Keywords

Chemotherapeutic Agents in Gynecologic Oncology

Introduction

The most commonly used agents in the treatment of gynecologic cancers are the platinums (carboplatin and cisplatin) and taxanes (paclitaxel and docetaxel). While these agents are used frequently, there are a number of other drugs employed in the recurrent setting and in the treatment of rare diseases.

Pharmacology and Clinical Pearls

Mechanism of action, common and severe toxicities, and clinical pearls of each agent used in the treatment of gynecologic malignancies are outlined in Table 6.1.

Table 6.1. Mechanism of action, common and severe toxicities, and clinical pearls of agents used in the treatment of gynecologic malignancies.
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Treatment Regimens

Regimens used for the treatment of gynecologic cancers including the drugs, dosage, and frequency are detailed in Table 6.2.

Table 6.2. Common gynecologic oncology treatment regimens [31–153].
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Chemotherapy-Induced Nausea and Vomiting (CINV)

Background [154–157]

Nausea /Vomiting (N/V) are two of the most feared adverse effects of chemotherapy. 70–90 % of patients will experience some form of N/V during their treatment. Since the advent of 5-Hydroxytryptamine-3 (5HT3) antagonists the incidence of vomiting has been decreased to 30 %. However, nausea still remains a significant adverse effect that can have a major impact on the treatment of gynecologic cancers.

Definitions [155, 158]

  • Nausea—a feeling of sickness in the stomach characterized by an urge to vomit.

  • Vomiting—an expulsion of gastrointestinal contents through the mouth.

  • Acute emesis—occurs in the first 24 h after chemotherapy.

  • Delayed emesis—takes place 24 h or more after chemotherapy administration.

  • Anticipatory emesis—result of a learned response to chemotherapy.

  • Breakthrough emesis occurs despite prophylactic antiemetics.

  • Refractory emesis failure to respond to prevention or intervention in the previous cycle.

Alternative Etiologies [159]

  • Medications (opioids, antimicrobials).

  • Surgery/radiation.

  • Electrolyte imbalances/dehydration.

  • Gastrointestinal: obstruction, gastroparesis, constipation.

  • Psychological (anxiety, anticipatory).

  • Brain metastasis.

Complications [157, 158]

  • Metabolic imbalances.

  • Decreased performance status.

  • Nutrient depletion/Anorexia.

  • Wound dehiscence.

  • Esophageal tears.

  • Noncompliance with treatment.

  • Aspiration.

  • Decreased quality of life.

Risk Factors [154, 157, 158, 160, 161]

Patient Related

  • Age—increased risk in younger patients.

  • Gender—increased risk for females.

  • History of alcohol use—decreased with prior use.

  • History of CINV.

  • History of vertigo/motion sickness.

  • Non-chemotherapy related etiologies.

  • History of nausea/vomiting with pregnancy.

Chemotherapy Related

  • >90 % = High risk.

  • 31–90 % = Moderate risk.

  • 10–30 % = Low risk.

  • <10 % = Minimal risk.

See Table 6.3 for CINV risk for agents used to treat gynecologic cancers.

Table 6.3. Chemotherapy induced nausea/vomiting (CINV) risk by agent.
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Therapeutic Options [2, 160, 168]

High Therapeutic Index Agents

Used primarily for prevention first line breakthrough. Dosing outlined in Table 6.4.

Table 6.4. High therapeutic index antiemetic common dosing.
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  • 5HT3 receptor antagonists:

    Agents: Ondansetron, Palonosetron, Granisetron, Dolasetron.

    Adverse effects: headache, constipation, QT prolongation.

  • Corticosteroids.

    Agents: Dexamethasone, Prednisone, Methylprednisolone.

    Adverse effects: hyperglycemia, insomnia, hypertension, immunosuppression.

  • Neurokinin-1 receptor antagonists.

    Agents: Aprepitant, Fosaprepitant.

    Adverse effects: headache, hiccups, fatigue.

    Moderate inhibitor and inducer of CYP3A4, weak inducer of CYP2C9.

Low Therapeutic Index Agents

Used primarily for breakthrough N/V. Dosing outlined in Table 6.5.

Table 6.5. Low therapeutic index antiemetic common dosing.
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  • Phenothiazines.

    Agents: Prochlorperazine, Promethazine.

