Chapter 30: Pancreatic Endocrine Tumors

Sara Ekeblad; Britt Skogseid

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

1/100,000

~85% sporadic; ~15% hereditary, for example, multiple endocrine neoplasia (MEN1), von Hippel-Lindau disease

Median age:

53–57 years

Male to female ratio:

0.8–1.3:1

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Hochwald SN et al. J Clin Oncol 2002;20:2633–2642

Öberg K, Eriksson B. Best Pract Res Clin Gastroenterol 2005;19:753–781

Tomassetti PD et al. Ann Oncol 2005;16:1806–1810

Pathology

WHO classification: Pancreatic endocrine tumors

Well-differentiated neuroendocrine tumor (20–35%): no gross invasion
- Benign: no angio- or perineural invasion, size <2 cm, <2 mitoses/10 high-power fields (HPF), <2% of cells Ki67-positive
- Of uncertain behavior: angio- and/or perineural invasion and/or >2 cm and/or 2–10 mitoses/10 HPF and/or >2% of cells Ki67-positive
Well-differentiated neuroendocrine carcinoma (51–71%): gross local invasion and/or metastases
Poorly differentiated neuroendocrine carcinoma (9–21%): >10 mitoses/10 HPF

Functional status:

Nonfunctioning: 59–76%

Insulinoma: 8–17%

Gastrinoma: 10–14%

Glucagonoma: 1–6%

VIPoma: 2–5%

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Pape U-F et al. Cancer 2008;113:256–265

Rindi G, Klöppel G. Neuroendocrinology 2004;80 (Suppl 1):12–15

Work-up

Radiology

Body CT or MRI
Somatostatin receptor scintigraphy: Uses radioactive octreotide, a drug similar to somatostatin that attaches to tumor cells that have somatostatin receptors
Positron emission tomography (PET) scan (in selected cases)
- [¹¹C]5-hydroxy-l-tryptophan (5-HTP) PET for well-differentiated tumors
- Fluorodeoxyglucose (FDG) PET for poorly differentiated tumors
Endoscopic ultrasound
Intraoperative ultrasound
- To localize small tumors not visualized by other modalities but suspected because of biochemical findings
- To localize multiple tumors in MEN1 patients

Biochemistry

In all patients with suspected pancreatic endocrine tumor
- Fasting levels of:
  - insulin, proinsulin, blood glucose
  - gastrin
  - glucagon
  - pancreatic polypeptide
  - vasoactive intestinal peptide (VIP)
  - chromogranin A
If insulinoma is suspected (high fasting insulin or symptoms of hypoglycemia):
- 72-hour fast with measurements of insulin, proinsulin, and plasma glucose
- Consider differential diagnoses, for example, measurement of sulfonylurea in blood to exclude abuse of oral hypoglycemic drugs
If gastrinoma is suspected (high fasting gastrin in the absence of treatment with proton pump inhibitors, multiple ulcers, and/or steatorrhea):
- Measure gastrin after secretin stimulation test (after withdrawal of proton pump inhibitors, ideally for 1 week)
- Measure gastric pH together with fasting gastrin
If ectopic Cushing syndrome is suspected to be caused by a pancreatic tumor:
- Measure 24-hour urine free cortisol excretion, or free cortisol to creatinine ratio
  
  A ratio of cortisol >95 mcg per gram of creatinine helps confirm hypercortisolism
- Measure adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor (CRF)

Biopsies

If possible, radiologically verified tumors should be biopsied under ultrasound guidance
Ideally, biopsy specimens should be evaluated by pathologists knowledgeable in endocrine pathology and stained for:
- General markers for pancreatic endocrine tumors: Chromogranin A, synaptophysin
- Specific hormones: Insulin, gastrin, glucagon, VIP, pancreatic polypeptide
- Markers of proliferation: Ki67

MEN1 investigation

If MEN1 is suspected (family history, hyperparathyroidism)
- Measure serum calcium, PTH, prolactin
- Perform genetic testing

Staging

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Staging

Stage

Location/Size/Extension

Percent of Cases

Limited to pancreas, <2 cm

5–31

IIa

Limited to pancreas, 2–4 cm

8–9

IIb

Limited to pancreas, >4 cm, or

Invading duodenum or bile duct

5–7

IIIa

Invading adjacent organs (stomach, spleen, colon, adrenal gland), or

Invading the wall of large vessels (celiac axis or superior mesenteric artery)

3–8

IIIb

Regional lymph node metastasis

14–15

Distant metastasis

29–60

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Pape U-F et al. Cancer 2008;113:256–265

Rindi G, Klöppel G. Virchows Arch 2006;449:395–401

Survival

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Survival

5-Year: 55–64%

10-Year: 44%

Median survival: 90–99 months

Stage

Mean Survival

231 months (≈19 years)

IIa

222 months (≈18.5 years)

IIb

153 months (≈13 years)

IIIa

94 months (≈8 years)

IIIb

133 months (≈11 years)

76 months (≈6 years)

Expert Opinion

Pancreatic endocrine tumors are rare, and there is a lack of solid evidence on treatment and outcomes. The following is our view of their management, based on available evidence and many years of clinical experience

Diagnosis and work-up

Always measure hormone levels if symptoms of a functioning tumor occur or a pancreatic mass is demonstrated
Obtain a CT scan if hormone levels are elevated
Obtain somatostatin receptor scintigraphy (radioactive octreotide scan) or 5-HTP PET if unclear
Patient history: always probe for family history, history of kidney stones, and history of hyperparathyroidism (MEN1)
If MEN1 is suspected, discuss performing genetic testing
For known MEN1 carriers, perform annual biochemical screening beginning in adolescence. CT and/or 5-HTP PET if hormone levels are elevated
Radiologically visualized tumor: biopsy if radical surgery seems impossible

Surgery

Preferably performed by experienced endocrine surgeon at a high-volume center
Radical surgery of tumors that can be demonstrated by imaging
For tumors that can only be detected biochemically, if fully confident of the analyses, perform a surgical exploration. If a tumor is identified, proceed to resection if possible
Aim for pancreas-preserving surgery. If MEN1, distal pancreatectomy in combination with enucleation of lesions in the head of the pancreas are preferable. In addition, consider duodenotomy in case of MEN1 gastrinoma
Use intraoperative ultrasound to localize possible additional tumors or very small functioning tumors (especially important for MEN1 tumors)
If there is evidence of disease dissemination, consider:
- Radiofrequency ablation of liver metastases
  - Useful for limited numbers of liver metastases
  - One study showed 45% of patients rendered tumor-free with relatively few complications (Eriksson J et al. World J Surg 2008;32:930–938)
  - Metastases usually recur, but radiofrequency ablation can be performed repeatedly
  - Can alleviate hormonal symptoms
- Liver embolization
  - Useful if there are a larger number of liver metastases than can be treated with radiofrequency ablation
  - Lessens tumor burden in many patients
  - Can alleviate hormonal symptoms

Systemic treatment

Treat inoperable tumors at once; do not wait for tumor progression to initiate treatment

Streptozocin + fluorouracil or streptozocin + doxorubicin have long been considered is the first choice for patients with well-differentiated tumors
Carboplatin + etoposide is effective, and, generally, the first choice in patients with poorly differentiated carcinomas
Temozolomide used as second-line treatment after the combinations mentioned above, or for patients who cannot tolerate more intensive chemotherapy
- Easy to use for the patient as it is taken orally; thus, it can easily be taken in an outpatient setting
- Test tumor material for O₆-methylguanine-methyltranferase, low levels of which might predict a favorable response to temozolomide
Two additional options for patients with well and moderately differentiated tumors include sunitinib malate and everolimus. There is no consensus on whether these agents should be used before or after cytotoxic chemotherapy regimens such as streptozocin + fluorouracil
Somatostatin analogs should be used to alleviate hormonal symptoms, and might possibly also have antitumor effects, although this is still unclear. Somatostatin analogs can be used in combination with chemotherapy
Radionuclide-tagged somatostatin analogs (¹⁷⁷Lu-DOTA⁰, Tyr³) are increasingly used although only in a trial setting
- A recent study showed a 42% response rate with an acceptable safety profile

Supportive care:

Regardless of the therapy used, attention should be given to symptom management as many patients present with debilitating symptoms for which amelioration can significantly improve the quality of their lives:

Gastric hyperacidity (patients with a diagnosis of gastrinoma):

Omeprazole 40–60 mg per day orally, or an equivalent proton pump inhibitor or histamine (H₂) receptor antagonist may be used
Steatorrhea:

Consider supplementation with pancreatic enzymes whenever steatorrhea or changes in bowel habits suggest malabsorption
Diarrhea^✫:

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

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

Loperamide 4 mg; administer 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:

Tincture of opium: Doses are individually titrated. Begin with 2–4 drops mixed in water; administer orally 2–3 times per day, and titrate by decreasing or increasing the number of drops per dose as needed

Octreotide 50–200 mcg; administer subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Diarrhea in patients who have undergone ileocecal resection:

Cholestyramine 4 g/dose; administer orally for 2–6 doses per day (up to 24 g/day)

Antibiotic therapy during latent or delayed onset diarrhea:

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

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

Arnold R et al. Gut 1996;38:430–438

de Keizer B et al. Eur J Nucl Med Mol Imaging 2008;35:749–755

Ekeblad S et al. Clin Cancer Res 2007;13:2986–2991

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Eriksson B et al. Cancer 1990;65:1883–1890

Eriksson J et al. World J Surg 2008;32:930–938

Fischer L et al. Br J Surg 2008;95:627–635

Fjällskog M–LH et al. Cancer 2001;92:1101–1107

Hochwald SN et al. J Clin Oncol 2002;20:2633–2642

Kwekkeboom DJ et al. J Clin Oncol 2008;26:2124–2130

Moertel CG et al. Cancer 1991;68:227–232

Moertel CG et al. N Engl J Med 1980;303:1189–1194

Moertel CG et al. N Engl J Med 1992;326:519–523

Öberg K, Eriksson B. Best Pract Res Clin Gastroenterol 2005;19:753–781

Pape U-F et al. Cancer 2008;113:256–265

Rindi G, Klöppel G. Neuroendocrinology 2004;80(Suppl 1):12–15

Rindi G, Klöppel G. Virchows Arch 2006;449:395–401

Tomassetti PD et al. Ann Oncol 2005;16:1806–1810

REGIMEN: SOMATOSTATIN ANALOGS OCTREOTIDE ACETATE

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Regimen: Somatostatin Analogs Octreotide Acetate

Arnold R et al. Gut 1996;38:430–438

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Starting dose:

Octreotide acetate 50 mcg; administer by subcutaneous injection 3 times daily for 3 days

Followed by:

Octreotide acetate 100 mcg; administer by subcutaneous injection 3 times daily for 3 days

Followed by:

Octreotide acetate 200 mcg; administer by subcutaneous injection 3 times daily continually, starting on day 7

Duration of treatment: Treatment is continued indefinitely

Supportive Care

Supplemental therapy for all somatostatin analogs: Pancreatic enzymes to avoid steatorrhea. Individualize dosage by giving the number of tablets or capsules that optimally minimize steatorrhea

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

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Steatorrhea

Increase dose of pancreatic enzyme supplement to 3 capsules with every meal

Toxicity

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Toxicity

All Grades

Diarrhea

34%

Flatulence

27%

Pain at injection site

27%

Vomiting

11%

Steatorrhea

Hyperglycemia

Gall stones

Septicemia

Patient Population Studied

One-hundred three patients with gastroenteropancreatic neuroendocrine tumors given somatostatin analogs in a multicenter phase II trial
Patients with functional or nonfunctional, poorly differentiated, intermediate or small cell carcinoma with high-grade malignant behavior were not included

Efficacy (N = 52)

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Efficacy (N = 52)

No objective tumor regression was seen
Of patients with progressive pancreatic endocrine tumor, 28% had stabilization of tumor growth for ≥3 months

Tumor Growth in 52 Patients with Confirmed Progression Before Treatment

Responses at Month 3

Responses Reassessed During Months 6–12

Death

Progression

Stable Disease

Regression

Death (8)

Progression (30)

Stable disease (14)

Regression (0)

Total (52)

Response to octreotide occurred in 19 patients according to the study protocol. WHO criteria used. However, tumors growing slowly but continuously with progression of ≤25% within 3 months were also judged as "progression" if progression ≥25% occurred within 12 months

Response = stable disease or decrease in tumor growth after confirmed progression before treatment, or decrease in tumor growth after stable disease within the pretreatment period, if lasting for at least 3 months

Effect of Octreotide on Flushing, Diarrhea, and Hormone Secretion in Patients with Functional Endocrine GEP Tumors

Symptoms

Normalization

Improvement >50%

No Change

Worse

Diarrhea^✫

Month 3 (n = 28)

32.1%

21.5%

14.3%

Month 12 (n = 20)

45%

40%

10%

Flushing^✫

Month 3 (n = 40)

35%

40%

22.5%

2.5%

Month 12 (n = 27)

44.4%

40.8%

11.1%

3.7%

Hormone secretion

Month 3 (n = 61)

11.5%

29.5%

34.4%

24.6%

Month 12 (n = 39)

5.1%

28.2%

38.5%

28.2%

GEP tumors, gastroenteropancreatic neuroendocrine tumors

^✫Patients with carcinoid syndrome, patients with functional tumors

Therapy Monitoring

Every 3 months: Complete history and physical examination
Every 3–6 months: Conventional imaging (CT, MRI, or ultrasound), serum electrolytes and serum glucose
Every year: Somatostatin receptor scintigraphy (OctreoScan Kit for the Preparation of Indium In-111 Pentetreotide; Mallinckrodt Inc., St. Louis, MO) is controversial
New symptoms: Somatostatin receptor scintigraphy (OctreoScan)

REGIMEN: LONG-ACTING SOMATOSTATIN ANALOGS

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Regimen: Long-Acting Somatostatin Analogs

Kvols LK et al. N Engl J Med 1986;315:663–666

Öberg K et al. Ann Oncol 2004;15:966–973

Octreotide acetate injection 100–500 mcg per dose subcutaneously 2 or 3 times daily, doubling the dose at 3- to 4-day intervals until maximum control of symptoms is achieved

Octreotide acetate for injectable suspension 10–30 mg per dose intragluteally every 4 weeks (avoid intramuscular injection into the deltoids)

Lanreotide acetate (powder for suspension for injection) 30 mg per dose intramuscularly every 10–14 days (not available in the United States)

Supportive Care

Supplemental therapy for all somatostatin analogs: Pancreatic enzymes to avoid steatorrhea. Individualize dosage by giving the number of tablets or capsules that optimally minimize steatorrhea

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

Patient Population Studied

Primary symptomatic treatment in 25 patients with hormonally active tumors

Efficacy (N = 25)

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Efficacy (N = 25)

(Octreotide 150 mcg/dose 3 times daily; 18 months' follow-up)

Biochemical response^✫

72%

Biochemical stable disease

28%

Tumor size stable (n = 13)

100%

Symptomatic relief^†

76%

^✫>50% decrease in 24-hour urinary 5-HIAA

^†>50% decrease in flushing and diarrhea

Kvols LK et al. N Engl J Med 1986;315:663–666

Toxicity (N = 25)

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Toxicity (N = 25)

Steatorrhea^✫,†

Frequent (~66%)

Loose stools^†

Common

Nausea^†

Common

Abdominal cramps^†

Common

Flatulence^†

Common

Hyperglycemia^‡/hypoglycemia

<10%

Gallbladder stone/sludge

50%

Bradycardia

<2%

Pain/erythema at injection site

Occasional

Gastric atony

Very rare

^✫Occurs frequently unless pancreatic enzyme supplements are administered. Etiology is presumed to be transient inhibition of pancreatic exocrine function and malabsorption of fat

^†Starts within hours of the first subcutaneous injection and usually subsides spontaneously within the first few weeks of treatment

^‡From transient inhibition of insulin secretion

Kvols LK et al. N Engl J Med 1986;315:663–666

Öberg K et al. Ann Oncol 2004;15:966–973

Treatment Modifications

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Treatment Modifications

(Patients Receiving Octreotide Acetate for Injectable Suspension or Lanreotide Acetate)

Escape from antisecretory response

Administer octreotide acetate injection 100–500 mcg per dose subcutaneously 2 or 3 times daily. Increase dose or reduce interval between doses of the long-acting preparation as needed

Steatorrhea

Increase dose of pancreatic enzyme supplement to 3 capsules with every meal

Therapy Monitoring

Every 3 months: Complete history and physical examination
Every 3–6 months: Conventional imaging (CT, MRI, or ultrasound), serum electrolytes, and serum glucose
Every year: Somatostatin receptor scintigraphy (OctreoScan Kit for the Preparation of Indium In-111 Pentetreotide; Mallinckrodt Inc., St. Louis, MO) is controversial
New symptoms: Somatostatin receptor scintigraphy (OctreoScan)

