Chapter 14: Head and Neck Cancers

Epidemiology

Pathology

1. Squamous carcinomas (90%)

2. Lymphomas

3. Salivary gland tumors (adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma)

4. Sarcomas

5. Melanomas

Work-up

1. History and physical examination

2. ENT examination

3. Laryngoscopy with biopsy of suspicious lesions

4. CT and/or MRI of the head and neck

5. X-ray or CT of chest (to rule out metastatic disease or second primary tumor)

6. Needle biopsy of lymph node not associated with obvious primary tumor

Organ Site Specific Work-up

1. Ethmoid sinus: H&P, CT and/or MRI, CXR, pathology review if diagnosis with incomplete excision

2. Maxillary sinus: H&P, Head and neck CT with contrast ± MRI, CXR, dental/prosthetic consultation as indicated

3. Salivary glands: H&P, CT/MRI, CXR, pathology review

4. Lip, oral cavity: H&P, CT/MRI, parorex, biopsy, preanesthesia studies, dental evaluation

5. Hypopharynx: H&P, biopsy, CXR or chest CT, CT with contrast or MRI of primary and neck, examination under anesthesia with laryngoscopy/esophagoscopy, preanesthesia studies, dental evaluation, multidisciplinary consultation as indicated

6. Glottic larynx: Same work up as for hypopharynx + CT scan with contrast and thin cuts of the larynx or MRI of primary, speech and swallowing studies

Staging

Concomitant Chemoradiation Regimens: Cisplatin with Radiation Therapy

Adelstein DJ et al. J Clin Oncol 2003;21:92–98

Forastiere AA et al. N Engl J Med 2003;349:2091–2098

Pretreatment:

Dental evaluation; percutaneous feeding tube; nutrition evaluation

As noted in the Expert Opinion section: Concurrent chemoradiation using cisplatin every 3 weeks for 3 doses should still be considered the standard regimen

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer with potassium and magnesium supplementation as needed based on measured values

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for 3 cycles during radiation (total dosage/cycle = 100 mg/m²)

Radiation therapy at least 70 Gy to primary site and clinically positive nodes given in daily (Monday–Friday) fractions of 2 Gy/day over 7 weeks; at least 50 Gy to entire neck

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

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

Oral care (mucositis prophylaxis and management)

Risk of mucositis/stomatitis is HIGH

  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

Efficacy

Efficacy

Patient Population Studied

Organ preservation: Patients with previously untreated stage III or stage IV squamous cell carcinoma of the glottic or supraglottic larynx, the surgical treatment of which would require total laryngectomy. The disease had to be considered curable with surgery and postoperative radiation therapy. Karnofsky performance status (PS) at least 60%; adequate organ function; creatinine clearance at least 50 mL/min (≥0.83 mL/s)

Unresectable: Patients with stages III/IV unresectable squamous cancer excluding nasopharyngeal cancer, or cancers of the paranasal sinuses or parotid glands. ECOG PS 0–1, adequate organ function

Toxicity (N = 266)

Therapy Monitoring

1. Before cisplatin and weekly after treatment: CBC with differential, serum electrolytes, calcium, and magnesium

2. Weekly follow-up recommended during therapy: Attention to signs and symptoms of dehydration as supplemental hydration and nutritional support often are required

3. Every 4–6 months: Thyroid function studies

Concomitant Chemoradiation Regimens: Cisplatin + Paclitaxel with Radiation Therapy

Garden AS et al. Preliminary results of RTOG 97–03. J Clin Oncol 2004;22:2856–2864

Pretreatment:

Dental evaluation; percutaneous feeding tube; nutrition evaluation

Premedication:

Dexamethasone 8–20 mg; administer by intravenous injection or short intravenous infusion 30 minutes before paclitaxel

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel

Ranitidine 50 mg; administer intravenously over 5–20 minutes, 30–60 minutes before paclitaxel

Paclitaxel 30 mg/m² per dose; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS), or 5% dextrose injection (D5W) sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 3–24 hours weekly, on day 1, for 7 consecutive weeks (total dosage/7-week cycle = 210 mg/m²)

Optional: Dexamethasone 4 mg; administer orally every 6 hours for 4 doses following paclitaxel with glucose monitoring if indicated