    Adverse effects: sedation, anticholinergic effects, extrapyramidal side effects.

  • Metoclopramide.

    Adverse effects: sedation, extrapyramidal side effects, diarrhea.

  • Olanzapine.

    Adverse effects: sedation, weight gain.

  • Benzodiazepines.

    Drug of choice for anticipatory N/V.

    Agents: Lorazepam, Alprazolam.

    Adverse effects: sedation, amnesia.

  • Butyrophenones.

    Agents: Haloperidol

    Adverse effects: sedation, constipation, arrhythmias, extrapyramidal side effects.

  • Cannabinoids.

    Agents: Dronabinol, Nabilone.

    Adverse effects: sedation, abnormal thinking, palpitations, tachycardia, euphoria.

General Principles of Treatment [155, 160, 161, 165]

  • Primary goal is prevention of CINV.

  • Agents are chosen based upon chemotherapy regimen.

  • Consider toxicity of antiemetics used.

  • Always provide “rescue” medication for breakthrough CINV.

Treatment Recommendations [160, 161, 165, 169, 170]

High Risk Chemotherapy

  • Acute Emesis Prevention.

    5HT3 antagonist + Dexamethasone + Neurokinin 1 antagonist +/− lorazepam +/− H2 blocker or proton pump inhibitor.

  • Delayed Emesis Prevention.

    If fosaprepitant 150 mg: dexamethasone 8 mg PO day 2 then 8 mg PO BID days 3–4.

    If aprepitant day 2–3: dexamethasone 8 mg PO days 2–4.

Moderate Risk Chemotherapy

  • Acute Emesis Prevention.

    5HT3 antagonist + dexamethasone +/− Neurokinin 1 antagonist +/− lorazepam +/− H2 blocker or proton pump inhibitor.

  • Delayed Emesis Prevention.

    5HT3 antagonist monotherapy for 2–3 days, OR.

    Dexamethasone monotherapy for 2–3 days, OR.

    Neurokinin 1 antagonist (if used day 1) + dexamethasone.

Low Risk

  • Prior to chemotherapy.

    Dexamethasone PO/IV, OR.

    Metoclopramide PO/IV, OR.

    Prochlorperazine PO/IV, OR.

    +/− Lorazepam and/or H2 blocker or proton pump inhibitor.

Minimal Risk

  • No prophylaxis recommended.

Multiday Chemotherapy Regimens

  • Consider emetogenic potential of each day.

  • 5-HT3 antagonist should be administered daily for moderately or highly emetogenic chemotherapy.

  • Dexamethasone should be given daily prior for moderately or highly emetogenic chemotherapy.

  • Prevent delayed emesis with 2–3 days of prophylaxis following chemotherapy.

  • Palonosetron or transdermal granisetron may be used in lieu of daily 5HT3 dosing.

  • Dosing of Aprepitant beyond 3 days has been shown to be safe and effective in phase II trials.

  • Repeat doses of palonosetron have been studied and shown to reduce CINV.

Breakthrough Emesis

  • Add agent from different class.

  • PO administration often unfeasible due to emesis.

  • Routine administration of “rescue” medication should be considered.

  • Multiple concurrent agents in alternating schedules.

  • Reevaluate for alternative etiologies.

  • Change regimen for next cycle.

Chemotherapy-Induced Diarrhea

Introduction [171–173]

Many chemotherapy agents can cause damage to the intestinal mucosa ultimately resulting in diarrhea. If not managed properly chemotherapy-induced diarrhea can result in treatment delays, dose reductions, and serious complications that may be fatal. Most agents for the primary treatment of gynecologic oncology do not commonly cause diarrhea but a number of agents used for recurrence or rare tumor types are known to cause diarrhea.

Pathogenesis [171–178]

  • Direct damage to intestinal mucosa (fluorouracil, capecitabine, Irinotecan late-onset, doxorubicin, gemcitabine, dacarbazine).

  • Cholinergic stimulation (Irinotecan acute-onset).

  • Inhibition of vascular endothelial growth factor (pazopanib).

  • Dihydropyrimidine dehydrogenase (DPD) deficiency and thymidylate synthetase gene (TYMS) polymorphism can increase severity of diarrhea with fluorouracil and capecitabine.

  • Irinotecan is metabolized by the enzyme uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1).

  • Patients that are heterozygous or homozygous for UGT1A1*28 may be at increased risk for diarrhea.

