Chapter 37: Thyroid Cancer

Epidemiology

Pathology

Papillary thyroid cancer (PTC)

1. Develops from the follicular cells in the normal thyroid

2. Usually found in 1 lobe; only 10–20% appear in both lobes

3. Considered a differentiated thyroid cancer

4. Together with follicular thyroid cancer, accounts for 80–90% of all thyroid cancers

5. Mutations in BRAF have been reported in 60–80% of patients with V600E (T1799A), the most common mutation

Follicular thyroid cancer (FTC)

1. Less common than PTC

2. Develops from the follicular cells in the normal thyroid

3. Considered a differentiated thyroid cancer

4. Together with PTC, accounts for 80–90% of all thyroid cancers

5. Hürthle cell carcinoma is usually assumed to be a variant of FTC, although its prognosis is worse

6. Mutations of codon 61 of N-RAS (N2) have been reported in as many as 19% of follicular tumors

Medullary thyroid cancer (MTC)

1. Accounts for 5–10% of thyroid cancers

2. Develops in the C cells of the thyroid; has very little, if any, similarity to normal thyroid tissue

3. Occurs with multiple endocrine neoplasia type 2 (MEN 2A and MEN 2B2), in familial medullary thyroid carcinoma (FMTC) and as a sporadic form (≈80% of cases are sporadic)

4. Germline mutations in the RET (REarranged during Transfection) protooncogene cause hereditary MTC (MEN 2A, MEN 2B, and FMTC). In addition, up to 50% of patients with sporadic MTC have somatic RET mutations

5. MEN 2B: RET mutations in codons 918, 883, or compound heterozygotes (V804M + E805K, Y806C or S904C)

6. MEN 2A and FMTC: RET mutations in codons 609, 611, 618, 620, 630, 634, 768, 790, 791, 804, or 891

7. The constitutively active RET oncoproteins associated with MTC are sensitive to agents that inhibit RET kinase providing a rationale for targeting RET in patients with MTC

Anaplastic thyroid cancer (ATC)

1. Rare and fast-growing tumors. The majority present with extensive local invasion. 15–50% have metastatic disease at presentation with lung and pleura most common sites of metastases followed by bone, brain, and other organs

2. A poorly differentiated thyroid cancer that starts from differentiated thyroid cancer or a benign tumor of the gland. Approximately 50% have either a prior or a coexistent differentiated carcinoma

3. Loss or mutation of the p53 tumor suppressor is commonly found

Work-up

Initial Work-up of Thyroid Nodule

Thyroid nodule in clinically euthyroid patient

1. TSH level

2. Ultrasound of thyroid and central neck area

3. Fine-needle aspiration (FNA) biopsy of thyroid nodule

Note: No role for thyroid scanning unless thyrotoxic (TSH suppressed):

• If thyrotoxic and palpated nodule is "hot" on scan, it is likely benign and biopsy is unnecessary. Refer to an endocrinologist

• If nodule is "cold," proceed to FNA

Neck lymph node

1. FNA biopsy is appropriate

   Mass at site distant from neck

2. Biopsy (resection) and immunohistochemistry for thyroglobulin; calcitonin

Initial Work-up (Histologic Diagnosis Established)

Papillary or follicular carcinomas and their subtypes (usually iodine avid)

1. Do not use iodinated contrast for radiography of any type of papillary or follicular carcinomas. This stable iodine can interfere with ¹³¹I scans and therapy for up to 10 months

2. Preop:

   • Neck ultrasound or neck MRI

   • Noncontrast chest CT

   • CT or MRI for fixed, bulky substernal lesions

   • Evaluate vocal cord mobility

3. Postop:

   • ¹³¹I scanning (see below)

   • Thyroglobulin (TG) level

Dedifferentiated papillary/follicular cancers (iodine nonavid, often not apparent initially)

1. CT scans (may use contrast if known to be nonavid for iodine): Often "fused" with PET scans

2. Preop:

   • Neck ultrasound or neck MRI

   • Noncontrast chest CT

   • CT or MRI for fixed, bulky substernal lesions

   • Evaluate vocal cord mobility

3. Postop:

   • ¹³¹I scanning (see below)

   • Thyroglobulin (TG) level

4. PET scans (¹⁸F-deoxyglucose): Sensitivity enhanced with recombinant human TSH pretreatment

5. Radiographic bone surveys (may not need if PET scan is negative and all other scans do not demonstrate any obvious evidence of disease in bone)