Cisplatin 20 mg/m² per dose; administer intravenously in 100–1000 mL 0.9% NS over 15–60 minutes weekly on day 2, for 7 consecutive weeks (total dosage/7-week cycle = 140 mg/m²)

Radiation at least 70 Gy to primary site and clinically positive nodes given in daily (Monday–Friday) fractions of 2 Gy/day over 7 weeks

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with paclitaxel is LOW

Emetogenic potential on days with cisplatin is HIGH

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—consider use during neutropenia and for anticipated mucositis

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

See Chapter 47 for more information

Oral care (mucositis prophylaxis and management)

Risk of mucositis/stomatitis is MODERATE

  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

Toxicity (N = 77)

Treatment Modifications

Efficacy (N = 77)

Patient Population Studied

A study of 77 patients with stage III or stage IV M0 squamous cancer of oral cavity, oropharynx, or hypopharynx, previously untreated, assigned to 1 of 3 arms in a randomized phase II RTOG trial. ECOG PS at least 70% and adequate organ function are required

Therapy Monitoring

1. Weekly: CBC with differential, serum electrolytes, calcium, and magnesium. Weekly follow-up recommended during therapy with attention to signs and symptoms of dehydration because supplemental hydration and nutritional support are often required

2. Every 4–6 months: Thyroid function studies

Concomitant Chemoradiation Regimens: Carboplatin + Fluorouracil with Radiation Therapy

Calais G et al. J Natl Cancer Inst 1999;91:2081–2086

Pretreatment:

Dental evaluation; percutaneous feeding tube; nutrition evaluation

Carboplatin 70 mg/m² per day; administer intravenously in 50–100 mL 5% dextrose injection (D5W) or 0.9% sodium chloride injection (0.9% NS) over 15–30 minutes for 4 consecutive days, given on days 1–4, every 3 weeks (total dosage/cycle = 280 mg/m²)

Fluorouracil 600 mg/m² per day; administer by continuous intravenous infusion in 50–1000 mL 0.9% NS or D5W over 24 hours for 4 consecutive days, given on days 1–4, every 3 weeks (total dosage/cycle = 2400 mg/m²)

Radiation 2 Gy/day, 5 fractions per week to tumor and clinically positive nodes to a total dose of 70 Gy

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

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 (mucositis prophylaxis and management)

Risk of mucositis/stomatitis is HIGH

  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

A study of 109 patients with previously untreated stage III or stage IV squamous cell carcinoma of the oropharynx without evidence of distant metastases. Patients were assigned to the chemoradiation arm of a randomized phase III trial with Karnofsky PS at least 60% and adequate organ function

Efficacy (N = 109)

Therapy Monitoring

1. Weekly: CBC with differential, serum electrolytes, calcium, and magnesium. Weekly follow-up recommended during therapy with attention to signs and symptoms of dehydration because supplemental hydration and nutritional support are often required

2. Every 4–6 months: Thyroid function studies

Treatment Modifications

Toxicity (N = 109)

Concomitant Chemoradiation Regimen: Cisplatin with Radiation Therapy Followed by Cisplatin + Fluorouracil

Al-Sarraf M et al. J Clin Oncol 1998;16:1310–1317

Pretreatment:

Dental evaluation; percutaneous feeding tube; nutrition evaluation

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short intravenous infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

During radiation therapy:

Cisplatin 100 mg/m² per dose; administer intravenously in 25–1000 mL 0.9% NS over 15–20 minutes every 21 days for 3 cycles, given on days 1, 22, and 43 of radiation therapy (total dosage/cycle = 100 mg/m²)

Radiation 1.8–2 Gy/day, 5 fractions per week to tumor and clinically positive nodes to a total dose of 70 Gy. A total of 50 Gy to entire neck is recommended

After radiation therapy:

Note: Start 4 weeks after radiation therapy or the last dose of cisplatin, regardless of response to cisplatin + radiation

Cisplatin 80 mg/m² per dose; administer intravenously in 25–1000 mL 0.9% NS over 15–30 minutes every 4 weeks for 3 cycles, given on days 71, 99, and 127 (total dosage/cycle = 80 mg/m²)

Fluorouracil 1000 mg/m² per day; administer by continuous intravenous infusion in 100–1000 mL 0.9% NS or 5% dextrose injection over 24 hours for 4 consecutive days every 4 weeks for 3 cycles (96-hour infusion; on days 71–74, 99–102, and 127–130) (total dosage/cycle = 4000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential during radiation therapy on days with cisplatin is HIGH. Potential for delayed symptoms