Signs and Symptoms [171–173, 179]

  • Increase in number of stools or ostomy output.

  • Dehydration.

  • Renal insufficiency.

  • Electrolyte abnormalities (hypokalemia, metabolic acidosis, hyponatremia, or hypernatremia).

  • Fatigue.

  • Decreased quality of life.

  • Noncompliance with treatment.

Evaluation [171–173, 179]

  • Determine onset and duration.

  • Assess for alternative etiologies (infection, medication, radiation, diet, colitis, etc.).

  • Consider testing for DPD deficiency, TYMS variants, or UGT1A1 polymorphism.

  • Determine severity (Table 6.6).

    Table 6.6. Severity/grade of chemotherapy-induced diarrhea.
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  • Identify causative agent.

Therapeutic Options [2, 162–164, 167, 171–173, 179, 180]

General Principles

  • Treat any alternative/underlying etiologies.

  • Provide supportive care in the form of hydration and electrolyte repletion.

  • Severe cases may require delays or dose reduction of chemotherapy.

  • Scheduled doses of antidiarrheal are usually necessary to control symptoms.

  • Once controlled medications can be titrated to maintain control.

Nonpharmacologic Treatment

  • Avoid diarrhea inducing foods (dairy, spicy foods, alcohol, caffeine, high fiber).

  • Discontinue all laxative, stool softeners, or promotility agents.

  • Aggressive oral hydration (8–10 glasses per day).

  • Small frequent meals.

Pharmacologic Treatment

  • Loperamide.

    • Rapid onset of action.

      Formulation

      • Tablet: 2 mg.

      • Capsule: 2 mg.

      • Solution: 1 mg/7.5 mL, 1 mg/5 mL.

      • Suspension: 1 mg/7.5 mL.

      Dose

      • Standard dose: 4 mg PO after initial loose stool, 2 mg PO every 4 h or after subsequent loose stool.

      • High dose: 4 mg PO after initial loose stool, 2 mg PO every 2 h until diarrhea free for 12 h.

      • Maximum dose (16 mg/day) listed in drug references may be exceeded.

  • Diphenoxylate and atropine.

    • Rapid onset of action.

      Formulation

      • Tablet: diphenoxylate 2.5 mg/atropine 0.025 mg.

      • Solution diphenoxylate 2.5 mg/atropine 0.025 mg per 5 mL.

        Dose: 5 mg diphenoxylate every 6 h until diarrhea controlled.

  • Deodorized tincture of opium.

    • Contains 10 mg/mL of morphine.

    • Doses are expressed in milligrams of morphine.

    • Dose: 6 mg (0.6 mL) PO every 6 h.

    • Use with caution.

  • Paregoric.

    • Contains 0.4 mg/mL of morphine.

    • Dose: 5–10 mL PO every 6 h.

  • Octreotide.

    • Somatostatin analog.

    • Best used for complicated or refractory chemotherapy induced diarrhea.

    Dose

    • 100–150 mcg subQ three times daily; may increase dose up to 500 mcg three times daily.

    • 25–50 mcg/h IV infusion.

Treatment Recommendations [172, 173, 180]

Uncomplicated Diarrhea

  • Grade 1–2 with no complicating signs or symptoms.

  • Nonpharmacologic therapy.

  • Hold chemotherapy for grade 2 until symptoms resolve.

  • Initiate standard dose loperamide and reevaluate in 12–24 h.

  • If symptoms resolve you may discontinue treatment after 12 h with no loose stool.

  • If symptoms persist increase to high dose loperamide, consider antibiotics, and reevaluate in 12–24 h.

  • If diarrhea persists discontinue loperamide, complete more comprehensive workup and begin octreotide or other second line agent.

  • If at any time the patients show worsening diarrhea or develop complication, they should be treated as such.

Complicated Diarrhea

  • Grade 3–4 or Grade 1–2 with cramping, nausea/vomiting, decrease performance status, fever, sepsis, neutropenia, bleeding, or dehydration.

  • Admit patient to hospital.

  • Give supportive care (IV hydration/electrolytes) and nonpharmacologic treatment.

  • Start octreotide and antibiotics as needed.

  • Hold all chemotherapy until symptoms resolve, restart at a reduced dose.

