DEFINITIONS: Neutropenia is defined as an Absolute Neutrophil Count (ANC) of 500 or less per microL or ANC less than 1000/microL and a predicted decline to 500 or less per microL over the next 48 hours. Febrile Neutropenia (FN) is defined as a temperature of 38.0 degrees C orally in a Neutropenic patient.
RISK FACTORS: The risk for of Febrile Neutropenia is not only dependent on the treatment regimen and delivered dose intensity but also on the overall condition of the patient. It is important that all these risk factors be taken into consideration before considering Primary Prophylaxis with CSF (Colony Stimulating Factors given prior to first chemotherapy cycle).
Patients at a risk of developing Febrile Neutropenia include
1) Patients 65 years of age or older
2) Poor Performance Status
3) Previous chemotherapy or radiation therapy
4) Preexisting Neutropenia
5) Tumor involving the bone marrow
6) Poor Liver function with elevated bilirubin
7) Poor renal function
8) Recent surgery
9) Preexisting Infection
10) Open wounds
Based on the treatment regimen and patient related risk factors, patients can fall in one of the three risk groups to develop Febrile Neutropenia (FN)
High Risk: More than 20% risk of FN
Intermediate Risk: 10-20% risk of FN
Low Risk: Less than 10% risk
Approximately 25%-40% of patients who had no prior chemotherapy develop FN with commonly prescribed chemotherapy regimens1. A notable group falling in the high risk category are those in whom dose intensity has to be maintained, in spite of a Neutropenic complication in the immediate previous chemotherapy cycle. The risk of FN associated with various chemotherapy regimens has been extensively published2 and is beyond the scope of this review.
BENEFITS OF CSF:
1) Use of G-CSF (Granulocyte – Colony Stimulating Factor) as recommended, reduces the incidence, severity and duration of chemotherapy induced Neutropenia. Neutropenic colitis or Typhlitis can be associated with prolonged neutropenia in patients with hematologic malignancies. The decreased duration of WBC (White Blood Cell) nadir in turn can decrease the chance of infectious complications including infection related mortality and improve quality of life3
2) There can be potential cost savings, preventing patient hospitalization4
3) G-CSF can facilitate delivery of full dose intensity of chemotherapy on schedule5
RISKS ASSOCIATED WITH CSF:
1) Mild to moderate bone pain
2) Rare cases of Splenic rupture
3) Allergic reactions involving the skin, cardiovascular and respiratory system with Filgrastim
FDA APPROVED MYELOID GROWTH FACTORS:
LEUKINE® (Granulocyte Macrophage-CSF, Sargramostim)
The first three are currently approved for use in preventing chemotherapy induced Neutropenia, whereas LEUKINE® is indicated for use in patients with Acute Myeloid Leukemia following induction therapy and in Stem Cell Transplantation
PREVENTION OF NEUTROPENIC COMPLICATIONS:
1) Primary prophylaxis (Prior to start of the first cycle of chemotherapy) with CSF’s is recommended for all patients who are considered to be at high risk for FN6, regardless of whether the treatment intent is palliative or curative
2) CSF’s should be considered on an individualized basis for patients who fall in the Intermediate risk category.
3) CSF’s are not usually recommended for patients considered to be at low risk for FN. The exception however will be for those patients who are being treated with a curative intent or receiving adjuvant therapy who cannot risk FN as this could lead to fatal complications.
4) Research in the area of pharmacogenomics may help us better understand how Neutropenic complications could be prevented
NEUTROPENIA AFTER FIRST CYCLE OF CHEMOTHERAPY:
1) FN or dose limiting Neutropenia (Unable to give treatment on schedule) following first cycle of chemotherapy warrants use of CSF
2) If a patient experiences dose limiting Neutropenia or FN inspite of primary prophylaxis with CSF’s, dose reductions or change in treatment regimen has to be considered
3) For a patient hospitalized with FN, CSF’s may be considered if the patient is deemed to be at high risk, provided the patient did not receive prophylactic NEULASTA® following chemotherapy. NEULASTA® is only indicated for the prevention of chemotherapy induced Neutropenia but not for therapy, when a patient presents with Neutropenia.