Notes

Performing an OctreoScan provides information about the somatostatin receptor status of the patient's tumor and should be performed before treatment with a somatostatin analog is initiated. Patients with receptor-positive tumors more frequently respond to such treatment than those with receptor-negative tumors
Because of adverse events, administration of the immediate-release formulation is recommended before administration of the intramuscular depot formulation
Patients should begin therapy with octreotide acetate injection subcutaneously for 3–7 days to test for tolerability before receiving a long-acting formulation (octreotide acetate for injectable suspension or lanreotide acetate) intramuscularly
Increase the dosage of the short-acting octreotide acetate injection until control of symptoms is achieved by doubling the dosage at 3- to 4-day intervals
Patients who are considered to be "responders" to the drug and who tolerate the short-acting formulation can then receive octreotide acetate for injectable suspension or lanreotide acetate
The subcutaneous injections should be continued for at least 14 days after the start of the long-acting formulation to allow time for therapeutic levels to be achieved
Conversion to the long-acting formulation provides greater patient convenience. If the dose of the short-acting formulation was 200–600 mcg per day, begin with a 20-mg dose of the long-acting formulation. If the dose of the short-acting formulation was 750–1500 mcg per day, begin with a 30-mg dose of the long-acting formulation
Supplementary ("rescue") administration of the short-acting octreotide acetate injection should be given to patients escaping the antisecretory effects of the long-acting octreotide acetate for injectable suspension. If the rescue therapy is required during the week before the next dose of the long-acting formulation, a reduction in the dosing interval by 1 week is recommended. If the rescue medication is administered sporadically throughout the month, then increasing the dose of octreotide acetate for injectable suspension stepwise in increments of 10 mg per month, up to 60 mg per month

Supplemental therapy for all somatostatin analogs: Pancreatic enzymes to avoid steatorrhea

Individualize dosage by giving the number of tablets or capsules that optimally minimize steatorrhea

Select Pancrelipase products with a high lipase content to avoid steatorrhea. In some patients, enteric-coated enzyme tablets may not dissociate as intended and may pass through the bowel intact

Administer Pancrelipase with meals or snacks

Adjust doses slowly; monitor symptoms and response

Do not crush or chew enteric-coated products or the enteric-coated contents of opened capsules
Capsules may be opened and shaken onto a small quantity of soft food that is not hot and does not require chewing
Pancrelipase should be immediately swallowed without chewing to prevent mucosal irritation
Ingested doses should be followed with a glass of juice or water to ensure complete ingestion
Avoid mixing pancrelipase with foods that have a pH >5.5, which can dissolve enteric coatings

REGIMEN: STREPTOZOCIN + FLUOROURACIL

Listen

Regimen: Streptozocin + Fluorouracil

Eriksson B et al. Cancer 1990;65:1883–1890

Moertel CG et al. N Engl J Med 1980;303:1189–1194

Moertel CG et al. N Engl J Med 1992;326:519–523

Premedications and hydration:

≥1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously, starting 1.5 hours before administration of chemotherapy, continuing during administration, and for approximately 1.5 hours afterward

Induction course:

Streptozocin 1000 mg/day; administer intravenously in 100–1000 mL 0.9% NS or 5% dextrose injection (D5W) over 30–120 minutes for 5 consecutive days, on days 1–5 (total dose/cycle = 5000 mg)

Fluorouracil 400 mg/m² per day; administer by intravenous injection over 1–2 minutes for 3 consecutive days, days 1–3 (total dosage/cycle = 1200 mg/m²)

Subsequent courses: (beginning 3 weeks after the induction cycle)

Streptozocin 2000 mg intravenously in 100–1000 mL 0.9% NS or D5W over 30–120 minutes on day 1, every 3 weeks (total dose/cycle = 2000 mg)

Fluorouracil 400 mg/m² by intravenous injection over 1–2 minutes on day 1, every 3 weeks (total dosage/cycle = 400 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with streptozocin 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—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Populations Studied

One-hundred eighteen patients with metastatic carcinoid tumor were randomly assigned to receive treatment with streptozocin combined with cyclophosphamide or with fluorouracil (Moertel CG et al. N Engl J Med 1980;303:1189–1194)
A prospective, nonrandomized trial. Of 84 patients with advanced pancreatic endocrine tumor, 19 received streptozocin + fluorouracil (Eriksson B et al. Cancer 1990;65:1883–1890)
A multicenter randomized trial in which responses to streptozocin + fluorouracil, streptozocin + doxorubicin, or chlorozotocin monotherapy were compared. One-hundred five patients with advanced pancreatic endocrine tumors (Moertel CG et al. N Engl J Med 1992;326:519–523)

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Creatinine clearance on day 1 of a second and subsequent cycles = 60–75 mL/min (1–1.25 mL/s)

Give streptozocin 1000 mg/day for 2 consecutive days, on days 1 and 2 (total dose/cycle = 2000 mg)

Creatinine clearance on day 1 of a second and subsequent cycles = 50–60 mL/min (0.83–1 mL/s)

Give streptozocin 1000 mg on day 1 only (total dose/cycle = 1000 mg)

Creatinine clearance on day 1 of a second and subsequent cycles <50 mL/min (<0.83 mL/s)

Discontinue streptozocin. Resume treatment after creatinine clearance >50 mL/min

Altered LFTs

No streptozocin adjustments recommended since hepatic metabolism does not appear to be important. Hold fluorouracil if total bilirubin >5 mg/dL (>85.5 μmol/L). In individual patients, titrate fluorouracil dosage to keep hematologic toxicities no greater than mild-to-moderate

Hematologic toxicities

Streptozocin and fluorouracil doses are titrated to produce no greater than mild-to-moderate hematologic toxicities

Efficacy

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Efficacy

Study

Objective Response Rate

Median Duration of Response

Moertel et al, 1980

63% (CR 33%)

17 months

Eriksson et al, 1990^✫

45%

27.5 months

Moertel et al, 1992

45%

6.9 months

^✫Combined results of streptozocin in combination with fluorouracil or doxorubicin as first-line treatment

Toxicity

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Toxicity

All Grades

Grades 1/2

Grades 3/4

Nausea

54–85%

—

22–41% (severe)

Anemia

N/A

Leukopenia

2–56%

—

25% G3; 4% G4

Thrombocytopenia

15–25%

6–11%

Elevated creatinine

30–36%

N/A

Renal failure

—

7% (G4)

Diarrhea

—

33% (mild)

2% (severe)

Stomatitis

—

5–19% (mild)

5% (severe)

Urinary albumin >30 mg/day

65%

—

>1.25-times increase in LFTs

34%

—

Therapy Monitoring

Before each cycle of treatment: WBC with differential and platelet count, liver function tests, renal function tests

REGIMEN: STREPTOZOCIN + DOXORUBICIN

Listen

Regimen: Streptozocin + Doxorubicin

Moertel CG et al. N Engl J Med 1992;326:519–523

Premedications and hydration:

1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously, starting 1.5 hours before administration of chemotherapy, continuing during administration and for approximately 1.5 hours afterward

Induction course:

Streptozocin 1000 mg/day; administer intravenously in 100–1000 mL 0.9% NS or 5% dextrose injection (D5W) over 30–120 minutes for 5 consecutive days, on days 1–5 (total dose/cycle = 5000 mg)

Doxorubicin 40 mg/m²; administer by intravenous injection over 3–5 minutes on day 1 (total dosage/cycle = 40 mg/m²)

Subsequent courses: (beginning 3 weeks after the induction cycle)

Streptozocin 2000 mg; administer intravenously in 100–1000 mL 0.9% NS or D5W over 30–120 minutes on day 1, every 3 weeks (total dose/cycle = 2000 mg)

Doxorubicin 40 mg/m²; administer by intravenous injection over 3–5 minutes on day 1 (total dosage/cycle = 40 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with streptozocin 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—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Populations Studied

A prospective study of 84 patients with neuroendocrine pancreatic tumors. Fifty-nine (70%) had malignant tumors and received 1 or more types of medical treatment (Eriksson B et al. Cancer 1990;65:1883–1890)
A multicenter randomized trial comparing streptozocin + fluorouracil, streptozocin + doxorubicin, and chlorozotocin alone. One-hundred five patients with advanced islet-cell carcinoma (Moertel CG et al. N Engl J Med 1992;326:519–523)

Therapy Monitoring

Before each cycle of treatment: WBC with differential and platelet count, liver function tests, renal function tests
Before initiation of treatment with doxorubicin, and before every third cycle: Myocardial scintigraphy to assess cardiac function

Toxicity

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Toxicity

All Grades

Grades 1/2

Grades 3/4

Nausea

80%

—

20% (severe)

Anemia

N/A

Leukopenia

57%

—

Elevated creatinine

46%

N/A

Renal failure

—

4% (G4)

Diarrhea

—

5% (mild)