Peripheral Neuropathy

Introduction [181–183]

Peripheral neuropathy is an often overlooked but serious adverse effect that is common in patients with gynecologic cancers. Over 2/3 of gynecologic oncology patients my experience some form of peripheral neuropathy. Onset may result in the need for dose reductions or treatment delays potentially effecting treatment outcomes as well as patient’s quality-of-life.

Risk Factors [1–6, 15, 182–186]

  • Diabetes.

  • Preexisting neuropathy.

  • History of alcohol abuse.

  • Nutritional deficiencies.

  • Metabolic abnormalities.

  • Paraneoplastic disorders.

  • Tumor compression or infiltration.

  • Chemotherapy use (Table 6.7).

    Table 6.7. Chemotherapy agents commonly causing peripheral neuropathy.
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Definitions [179]

  • Peripheral neuropathy: a disorder characterized by inflammation or degeneration of the peripheral sensory nerves.

  • Paresthesia: abnormal cutaneous sensations of tingling, numbness, pressure, cold and warmth experienced in the absence of stimulus.

  • Instrumental activities of daily living (ADL): preparing meals, shopping, using the telephone, etc.

  • Self-care ADL: bathing, dressing and undressing, feeding self, using toilet, taking medications, not bedridden.

Clinical Manifestations [181–184, 186, 187]

  • Sensory symptoms (paresthesia, numbness, pain) are most common.

  • Motor symptoms (weakness, loss of tendon reflexes) are uncommon.

  • Autonomic symptoms are rare (typically caused by vinca alkaloids).

  • Symmetrical “glove and stalking” distribution.

  • Starts distally in fingers and toes and moves proximally.

  • Symptoms may progress after discontinuation of offending agent.

  • Resolution usually occurs within 3 months but may persist.

Evaluation [179, 182, 183, 185]

  • Patients receiving neurotoxic agents should be questioned on the presence of peripheral neuropathy at each encounter.

  • Grade severity of symptoms and effect on functioning (Table 6.8).

    Table 6.8. Peripheral neuropathy severity/grading.
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  • Evaluate for the presence of pain.

  • Neurophysiologic testing is inconsistent and often unnecessary.

  • Need for interventions should be based upon severity of symptoms, and patient preference.

  • Referral to neurologist, physical/occupational therapy, or pain specialist may be needed.

Prevention [2, 182–190]

Chemotherapy Selection

  • For patients at high risk avoid chemotherapy regimens commonly associated with peripheral neuropathy.

  • Use docetaxel instead of paclitaxel.

  • Carboplatin use is preferred over cisplatin.

  • Avoid dose-dense paclitaxel.

  • Extend duration of paclitaxel infusion.

  • Avoid vinca alkaloids.

Pharmacologic Prevention

  • No treatment is proven to prevent the onset of chemotherapy-induced peripheral neuropathy.

  • Use of prophylactic medications cannot be recommended for routine use.

  • Amifostine.

    • Multiple randomized trials and a meta-analysis failed to show benefit.

    • Not recommended due to lack of evidence and potential toxicity.

  • Glutathione.

    • Meta-analysis of five trials showed no benefit for cisplatin-induced peripheral neuropathy.

    • Small trial of patient receiving oxaliplatin showed decreased grade II–IV neuropathy with glutathione use.

  • Vitamin E.

    • Patients having received 300 mg/m2 of cisplatin or more have shown decreased incidence and severity of peripheral neuropathy with vitamin E 400 international units daily during and 3 months following discontinuation of cisplatin.

    • Due to antioxidant effect there is theoretical concern about potential to decrease chemotherapy efficacy.

    • Further study evaluating efficacy and safety is needed.

  • Erythropoietin.

    • Animal studies suggest potential for prevention with cisplatin and docetaxel-induced peripheral neuropathy.

    • Study of patients receiving paclitaxel and erythropoietin for anemia suggests decreased peripheral neuropathy.

    • Risks of erythropoietin currently outweigh potential benefits for prophylaxis in patients being treated with curative intent or those without anemia.

  • IV calcium and magnesium.

    • Early trials in patient receiving infusion of calcium and magnesium with oxaliplatin showed potential benefit.

    • Randomized placebo controlled trial of 353 patients showed no difference in acute or cumulative neurotoxicity.

    • Expert consensus is to avoid use.

  • Glutamine and acetyl-l-carnitine.

    • Conflicting data from small trials with a variable design.

