC with differential count

3. Every 2-3 months: CT scans to assess response

Metastatic Disease Regimen: Irinotecan + Bolus Fluorouracil + Leucovorin (IFL)

Saltz LB et al. N Engl J Med 2000;343:905–914

Irinotecan 125 mg/m² per dose; administer intravenously in 250 mL 5% dextrose injection (D5W) over 90 minutes, given weekly for 4 consecutive weeks (4 doses), every 6 weeks (total dosage/cycle = 500 mg/m²)

Leucovorin calcium 20 mg/m² per dose; administer by intravenous injection over 30 seconds, given weekly for 4 consecutive weeks (4 doses), every 6 weeks (total dosage/cycle = 80 mg/m²)

Fluorouracil 500 mg/m² per dose; administer by intravenous injection over 1–2 minutes after leucovorin, given weekly for 4 consecutive weeks (4 doses), every 6 weeks (total dosage/cycle = 2000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25 – 1 mg administer subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

• If symptoms are severe, add as primary prophylaxis at least 30 min before irinotecan during subsequent cycles

• For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Treatment Modifications

Efficacy (N = 231)

Toxicity (N = 225)

Patient Population Studied

A study of 231 patients with metastatic colorectal cancer who had not previously received chemotherapy except adjuvant therapy that was completed more than 12 months before study entry. Patients had not previously received pelvic radiation

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA, serum electrolytes, and LFTs

2. Weekly: CBC with differential count and safety assessment

3. Every 6 weeks × 4 (24 weeks), then every 12 weeks: CT scans to assess response

Metastatic Disease Regimen: Leucovorin + Infusional Fluorouracil + Irinotecan (FOLFIRI)

Douillard JY et al. Lancet 2000;355:1041–1047

Tournigand C et al. J Clin Oncol 2004;22:229–237

Common to both alternative regimens (Douillard et al. and Tournigand et al.):

Irinotecan 180 mg/m²; administer intravenously over 90 minutes in 500 mL 5% dextrose injection (D5W) on day 1, every 2 weeks (total dosage/cycle = 180 mg/m²), plus one of the following alternative regimens:

Douillard et al. Lancet 2000;355:1041–1047

(Racemic) Leucovorin calcium 200 mg/m² per day; administer intravenously over 1 hour in 25–500 mL 0.9% sodium chloride injection (0.9% NS) or D5W for 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 400 mg/m²) followed by:

Fluorouracil 400 mg/m² per day; administer by intravenous injection over 1–2 minutes after leucovorin for 2 consecutive days, on days 1 and 2, every 2 weeks, followed by:

Fluorouracil 600 mg/m² per day; administer by continuous intravenous infusion over 22 hours in 100–1000 mL 0.9% NS or D5W for 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 2000 mg/m²)

or

Tournigand et al. J Clin Oncol 2004;22:229–237

Either: (racemic) Leucovorin calcium 400 mg/m² or levoleucovorin calcium 200 mg/m²; administer intravenously over 2 hours in 25–500 mL 0.9% NS or D5W on day 1, every 2 weeks (total dosage/cycle for racemic leucovorin = 400 mg/m², for levoleucovorin = 200 mg/m²), followed by:

Fluorouracil 400 mg/m²; administer by intravenous injection over 1–2 minutes after leucovorin on day 1, every 2 weeks, followed by:

Fluorouracil 2400 mg/m²; administer by continuous intravenous infusion over 46 hours in 100–1000 mL 0.9% NS or D5W, starting on day 1 every 2 weeks (total dosage/cycle = 2800 mg/m²)

• Infusional fluorouracil dosage may be increased to 3000 mg/m² by continuous intravenous infusion over 46 hours, starting on cycle 3, day 1, and repeated every 2 weeks in patients who do not develop adverse effects G >1 during the first 2 cycles (total dosage/cycle = 3400 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE

Emetogenic potential on day 2 is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25 – 1 mg administer subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