Medullary thyroid carcinoma

1. Complete CT survey (with contrast)

2. Neck ultrasound

3. Evaluate vocal cord mobility

4. Calcitonin level

5. CEA level

6. Serum calcium

7. MEN2A and MEN2B: Pheochromocytoma screening. Evaluate and treat appropriately before continuing

Note: If a germline mutation is found, genetic counseling and testing of first-degree relatives are recommended

Anaplastic carcinoma

1. Complete CT survey (with contrast)

2. Consider bone scan or PET scan (may not need bone scan if PET scan is done)

3. May need restaging at 2- to 4-week intervals because of rapid rate of tumor progression

Follow-up (Histologic Diagnosis Established)

Papillary or follicular carcinomas (and their subtypes)

In patients who have had thyroidectomy and are receiving suppressive doses of levothyroxine (maintain TSH ≤0.1 mIU/L):

1. Serial TG levels every 6 months (monitor for presence of interfering anti-TG antibodies)

   Note: The "normal range" for TG in this situation is "undetectable"

2. Physical exams, patient neck self-exams

3. ¹³¹I whole-body scans (WBS) every 6 months until scan and TG are negative. ¹³¹I therapy is administered if WBS is positive (see Initial ¹³¹I WBS below)

4. CT of chest (noncontrast only) (interval defined by disease status)

5. PET scans if ¹³¹I WBS is negative but TG is positive. Sensitivity correlates with tumor dedifferentiation and hexokinase I expression (interval defined by disease status)

6. Radiographic bone survey (interval defined by disease status)

7. Neck ultrasonography (interval defined by disease status)

Initial ¹³¹I WBS: Prepare with hypothyroid protocol:

• ≈6 Weeks before scan: Stop levothyroxine therapy. Continue without levothyroxine >6 weeks if needed until TSH >30 mIU/L (first 4 weeks on liothyronine sodium 25 mcg orally twice per day)

• 2 Weeks before and during scan: Institute low-iodine diet

Follow-up ¹³¹I WBS: Prepare with recombinant human TSH (thyrotropin alfa, Thyrogen^®) protocol:

• 2 Weeks before and during scan: Institute low-iodine diet

• Days 1 and 2: Administer recombinant human TSH 0.9 mg/day intramuscularly for 2 consecutive days

• Day 3: Administer 4–5 mCi ¹³¹I orally

• Day 5: Perform ¹³¹I WBS (≥30 min/view; ≥140,000 counts)

• Day 5: Obtain serum TG, antithyroglobulin autoantibody, and TSH levels

Note: Frequency of follow-up ¹³¹I WBS and TG levels: Every 6 months until both ¹³¹I WBS and TG levels are negative, then double the time interval between each negative study. Follow-up is life-long, considering current diagnostic modalities. Maximum interval between negative studies is 5 years

Note: A TG level greater than the lowest detectable limit is sufficient evidence for persistent/recurrent disease, even in the absence of positive ¹³¹I WBS

Antithyroglobulin autoantibodies occur in 20% of patients and interfere with the TG assay making it insensitive, but can sometimes be a surrogate marker for persistent disease

Medullary carcinoma

1. Complete CT survey (with contrast)

2. Calcitonin and CEA levels

Staging

Three-Year Survival

Regimen: Neoadjuvant + Adjuvant Doxorubicin and Radiation with Debulking Surgery

Nilsson O et al. World J Surg 1998;22:25–30

Tennvall J et al. Cancer 1994;74:1348–1354

Preoperative treatment:

Doxorubicin 20 mg/dose; administer by intravenous injection over 3–5 minutes starting 1–2 hours before radiation therapy, weekly, for 3 weeks (total dose/3-week course = 60 mg)

Radiation 100 cGy per fraction twice daily for 30 fractions with a minimum of 6 hours between fractions 5 days/week to a target dose of 3000 cGy in 3 weeks

Debulking surgery:

Around week 5 approximately 10–14 days after completing preoperative radiation therapy

Postoperative treatment:

Doxorubicin 20 mg/dose; administer by intravenous injection over 3–5 minutes, weekly, starting 1–2 hours before radiation therapy (total dose/week = 20 mg)

Radiation 100 cGy per fraction twice daily for 16 fractions with a minimum of 6 hours between fractions 5 days/week to a target dose of 1600 cGy (total cumulative radiation including preoperative dose = 4600 cGy over approximately 70 days)