    • Further study needed to determine benefit.

  • Serotonin-norepinephrine reuptake inhibitors.

    • Venlafaxine has been shown to decrease oxaliplatin-induced acute peripheral neuropathy.

    • No information regarding efficacy for chronic neuropathy.

    • Not recommended due to limited evidence.

Treatment

General Principles [2, 182, 183, 185, 187]

  • Treat any underlying neuropathy or metabolic abnormalities that may cause neuropathy.

  • Chemotherapy may be switched to an agent that causes less CIPN (i.e., paclitaxel to docetaxel) if clinically appropriate.

  • Dose reduction or discontinuation of offending agent may be necessary.

Pharmacologic Treatment

  • There are no approved medications for the treatment of CIPN.

  • Most medications available have been approved based upon their ability to treat pain in patients with diabetic neuropathy.

  • A variety of agents have been used (Table 6.9).

    Table 6.9. Agents commonly used for chemotherapy-induced peripheral neuropathy pain.
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  • Motor weakness and loss of light touch and proprioception are not treatable with medication.

  • Start with low dose and titrate to doses that maximize symptom control while limiting side effects.

  • A trial of 2–8 weeks should be given to determine efficacy.

  • Addition of a second agent with a different mechanism of action may be necessary.

  • Dietary supplements such as acetyl-l-carnitine, glutamine, vitamin E, and glutathione have been studied but efficacy has not been established.

Nonpharmacologic Treatment

  • Acupuncture.

  • Neurostimulation.

  • Massage.

  • Meditation.

  • Occupational/physical therapy.

Febrile Neutropenia

Introduction [191, 192]

Febrile neutropenia (FN) is one of the major dose-limiting toxicities of chemotherapy regimens used in patients with gynecologic oncology. It often requires hospitalization and broad spectrum antibiotics. Without prompt recognition and treatment, FN is associated with substantial morbidity, mortality, and cost. This section reviews some key points of management of FN and common drugs used in the clinical practice.

Definitions [193]

  • Neutropenia: absolute neutrophil count (ANC) <0.5 × 109/L or ANC <1 × 109/L with predicted decrease to ≤0.5 × 109/L with the next 48 h.

  • Febrile neutropenia: ANC < 0.5 × 109/L and a single oral temperature of ≥38.3 °C (101 °F) or ≥38.0 °C (100.4 °F) for at least an hour.

Risk Factors [194]

  • Patient related.

    • Neutropenia.

    • Type of malignancy (hematologic malignancies have higher risk).

    • Asplenic.

    • Genetic factors.

  • Chemotherapy regimen related.

  • Immune system dysfunction.

  • Corticosteroids and other lymphotoxic agents.

  • Other defects in host defense.

Microbiology [193, 195]

  • Bacterial infection (80–85 %).

  • Most common bacterial pathogen for febrile neutropenia has changed over the past two decades from gram-negative to gram-positive organisms.

  • Extended-spectrum β-lactamase (ESBL)-producing E. coli and Klebsiella species are emerging.

  • Gram-negative organisms:

    • E. coli.

    • Klebsiella spp.

    • “SPICE” organisms: Serratia, Pseudomonas spp, indole-positive Proteus species, Citrobacter freundii, Enterobacter cloacae.

  • Gram-positive organisms:

    • Staphylococcus species (most coagulase negative).

    • Streptococcus species.

    • Enterococci.

  • Polymicrobial.

  • Fungal infection.

    • Candida species.

    • Aspergillus species.

    • Others.

  • Other infections: viral.

Diagnosis and Workup [193, 195]

  • Diagnosis: Fever and ANC <0.5 × 109/L.

  • Workup:

  • History.

  • Complete physical exam (rectal exam not recommended due to a risk of transient bacteremia).

  • Two sets of blood cultures and any site-specific culture (i.e., port-a-cath, PICC line; results often negative).

  • Chest X-ray.

  • CBC with differential.

  • Chemistry including liver and renal function.

Initial Risk Assessment [193, 194, 196]

Low Risk

Outpatient status at time of development of fever.

  • No acute comorbidity.

  • Anticipated short duration of profound neutropenia.

  • Good performance status (PS 0–1).

  • No hepatic insufficiency.

  • No renal insufficiency

    OR

  • MASCC Risk index score ≥21 (see Table 6.10).