Emetogenic potential after radiation therapy on days with cisplatin is HIGH. Potential for delayed symptoms

Emetogenic potential after radiation therapy on days with fluorouracil alone 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 (mucositis prophylaxis and management)

Risk of mucositis/stomatitis is MODERATE–HIGH

  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

A study of 78 patients with stage III or stage IV nasopharyngeal cancer without evidence of systemic metastasis and no history of previous radiation therapy or chemotherapy. Patients were randomized to the combined modality arm of a 2-arm randomized phase III trial

Efficacy (N = 78)

Therapy Monitoring

1. Weekly: CBC with differential, serum electrolytes, calcium, and magnesium. Weekly follow-up recommended during therapy with attention to signs and symptoms of dehydration, as supplemental hydration and nutritional support are often required

2. For 2 days, starting the day after cisplatin administration, and as needed: Serum electrolytes and magnesium

3. Every 4–6 months: Thyroid function studies

Toxicity (N = 78/53)

Advanced Disease Induction Chemotherapy Followed by Chemoradiation: Docetaxel + Cisplatin + Fluorouracil (TPF) or Cisplatin + Fluorouracil (PF)

Posner MR et al. N Engl J Med 2007;357:1705–1715

As noted in the Expert Opinion section:TPF (docetaxel + cisplatin + fluorouracil) is to be considered the current standard induction chemotherapy regimen in cases where induction chemotherapy is considered appropriate

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short intravenous infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

TPF induction chemotherapy:

Dexamethasone 8 mg/dose; administer orally or intravenously twice daily for 6 doses starting the day before docetaxel administration (total dose/cycle = 48 mg)

• As prophylaxis against docetaxel-related hypersensitivity reactions, skin toxic effects, and fluid retention

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% NS or 5% dextrose injection (D5W) sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 60 minutes on day 1, every 21 days for 3 cycles (total dosage/cycle = 75 mg/m²), followed by:

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 0.5–3 hours on day 1, every 21 days for 3 cycles (total dosage/cycle = 100 mg/m²), followed by:

Fluorouracil 1000 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 4 consecutive days, on days 1–4, every 21 days for 3 cycles (total dosage/cycle = 4000 mg/m²)

Prophylactic antibiotics days 5–14

or

PF induction chemotherapy:

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 0.5–3 hours on day 1, every 21 days for 3 cycles (total dosage/cycle = 100 mg/m²), followed by

Fluorouracil 1000 mg/m² per day; administer intravenously in 50–1000 mL 0.9% NS or D5W by continuous infusion over 24 hours for 5 consecutive days, days 1–5, every 21 days for 3 cycles (total dosage/cycle = 5000 mg/m²)

Note: Induction chemotherapy is discontinued in case of (a) disease progression; (b) a reduction in tumor after 2 cycles <25% (WHO) or <30% (RECIST); or (c) unacceptable toxicity

Supportive Care for Patients Receiving Either TPF or PF Chemotherapies

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil alone is LOW

See Chapter 39 for antiemetic recommendations

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

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

Risk of mucositis/stomatitis is HIGH

  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

For Patients Who Receive TPF Chemotherapy

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with 1 of the following:

  Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

  Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

• Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—consider a fluoroquinolone or no prophylaxis

  • Posner et al gave antibiotic prophylaxis to patients who received the TPF regimen for 10 days starting on cycle day 5. Choice of antibiotics was not specified

• Antifungal—consider use during neutropenia and for anticipated mucositis

• Antiviral—antiherpes antivirals (eg, acyclovir)

See Chapter 47 for more information

For Patients Who Receive PF Chemotherapy

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

  • Posner et al gave antibiotic prophylaxis only to patients who received the TPF regimen: patients who received the PF regimen did not receive antimicrobial primary prophylaxis

• Antifungal—not indicated

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

See Chapter 47 for more information

Chemoradiation: (Follows Induction Chemotherapy)

Seven weeks of chemoradiation: Starting between days 22 and 56 of induction chemotherapy cycle 3 (3–8 weeks after the start of cycle 3 of induction chemotherapy)

Radiotherapy:

70–74 Gy to primary tumor in 5 daily fractions/week of 2 Gy/fraction

At least 50 Gy to uninvolved lymph nodes

At least 60–74 Gy to involved lymph nodes

Concurrent chemotherapy:

Carboplatin^✫ (calculated dose) AUC = 1.5 mg/mL · min per dose; administer intravenously diluted to concentrations as low as 0.5 mg/mL with either D5W or 0.9% NS over 1 hour, once weekly for up to 7 doses during the course of radiotherapy (total dose/week calculated to produce a target AUC = 1.5 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. FDA identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States were required to use the standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine, which can result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula can exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommended for patients with normal renal function capping an estimated GFR at 125 mL/min for any targeted AUC value. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm [accessed February 26, 2014]

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days when carboplatin is administered 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

Dose Modification

Efficacy

Surgery: (Elective Neck Dissection)

Elective neck dissection 6–12 weeks after end of chemoradiation for patients with initial N2 disease and a partial response to induction chemotherapy, N3 disease, or residual disease after chemoradiation

Patient Population Studied

A study of 539 patients with measurable, nonmetastatic, stage III or IV, histologically proven, previously untreated squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx with a tumor deemed to be unresectable (because of tumor fixation, involvement of the nasopharynx, or fixed lymph nodes), or of low surgical curability on basis of advanced tumor stage (3 or 4) or regional node stage (2–3, except T1N2), or if a patient was a candidate for organ preservation. WHO performance status 0 or 1. Adequate organ function and age ≥18 years

Therapy Monitoring

1. Pretreatment evaluation: Medical history and tumor assessment by clinical evaluation and imaging studies

2. Toxicity assessment: Weekly during treatment with chemotherapy

3. Tumor assessment: After cycles 2 and 3; then, 6–12 weeks after chemoradiation

Toxicity

Advanced Disease Induction Chemotherapy Followed By Radiotherapy: Docetaxel + Cisplatin + Fluorouracil (TPF) or Cisplatin + Fluorouracil (PF)

Vermorken JB et al. N Engl J Med 2007;357:1695–1704

As noted in the Expert Opinion section: TPF (docetaxel + cisplatin + fluorouracil) is to be considered the current standard induction chemotherapy regimen in cases where induction chemotherapy is considered appropriate

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Premedication:

Dexamethasone 8 mg/dose; administer orally or intravenously twice daily for 6 doses starting the day before docetaxel administration (total dose/cycle = 48 mg)

• As prophylaxis against docetaxel-related hypersensitivity reactions, skin toxic effects, and fluid retention

Induction chemotherapy:

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% NS or 5% dextrose injection (D5W) sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 60 minutes on day 1, every 3 weeks for up to 4 cycles (total dosage/cycle = 75 mg/m²), followed by:

Cisplatin 75 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for up to 4 cycles (total dosage/cycle = 75 mg/m²), followed by:

Fluorouracil 750 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 5 consecutive days, on days 1–5, every 3 weeks for up to 4 cycles (total dosage/cycle = 3750 mg/m²)

or

Induction chemotherapy:

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for up to 4 cycles (total dosage/cycle = 100 mg/m²), followed by:

Fluorouracil 1000 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 5 consecutive days, on days 1–5, every 3 weeks for up to 4 cycles (total dosage/cycle = 5000 mg/m²)

Supportive Care for Patients Receiving Either TPF or PF Chemotherapies

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil alone is LOW

See Chapter 39 for antiemetic recommendations

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

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

Risk of mucositis/stomatitis is MODERATE

  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

For Patients Who Receive TPF Chemotherapy

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

• Particularly in patients who do not receive antibiotic prophylaxis

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—consider a fluoroquinolone or no prophylaxis

  • Vermorken et al gave antibiotic prophylaxis to patients who received the TPF regimen from cycle days 5–15

• Antifungal—consider use during neutropenia and for anticipated mucositis

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

See Chapter 47 for more information

For Patients Who Receive PF Chemotherapy

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

  • Vermorken et al gave antibiotic prophylaxis only to patients who received the TPF regimen

• Antifungal—not indicated

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

See Chapter 47 for more information

Radiotherapy

Starting within 4–7 weeks after completion of chemotherapy

Surgery: (Elective Neck Dissection)

Elective neck dissection can be considered before radiotherapy and again 3 months after the completion of radiotherapy