• If symptoms are severe, add as primary prophylaxis at least 30 min before irinotecan during subsequent cycles

• For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Treatment Modifications

Patient Population Studied

A study of 199 patients with previously untreated advanced colorectal cancer

Efficacy (N = 169/198)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA serum electrolytes, and LFTs

2. Every 2-3 months: CT scans to assess response

Toxicity (N = 54)

Metastatic Or Adjuvant Regimen: Leucovorin + Infusional Fluorouracil + Oxaliplatin (FOLFOX)

André T et al. N Engl J Med 2004;350:2343–2351

de Gramont A et al. J Clin Oncol 2000;18:2938–2947

Rothenberg ML et al. J Clin Oncol 2003;21:2059–2069

Tournigand C et al. J Clin Oncol 2004;22:229–237

FOLFOX-4 (de Gramont et al., Rothenberg et al., André et al.):

Oxaliplatin 85 mg/m²; administer intravenously over 2 hours in 250 mL 5% dextrose injection (D5W) on day 1, every 2 weeks, concurrently with leucovorin administration (total dosage/cycle = 85 mg/m²)

Note: Oxaliplatin must not be mixed with sodium chloride injection. Therefore, when leucovorin and oxaliplatin are given concurrently via the same administration set tubing, both drugs must be administered in D5W

Leucovorin calcium 200 mg/m² per day; administer intravenously over 2 hours in 25–500 mL D5W for 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 400 mg/m²) followed by:

Fluorouracil 400 mg/m² per day; administer by intravenous injection over 1–4 minutes after leucovorin for 2 consecutive days, on days 1 and 2, every 2 weeks, followed by:

Fluorouracil 600 mg/m² per day; administer by continuous intravenous infusion over 22 hours in 100–1000 mL 0.9% sodium chloride injection (0.9% NS) or D5W for 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 2000 mg/m²)

or

FOLFOX-6 (Tournigand et al.)

Oxaliplatin 100 mg/m²; administer intravenously over 2 hours in 500 mL D5W on day 1, every 2 weeks, concurrently with leucovorin administration (total dosage/cycle = 100 mg/m²)

Note: Oxaliplatin must not be mixed with sodium chloride injection. Therefore, when leucovorin and oxaliplatin are given concurrently via the same administration set tubing, both drugs must be administered in D5W

Either: (racemic) Leucovorin calcium 400 mg/m² or levoleucovorin calcium 200 mg/m²; administer intravenously over 2 hours in 25–500 mL 0.9% NS or D5W on day 1, every 2 weeks (total dosage/cycle for racemic leucovorin = 400 mg/m², for levoleucovorin = 200 mg/m²), followed by:

Fluorouracil 400 mg/m²; administer by intravenous injection over 1–2 minutes after leucovorin on day 1, every 2 weeks, followed by:

Fluorouracil 2400 mg/m²; administer by continuous intravenous infusion over 46 hours in 100–1000 mL 0.9% NS or D5W, starting on day 1 every 2 weeks (total dosage/cycle = 2800 mg/m²)

• Infusional fluorouracil dosage may be increased to 3000 mg/m² by continuous intravenous infusion over 46 hours, starting on cycle 3, day 1, and repeated every 2 weeks in patients who do not develop adverse effects G >1 during the first 2 cycles (total dosage/cycle = 3400 mg/m²)

Note: The fluorouracil loading dose (400 mg/m²) can be omitted for better hematologic tolerance

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE

Emetogenic potential on day 2 is LOW to MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Patient Population Studied

Patients with previously untreated advanced colorectal cancer

Treatment Modifications (FOLFOX-4)

Treatment Modifications (FOLFOX-6)

Toxicity (N = 209) (FOLFOX-4)

Toxicity (N = 110) (FOLFOX-6)

Efficacy (N = 210)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA serum electrolytes, and LFTs

2. Every 2-3 months: CT scans to assess response in patients presenting with advanced colorectal cancer

Metastatic Disease Regimen: Leucovorin + Bolus Fluorouracil + Irinotecan (IFL) + Bevacizumab