    Table 6.10. MASCC scoring index for evaluation of febrile neutropenia [196].
    Full size table

High Risk

Inpatient status at time of development of fever.

  • Significant medical comorbidity or clinically unstable.

  • Anticipated prolonged profound neutropenia (ANC ≤0.1 × 109/L and ≥7 days).

  • Hepatic insufficiency (AST/ALT ≥5 × UNL).

  • Renal insufficiency (CrCL <30 ml/min).

  • Uncontrolled/progressive cancer.

  • Pneumonia or other complex complications.

  • Alemtuzumab.

  • Mucositis grade 3–4.

    OR

  • MASCC Risk index score <21 (see Table 6.10).

Primary Prophylaxis [193, 194]

Low risk: Not recommended (included most solid tumor patients).

High Risk: Consider fluoroquinolones prophylaxis (levofloxacin is preferred).

Therapeutic Options [193, 194]

Common antibiotic and antifungal treatments are outline in Tables 6.11 and 6.12.

Table 6.11. Common antibiotics used for FN [2, 194].
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Table 6.12. Common antifungals used for FN [2, 194].
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Low Risk Patients

  • Patients can be managed in home, ambulatory clinic, or hospital.

  • Both IV and/or oral antibiotics are reasonable.

  • Close monitoring before and after antibiotics administration, especially within the first 72 h, is required.

  • Anti-pseudomonas antibiotics should be used the first line.

  • If oral antibiotics are chosen, ciprofloxacin plus amoxicillin/clavulanate are the first line therapy.

High Risk Patients

  • Patients should be managed in the hospital setting.

  • IV antibiotics is required.

  • Monotherapy with anti-pseudomonas antibiotics can be used as the first line for uncomplicated patients.

  • Details of drug dose and spectrum (see Tables 6.11 and 6.12).

  • Add site-specific evaluation and therapy when indicated.

Clinically Unstable Patients

  • Empiric treatment: broad spectrum β-lactam (meropenem, imipenem/cilastatin, pipercillin/tazobactam plus an aminoglycoside and vancomycin).

  • Strongly consider adding fluconazole and echinocandin antifungal if patient not on antifungal prophylaxis.

  • Consider additional stress dose of hydrocortisone, especially for patients with septic shock.

Indications for Antibiotics with Gram-Positive Coverage

  • Clinically apparent, serious, catheter-related infection.

  • Blood culture positive for gram-positive bacteria prior to final identification and susceptibility test.

  • Known colonization with penicillin/cephalosporin-resistant pneumococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococus.

  • Severe mucositis.

  • Hypotension or septic shock without identified pathogen (clinically unstable).

  • Soft tissue or skin infection.

Follow-Up [193]

  • Changes of empiric antibiotics should be based on clinical and microbiology data.

  • If infection is identified, then change antibiotics to appropriate coverage for the site and the drug susceptibility of the pathogen.

  • If vancomycin or other gram-positive coverage antibiotics are part of the initial empiric therapy, it can be discontinued after 2 days without evidence of infection.

  • After initial empiric standard regimen, antibiotics for hemodynamically unstable patients should be expanded to include coverage for persistent gram-negative, gram-positive, anaerobic bacteria and antifungals.

  • Empiric antifungals can be considered for patients with persistent fever over 4–7 days of broad spectrum antimicrobials and with no identified source of fever.

Treatment Duration [194]

  • For fever of unknown origin, initial antibiotic therapy should continue until ANC ≥0.5 × 109/L and increasing.

  • For documented infection, continue antibiotics at least to ANC ≥0.5 × 109/L; however, a full course of therapy can also be based on the infection site and pathogen. Can consult with institutional infectious disease specialist.

  • Skin/soft tissue: 7–14 days.

  • Bloodstream infection (uncomplicated).

    • Gram-positive: 7–14 days.

    • Gram-negative: 10–14 days.

    • S. aureus: at least 2 weeks after first negative blood culture, treatment course can be prolonged with the involvement of endovascular structure.

    • Yeast: at least 2 weeks after the first negative blood culture.

  • Sinusitis/bacterial pneumonia: 10–21 days.

  • Invasive fungal infection:

    • Candida: at least 2 weeks after the first negative blood culture.

    • Mold: (e.g., Aspergillus): at least 12 weeks.

  • Viral infection.