Additional doxorubicin:

Doxorubicin 20 mg/dose; administer by intravenous injection over 3–5 minutes, weekly, in patients considered to be in "reasonably good condition" (maximum dosage/complete treatment = 750 mg/m²)

Note: Doxorubicin is administered as a fixed dose (20 mg), but cumulative dosage is calculated as mg/m²

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days doxorubicin 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

Preoperative treatment:

Doxorubicin 20 mg/dose; administer by intravenous injection over 3–5 minutes, weekly, starting 1–2 hours before radiation therapy for 3 weeks (total dose/3-week course = 60 mg)

Radiation 130 cGy/per fraction twice daily for 23 fractions with a minimum of 6 hours between fractions, 5 days/week to a target dosage of 3000 cGy

Debulking surgery:

Around week 4 (approximately 2 weeks after completing preoperative radiation therapy)

Postoperative treatment:

Doxorubicin 20 mg/week; administer by intravenous injection over 3–5 minutes, weekly, starting 1 hour before radiation therapy (total dose/week = 20 mg)

Radiation 130 cGY/per fraction twice daily for 12 fractions with a minimum of 6 hours between fractions 5 days/week to a target dosage of 1600 cGY (total cumulative radiation dose including preoperative dose = 4600 cGy over approximately 50 days)

Additional doxorubicin:

Doxorubicin 20 mg/week; administer by intravenous injection over 3–5 minutes, weekly, in patients considered to be in "reasonably good condition" (maximum dosage/complete treatment = 400–440 mg)

Treatment Modifications

Postoperative doxorubicin was administered to patients with good performance status and in the absence of disease progression

Patient Population Studied

A study of 33 patients with anaplastic thyroid carcinoma treated with combined radiation, chemotherapy, and surgery. In later review, 160 patients were studied

Efficacy (N = 33)

Toxicity (N = 33)

1. WHO grades I and II mucosal and skin toxicity

2. Hematologic toxicity not observed

3. Treatment-related toxicities did not prevent any patient from completing planned treatment

Therapy Monitoring

1. Weekly: CBC with differential

2. Before each treatment: CBC with differential

3. Every 2–3 cycles: Imaging studies to evaluate response

Notes

Doxorubicin has been used historically; however, as a single agent, it is not considered an effective chemotherapeutic drug for anaplastic carcinoma

Regimen: 96-Hour Continuous-Infusion Paclitaxel and Weekly Paclitaxel

Ain KB et al. Thyroid 2000;10:587–594

Continuous 96-Hour IV Infusion

Optional premedication^✫ (Primary prophylaxis against hypersensitivity reactions from paclitaxel):

Dexamethasone 20 mg/dose; administer orally for 2 doses on the evening before and the morning of chemotherapy before paclitaxel plus

Diphenhydramine 50 mg for 1 dose; administer by intravenous injection 30 minutes before paclitaxel and

Ranitidine 50 mg or cimetidine 300 mg for 1 dose; administer by intravenous infusion in 25–100 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 5–30 minutes given 30 minutes before paclitaxel

Paclitaxel 30–35 mg/m² per day; administer by continuous intravenous infusion in a volume of 0.9% NS or D5W sufficient to produce a solution with concentration within the range 0.3–1.2 mg/mL over 24 hours for 4 consecutive days, on days 1–4, every 3 weeks, for up to 6 cycles (total dosage/cycle for 30 mg/m² per day = 120 mg/m² for 35 mg/m² per day = 140 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

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

See Chapter 47 for more information

Intermittent Weekly Administration

Note: Subsequent clinical experience suggests that optimal use of paclitaxel uses a 1-hour infusion of 175 mg/m² given weekly for 3 weeks every month, with restaging each month, and continuing until there is progressive disease or limiting toxicity. This dose must be administered carefully with premedication against hypersensitivity reactions and growth factor support assessing patient before each dose with attention to occurrence of mucositis and neutropenia

Primary prophylaxis against hypersensitivity reactions from paclitaxel:

Dexamethasone 20 mg/dose; administer orally for 2 doses on the evening before and the morning on which chemotherapy is given (eg, one dose 12 to 14 hours before paclitaxel plus a second dose 6 to 7 hours before paclitaxel):

Diphenhydramine 50 mg; administer by intravenous injection 30 minutes before paclitaxel, and:

Ranitidine 50 mg or cimetidine 300 mg; administer intravenously in 25–100 mL of 0.9% NS or D5W over 5–30 minutes, 30 minutes before paclitaxel

Paclitaxel 175 mg/m²; administer by intravenous infusion in a volume of 0.9% NS or D5W sufficient to produce a solution with concentration of 0.3–1.2 mg/mL over 3 hours for 3 doses on 3 consecutive weeks every 28 days (monthly) (total dosage/cycle = 525 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

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

See Chapter 47 for more information

Treatment Modifications

Toxicity (N = 11/8)

Patient Population Studied

A study of 20 patients with metastatic anaplastic thyroid cancer

Efficacy (N = 19)

Therapy Monitoring

1. Before every cycle: CBC with differential, platelet count, and LFTs

2. Radiologic studies: Every 2 cycles

Regimen: Medullary Thyroid Cancer Vandetanib

Wells SA Jr et al. J Clin Oncol 2010;28:767–772

Wells et al. J Clin Oncol 2012;30:134–141

Vandetanib 100–300 mg per day; administer orally, continually (total dose/week = 700–2100 mg)

Note:

• Patients should take vandetanib once daily at the same time each day. Vandetanib absorption is not affected by a meal, so it may be administered with or without food. Tablets should be swallowed whole (without chewing)

  • If a patient misses a scheduled dose of vandetanib, they may take the missed dose if the next scheduled dose is not due to be taken within the next 12 hours

  • If <12 hours remain before the next scheduled dose is due, the patient should not take the missed dose but should wait and take the next regularly scheduled dose

  • If the patient vomits ≤15 minutes after taking vandetanib, another dose may be administered. The dose may only be repeated only once

  • If a patient vomits >15 minutes after an oral dose was administered, no attempt to supplement or replace the dose should be made

• If vandetanib tablets cannot be swallowed whole, they may be dispersed in a glass containing 2 ounces of non-carbonated water and stirred for approximately 10 minutes until the tablet is dispersed (tablets will not completely dissolve)

  • No other liquids should be used

  • The dispersion should be immediately swallowed or administered through nasogastric or gastrostomy tubes

  • To ensure the full dose is received, any residue in the glass should be mixed again with an additional 4 ounces of non-carbonated water and swallowed

• Vandetanib should be withheld in patients who develop electrolyte abnormalities associated with diarrhea until the electrolyte abnormalities are corrected because of the risk of QTc prolongation and subsequent arrhythmias

Note: Patients receive once-daily oral doses of vandetanib 300 mg until disease progression, or unacceptable toxicity

Note: Although the starting dose is 300 mg per day, a majority of patients will experience an adverse event making a dose reduction necessary. In the study cited:

1. Vandetanib dose was reduced or interrupted in 24 patients because of adverse events, most commonly diarrhea (n = 7)

2. Among the 24 patients who required dose reduction or interruption, 21 patients had a combination of dose reduction and dose interruption and 3 patients had a dose interruption without dose reduction

3. Some patients required more than a single dose reduction

4. For patients who required dose reductions, vandetanib was decreased to:

   200 mg/day (60%, 18/30)

   150 mg/day (3%, 1/30)

   100 mg/day (23%, 7/30)

   50 mg/day (6.6%, 2/30)

5. The median time to first dose reduction was 4.9 months (95% CI, 2.7–8.4 months)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–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

Patient Population Studied

Treatment Modifications

Toxicity

Therapy Monitoring

1. ECGs: Unless additional ECGs are clinically indicated, 12-lead ECGs are performed before the start of treatment, weekly for the first 8 weeks, and then every 12 weeks thereafter. If the dose is increased then weekly monitoring is indicated for approximately 6 weeks

2. Response assessment: Every 2–3 cycles

Efficacy

Medullary Thyroid Cancer Regimen: Cabozantinib

Elsei et al. J Clin Oncol 2013;31:3639–3646

Cabozantinib 140 mg orally at least 2 hours after or at least 1 hour before after eating food, continually (total dose/week = 980 mg)

Notes:

• Capsules are swallowed whole (without opening or breaking)

• Do not take a missed dose within 12 hours of the next scheduled dose

• In light of the fact that 79% of patients starting at the 140-mg dose had a subsequent dose reduction and 27% discontinued the medication because of adverse effects, clinicians are advised to consider the following:

  • Patients Taking CYP3A4 Inhibitors

    • Avoid the use of concomitant strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