Hurwitz H et al. N Engl J Med 2004;350:2335–2342

Bevacizumab 5 mg/kg; administer intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) every 2 weeks (total dosage/6-week cycle = 15 mg/kg)

Note: Administration duration for the initial dose is 90 minutes. If administration is well tolerated, the administration duration may be decreased stepwise during subsequent administrations to 60 minutes and, finally, to a minimum duration of 30 minutes

Irinotecan 125 mg/m² per dose; administer intravenously in 250 mL 5% dextrose injection (D5W) over 90 minutes, weekly for 4 consecutive weeks, every 6 weeks (total dosage/6-week cycle = 500 mg/m²)

Leucovorin calcium 20 mg/m² per dose; administer intravenously over 2 hours in 25–500 mL 0.9% NS or D5W, weekly for 4 consecutive weeks, every 6 weeks (total dosage/6-week cycle = 80 mg/m²), followed by:

Fluorouracil 500 mg/m² per dose; administer by intravenous injection over 1–2 minutes, after leucovorin, weekly for 4 consecutive weeks, every 6 weeks (total dosage/cycle = 2000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with or without bevacizumab is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25 – 1 mg administer subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

• If symptoms are severe, add as primary prophylaxis at least 30 min before irinotecan during subsequent cycles

• For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count is <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Oral care

Prophylaxis and treatment for mucositis/stomatitis

  General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

  Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

  If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Patient Population Studied

First-line therapy of metastatic colorectal cancer. Exclusion criteria included prior chemotherapy or biologic therapy for metastatic disease, although adjuvant or radiosensitizing use of fluoropyrimidines with or without leucovorin or levamisole was permitted

Efficacy (N = 402)

Toxicity (N = 393)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, serum electrolytes, CEA BUN, creatinine, and LFTs. Urine for protein analysis including 24-hour urine for protein if needed

2. Twice per week initially, then at a minimum of once per week: Blood pressure

3. Every 6 weeks for the first 24 weeks: CT scans to assess response

Treatment Modifications

Metastatic Disease Regimen: Cetuximab

Cunningham et al. N Engl J Med 2004;351:337–345

Saltz LB et al. J Clin Oncol 2004;22:1201–1208

Warning: Despite the use of prophylactic antihistamines, severe infusion reactions occur with the administration of cetuximab in about 3% of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions are associated with initial cetuximab administration and are characterized by the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. Exercise caution with every cetuximab infusion

Notes:

1. Test doses do not reliably predict hypersensitivity reactions to cetuximab administration and are not recommended

2. Mild to moderate infusion reactions

   • Interrupt or slow the cetuximab infusion rate

   • Permanently decrease administration rate by 50%

   • Give antihistamine prophylaxis before repeated treatments

3. Severe reactions

   • Immediately interrupt cetuximab therapy

   • Administer epinephrine, glucocorticoids, intravenous antihistamines, bronchodilators, and oxygen as needed

   • Permanently discontinue further treatment

Cetuximab premedication:

Administer a H₁-receptor antagonist (eg, diphenhydramine 50 mg) intravenously 30–60 minutes before starting cetuximab administration. Hypersensitivity prophylaxis should be administered for subsequent cetuximab doses based on clinical judgment and presence and severity of infusion reactions during prior exposures

Initial cetuximab dose:

Cetuximab 400 mg/m²; administer intravenously over 120 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) as a single dose (total initial dosage = 400 mg/m²), followed after an interval of 1 week by:

Weekly maintenance cetuximab doses:

Cetuximab 250 mg/m²; administer intravenously over 60 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) every week (total weekly dosage = 250 mg/m²)

Notes:

• Cetuximab is intended for direct administration and should not be diluted

• Maximum infusion rate = 5 mL (10 mg)/min (300 mL/h, or 600 mg/h)