    • HSV/VZV: 7–10 days.

    • Influenza: at least 5 days, maybe prolonged until symptom resolution in immunocompromised patients.

Extravasation

Background [197]

Extravasation causes 0.5–6 % of adverse events associated with chemotherapy administration. Based on the characteristics and potential tissue damage, chemotherapy agents can be classified as irritant, vesicant and nonirritant, non-vesicant. However, it is often controversial regarding which drugs are vesicants or irritants. Because of limited clinical trial data, treatment for extravasation may vary from institution to institution.

Definitions [198]

  • Irritant: An agent which may cause a local inflammatory reaction, but without tissue necrosis.

  • Vesicant: An agent which may cause severe tissue necrosis.

Table 6.13 compares and contrasts irritants and vesicants.

Table 6.13. Comparison of irritant and vesicant.
Full size table

Risk Factors [197]

  • Vein physiology—fragile, small, sclerotic veins, blood flow, and vessel size.

  • Pharmacologic—duration and amount of chemotherapy exposure, drug administration sequence (see Table 6.13).

  • Physiologic—superior vena cava syndrome, peripheral neuropathy, lymphedema, phlebitis.

  • Radiologic—previous local irradiation.

  • Mechanical—needle insertion technique, injection site, multiple venipuncture attempts.

Prevention [197–200]

  • Use of central venous catheter if possible.

  • Careful administration with frequent checking of blood return.

  • IV sites should be started from as distant from hand, dorsum of the foot, or any joints as possible.

  • Do not administer chemotherapy distal from a recent venipuncture site.

  • Consider using hot compress to dilate veins before administration.

  • Educate patients to report any pain, tingling, burning symptoms.

  • Monitor IV sites frequently during infusion.

Clinical Management [199, 200]

General Management Protocol (see Table 6.14)

Table 6.14. Classification of chemotherapy agents and management of extravasation.
Full size table

  • Stop infusion.

  • Aspirate any drugs via intravenous cannula.

  • Do not flush the line.

  • Instill antidotes if available.

  • Remove the catheter.

  • Cold or warm packs as recommended.

  • Consider taking a picture of the site with extravasation and mark the border.

  • Monitor the site for 24 h, at 1 and 2 weeks and as necessary for redness, swelling, pain, ulceration and necrosis.

  • Early surgery for severe and large amount of extravasation when necessary.

Cold Protocol

  • Immediately after medical treatment is completed, apply ice pack to the affected area for 15–20 min at least 4 times per day for the first 24–48 h by any of the following means:

    • Cool wash cloth.

    • Instant cool/ice pack.

  • Elevate limb at all times and exercise at least every 4–6 h to reduce immobility.

Warm Protocol

  • Immediately after medical treatment is completed apply warmth to the affected area for 15–20 min at least 4 times per day for the first 24–48 h by any of the following means:

    • Heating pad (K pad) on moderate setting.

    • Instant warm pack.

  • Elevate and extend limb to promote circulation at all times and exercise at least every 4–6 h to reduce immobility.

Antidotes [197, 199–202]

  • Sodium Thiosulfate.

    • Mix 0.4 mL of 25 % sodium thiosulfate with 2.1 mL Sterile Water for Injection (resulting in 1/6 molar solution).

    • Inject 2 mL of the sodium thiosulfate solution subQ into the extravasation site using a 25-gauge or smaller needle.

    • Follow cold protocol.

  • Hyaluronidase.

    • Inject 1 mL (200 units) as five separate injections in a clockwise manner, each containing 0.2 mL of hyaluronidase, subQ around the extravasation site.

    • Change needle with each injection.

    • Hyaluronidase must not be given IV; death has resulted.

    • Follow warm protocol.

    • DO NOT APPLY ICE.

    • Dimethylsulfoxide (DMSO).

    • For anthracycline extravasation management:

      • Consider for cases that may be difficult to delineate between a local infusion reaction (phlebitis, irritation) versus a small volume extravasation.

      • When opposite arm/extremity/area other than affected area is not available for IV access.

        • Begin DMSO immediately after the nurse has aspirated any residual extravasate and removed the IV device.

    • Conflicting literature exists as to the benefit of this adjuvant therapy.

    • Dimethylsulfoxide 99 %: Using cotton ball or small gauze pad, invert DMSO bottle to wet cotton ball or small gauze then apply topically every 6 h for 14 days or every 8 h for 7 days, leave uncovered.