    • For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily cabozantinib dose by 40 mg. Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuing a strong inhibitor

  • Patients Taking Strong CYP3A4 Inducers

    • Avoid use of strong CYP3A4 inducers (eg, carbamazepine, phenobarbital phenytoin, rifabutin, rifampin, rifapentine) concomitantly with cabozantinib if alternative therapy is available

    • Inform patients not to ingest foods or nutritional supplements (eg, St. John's wort (Hypericum perforatum) known to induce cytochrome P450 activity

    • For patients who require treatment with a strong CYP3A4 inducer, increase the daily cabozantinib dose by 40 mg only if tolerability on the dose without the inducer has been convincingly demonstrated. Resume the dose that was used prior to initiating a CYP3A4 inducer 2 to 3 days after discontinuing a strong inducer. The daily cabozantinib dose should not exceed 180 mg

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–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; administer orally initially after the first loose or liquid stool, then

  Loperamide 2 mg every 2 hours while awake; every 4 hours during sleep

  Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil^®) two tablets four times daily until control achieved.

Persistent diarrhea:

  Octreotide acetate (solution) 100–150 mcg; administer subcutaneously 3 times daily.

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³

Abigerges D et al. J Natl Cancer Inst 1994;86:446–449

Rothenberg ML et al. J Clin Oncol 2001;19:3801–3807

Wadler S et al. J Clin Oncol 1998;16:3169–3178

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

Use topical emollients (eg, Aquaphor^®), topical or orally administered steroids, antihistamines, or pyridoxine 50 to 200 mg/day

Dose Modifications

Patient Population Studied

Locally advanced on metastatic medullary thyroid cancer. All had RECIST documented progressive disease within 14 months before screening, although the interval between scans was not fixed. There were no limits on the number of prior therapies; 95% had ECOG 0/1 PS. RET mutation status was "positive" in 46%, "negative" in 14%, and unknown in 40%. Of the studied population, 51% had bone metastases at baseline

Efficacy

Toxicity

Regimen: Sorafenib Tosylate: Late-Stage (Metastatic) Differentiated Thyroid Cancer

Brose et al. ASCO 2013 Annual Meeting, J Clin Oncol 31, 2013 (Suppl; abstr 4)

Sorafenibtosylate 400 mg administer orally every 12 hours (eg, morning and evening) continually in 28-day cycles (total dose/day = 800 mg; total dose/cycle = 22,400 mg)

Notes:

• Patients should swallow tablets whole with approximately 250 mL (8 oz) of water. Tablets may be taken with or without food

• Special precautions: Sorafenib is metabolized by cytochrome P450 (CYP) CYP3A subfamily enzymes and has been shown in preclinical studies to inhibit multiple CYP isoforms. Therefore, all patients who are taking concomitant medications metabolized by CYP enzymes should be closely observed for side effects associated with concomitantly administered medications. Special caution should be used with any of the following medications: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, cyclosporine, carbamazepine, phenytoin, and phenobarbital. Furthermore, patients taking medications with a low therapeutic index (eg, warfarin, quinidine, digoxin) should be monitored proactively. Patients using sorafenib should be advised to avoid consuming grapefruit products for as long as they continue to use sorafenib

Supportive Care: Hand-foot reaction

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor^®), topical and/or oral steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine 50–150 mg/day orally

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

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, stoploperamide 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 neutrophilcount <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

Abigerges D et al. J Natl Cancer Inst 1994;86:446–449

Rothenberg ML et al. J Clin Oncol 2001;19:3801–3807

Wadler S et al. J Clin Oncol 1998;16:3169–3178

Treatment Modifications

Patient Population Studied

Multicenter, double-blind, placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment. Patients had papillary (57 percent), follicular (25 percent), and poorly differentiated (10 percent) carcinomas. Metastases were present in 96% of the patients: lungs in 86%, lymph nodes in 51%, and bone in 27%. Approximately half of the patients were male, the median age was 63 years, 68 percent had no uptake of radioactive iodine (RAI), and 34 percent had received a cumulative dose of at least 600 mCi of RAI. The median cumulative RAI activity administered prior to study entry was 400 mCi

Efficacy (N = 417)

Therapy Monitoring

1. Every 6 weeks to 3 months: Physical examination and routine laboratory tests

2. Response assessment: Every 2–3 cycles. A cycle defined as 28 days of oral therapy

Toxicity