ADMINISTRATION OF CSF:
1) Start NEUPOGEN® within 24-72 hours after completion of chemotherapy and continue until post nadir ANC is normal or close to normal
2) NEULASTA® is administered 24 hours after completion of chemotherapy and is not recommended for administration on a schedule less than 2 weeks.
3) NEULASTA® is not recommended following weekly chemotherapy2.
MANAGEMENT of Febrile Neutropenia – OTHER ASPECTS:
1) Hospitalization is recommended
2) Patients should be started on broad spectrum antibiotics, following appropriate cultures
3) Start CSF if appropriate
4) Good hand hygiene
5) If prolonged Neutropenia is anticipated, minimize exposure to pets and live plants
1. Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 2002;62 Suppl 1:1-15.
2. Crawford J, Allen J, Armitage J et al. Myeloid growth factors. J Natl Compr Canc Netw 2011;9(8):914-932.
3. Fortner BV, Schwartzberg L, Tauer K, Houts AC, Hackett J, Stolshek BS. Impact of chemotherapy-induced neutropenia on quality of life: a prospective pilot investigation. Support Care Cancer 2005;13(7):522-528.
4. Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol 2004;50(2):129-146.
5. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21(8):1431-1439.
6. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-3205.
Mucositis or inflammation of the mucous membranes is one of the most common complications of cancer treatment. This condition is often underestimated and involves the entire gastrointestinal tract. Oral mucositis can result in significant morbidity and for this reason properly managing oral mucositis can have a significant impact on the patient’s quality of life. With the breakdown in the mucosal barrier, patients with severe myelosuppression and mucositis can potentially contract serious infections, requiring hospitalization1. Further, appropriate management of oral mucositis will allow optimal treatment of the patient’s cancer without treatment interruptions.
Pathogenesis of Mucositis
It involves the production of reactive oxygen species (ROS) which damages the mucosal cells and its vasculature, followed by active inflammation, ulceration, and subsequent healing2,3. Genetics may also play a role in increasing the incidence and duration of mucositis in certain individuals4,5.
WHO (World Health Organization) Mucositis Scale
Grade 1 – Oral Soreness,Erythema
Grade 2 – Ulcers but able to eat solids
Grade 3 – Oral ulcers and able to take liquids only
Grade 4 – Oral alimentation impossible
The risk to develop mucositis can be Treatment Related or Patient Related
Risk Factors-Treatment Related
1. Multiple cycles of chemotherapy with agents such as 5-FU, Methotrexate, Cisplatin and Cyclophosphamide.
2. Concurrent chemotherapy and radiation
3. Myeloablative therapy and Transplantation
Risk Factors-Patient Related
1. Women are at a greater risk6
2. African Americans tend to have a lower incidence of mucositis with Fluorouracil than Caucasians7
3. Oral mucosa dryness
4. Irritation and trauma caused by ill fitting dentures
5. Dental hygiene
Prevention of Oral Mucositis
• Oral hygiene should be rigorously maintained by flossing every day, brushing teeth with a soft toothbrush twice a day and rinsing the mouth with bland rinses such as normal saline, baking soda or water.
• Cryotherapy (Ice chips) for 30 minutes before and for 4 to 6 hours after therapy. Cryotherapy causes vasoconstriction resulting in decreased drug delivery to the oral mucosa8.
• KEPIVANCE® (Palifermin), a keratinocyte growth factor, given IV, only for patient’s undergoing myeloablative therapy and transplantation9. This agent increases the thickness of the mucosa.
• ETHYOL® (Amifostine), an organic, thiophosphate given IV, which scavenges reactive oxygen species (ROS), thereby reducing toxicity to the normal mucosa. It is recommended for prevention of xerostomia associated with head and neck radiation, as well as mucositis associated with high-dose melphalan. It is also approved for the prevention of renal toxicity associated with platinum compounds10.
Treatment of Oral Mucositis
• Bland rinses as mentioned above
• Topical anesthetics such as lidocaine viscous or gel
• Magic mouthwash, which is a combination of viscous lidocaine, nystatin, diphenhydramine, and dyclonine magnesium hydroxide. When using topical anesthetics, patients should be instructed not to swallow or gargle, as this can impair the gag reflex and put the patient at a risk for aspiration pneumonia. No more than 25 ml of topical anesthetic is recommended over a 24 hr period, as there is a chance for systemic absorption.