• Administer cetuximab through a low protein-binding inline filter with pore size = 0.22 μm

• Use 0.9% sodium chloride injection to flush vascular access devices after administration is completed

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

In the pivotal trial, cetuximab was given alone or in combination with irinotecan. All patients received a 20-mg test dose on day 1, then cetuximab was given at 400 mg/m² intravenously as an initial dose, followed by 250 mg/m² per week intravenously until disease progression or unacceptable toxicity. Cetuximab was added to irinotecan using the same dose and schedule for irinotecan on which the patient's tumor had previously progressed

Patient Population Studied

A study of patients with metastatic colorectal cancer whose tumor expresses EGFR and whose disease had progressed after receiving an irinotecan-containing regimen

Efficacy

Toxicity

Treatment Modifications

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA serum electrolytes, BUN, creatinine, and LFTs. Urine for protein analysis including 24-hour urine for protein if needed

2. Every 6 weeks for the first 24 weeks: CT scans to assess response

3. Monitor patients for 1 hour after completing cetuximab administration in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, intravenous glucocorticoids and antihistamines, bronchodilators, and oxygen)

   • Monitor for longer periods to confirm resolution of signs and symptoms of hypersensitivity in patients who require treatment for infusion reactions

4. Interrupt cetuximab for acute onset or worsening of pulmonary symptoms (dyspnea, cough). Permanently discontinue cetuximab for confirmed Interstitial lung disease (ILD occurred in <0.5% of patients receiving cetuximab in clinical trials)

5. Instruct patients to limit sun exposure. Monitor for inflammation and infection involving the skin and nails

   • Dermatologic toxicities, including: acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, Staphylococcus aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis have occurred in patients receiving cetuximab

   • Acneform rash occurred in 76–88% of patients who received cetuximab in clinical trials; severe acneform rash occurred in 1–17% of patients

   • Acneform rash usually develops within the first 2 weeks after starting therapy and resolves in a majority of the patients after treatment cessation, although in nearly half of patients studied rash continued beyond 28 days after treatment ceased

Metastatic Colorectal Cancer Regimen: Cetuximab + FOLFOX-4

Bokemeyer C et al. J Clin Oncol 2009;27:663–671

Cunningham D et al. N Engl J Med 2004;351:337–345

de Gramont A et al. J Clin Oncol 2000;18:2938–2947

Warning:

1. Severe infusion reactions occurred with the administration of cetuximab in approximately 3% (17/633) of patients, rarely with fatal outcome (<1 in 1000)

2. Approximately 90% of severe infusion reactions are associated with the first infusion of cetuximab despite the use of prophylactic antihistamines

3. Infusion reactions are characterized by the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension

4. Caution must be exercised with every cetuximab infusion, as there were patients who experienced their first severe infusion reaction during later infusions

5. Provocative test doses do not reliably predict hypersensitivity reactions to cetuximab administration and are not recommended

Mild to moderate infusion reactions

• Interrupt or slow the cetuximab infusion rate

• Permanently decrease the administration rate by 50%

• Give antihistamine prophylaxis before repeated treatments

Severe reactions

• Immediately interrupt cetuximab therapy

• Administer epinephrine, glucocorticoids, intravenous antihistamines, bronchodilators, and oxygen as needed

• Permanently discontinue further treatment

Cetuximab premedication:

Diphenhydramine 50 mg by intravenous injection before cetuximab administration (other H₁-receptor antagonists may be substituted)

Initial cetuximab dose:

Cetuximab 400 mg/m²; administer intravenously over 120 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) as a single dose (total initial dosage = 400 mg/m²)

Maintenance cetuximab doses:

Cetuximab 250 mg/m²; administer intravenously over 60 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) every week (total weekly dosage = 250 mg/m²)

Notes:

• Cetuximab is intended for direct administration and should not be diluted

• Maximum infusion rate = 5 mL (10 mg)/min (300 mL/h, or 600 mg/h)