—

Stomatitis

—

5% (mild)

—

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Creatinine clearance on day 1 of a second and subsequent cycles = 60–75 mL/min (1–1.25 mL/s)

Give streptozocin 1000 mg/day for 2 consecutive days, on days 1 and 2 (total dose/cycle = 2000 mg)

Creatinine clearance on day 1 of a second and subsequent cycles = 50–60 mL/min (0.83–1 mL/s)

Give streptozocin 1000 mg on day 1 only (total dose/cycle = 1000 mg)

Creatinine clearance on day 1 of a second and subsequent cycles <50 mL/min (<0.83 mL/s)

Discontinue streptozocin. Resume treatment after creatinine clearance >50 mL/min

Cumulative dose of doxorubicin ≥550 mg/m² (450 mg/m² in patients >70 years of age)

Monitor cardiac ejection fraction at baseline and reevaluate before repeating a treatment cycle or every other cycle

Altered LFTs

No streptozocin adjustments recommended since hepatic metabolism does not appear to be important

Hold doxorubicin if total bilirubin >5 mg/dL (>85.5 μmol/L)

Hematologic toxicities

Streptozocin and doxorubicin doses are titrated to produce no greater than mild-to-moderate hematologic toxicities

Efficacy

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Efficacy

Study

Objective Response Rate

Median Duration of Response

Eriksson et al, 1990^✫

45%

27.5 months

Moertel et al, 1992

69%

20 months

^✫Combined results of streptozocin in combination with fluorouracil or doxorubicin as first-line treatment

REGIMEN: SUNITINIB MALATE

Listen

Regimen: Sunitinib Malate

Raymond E et al. N Engl J Med 2011;364:501–513

Sunitinib malate 37.5 mg per day orally, continually (total dose/week = 262.5 mg)

Notes:

In patients without an objective tumor response who had grade ≤1 nonhematologic or grade ≤2 hematologic treatment-related adverse events during the first 8 weeks, the dose may be increased to 50 mg per day

Patients can receive somatostatin analogs as needed

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

Diarrhea management

Latent or delayed onset diarrhea^✫:

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

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

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

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

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide acetate (solution) 100–150 mcg; subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

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

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

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of nonalcoholic 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 ultrasoft 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, nonalcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist using 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 1 quart (~950 mL) of warm water. Follow with a plain water rinse
- Do not use mouthwashes that contain alcohols
Foam-tipped swabs (eg, Toothettes) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
- Choose foods that are easy to chew and swallow
- Take small bites of food, chew slowly, and sip liquids with meals
- Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
- For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
- Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

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

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

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

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

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Sunitinib Dose Levels

Starting dose: Level 1

37.5 mg once daily

Level −1

25 mg once daily

Level +1

50 mg once daily

Cutaneous Toxicities

Rash G ≥2

Hold sunitinib and provide immediate symptomatic treatment

If treatment is withheld for more than 3 weeks because of cutaneous toxicity

Discontinue therapy

When cutaneous toxicity resolves to G ≤1

Restart sunitinib at 1 dose level lower than the dose level administered at the time toxicity developed. Treatment for symptoms may continue indefinitely as a preventive measure

If cutaneous toxicity G3/4 recurs at reduced sunitinib doses

Again, hold sunitinib until the toxicity resolves to G ≤1, at which time sunitinib should be restarted at 1 dose level lower than the dose level administered at the time toxicity developed. Treatment for symptoms may continue indefinitely as a preventive measure

If cutaneous toxicity G3/4 recurs at dose level −1

Discontinue therapy

If cutaneous toxicity does not recur at reduced sunitinib doses with or without continued treatment for symptoms

The dose of sunitinib may be increased 1 dose level to the dose level administered at the time the cutaneous toxicity developed. Interrupt treatment by withholding sunitinib if toxicity recurs following the increase. When toxicity again resolves to G ≤1, resume sunitinib at the reduced dose previously tolerated

Diarrhea

G1/2 diarrhea

Focus on treatment for symptoms designed to resolve the diarrhea. No dose modifications will be made for G1/2 diarrhea unless G2 diarrhea persists for >2 weeks

If G2 diarrhea persists for more than 2 weeks

Follow the guidelines below for G3/4 diarrhea

If the diarrhea cannot be controlled with the preventive measures outlined, and is G3/4 or worsens by 1 grade level (G3 to G4) while on sunitinib and is not alleviated within 48 hours by antidiarrheal treatment

Hold sunitinib. Also withhold sunitinib if persistent G2 diarrhea (lasting >2 weeks) is not alleviated by antidiarrheal treatment while sunitinib use continues

If sunitinib is held for more than 3 weeks and the diarrhea does not resolve to G ≤1

Discontinue therapy

If within 3 weeks of holding sunitinib, diarrhea resolves to G ≤1

Restart sunitinib at 1 dose level less than the dose level administered at the time toxicity developed

If G3/4 diarrhea or persistent G2 diarrhea recurs at reduced sunitinib doses and the dose level at which persistent G2 diarrhea occurs is greater than dose level −1 (persistent is defined as lasting for >2 weeks)

Again, withhold sunitinib until the toxicity resolves to CTCAE (Common Terminology Criteria for Adverse Events) G ≤1, at which time sunitinib should be restarted at 1 dose level less than the dose level administered at the time toxicity developed. Treatment for symptoms may continue indefinitely as a preventive measure

If G3/4 diarrhea or persistent G2 diarrhea recurs at dose level −1 (persistent defined as lasting for more >2 weeks)

Discontinue therapy

If diarrhea does not recur at the reduced sunitinib doses with or without continued treatment for symptoms

The dose of sunitinib may be increased 1 dose level to the dose level administered at the time diarrhea developed. Interrupt treatment by withholding sunitinib if toxicity recurs following the increase. When toxicity again resolves to G ≤1, resume sunitinib at the reduced dose previously tolerated

Hypertension

Note: Patients should have their blood pressure checked once weekly during their first 24 weeks of therapy and for an 8-week period after an adjustment in their sunitinib dose

G1 Hypertension

Continue sunitinib at same dose and schedule

G2 Asymptomatic

Treat with antihypertensive medications and continue sunitinib at same dose and schedule

G2 Symptomatic, or persistent G2 despite antihypertensive medications, or diastolic BP >110 mm Hg, or G3 hypertension

Treat with antihypertensive medications. Hold sunitinib (maximum 3 weeks until symptoms resolve and diastolic BP <100 mm Hg); then continue sunitinib at 1 dose level lower. Note: Discontinue therapy if sunitinib is withheld >3 weeks

G4 Hypertension

Discontinue therapy

Other Adverse Events

Any other adverse event

Interrupt treatment. Resume at 25 mg/day when toxicity resolves to G ≤1. If symptoms do not recur, try increasing dose to the starting dose level, 37.5 mg daily

Recurrence of adverse event once dose increased to 37.5 mg/day

Interrupt treatment. Resume at 25 mg/day when toxicity resolves to G ≤1 but do not increase dose to the starting dose level, 37.5 mg daily

Coadministration of potent CYP3A4 inhibitors (eg, atazanavir, clarithromycin, itraconazole, ketoconazole, ritonavir, telithromycin, voriconazole)

Reduce sunitinib dose

Coadministration of potent CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenytoin, phenobarbital, rifampin, St. John's wort)

Increase sunitinib dose (to a maximum of 87.5 mg daily)

Efficacy

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Efficacy

Summary of Efficacy Measures in the Intention-to-Treat Population^✫

Outcome

Sunitinib (N = 86)

Placebo (N = 85)

p Value

Progression-Free Survival^✫

Patients with events—no. (%)

30 (35)

51 (60)

Progression

27 (31)

48 (56)

Death without progression

3 (3)

3 (4)

Patients with data censored—no. (%)

56 (65)

34 (40)

Probability event-free at 6 months—% (95% CI)

71.3 (60.0–82.5)

43.2 (30.3–56.1)

Estimated median progression-free survival, months

11.4 (7.4–19.8)

5.5 (3.6–7.4)

Hazard ratio for progression or death (95% CI)

0.42 (0.26–0.66)

<0.001

Overall Survival

Deaths—no. (%)

9 (10)

21 (25)

Patients with data censored—no. (%)

77 (90)

64 (75)

Survival probability at 6 months—% (95% CI)

92.6 (86.3–98.9)

85.2 (77.1–93.3)

Estimated median overall survival

Not reached

Hazard ratio for death (95% CI)

0.41 (0.19–0.89)

0.02

Objective Tumor Response

Best observed RECIST response—no. (%)

Complete response

2 (2)

Partial response

6 (7)

Stable disease

54 (63)

51 (60)