• Other agents that may benefit include GELCLAIR®, MUGARD®, CAPHOSOL®, and MUCOTROL®.
• Myelosuppressed patients with severe mucositis can be at an increased risk of contracting viral and fungal infections. Prophylactic antiviral and antifungal agents must be considered along with prophylactic antibiotics and hematopoietic growth factors.
• Severe mucositis can be associated with pain. If narcotics are indicated, transdermal or liquid preparations should be considered. Managing constipation while on narcotics should not be overlooked.
• Some patients receiving radiation treatment for head and neck cancer may benefit from a prophylactic percutaneous endoscopy gastrostomy (PEG) tube.
• Patient’s with excess oral secretions secondary to mucositis may benefit from antihistamines and scopolamine patches.
• Chlorhexidine and alcohol-containing mouthwashes should be avoided.
• It is important that these patients are adequately hydrated and nourished, avoiding any food products that could traumatize the mucosa.
1. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003; 98(7):1531-1539.
2. Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 2007; 5(9 Suppl 4):3-11.
3. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004; 4(4):277-284.
4. Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98(1):231-234.
5. Zhang X, Diasio RB. Regulation of human dihydropyrimidine dehydrogenase: implications in the pharmacogenetics of 5-FU-based chemotherapy. Pharmacogenomics 2007; 8(3):257-265.
6. Chansky K, Benedetti J, Macdonald JS. Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 2005; 103(6):1165-1171.
7. McCollum AD, Catalano PJ, Haller DG et al. Outcomes and toxicity in african-american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst 2002; 94(15):1160-1167.
8. Tartarone A, Matera R, Romano G, Vigliotti ML, Di RN. Prevention of high-dose melphalan-induced mucositis by cryotherapy. Leuk Lymphoma 2005; 46(4):633-634.
9. Spielberger R, Stiff P, Bensinger W et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351(25):2590-2598.
10. Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-spectrum radioprotector. Oncologist 2007; 12(6):738-747.
Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy1,2. It is important to differentiate nausea from vomiting, as more patients experience nausea rather than vomiting3. There are 6 different categories of CINV
1. Acute CINV
2. Delayed CINV
3. Breakthrough CINV
4. Refractory CINV
5. Anticipatory CINV
6. Radiation Induced Nausea and Vomiting
ACUTE CINV: Acute CINV by definition begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment.
DELAYED CINV: This is defined as nausea and vomiting occurring more than 24 hours after chemotherapy administration and can persist for several days4. This is often underestimated, as a third of the patients receiving chemotherapy may experience delayed nausea and vomiting with out prior acute nausea or vomiting.
BREAKTHROUGH CINV: This is defined as nausea and/or vomiting experienced by patients despite prophylactic treatment with antiemetics. These patients require additional intervention with antiemetics to treat their symptoms.
REFRACTORY CINV: Patients on chemotherapy may experience nausea and vomiting following subsequent cycles of chemotherapy administration when prophylaxis/rescue for nausea and vomiting have failed in earlier cycles.
ANTICIPATORY CINV: This is a “learned conditioned response” with psychologic undertones as a result of prior experience of nausea and vomiting with chemotherapy. It usually occurs about 12 hours leading up to chemotherapy administration5,6. The incidence varies from 20%-50%. It is more often seen in younger patients and nausea is more common than vomiting. This entity is difficult to treat and may require psychologic counseling.
RADIATION INDUCED NAUSEA AND VOMITING: This is often experienced by patients undergoing Total Body Irradiation (TBI), a technique that is used prior to bone marrow transplantation7. Patients undergoing radiation to the upper abdomen will also experience nausea and vomiting8.
Pathophysiology of Nausea and Vomiting
The brain controls the multistep pathway that results in vomiting. There are two separate units in the medulla that play a vital role in the causation of nausea and vomiting.