Dose Modification

Patient Population Studied

A study of 358 patients with measurable, nonmetastatic stages III or IV, histologically or cytologically proven, previously untreated squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx, with a tumor considered to be unresectable by a multidisciplinary team. WHO performance status 0 or 1, adequate organ function, and ages 18–70 years

Efficacy

Therapy Monitoring

1. Day 1 of each cycle: Medical history and physical exam, CBC with differential, LFTs, electrolytes, BUN, and creatinine

2. At end of cycles 2 and 4: Diagnostic imaging

Toxicity

Advanced Disease Chemoradiation in Unresectable Disease: Cisplatin Alone or Cisplatin + Fluorouracil

Adelstein DJ et al. J Clin Oncol 2003;21:92–98

As noted in the Expert Opinion section: chemoradiation concurrent with cisplatin 100 mg/m² every 3 weeks × 3 doses should still be considered the standard regimen

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for 3 cycles during radiation (total dosage/cycle = 100 mg/m²)

Radiation therapy administered to a total dose of 70 Gy given continually in single, daily, 2-Gy fractions over 7 weeks

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

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

or

Cisplatin 75 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 4 weeks for 3 cycles during radiation (total dosage/cycle = 75 mg/m²), followed by:

Fluorouracil 1000 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 4 consecutive days, on days 1–4, every 4 weeks for 3 cycles during radiation (total dosage/cycle = 4000 mg/m²)

Concurrent radiation therapy, at a rate of 2 Gy/day, split as follows:

• First chemotherapy cycle: A total of 30 Gy administered as 15 daily fractions of 2 Gy/fraction, 5 days/week, starting on day 1 of cycle 1

• Third chemotherapy cycle: A total of 30–40 Gy administered as 15–20 daily fractions of 2 Gy/fraction, 5 days/week, starting on day 1 of cycle 3

• Administer 30–40 Gy for a total dose of 60–70 Gy depending on response

Note: The radiation therapy break is planned to allow for the possibility of surgical resection in patients whose disease is rendered resectable after the first 2 courses of chemotherapy and the first 30 Gy of radiation. Patients who do not achieve a complete response after the first 2 courses of chemotherapy and the first 30 Gy of radiation, or whose disease remains unresectable complete chemoradiation without surgery

As a result of the break, almost 7 additional weeks were required to complete treatment

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil ± RT is LOW–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

Oral care

Risk of mucositis/stomatitis is HIGH

  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

A study of 295 patients with a histologically confirmed diagnosis of squamous cell or undifferentiated stage III or IV, nonmetastatic, carcinoma of the head and neck, excluding tumors originating in the nasopharynx, paranasal sinus, or parotid gland Unresectability was predefined for each tumor site as follows:

• Hypopharynx: tumor extension across the midline of the posterior pharyngeal wall or fixed to the cervical spine

• Larynx: direct extension into surrounding muscle or skin or greater than 3 cm subglottic extension

• Oral cavity: functional reconstruction not possible

• Base of tongue: extension into the root of tongue or refusal of total glossectomy

• Tonsil: extension into the pterygoid region as manifested by clinical trismus or demonstrated radiographically, or tumor extension across the midline of the pharyngeal wall or direct invasion into the soft tissue of the neck

Adequate organ function and an ECOG performance score ≤1 were required

Dose Modification

Efficacy

G3–5 Toxicity

Therapy Monitoring

1. Day 1 of each cycle: Medical history and physical exam, CBC with differential, LFTs, electrolytes, BUN, and creatinine

2. Diagnostic imaging: At treatment completion and 3 months later

Chemoradiation with Cisplatin in Unresectable Disease: Chemoradiation for Larynx Preservation Cisplatin with Radiation Therapy

Forastiere AA et al. N Engl J Med 2003;349:2091–2098

As noted in the Expert Opinion section: Concurrent chemoradiation using cisplatin 100 mg/m² every 3 weeks × 3 doses should still be considered the standard regimen

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for 3 cycles during radiation (total dosage/cycle = 100 mg/m²)

Radiotherapy 70 Gy given in 35 fractions of 2 Gy/fraction over 7 weeks to the primary tumor and clinically positive nodes; 50 Gy in fractions of 2 Gy to the entire neck

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cisplatin is HIGH. Potential for delayed symptoms

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

Oral care

Risk of mucositis/stomatitis is HIGH

  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

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for 3 cycles (total dosage/cycle = 100 mg/m²), followed by:

Fluorouracil 1000 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 5 consecutive days on days 1–5, every 3 weeks for 3 cycles (total dosage/cycle = 5000 mg/m²)

After 2 cycles of cisplatin + fluorouracil, evaluate extent of response and disease status in the neck with indirect laryngoscopy and CT imaging of the neck

• If evaluation reveals a complete or partial response of the primary tumor and no sign of progression in the neck, a third course of cisplatin plus fluorouracil is given, followed by radiotherapy

• If evaluation reveals less than partial response of the primary tumor or with progression in the neck, laryngectomy followed by adjuvant radiotherapy is recommended

Radiotherapy, 70 Gy given in 35 fractions of 2 Gy/fraction over 7 weeks to the primary tumor and clinically positive nodes; 50 Gy in fractions of 2 Gy to the entire neck

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cisplatin is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil alone 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

Oral care

Risk of mucositis/stomatitis is HIGH

  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

Surgery

Patients with either a single lymph node ≥3 cm or with multiple lymph node metastases on initial clinical staging of the neck should undergo neck dissection 8 weeks after completing radiotherapy. Laryngectomy should be performed in patients who had histologically proven persistent or recurrent carcinoma after the completion of treatment, or who had an inadequate response after 2 courses of induction chemotherapy

Toxicity

Patient Population Studied

A study of 547 patients with biopsy-proven, previously untreated, stage III or IV squamous cell carcinoma of the larynx for whom surgical treatment would require total laryngectomy. Excluded were patients with large T4 tumors, defined as tumors penetrating through the cartilage or extending >1 cm into the base of tongue, and patients with a stage T1 primary tumor. Karnofsky performance score of ≥60 and adequate organ function were required

Dose Modification

Efficacy

Therapy Monitoring

1. Day 1 of each cycle: Medical history and physical exam, CBC with differential, LFTs, electrolytes, BUN, and creatinine

2. Posttreatment reevaluation: 8 weeks after the completion of therapy by examination of the head and neck and CT imaging. If persistent disease is suspected, perform the examination while the patient is under anesthesia so that direct laryngoscopy can be performed

3. Scheduled follow-up visits: Complete examination of the head and neck, with evaluation for late toxicity

High-Risk Patients: Postoperative Chemoradiation with Cisplatin

Bernier J et al. N Engl J Med 2004;350:1945–1952

Cooper JS et al. N Engl J Med 2004;350:1937–1944

Note: Among high-risk patients with resected head and neck cancer, the chemoradiation therapy regimen described significantly improved the rates of local and regional control and disease-free survival. However, compared to RT alone, chemoradiation is associated with a substantial increase in adverse effects

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Cisplatin 100 mg/m²; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes on day 1, every 3 weeks for 3 cycles during radiation (total dosage/cycle = 100 mg/m²)

Radiotherapy 60–66 Gy in 30–33 fractions of 2 Gy/fraction given continually over 6–6.6 weeks

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cisplatin is HIGH. Potential for delayed symptoms

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 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

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

Risk of mucositis/stomatitis is HIGH

  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

EORTC 22931

A study of 334 patients with previously untreated, histologically proven, squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx with: (a) tumor stage pT3 or pT4 and any nodal stage except T3N0 of the larynx with negative resection margins, (b) N2/N3 disease, (c) T1/2N1/N2 disease with extranodal spread, (d) positive section margins, (e) perineural involvement, (f) vascular involvement, or (g) oral cavity or oropharyngeal tumors with involvement of lymph nodes at levels IV or V. Adequate organ function, WHO performance status of 0–2, and age ≥18 years

RTOG 9501/Intergroup

A study of 459 patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, who underwent macroscopically complete resection but had at least 1 high-risk characteristic defined as: (a) invasion of at least 2 lymph nodes, (b) extracapsular extension of nodal disease, or (c) microscopically involved mucosal margins of resection. Adequate organ function and Karnofsky performance status of ≥60 were required

Dose Modification

Efficacy

G3/4 Toxicity

Therapy Monitoring

1. Day 1 of each cisplatin treatment: Medical history and physical exam, CBC with differential, LFTs, electrolytes, BUN, and creatinine

2. Posttreatment reevaluation: 8 weeks after the completion of therapy by examination of the head and neck and CT imaging. If persistent disease is suspected, perform the examination while the patient is under anesthesia so that direct laryngoscopy can be performed