Progressive disease

12 (14)

23 (27)

Could not be evaluated

12 (14)

11 (13)

Objective response rate—%

9.3

0.007

CI, confidence interval; RECIST, Response Evaluation Criteria in Solid Tumors (Therasse P et al. J Natl Cancer Inst 2000;92:205–216)

^✫Data for a total of 3 patients (1 in the sunitinib group and 2 in the placebo group) were censored at day 1 in the analysis of PFS because of inadequate baseline tumor assessment

Patient Population Studied

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Patient Population Studied

A multinational, double-blind, placebo-controlled, phase III trial that randomly assigned patients in a 1:1 ratio to receive orally once daily placebo or sunitinib 37.5 mg. Patient characteristics included the following:

Demographic and Baseline Characteristics of the Patients

Sunitinib (N = 86)

Placebo (N = 85)

Variable

Age

Median—years

Range—years

25–84

26–78

≥65 y—no. (%)

22 (26)

23 (27)

Sex—no. (%)

Male

42 (49)

40 (47)

Female

44 (51)

45 (53)

ECOG performance status—no. (%)

53 (62)

41 (48)

33 (38)

43 (51)

1 (1)

Inherited genetic conditions—no. (%)

Multiple endocrine neoplasia type 1

2 (2)

von Hippel–Lindau disease

2 (2)

Time since diagnosis—years

Median

2.4

3.2

Range

0.1–25.6

0.1–21.3

Tumor functionality—no. (%)^✫

Nonfunctioning

42 (49)

44 (52)

Functioning

25 (29)

21 (24)

Not specified

19 (22)

20 (24)

Ki-67 index

Number of patients with data that could be evaluated

Index—no. (%)

≤2%

7 (19)

6 (17)

>2%–5%

16 (44)

14 (39)

>5%–10%

5 (14)

10 (28)

>10%

8 (22)

6 (17)

No. of sites of disease—no. (%)°

30 (35)

23 (27)

31 (36)

26 (31)

≥3

24 (28)

35 (41)

Not reported

1 (1)

Presence of distant metastases—no. (%)

Any, including hepatic

82 (95)

80 (94)

Extrahepatic

21 (24)

34 (40)

Previous treatment—no. (%)

Surgery

76 (88)

77 (91)

Radiation therapy

9 (10)

12 (14)

Chemoembolization

7 (8)

14 (16)

Radiofrequency ablation

3 (3)

6 (7)

Percutaneous ethanol injection

1 (1)

2 (2)

Somatostatin analogs^†

30 (35)

32 (38)

Previous systemic chemotherapy—no. (%)

Any

57 (66)

61 (72)

Streptozocin

24 (28)

28 (33)

Anthracyclines

27 (31)

35 (41)

Fluoropyrimidines

20 (23)

25 (29)

^✫Tumor functionality was reported by investigators. On the basis of the investigators' assessment, patients included in the "unknown" category had clinical symptoms but no identified corresponding neuropeptide secretion

^†This category includes patients who received somatostatin analogs (predominantly octreotide acetate and lanreotide acetate) before the first dose of study drug, regardless of whether they continued receiving somatostatin analogs concomitantly with the study drug

Toxicity

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Toxicity

Common Adverse Events in the Safety Population^✫

Sunitinib (N = 83)

Placebo (N = 82)

Event

All Grades

G1/2

G3/4

All Grades

G1/2

G3/4

Number of Patients (%)

Diarrhea

49 (59)

45 (54)

4 (5)

32 (39)

30 (37)

2 (2)

Nausea

37 (45)

36 (43)

1 (1)

24 (29)

23 (28)

1 (1)

Asthenia

28 (34)

24 (29)

4 (5)

22 (27)

19 (23)

3 (4)

Vomiting

28 (34)

25 (30)

23 (28)

2 (2)

Fatigue

27 (32)

23 (28)

4 (5)

22 (27)

15 (18)

7 (8)

Hair-color changes

24 (29)

23 (28)

1 (1)

Neutropenia

24 (29)

14 (17)

10 (12)

3 (4)

Abdominal pain

23 (28)

19 (23)

4 (5)

26 (32)

18 (22)

8 (10)

Hypertension

22 (26)

14 (17)

8 (10)

4 (5)

3 (4)

1 (1)

Palmar–plantar erythrodysesthesia

19 (23)

14 (17)

5 (6)

2 (2)

Anorexia

18 (22)

16 (19)

2 (2)

17 (21)

16 (20)

1 (1)

Stomatitis

18 (22)

15 (18)

3 (4)

2 (2)

Dysgeusia

17 (20)

4 (5)

Epistaxis

17 (20)

16 (19)

1 (1)

4 (5)

Headache

15 (18)

11 (13)

10 (12)

1 (1)

Insomnia

15 (18)

10 (12)

Rash

15 (18)

4 (5)

Thrombocytopenia

14 (17)

11(13)

3 (4)

4 (5)

Mucosal inflammation

13 (16)

12 (14)

1 (1)

6 (7)

Weight loss

13 (16)

12 (14)

1 (1)

9 (11)

Constipation

12 (14)

16 (20)

15 (18)

1 (1)

Back pain

10 (12)

14 (17)

10 (12)

4 (5)

^✫Adverse events were defined on the basis of the National Cancer Institute, Common Terminology Criteria for Adverse Events, version 3.0. Events listed are those of any grade that occurred in more than 15% of patients in either group.

Therapy Monitoring

Every 6 weeks to 3 months: Physical examination and routine laboratory tests including thyroid function tests
Response assessment: Every 2–3 cycles. A cycle is defined as a 6-week period

REGIMEN: EVEROLIMUS

Listen

Regimen: Everolimus

Yao JC et al. N Engl J Med 2011;364:514–523

Everolimus 10 mg/day orally, continually (total dose/week = 70 mg)

Notes:

Everolimus tablets should be swallowed whole (without breaking, crushing, or chewing) with water
Everolimus tablets and tablets for oral suspension may be taken with or without food, but should be taken consistently either with or without food
Commercially available formulations (a) tablets and (b) tablets for oral suspension should not be used in combination to administer a dose

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

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of nonalcoholic 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 ultrasoft 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, nonalcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist using 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 1 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

Diarrhea management

Latent or delayed onset diarrhea^✫:

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

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

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

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

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide acetate (solution) 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

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Invasive systemic fungal infection

Discontinue everolimus and treat with appropriate antifungal therapy

Noninfectious pneumonitis without symptoms with only radio-logic changes

Observe carefully. Specific therapies or drug interruption may not be necessary

Noninfectious pneumonitis with mild-to-moderate symptoms

Withhold therapy. Glucocorticoids may be initiated. Resume everolimus at a reduced dose depending on the individual clinical circumstances

Noninfectious pneumonitis with severe symptoms (including a decrease in DL_CO on pulmonary function tests)

Discontinue therapy and consider administering high doses of glucocorticoids

ANC <1000/mm³ or platelet count <75,000/mm³

Withhold therapy. Resume everolimus when symptoms improve to G ≤2 with everolimus dose reduced to 5 mg/day or 5 mg every other day but not <15 mg/week

Any nonhematologic G3/4 toxicity

Withhold therapy. Restart everolimus when symptoms improve to G ≤2 with everolimus dose reduced to 5 mg/day or 5 mg every-other-day but not <15 mg/week

G1/2 oral ulcerations

Topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Focus on pain control, oral hygiene, and IV fluid replacement or parenteral nutrition if severe

Hyperglycemia

Monitor blood sugar levels and institute oral hypoglycemic agent or insulin as needed

Hypertriglyceri-demia

Monitor triglycerides, instituting dietary interventions for minor elevations and lipid-lowering agents for levels >500 mg/dL (>5.65 mmol/L)

Patient Population Studied

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Patient Population Studied

International, multicenter, double-blind, phase III study. Patients were randomly assigned to treatment with oral everolimus 10 mg or matching placebo, both administered once daily in conjunction with best supportive care. Patients initially assigned to placebo who met criteria for disease progression could switch to open-label everolimus. Of the 203 patients initially assigned to receive placebo, 148 (73%) crossed over to open-label everolimus

Demographic and Baseline Clinical Characteristics of the Patients

Characteristic

Everolimus (N = 207)

Placebo (N = 203)

Age—years

Median

Range

23–87

20–82

Sex—no. (%)

Male

110 (53)

117 (58)

Female

97 (47)

86 (42)

WHO performance status—no. (%)

139 (67)

133 (66)

62 (30)

64 (32)

6 (3)

Histologic status of tumor—no. (%)

Well differentiated

170 (82)

171 (84)

Moderately differentiated

35 (17)

30 (15)