• Chemoreceptor trigger zone (CTZ) also called Area Postrema, present on the floor of the fourth ventricle. This area is very sensitive to chemical stimuli and is easily accessible to emetogenic substances in the general circulation.
• Vomiting Center (Emetic Center) located in the reticular formation of the medulla. This center integrates the emetic response and coordinates the act of vomiting.
The neuroreceptors involved in mediating vomiting include Serotonin (5HT), Dopamine (D2), Neurokinin-1(NK-1), Cannabinoid(CB1), Opiate, Histamine(H1), Corticosteroid and Acetylcholine or Muscarinic(M) receptors. These receptors are located in the vomiting and vestibular centers of the brain9. The most important receptors involved in the emetic response however are Serotonin and Dopamine receptors10. Vomiting is triggered by the Vomiting Center after it receives impulses from CTZ, GI tract, and cerebral cortex and vestibular apparatus in the inner ear. Chemotherapeutic agents and radiation therapy generally induce vomiting by producing free radicals, which in turn act on the enterochromaffin cells, resulting in the release of Serotonin(5-hydroxytryptamine-5HT3). Serotonin activates the serotonin receptors. Activation of the receptors then activates the vagal afferent pathway, which in turn activates the vomiting center and causes an emetic response. Chemotherapeutic agents along with its metabolites also directly stimulate the CTZ by way of general circulation, triggering vomiting through the Vomiting Center.
Classification of Chemotherapeutic agents based on Emetogenicity11
High Risk: More than 90% of the patients experience acute emesis
Moderate Risk: 30-90% of the patients experience acute emesis
Low Risk: 10-30% of the patients experience acute emesis
Minimal Risk: Less than 10% of the patients experience acute emesis
Risk Factors for Nausea and Vomiting
• Emetogenic potential of the chemotherapy agent used
• Younger age
• Female gender
• History of motion sickness
• Alcohol consumption
Classification of Antiemetics
Serotonin (5-HT3) Receptor Antagonists
ZOFRAN ® (Ondansetron): This agent is the first in its class approved by the FDA in 1991 for the treatment of CINV. This first generation 5-HT3 receptor antagonist is available as an IV preparation, sublingual/chewable tablet, oral tablet and oral solution. This agent has a shorter half life than KYTRIL® and ALOXI®.
KYTRIL® (Granisetron): This first generation 5-HT3 receptor antagonist provides 24-hour protection against chemotherapy induced nausea and vomiting. It is available as a single dose Injection as well as tablets or oral solution
ALOXI ® (Palonosetron): This second generation 5-HT3 antagonist has a 100 fold higher binding affinity to 5-HT3 receptor than other 5-HT3 receptor antagonists12. This agent is effective in preventing both acute and delayed onset nausea and vomiting. This agent has to be given IV and oral administration is not feasible due to poor bioavailability, unlike the first generation 5-HT3 antagonists.
Neurokinin-1 (NK-1) Receptor Antagonist
EMEND® (Aprepitant): This agent selectively blocks the binding of substance P to the NK-1 receptor in the central nervous system and thereby complements the antiemetic activity of 5-HT3 receptor antagonists by virtue of its different mechanism of action. It is available as tablets as well as parenteral preparation. This agent can interact with several other drugs more, so when given orally because of first-pass metabolism13. It is therefore important to check the package insert for drug interactions.
Dopamine Receptor Antagonists
These agents antagonize dopamine (D2)-receptors which are involved in the emetic signaling through the chemoreceptor trigger zone. Dopamine receptor antagonists also counteract dopamine receptors in the stomach, implicated in decreasing stomach motility during nausea and vomiting. The three main classes of dopamine receptor antagonists are phenothiazines, butyrophenones, and benzamides.
Phenothiazines – PHENERGAN® (promethazine) belongs to this class. Low doses of phenothiazines antagonize interaction of dopamine with D2-receptors and thus exert an antiemetic effect.
Benzamides – Are strong central and peripheral D2-antagonists. They exert antiemetic effects by increasing lower esophageal sphincter tone and decreasing transit time through the upper gastrointestinal tract. REGLAN® (metoclopramide) belongs to this class.
HALDOL® (Haloperidol) belongs to this group of agents.