3. Scheduled follow-up visits: Complete examination of the head and neck, with evaluation for late toxicity

High-Risk Patients: Postoperative Chemoradiation with Cisplatin + Fluorouracil

Fietkau R et al. Proc Am Soc Clin Oncol 2006;24(18S, Part 1 of 2):281s (abstract 5507)

Hydration before, during, and after cisplatin administration:

• Pre-cisplatin hydration with 500–1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Post-cisplatin hydration with 500–1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Cisplatin 20 mg/m² per day; administer intravenously in 50–1000 mL 0.9% NS over 60 minutes for 5 consecutive days, on days 1–5, every 4 weeks for 2 cycles during radiation (total dosage/cycle = 100 mg/m²), and

Fluorouracil 600 mg/m² per day; administer in 50–1000 mL 0.9% NS or D5W by continuous intravenous infusion over 24 hours for 5 consecutive days, on days 1–5, every 4 weeks for 2 cycles during radiation (total dosage/cycle = 3000 mg/m²)

Radiotherapy (50 Gy in case of pN0, 56 Gy in case of pN+ without extracapsular spread, 64 Gy in case of pN+ with extracapsular spread)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cisplatin is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil alone 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 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

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

Risk of mucositis/stomatitis during chemoradiation is MODERATE–HIGH

  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

A study of 440 patients with pTR1, PT4, or ≥3 positive lymph nodes, or extracapsular spread and no macroscopic residual tumor

Dose Modification

G3/4 Toxicity (%)

Efficacy

Therapy Monitoring

1. Days 1 and 29: Medical history and physical exam, CBC with differential, LFTs, electrolytes, BUN, and creatinine

2. Posttreatment reevaluation: 8 weeks after the completion of therapy by examination of the head and neck and CT imaging. If persistent disease is suspected, perform the examination while the patient is under anesthesia so that direct laryngoscopy can be performed

3. Scheduled follow-up visits: Complete examination of the head and neck, with evaluation for late toxicity

Initial or Metastatic Disease Regimen: Cetuximab ± Radiation

Bonner JA et al. N Engl J Med 2006;354:567–578

Premedication:

Diphenhydramine 50 mg (or an equivalent [H₁] antihistamine); administer by intravenous injection or as a short infusion 30 minutes prior to cetuximab administration

Note: Severe infusion reactions can occur with the administration of cetuximab Approximately 90% of severe reactions were associated with the first infusion despite the use of prophylactic antihistamines

Initial dose:

Cetuximab 400 mg/m²; administer intravenously over 120 minutes (maximum infusion rate = 5 mL [10 mg] per min) 1 week prior to radiation therapy

Maintenance doses:

Cetuximab 250 mg/m² per dose; administer intravenously over 60 minutes (maximum infusion rate = 5 mL [10 mg] per min), weekly ± radiation

Note: If administering radiation, administer cetuximab weekly for the duration of radiation

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with cetuximab is MINIMAL

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

Oral care

Risk of mucositis/stomatitis is HIGH

  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

Dose Modification

Efficacy (N = 211)

Patient Population Studied

A study of 424 patients with stage III or IV nonmetastatic measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who were randomly assigned to receive high-dose radiotherapy alone (n = 213) or high-dose radiotherapy plus cetuximab (n = 211)

Therapy Monitoring

Weekly: CBC with differential, serum electrolytes, calcium, and magnesium weekly during radiation

Toxicity (N = 208)

Notes

1. Indications:

   Cetuximab, in combination with radiation therapy, is indicated for the treatment of locally or regional advanced squamous cell carcinoma of the head and neck

   Bonner JA et al. N Engl J Med 2006;354:567–578

   Cetuximab as a single agent is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck after prior platinum based therapy has failed

    

   Trigo J et al. Proc Am Soc Clin Oncol 2004;23:488s [abstract 5502]

    