  • Dexrazoxane (Totect™).

    • As an alternative treatment of anthracycline extravasations.

    • Consider systemic treatment when:

      • Centrally placed venous catheter extravasations may result in extensive underlying soft tissue involvement, Large volume extravasations (when ulceration and necrosis is likely to occur),

      • Significant amount of time (>1 h) has elapsed between discovery of the extravasation and initiation of extravasation management.

      • Therapy must be initiated within 6 h of extravasation.

  • Cold protocol should be held 15 min prior to infusion through 15 min after infusion.

  • Recommended dose:

    • Days 1 and 2: 1,000 mg/m2 (2,000 mg max dose) IV.

    • Day 3: 500 mg/m2 (1,000 mg max dose).

    • Reduce dose by 50 % for patients with a creatinine clearance less than 40 mL/min.

    • Dilute in 1,000 mL 0.9 % NaCl and infuse over 1–2 h in opposite extremity/area than the one affected by the extravasation.

    • On days 2 and 3, premedicate with prochlorperazine 10 mg PO or dexamethasone 12 mg PO.

Background [203]

Hypersensitivity reactions (HSRs) are most commonly seen in gynecologic oncology patients receiving platinums (carboplatin, cisplatin, and oxaliplatin) and taxanes (paclitaxel and docetaxel); however, they were reported in other agents such as liposomal doxorubicin. HSRs are often unpredictable and symptoms vary dramatically. This article focuses on carboplatin/cisplatin and paclitaxel/docetaxel HSRs and their clinical management.

Incidence [1–5, 204]

  • Carboplatin: 1–6 % overall, however, incidence is up to 44 %.

  • Cisplatin: 5–20 %.

  • Paclitaxel and docetaxel: 10 % without premedication and 2 % with premedication.

Mechanism [203–205]

  • Platinums: true allergic reactions and most acute HSR if IgE mediated activation of basophils and mast cells. Types of HSRs are outlined in Table 6.15.

    Table 6.15. Type of hypersensitivity reaction of platinums and their characteristics.
    Full size table

  • Taxanes: generally an infusion-related, but not Ig-E mediated. Often attributed to Cremophor (paclitaxel) and Tween 80 (docetaxel). It is the direct activation of basophils and mast cells.

Clinical Presentation and Grading [179, 203]

Severity grading of HSR is outlined in Table 6.16.

Table 6.16. Grading of HSR.
Full size table

Platinum Hypersensitivity

  • Often occurs following re-exposure, after the completion of the initial treatment (>6 doses).

  • Symptoms can occur anytime during the infusion, or after completion of the infusion.

  • Commonly HSR symptoms are more severe.

  • Half of HSR are still mild but anaphylaxis can occur.

Taxane Hypersensitivity

  • Often occurs during the first and second cycle of paclitaxel/docetaxel.

  • Typically occurs with the first a few minutes.

  • Symptoms are often milder, but anaphylaxis can still occur.

Prevention [195, 203, 204]

  • Preparation for the possible HSR.

    • Obtain all necessary treatment/monitoring equipment including blood pressure monitor, IV antihistamines, IV emergent steroids (e.g., hydrocortisone), IV epinephrine, and oxygen.

  • Premedication 30 min before chemotherapy (most taxanes).

    • H1 antagonist (diphenhydramine 50 mg IV).

    • H2 antagonist (ranitidine 50 mg IV or famotidine 20 mg IV).

    • Steroid (dexamethasone 20 mg IV).

Desensitization [203, 206]

  • Gradual reintroduction of small amounts of drug antigen titrating to the full dose, on prolonged infusion and premedication.

  • Various desensitization protocols have been published.

  • No single protocol is preferred.

  • Desensitization typically takes a much longer time, but recent rapid desensitization protocols have been tested with success. Table 6.17 describes desensitization protocol from the largest study to date.

    Table 6.17. 12-Step rapid desensitization protocol for chemotherapy agents.
    Full size table

  • Consider substitute with a different platinum or taxane drug.

  • Cisplatin for patients with a history of severe carboplatin HSR.

  • Docetaxel or nanoalbumin paclitaxel for patients with a history of severe paclitaxel HSR.

  • Monitor patients closely for any signs/symptoms of breakthrough reactions during desensitization.