Recurrent/Metastatic Disease: Cisplatin or Carboplatin with Fluorouracil + Cetuximab
Vermorken JB et al. N Engl J Med 2008;359:1116–1127
Cetuximab premedication:
Diphenhydramine 50 mg; administer by intravenous injection or infusion 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 [10 mg] per min) as a single loading dose (total initial dosage = 400 mg/m2)
Maintenance cetuximab doses:
Cetuximab 250 mg/m2 per dose; administer intravenously over 60 minutes (maximum infusion rate = 5 mL [10 mg] per 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
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
One hour after completing cetuximab administration, either cisplatin or carboplatin is given
Cisplatin-Containing 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 (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 3 weeks (total dosage/cycle = 4000 mg/m2)
Carboplatin-Containing Regimen Carboplatin✫ (calculated dose) AUC = 5 mg/mL · min per dose; administer by intravenous infusion diluted to concentrations as low as 0.5 mg/mL with either D5W or 0.9% NS over 1 hour, on day 1, every 3 weeks (total dose/cycle calculated to produce a target AUC = 5 mg/mL · min), 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 3 weeks for 4 cycles (total dosage/cycle = 4000 mg/m2)

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 recommends, 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] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm [accessed February 26, 2014]
Treatment duration:
Until evidence of disease progression or unacceptable toxicity for a maximum of 6 cycles of chemotherapy. Cetuximab may be continued as a single agent until unacceptable toxicity or disease progression
Supportive Care
Antiemetic prophylaxis
Emetogenic potential on days with cetuximab alone is MINIMAL
Emetogenic potential on days with cisplatin or carboplatin 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:
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 two tablets four 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 two 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
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
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 442 patients with measurable histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck (except nasopharyngeal carcinoma) that was not curable with surgery or radiation. Prior chemotherapy for recurrent disease was not allowed. Prior chemotherapy delivered as part of initial curative therapy was allowed provided it was completed at least 6 months before study entry. Age ≥18 years, adequate organ function, and Karnofsky performance status of ≥70 were required