   Evaluated the efficacy of cetuximab monotherapy in 103 patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck in a multicenter phase II study. An initial dose of cetuximab 400 mg/m² was followed by cetuximab 250 mg/m² weekly, until disease progression, with an option to switch to cetuximab plus the same platinum agent on which patients' disease had previously progressed after disease progression occurred with cetuximab monotherapy. Drug-related adverse events in >10% of patients included skin rash/acne 80% (1% G3), fatigue 24% (4% G3), fever/chills 19% (2% G3), nail changes 15% (all G1/2), and nausea 13% (1% G3). There was 1 treatment-related death as a result of a hypersensitivity reaction in a patient for whom mechanical ventilation was not suitable. Preliminary efficacy data were as follows: 5 CR, 12 PR, 38 SD, 47 PD, and 1 not assessable, for an overall objective response rate of 16.5% (95% CI, 9.9–25.1%). The disease control rate was 53.4% (95% CI, 43.3–63.3%). Median TTP and median survival were 85 days and 175 days, respectively

Metastatic Disease Regimen: Methotrexate: (see also Cisplatin + Fluorouracil and CARBOPLATIN + FLUOROURACIL)

Note: These 3 regimens were compared in a randomized trial. The Efficacy and Toxicity tables provide the comparative data

Forastiere AA et al. J Clin Oncol 1992;10:1245–1251

Methotrexate 40 mg/m²; administer by intravenous injection over 15–30 seconds, or as a short infusion in 10–100 mL 0.9% sodium chloride injection or 5% dextrose injection over 5–15 minutes every week, continually (total dosage/week = 40 mg/m²)

Note: Increase methotrexate dosage to 50 mg/m² weekly if patients experience only grade 0 (zero) mucositis or myelosuppression after 40 mg/m² per week

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

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

Oral care (mucositis prophylaxis and management)

  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

A randomized comparison of 3 treatments: (a) single-agent methotrexate; (b) cisplatin plus fluorouracil; and (c) carboplatin plus fluorouracil. The study enrolled 277 patients with recurrent and metastatic squamous cell carcinoma of the head and neck. The primary objective was to compare separately the response rates of each regimen. Eligible patients had histologically proven squamous cell carcinoma of the head and neck that was either recurrent after attempted cure with surgery and radiation therapy or newly diagnosed disease with distant metastases. Patients with recurrent disease had not previously received chemotherapy for treatment of the recurrence, although they could have received induction chemotherapy ≥6 months before study entry. All patients were required to have measurable disease; a life expectancy of at least 12 weeks; a performance status of 0, 1, or 2 on the SWOG criteria; and a 24-hour creatinine clearance >50 mL/min (>0.83 mL/s)

Treatment Modifications

Therapy Monitoring

Weekly: CBC with differential. Serum creatinine and LFTs as needed

Notes

Median duration of therapy is 8 weeks

Efficacy

Toxicity

Metastatic Disease Regimen: Cisplatin + Fluorouracil: (see also Methotrexate and Carboplatin + Fluorouracil)

Note: These 3 regimens were compared in a randomized trial. The Efficacy and Toxicity tables provide the comparative data

Forastiere AA et al. J Clin Oncol 1992;10:1245–1251

Hydration before, during, and after cisplatin administration ± mannitol:

• Pre-cisplatin hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously with potassium and magnesium supplementation as needed based on pretreatment laboratory results

• Mannitol diuresis: May be given to patients who have received adequate hydration. A dose of mannitol 12.5–25 g may be administered by intravenous injection or a short infusion before or during cisplatin administration, or prepared as an admixture with cisplatin. Continued intravenous hydration is essential

• Continued mannitol diuresis: In an inpatient or day-hospital setting, one may administer additional mannitol in the form of an intravenous infusion: mannitol 10–40 g; administer intravenously over 1–4 hours. This can be done either during or immediately after cisplatin, but requires maintenance of adequate intravenously administered fluids during and for hours after mannitol administration

• Post-cisplatin hydration with ≥1000 mL 0.9% NS; administer intravenously with potassium and magnesium supplementation as needed based on measured values

Cisplatin 100 mg/m²; administer intravenously in 25–250 mL of 0.9% NS over 15–30 minutes, given on day 1 every 21 days (total dosage/cycle = 100 mg/m²)

Fluorouracil 1000 mg/m² per day; administer by continuous intravenous infusion in 100–1000 mL 0.9% NS or 5% dextrose injection over 24 hours for 4 consecutive days (96-hour infusion), given on days 1–4 every 21 days (total dosage/cycle = 4000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with cisplatin is HIGH. Potential for delayed symptoms

Emetogenic potential on days with fluorouracil alone 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 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

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 (mucositis prophylaxis and management)

  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