H1 Receptor Antagonists
Antihistamines antagonize the H1 receptors and inhibit the action of histamine. They also affect the vestibular system, decreasing stimulation of the vomiting center. Further, they also exhibit activity by inhibiting the muscarinic receptor. However, second generation antihistamines such as CLARITIN® (Loratidine), ALLEGRA® (Fexofenadine) and ZYRTEC® (Cetirizine) do not cross the blood brain barrier, and as such do not cause drowsiness and cannot be used as antiemetics. Some examples of H1 receptor antagonists include
• DRAMAMINE® (Dimenhydrinate)
• ANTIVERT® (Meclizine)
• BENADRYL® (Diphenhydramine)
Muscarinic Receptor Antagonists
These agents are good for motion sickness. They antagonize the acetylcholine receptors in the brain. Scopolamine transdermal belongs to this class
Cannabinoids Receptor Antagonists
These agents antagonize the CB1 receptors in the brain. The two drugs in this class
• MARINOL® (Dronabinol)
• CESAMET® (Nabilone)
The mechanism of action not clear. It may be related to the inhibition of arachidonic acid release. The agents in this class include
• DECADRON® (Dexamethasone)
• SOLUMEDROL® (Methylprednisolone)
These agents are sometimes effective for anticipatory nausea and vomiting associated with cancer therapy. It may also be useful for vestibular disorders.
• VALIUM® (Diazepam)
• ATIVAN® (Lorazepam)
• XANAX®: (Alprazolam) Miscellaneous
• TIGAN® (Trimethobenzamide)
General Principles of treating Nausea and Vomiting
1) Prevention is better than cure. Aggressively preventing nausea and vomiting will not only improve patients quality of life but will also decrease the incidence of anticipatory nausea and vomiting.
2) The addition of DECADRON® to 5-HT3 and NK-1 receptor antagonists improves the efficacy of the antiemetic regimen.
3) The choice of an antiemetic regimen should be based on patient risk factors as well as emetogenic potential of a given chemotherapy regimen.
4) The toxicity of a given antiemetic agent and potential drug interactions should be taken into consideration before prescribing.
5) Breakthrough emesis should be aggressively managed with round the clock dosing rather than PRN dosing and a drug from a different class should be considered for treatment of this entity. Also consider rectal or IV route of administration rather than PO route.
6) Ensure patients are well hydrated and electrolyte imbalances are promptly addressed.
7) Think “outside the box” when addressing nausea and vomiting in cancer patients. Do not overlook bowel obstruction, brain metastases, uremia, nausea from pain meds such as opiates, chemo or tumor related gastroparesis and anticipatory nausea and vomiting.
8) Anticipatory nausea and vomiting can be difficult to treat and benzodiazepines (ATIVAN®, XANAX®) along with behavioral therapy may be beneficial.
1. Morran C, Smith DC, Anderson DA, McArdle CS. Incidence of nausea and vomiting with cytotoxic chemotherapy: a prospective randomised trial of antiemetics. Br Med J 1979; 1(6174):1323-1324.
2. Jenns K. Importance of nausea. Cancer Nurs 1994; 17(6):488-493.
3. Hickok JT, Roscoe JA, Morrow GR et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol 2005; 6(10):765-772.
4. Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985; 3(10):1379-1384.
5. Moher D, Arthur AZ, Pater JL. Anticipatory nausea and/or vomiting. Cancer Treat Rev 1984; 11(3):257-264.
6. Jacobsen PB, Redd WH. The development and management of chemotherapy-related anticipatory nausea and vomiting. Cancer Invest 1988; 6(3):329-336.
7. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
8. Harding RK. Prodromal effects of radiation: pathways, models, and protection by antiemetics. Pharmacol Ther 1988; 39(1-3):335-345.
9. Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm 1985; 10(2):143-166.
10. BORISON HL, WANG SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953; 5(2):193-230.
11. Grunberg SM, Osoba D, Hesketh PJ et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–an update. Support Care Cancer 2005; 13(2):80-84.
12. Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother 2003; 4(12):2297-2303.
13. Shadle CR, Lee Y, Majumdar AK et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004; 44(3):215-223.