Unknown

2 (1)

Time from initial diagnosis—no. (%)

≤6 months

24 (12)

33 (16)

>6 months to ≤2 years

65 (31)

43 (21)

>2 years to ≤5 years

54 (26)

81 (40)

>5 years

64 (31)

46 (23)

Time from disease progression to randomization—no. (%)

≤1 months

73 (35)

61 (30)

>1 months to ≤2 months

43 (21)

53 (26)

>2 months to ≤3 months

30 (14)

29 (14)

>3 months to ≤12 months

58 (28)

54 (27)

>12 months

3 (1)

1 (<1)

No. of disease sites—no. of patients (%)

51 (25)

62 (31)

85 (41)

64 (32)

≥3

70 (34)

77 (38)

Organ involved—no. (%)

Liver

190 (92)

187 (92)

Pancreas

92 (44)

84 (41)

Lymph nodes

68 (33)

73 (36)

Lung

28 (14)

30 (15)

Bone

13 (6)

29 (14)

Efficacy

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Efficacy

Variable

Everolimus (N = 207)

Placebo (N = 203)

Progression-Free Survival (PFS)

Assessment by local investigator

Progression-free survival events—no. (%)

109 (53)

165 (81)

Censored data—no. (%)

98 (47)

38 (19)

Median progression-free survival—months

11.0

4.6

Hazard ratio for PFS with everolimus (95% CI); p value

0.35 (0.27–0.45); <0.001

Review by central adjudication committee

Progression-free survival events—no. (%)

95 (46)

142 (70)

Censored data—no. (%)

112 (54)

61 (30)

Median progression-free survival—months

11.4

5.4

Hazard ratio for PFS with everolimus (95% CI); p value

0.34 (0.26–0.44); <0.001

Estimated proportion of patients alive and progression-free at 18 months—% (95% CI)

34% (26–43)

9% (4–16)

Response According to RECIST Criteria

Partial response—no. (%)

10 (5)

4 (2)

Percent with stable disease

73%

51%

Percent with some tumor shrinkage

64%

21%

Overall Survival^✫

Hazard ratio for death with everolimus

1.05; 95% CI, 0.71–1.55; p = 0.59

^✫Median overall survival not reached. Of the 203 patients initially assigned to receive placebo, 148 (73%) crossed over to receive open-label everolimus

Toxicity^✫,†

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Toxicity^✫,†

Everolimus (N = 204)

Placebo (N = 203)

Median treatment duration, months (range)

8.79 (0.25–27.47)

3.74 (0.01–37.79)

Treatment a minimum of 12 months

31%

11%

Mean relative dose intensity^‡

0.86

0.97

Percentage requiring dose adjustments^§

59%

28%

Adverse Event

All Grades

G3/4

All G

G3/4

Number of Patients (%)

Stomatitis

131 (64)

14 (7)

34 (17)

Everolimus (N = 204)

Placebo (N = 203)

Rash

99 (49)

1 (<1)

21 (10)

Diarrhea

69 (34)

7 (3)

20 (10)

Fatigue

64 (31)

5 (2)

29 (14)

1 (<1)

Infections^✫✫

46 (23)

5 (2)

12 (6)

1 (<1)

Nausea

41 (20)

5 (2)

37 (18)

Peripheral edema

41 (20)

1 (<1)

7 (3)

Decreased appetite

40 (20)

14 (7)

2 (1)

Headache

39 (19)

13 (6)

Dysgeusia

35 (17)

8 (4)

Anemia

35 (17)

12 (6)

6 (3)

Epistaxis

35 (17)

Pneumonitis^††

35 (17)

5 (2)

Weight loss

32 (16)

9 (4)

Vomiting

31 (15)

13 (6)

Pruritus

30 (15)

18 (9)

Hyperglycemia

27 (13)

11 (5)

9 (4)

4 (2)

Thrombocytopenia

27 (13)

8 (4)

1 (<1)

Asthenia

26 (13)

2 (1)

17 (8)

2 (1)

Nail disorder

24 (12)

1 (<1)

2 (1)

Cough

22 (11)

4 (2)

Pyrexia

22 (11)

Dry skin

21 (10)

9 (4)

^✫Drug-related adverse events occurring in ≥10% of patients

^†Median follow-up period of 17 months

^‡Ratio of administered doses to planned doses

^§Reductions or temporary interruptions

Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration

^✫✫Includes all types of infections

^††Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis

Therapy Monitoring

Prior to starting treatment and periodically thereafter: Renal function, CBC with differential, blood glucose, and serum lipid profiles
ECG: A 12-lead ECG should be performed before the start of treatment, weekly for at least the first 2 weeks. Additional ECGs may be performed depending on the QTc. If the dose is increased, then at least 1 additional ECG should be obtained
Safety assessment: Every 2–4 weeks for the first 3 cycles; every 4–8 weeks, thereafter
Response assessment: Every 8–12 weeks

REGIMEN: CISPLATIN + ETOPOSIDE

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Regimen: Cisplatin + Etoposide

Fjällskog M-LH et al. Cancer 2001;92:1101–1107

Moertel CG et al. Cancer 1991;68:227–232

Hydration days 2 and 3:

≥1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously at a rate that produces a diuresis ≥100 mL/h, starting at least 2 hours before chemotherapy administration. Continue hydration during chemotherapy administration and for at least 2 hours afterward. Mannitol or furosemide may be given as needed to enhance diuresis and prevent excessive fluid retention. Encourage increased oral intake of nonalcoholic fluids. Monitor and replace electrolytes as needed (potassium, magnesium, sodium)

Etoposide 100 mg/m² per day; administer intravenously, diluted in a volume of 0.9% NS to a concentration within the range of 0.2–0.4 mg/mL, over 60 minutes on 3 consecutive days, on days 1–3, every 4 weeks (total dosage/cycle = 300 mg/m²)

Cisplatin 45 mg/m² per day; administer intravenously in 100–250 mL 0.9% NS over 1 hour on 2 consecutive days, on days 2 and 3, every 4 weeks (total dosage/cycle = 90 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is LOW

Emetogenic potential on days 2 and 3 is HIGH, with a potential for delayed symptoms

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

Toxicity

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Toxicity

All Grades

Grades 1/2

Grades 3/4

Nephrotoxicity

53–66%

—

2% (severe)

Anemia

89%

Decreased Hb: 1–3 g/dL (38%); 3–4 g/dL (29%); >4 g/dL (22%)

Leukopenia

100%

35%

65%

Thrombocytopenia

—

49%

35%

Peripheral neuropathy

—

17%

75%

Ototoxicity

—

2–8%

—

Diarrhea

16%

—

Stomatitis

13%

11%

Nausea

96%

83%

13%

Alopecia

100%

—

Dermatitis

—

4%,

—

Fever

—

Patient Populations Studied

Nonrandomized study of 15 patients with malignant pancreatic endocrine tumors (4 were poorly differentiated endocrine carcinomas) treated with cisplatin + etoposide as second- or third-line treatment (Fjällskog M-LH et al. Cancer 2001;92:1101–1107)
Prospective, nonrandomized study of 45 patients with neuroendocrine tumors among whom 14 had well-differentiated pancreatic endocrine tumors (Moertel CG et al. Cancer 1991;68:227–232)

Efficacy

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Efficacy

Study

Objective Response Rate

Median Duration of Response

Moertel et al, 1991^✫

67%

8 months

Fjällskog et al, 2001^†

53%

9 months

^✫Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months

^†Includes foregut carcinoids and endocrine pancreatic tumors. No difference in response between patients with well-differentiated or poorly differentiated endocrine pancreatic carcinoma

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Day 1 ANC <1500/mm³ or platelets <100,000/mm³

Delay treatment 1 week or until ANC >1500/mm³ and platelets >100,000/mm³, then administer full doses

ANC at nadir <500/mm³

Administer filgrastim during subsequent cycles:

Administer filgrastim on days 4–11, or
Administer pegfilgrastim at least 24 hours after completing chemotherapy, and/or
Decrease etoposide dosage by 25%

Albumin <3.2 g/dL (<32 g/L)

Reduce etoposide dosage by 50%

Albumin <2.5 g/dL (<25 g/L)

Discontinue etoposide until albumin ≥2.5 g/dL (≥25 g/L)

Therapy Monitoring

Before and during each cycle of treatment: Body weight to detect excessive fluid retention
Days 7, 10, and 14 of each cycle: WBC with differential count
Every cycle: Liver and renal function tests

SECOND-LINE REGIMEN FOR INOPERABLE WELL- AND POORLY-DIFFERENTIATED NEUROENDOCRINE TUMORS AND FOR PATIENTS WHO CANNOT TOLERATE MORE INTENSIVE THERAPIES: TEMOZOLOMIDE

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Second-Line Regimen for Inoperable Well- and Poorly-Differentiated Neuroendocrine Tumors and for Patients WHO Cannot Tolerate More Intensive Therapies: Temozolomide

Ekeblad S et al. Clin Cancer Res 2007;13:2986–2991

Induction course:

Temozolomide 150 mg/m² per day; administer orally for 5 consecutive days, days 1–5 (total dosage during cycle 1 = 750 mg/m²)

Subsequent courses:

Temozolomide 200 mg/m² per day; administer orally for 5 consecutive days, days 1–5, every 4 weeks (total dosage/cycle = 1000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

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

See Chapter 47 for more information

Patient Populations Studied

Retrospective study of 36 patients with advanced neuroendocrine tumors, among whom 12 had a diagnosis of pancreatic endocrine tumor

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Leukopenia G ≥2 on day 1 of a new cycle

Delay starting the cycle for 1 week. Then, decrease temozolomide dosage by 50 mg/m² each day it is given; eg, from 200 mg/m² per day to 150 mg/m² per day, from 150 mg/m² per day to 100 mg/m² per day

Therapy Monitoring

Before each treatment cycle: WBC including differential and platelet count

Efficacy (N = 12)

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Efficacy (N = 12)

Ekeblad S et al. Clin Cancer Res 2007;13:2986–2991

Complete response

Partial response

Stable disease

67%

Progressive disease

25%

Median time to progression for whole group

7 months

Toxicity

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Toxicity

Ekeblad S et al. Clin Cancer Res 2007;13:2986–2991

Grade 1

Grade 2

Grade 3

Grade 4

Anemia

9 (26%)

1 (3%)

Thrombocytopenia

8 (23%)

5 (14%)

Leukopenia

3 (9%)

1 (3%)

Neutropenia

1 (3%)

Fatigue

8 (23%)

3 (9%)

2 (6%)

1 (3%)

Nausea (with premedication)

10 (29%)

SECOND-LINE REGIMEN FOR INOPERABLE WELL- AND POORLY DIFFERENTIATED NEUROENDOCRINE TUMORS: ¹⁷⁷LU-OCTREOTATE ([¹⁷⁷LU-DOTA⁰, TYR³] OCTREOTATE) SOMATOSTATIN ANALOGS LABELED WITH RADIOACTIVE [¹⁷⁷LU-DOTA⁰, TYR³]

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Second-Line Regimen for Inoperable Well- and Poorly Differentiated Neuroendocrine Tumors: ¹⁷⁷Lu-Octreotate ([¹⁷⁷Lu-DOTA⁰, Tyr³] Octreotate) Somatostatin Analogs Labeled with Radioactive [¹⁷⁷Lu-DOTA⁰, Tyr³]

de Keizer B et al. Eur J Nucl Med Mol Imaging 2008;35:749–755

Pretreatment:

Long-acting somatostatin analogs were discontinued 1 month before starting ¹⁷⁷Lu-octreotate therapy, and replaced with octreotide acetate solution. Octreotide acetate solution was discontinued 1 day before starting ¹⁷⁷Lu-octreotate

Preparation of ¹⁷⁷Lu-octreotate ([¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate)

[DOTA⁰,Tyr³]octreotate is obtained from Mallinckrodt Inc., St. Louis, MO

¹⁷⁷LuCl₃ is obtained from a facility with a nuclear reactor

¹⁷⁷Lu-octreotate is prepared locally

Premedication:

Granisetron 1–3 mg or ondansetron 8 mg acetate solution intravenously

An admixture of amino acids (lysine 2.5% and arginine 2.5%) in 1000 mL 0.9% sodium chloride injection) acetate solution intravenously over 4 hours starting 30 minutes before ¹⁷⁷Lu-octreotate administration

Administration of ¹⁷⁷Lu-octreotate ([¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate)

¹⁷⁷Lu-octreotate is administered intravenously over 30 minutes

Cycle dosages: 100 mCi (3.7 GBq), 150 mCi (5.6 GBq) or 200 mCi (7.4 GBq) with 200 mCi (7.4 GBq) used most frequently

Interval between treatments: 6–10 weeks

Treatment duration: Treatment is continued up to a cumulative dose of 750–800 mCi (27.8–29.6 GBq; corresponding with a radiation dose to the bone marrow of 2 Gy)

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

Patient Populations Studied

Nonrandomized prospective study of 310 patients with gastroenteropancreatic neuroendocrine tumors, among whom 91 had a diagnosis of pancreatic endocrine tumor. Of the whole group, 89% had liver metastases (Kwekkeboom DJ et al. J Clin Oncol 2008;26:2124–2130)
Retrospective analysis of 479 patients with gastroenteropancreatic neuroendocrine tumors, among whom 159 had a diagnosis of pancreatic endocrine tumor. Of the group, 88% had liver metastases and 26% had bone metastases (de Keizer B et al. Eur J Nucl Med Mol Imaging 2008;35:749–755)

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

If dosimetric calculations indicate radiation dose to the kidneys will exceed 23 Gy

Reduce the cumulative dose to 500–700 mCi

Toxicity

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Toxicity

de Keizer B et al. Eur J Nucl Med Mol Imaging 2008;35: 749–755

Kwekkeboom DJ et al. J Clin Oncol 2008;26:2124–2130

Toxicity

All Grades

Nausea

25%

Vomiting

10%

Abdominal discomfort

10%

G3/4 hematologic toxicity

9.5% of patients (3.6% of administrations)

WHO G1 reversible hair loss

62%

Serious liver toxicity

<1%

Myelodysplastic syndrome^✫

<1%

Hormonal crisis

1.3%^†,‡

^✫Two to 3 years after the last treatment with ¹⁷⁷Lu-octreotate

^†Two of 3 patients with VIPoma

^‡Hormone-release crisis occurred immediately or within 48 hours after ¹⁷⁷Lu-octreotate administration during 10 of 1691 (0.6%) treatments. The crisis was characterized by flushing and severe diarrhea in all patients ± nausea, hypotension, and metabolic abnormalities

Efficacy (N = 91)

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Efficacy (N = 91)

A 43% objective radiologic response
Median time to progression 40 months in patients who did not have progressive disease

Tumor Responses 3 Months After the Last Administration of ¹⁷⁷Lu-Octreotate

Tumor Type

Response: Number of Patients (%)

Nonfunctioning pancreatic

4 (6%)

26 (36%)

13 (18%)

19 (26%)

10 (14%)

Gastrinoma

—

5 (42%)

4 (33%)

2 (17%)

1 (8%)

Insulinoma

—

3 (60%)

—

1 (20%)

VIPoma

—

1 (50%)

—

1 (50%)

Total

4 (5%)

35 (38%)

17 (19%)

22 (24%)

13 (14%)

CR, Complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease; VIPoma, vasoactive intestinal peptide-secreting tumor

Therapy Monitoring

Before each therapy: CBC with differential, and renal and liver function tests

PANCREATIC NEUROENDOCRINE TUMOR REGIMEN: CAPTEM (CAPECITABINE + TEMOZOLOMIDE)

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CAPTEM (CAPECITABINE + TEMOZOLOMIDE)

Strosberg JR et al. Cancer. 2011;117:268–275

Capecitabine 750 mg/m² per dose; administer orally twice daily (approximately every 12 hours), within 30 minutes after the end of a meal, for 14 consecutive days (28 doses) on days 1–14, every 28 days (total dosage/28-day cycle = 21,000 mg/m²)

Temozolomide 200 mg/m² per dose, administer orally once daily at bedtime for 5 consecutive days (5 doses) on days 10–14, every 28 days (total dosage/28-day cycle = 1000 mg/m²)

Notes:

Temozolomide doses are rounded to use combinations of 5-, 20-, 100-, 140-, 180-, and 250-mg capsules that most closely approximate calculated values
Capecitabine doses are rounded to use combinations of 500-mg and 150-mg tablets that most closely approximate calculated values
Patients who miss a dose of capecitabine should be instructed to continue with the usual dosing schedule without making up the missed dose and to contact their physician for further instructions
Patients who take too much (ie, overdose) capecitabine should contact their doctor immediately and present to the emergency department for further care and consideration for timely treatment with the antidote uridine triacetate
Although food decreases the rate and extent of drug absorption and the time to peak plasma concentration and systemic exposure (AUC) for capecitabine and fluorouracil, product labeling recommends giving capecitabine within 30 minutes after the end of a meal because established safety and efficacy data are based on administration with food
Initial capecitabine dosage should be decreased by 25% in patients with moderate renal impairment (baseline creatinine clearance = 30–50 mL/min [0.5–0.83 mL/s]); ie, a dosage reduction from 750 mg/m² per dose, to 550 mg/m² per dose, twice daily. Capecitabine use is contraindicated in persons with severe renal impairment (creatinine clearance <30 mL/min [<0.5 mL/s])

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–9 (capecitabine alone) is MINIMAL-LOW

Emetogenic potential on days 10–14 (temozolomide + capecitabine) is MODERATE-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—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV infection and for VZV post-exposure prophylaxis

See Chapter 47 for factors that modify risk of infection, caveats, and more information

Hand-and-foot syndrome (HFS) or palmar-plantar erythrodysesthesia (PPE)

For patients who develop HFS, use topical emollients (eg, Aquaphor), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

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

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

Patient Population Studied

The study involved 30 patients with metastatic, moderately to well-differentiated pancreatic endocrine carcinoma. Patients who had previously received octreotide, interferon-α, or locoregional therapy with hepatic artery embolization were eligible. Patients who had received prior systemic chemotherapy in the metastatic setting were not eligible. Patients received oral capecitabine 750 mg/m² twice daily on days 1–14 of a 28-day cycle. Patients also received oral temozolomide 200 mg/m² once daily (at bedtime) on days 10–14, with ondansetron 8 mg before each dose of temozolomide.

Efficacy (N = 30)

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Objective response rate

70% (95% CI 54–86%)

Median progression-free survival

18 months (95% CI 9–31 months)

Overall survival at 2 years

92% (95% CI 72–98%)

Duration of response^*

20 months (95% CI 14–26 months)

^*Among responding patients

Therapy Monitoring

During first cycle and in any cycle after a dose adjustment, weekly CBC with differential and platelet count to assess dose
Before each cycle: Physical examination, WBC with differential and platelet count, liver function tests, renal function tests. Serum chromogranin or other serum/urine hormones/peptides if these are being followed
Response assessment: Every 2–3 cycles. A cycle is defined as a 4-week period
Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly

Treatment Modifications

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CAPTEM (CAPECITABINE + TEMOZOLOMIDE)

Starting doses: Capecitabine 750 mg/m² twice daily (days 1–14); temozolomide 200 mg/m² once daily (days 10–14)

Adjusted capecitabine doses: 600 mg/m², 500 mg/m², and 375 mg/m²

Adjusted temozolomide doses: 150 mg/m² and 100 mg/m²

Note: Doses omitted for toxicity are not replaced or restored; instead patient resumes planned treatment cycles

Adverse Event

Treatment Modification

Baseline ANC <1500/mm³ or baseline platelets <100,000/mm³

Delay start of treatment until ANC ≥1500/mm³ and platelets ≥100,000/mm³

ANC <1000/mm³ or platelets <50,000/mm³during cycle

Withhold administration of therapy until recovery to ANC ≥1500/mm³ or baseline platelets ≥75,000/mm³. In subsequent cycle(s) administer 66–75% of the dose given at the time toxicity occurred

ANC <500/mm³ or platelets <25,000/mm³during cycle (G4 toxicity)

Discontinue permanently or if physician deems it to be in the patient’s best interest to continue, interrupt until recovery to £G1, then resume therapy £50% of the doses given at the time G4 toxicity occurred

Drug-related increase in serum bilirubin to >3× ULN (G3 toxicity)

Stop administration of capecitabine and temozolomide; provide supportive care. Do not resume capecitabine or temozolomide until serum bilirubin <3× ULN. When treatment is resumed administer 50–66% of the doses given at the time toxicity occurred. If serum bilirubin >10× ULN discontinue therapy. Note once the dose has been reduced, it should not be increased at a later time

Capecitabine-specific dose modifications

Patients receiving phenytoin and coumarin-derivative anticoagulants

Monitor carefully as the dose of phenytoin and coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine

G2–4 diarrhea

Stop administration of capecitabine; provide supportive care including fluids and loperamide; if severe send stool for culture. Do not resume capecitabine until diarrhea resolved to £G1. In subsequent cycle(s) administer a fraction of the capecitabine dose given at the time toxicity occurred or discontinue as follows: G2 = 66–80%; G3 = 50–66%; G4 = discontinue. Note once the dose has been reduced, it should not be increased at a later time

G2–4 mucositis

Stop administration of capecitabine; provide supportive care. Do not resume capecitabine until toxicity resolved to £G1. In subsequent cycle(s) administer a fraction of the capecitabine dose given at the time toxicity occurred or discontinue as follows: G2 = 66–80%; G3 = 50–66%; G4 = discontinue. Note once the dose has been reduced, it should not be increased at a later time

G2–4 dehydration

HFS or PPE or chemotherapy-induced acral erythema^*

Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN; severe mucocutaneous reactions, some with fatal outcome)

Discontinue treatment permanently

Moderate renal impairment (creatinine clearance = 30–50 mL/min)

Administer 75% of the starting capecitabine dose

Toxicity in the setting of DPD deficiency (early-onset severe mucositis, diarrhea, neutropenia, and neurotoxicity)

Occurs in individuals with homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near-complete absence of DPD activity (eg, mucositis, diarrhea, neutropenia, and neurotoxicity). Discontinue capecitabine permanently. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test

Adjustments for other nonhematologic toxicities due to capecitabine, temozolomide, or both

Continue treatment and maintain dose in subsequent cycle

G2 (1st occurrence)

Interrupt until resolved to £G1; administer 100% of the dose in subsequent cycle(s)

G2 (2nd occurrence)

Interrupt until resolved to £G1; administer 75–80% of the dose in subsequent cycle(s). Note once the dose has been reduced, it should not be increased at a later time

G2 (3rd occurrence)

Interrupt until resolved to £G1; administer 50% of the dose in subsequent cycle(s). Note once the dose has been reduced, it should not be increased at a later time

G2 (4th occurrence)

Discontinue treatment permanently

G3 (1st occurrence)

Interrupt until resolved to £G1; administer 75–80% of the dose in subsequent cycle(s). Note once the dose has been reduced, it should not be increased at a later time

G3 (2nd occurrence)

Interrupt until resolved to £G1; administer 50% of the dose in subsequent cycle(s). Note once the dose has been reduced, it should not be increased at a later time

G3 (3rd occurrence)

Discontinue treatment permanently

G4 (1st occurrence)

Discontinue permanently or if physician deems it to be in the patient’s best interest to continue, interrupt until resolved to £G1, then resume therapy at £50% of the dose given at the time G4 toxicity occurred. Note once the dose has been reduced, it should not be increased at a later time

^*Median time to onset = 79 days (range 11–360)

· G1: Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands or feet, or both, and/or discomfort that does not disrupt normal activities

· G2: Painful erythema and swelling of the hands or feet, or both, and/or discomfort affecting the patient’s activities of daily living

· G3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or both, and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living

Adverse Events (N = 30)

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Grade (%)*

Grade 1

Grade 2

Grade 3

Grade 4

Thrombocytopenia

HFS

Nausea

Fatigue

Anemia

Neutropenia

Herpes zoster

Vomiting

Elevated AST level

Elevated ALT level

Leukopenia

Vaginal bleeding

Diarrhea

Herpes labialis

^*According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed 12 December 2017]

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Chapter 30: Pancreatic Endocrine Tumors

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INTRODUCTION

Expert Opinion

REGIMEN: SOMATOSTATIN ANALOGS OCTREOTIDE ACETATE

REGIMEN: LONG-ACTING SOMATOSTATIN ANALOGS

REGIMEN: STREPTOZOCIN + FLUOROURACIL

REGIMEN: STREPTOZOCIN + DOXORUBICIN

REGIMEN: SUNITINIB MALATE

REGIMEN: EVEROLIMUS

REGIMEN: CISPLATIN + ETOPOSIDE

SECOND-LINE REGIMEN FOR INOPERABLE WELL- AND POORLY-DIFFERENTIATED NEUROENDOCRINE TUMORS AND FOR PATIENTS WHO CANNOT TOLERATE MORE INTENSIVE THERAPIES: TEMOZOLOMIDE

SECOND-LINE REGIMEN FOR INOPERABLE WELL- AND POORLY DIFFERENTIATED NEUROENDOCRINE TUMORS: ¹⁷⁷LU-OCTREOTATE ([¹⁷⁷LU-DOTA⁰, TYR³] OCTREOTATE) SOMATOSTATIN ANALOGS LABELED WITH RADIOACTIVE [¹⁷⁷LU-DOTA⁰, TYR³]

PANCREATIC NEUROENDOCRINE TUMOR REGIMEN: CAPTEM (CAPECITABINE + TEMOZOLOMIDE)

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