• Administer cetuximab through a low protein-binding inline filter with pore size = 0.22 μm

• Use 0.9% sodium chloride injection to flush vascular access devices after administration is completed

See Chapter 40 for more information about antineoplastic use

FOLFOX-4 (de Gramont A et al.):

Oxaliplatin 85 mg/m²; administer intravenously in 250 mL 5% dextrose injection (D5W) over 2 hours concurrently with leucovorin administration, on day 1 every 2 weeks, (total dosage/cycle = 85 mg/m²)

Note: Oxaliplatin must not be mixed with sodium chloride injection. Therefore, when leucovorin and oxaliplatin are given concurrently via a Y-connector, both drugs must be administered in D5W

Leucovorin calcium 200 mg/m² per dose; administer intravenously in 25–500 mL D5W over 2 hours on 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 400 mg/m²), followed by:

Fluorouracil 400 mg/m² per dose; administer by intravenous injection over 1–2 minutes after leucovorin on 2 consecutive days, on days 1 and 2, every 2 weeks, followed by:

Fluorouracil 600 mg/m² per dose; administer by continuous intravenous infusion in 100–1000 mL 0.9% sodium chloride injection (0.9% NS) or D5W over 22 hours on 2 consecutive days, on days 1 and 2, every 2 weeks (total dosage/cycle = 2000 mg/m²)

Note: Fluorouracil boluses (400 mg/m² by intravenous injection) may be omitted for better hematologic tolerance

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cetuximab is MINIMAL

Emetogenic potential on days with oxaliplatin is MODERATE

Emetogenic potential on days with fluorouracil and leucovorin alone is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

  Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)

• Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily

• Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Patient Population Studied

463 patients with histologically confirmed, first occurrence of a nonresectable, EGFR-expressing metastatic colorectal cancer (mCRC) with a life expectancy of >12 weeks; an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >2. Patients were ineligible if they had a history of previous exposure to EGFR-targeted therapy or previous chemotherapy (except adjuvant treatment) for mCRC

Efficacy

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA if initially elevated, serum electrolytes, serum magnesium, and LFTs

2. Every 2–3 months: CT scans to assess response in patients presenting with advanced colorectal cancer

Treatment Modifications

Relevant G3/4 Adverse Events Occurring in ≥3% of Patients

Metastatic Colorectal Cancer Regimen: Cetuximab + FOLFIRI

Van Cutsem E et al. N Engl J Med 2009;360:1408–1417

Warning:

1. Severe infusion reactions occurred with the administration of cetuximab in approximately 3% (17/633) of patients, rarely with fatal outcome (<1 in 1000)

2. Approximately 90% of severe infusion reactions are associated with the first infusion of cetuximab despite the use of prophylactic antihistamines

3. Infusion reactions are characterized by the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension

4. Caution must be exercised with every cetuximab infusion, as there were patients who experienced their first severe infusion reaction during later infusions

5. Provocative test doses do not reliably predict hypersensitivity reactions to cetuximab administration and are not recommended

Mild to moderate infusion reactions

• Interrupt or slow the cetuximab infusion rate

• Permanently decrease the administration rate by 50%

• Give antihistamine prophylaxis before repeated treatments

Severe reactions

• Immediately interrupt cetuximab therapy

• Administer epinephrine, glucocorticoids, intravenous antihistamines, bronchodilators, and oxygen as needed

• Permanently discontinue further treatment

Cetuximab premedication:

Diphenhydramine 50 mg; administer by intravenous injection before cetuximab administration (other H₁-receptor antagonists may be substituted)

Initial cetuximab dose:

Cetuximab 400 mg/m²; administer intravenously over 120 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) as a single dose (total initial dosage = 400 mg/m²)

Maintenance cetuximab doses:

Cetuximab 250 mg/m²; administer intravenously over 60 minutes (maximum infusion rate = 5 mL/min [10 mg/min]) every week (total weekly dosage = 250 mg/m²)

Notes:

• Cetuximab is intended for direct administration and should not be diluted

• Maximum infusion rate = 5 mL (10 mg)/min (300 mL/h, or 600 mg/h)

• Administer cetuximab through a low protein-binding inline filter with pore size = 0.22 μm

• Use 0.9% sodium chloride injection to flush vascular access devices after administration is completed

See Chapter 40 for more information about antineoplastic use

Irinotecan 180 mg/m²; administer intravenously over 90 minutes in 500 mL 5% dextrose injection (D5W) on day 1, every 2 weeks (total dosage/cycle = 180 mg/m²), plus:

Either: (racemic) leucovorin calcium 400 mg/m² or levoleucovorin calcium 200 mg/m²; administer intravenously over 2 hours in 25–500 mL 0.9% sodium chloride injection (0.9% NS) or D5W on day 1, every 2 weeks (total dosage/cycle for racemic leucovorin = 400 mg/m², for levoleucovorin = 200 mg/m²), followed by:

Fluorouracil 400 mg/m²; administer by intravenous injection over 1–2 minutes after leucovorin on day 1, every 2 weeks, followed by:

Fluorouracil 2400 mg/m²; administer by continuous intravenous infusion over 46 hours in 100–1000 mL 0.9% NS or D5W, starting on day 1, every 2 weeks (total dosage/cycle = 2800 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE

Emetogenic potential on day 2 is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25–1 mg subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

• If symptoms are severe, add as primary prophylaxis at least 30 minutes before irinotecan during subsequent cycles

• For irinotecan, acute cholinergic syndrome may be characterized by abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

• Continue for at least 12 hours after diarrhea resolves

• Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

• Rehydrate orally with fluids and electrolytes during a diarrheal episode

• If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

• Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

  Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Patient Population Studied

An open-label, multicenter study, comparing 14-day cycles of cetuximab plus FOLFIRI and FOLFIRI alone, randomized and treated 1198 patients. The primary end point was progression-free survival time. Inclusion criteria included histologically confirmed adenocarcinoma of the colon or rectum, first occurrence of metastatic disease that could not be resected for curative purposes, immunohistochemical evidence of tumor EGFR expression, and Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2 or less. Exclusion criteria were previous exposure to an anti-EGFR therapy or irinotecan-based chemotherapy, previous chemotherapy for metastatic colorectal cancer, adjuvant treatment that was terminated 6 months or less before the start of treatment on trial

Efficacy (N = 1198)

Therapy Monitoring

1. Before each cycle: H&P, CBC with differential, CEA if initially elevated, serum electrolytes, serum magnesium, and LFTs

2. Every 2–3 months: CT scans to assess response in patients presenting with advanced colorectal cancer

Treatment Modifications

Metastatic Colorectal Cancer Regimen: Panitumumab + Best Supportive Care

Van Cutsem E et al. J Clin Oncol 2007;25:1658–1664

Panitumumab 6 mg/kg; administer intravenously in 0.9% sodium chloride injection (100 mL for doses ≤1000 mg; 150 mL for doses >1000 mg; product concentration should be <10 mg/mL) over 60–90 minutes on day 1, every 2 weeks (total dosage/cycle = 6 mg/kg)

Notes:

• Severe infusion reactions occur in approximately 1% of patients (anaphylactic reactions, bronchospasm, fever, chills, and hypotension). Dose adjustment or discontinuation of panitumumab is warranted depending on the severity of the reaction

• Panitumumab should always be administered by a rate controlling device via a low-protein-binding 0.22-μm inline filter

• Flush line before and after panitumumab with 0.9% sodium chloride injection

• Doses ≤1000 mg should be administered over 60 minutes; >1000 mg should be administered over 90 minutes

• If tolerated, second and subsequent infusions may be administered over 30 minutes

• The routine use of an antihistamine prior to panitumumab administration is not recommended by the manufacturer; however, doing so may prevent infusion reactions

See Chapter 40 for more information about antineoplastic use

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL to LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV