Friday, December 1, 2023
| Rank | 1983 (Coates et al.2) | 1996 (Griffin et al.3) | 1997 (de Boer-Dennert et al.1) | 1999 (Lindley et al.4) | 2004 (Hofman et al.5) |
|---|---|---|---|---|---|
| 1 | Vomiting | Nausea | Nausea | Nausea | Fatigue |
| 2 | Nausea | Constantly tired | Hair loss | Hair loss | Nausea |
| 3 | Hair loss | Hair loss | Vomiting | Constantly tired | Sleep disturbances |
| 4 | Thought of treatment | Effect of family | Constantly tired | Vomiting | Weight loss |
| 5 | Length of treatment | Vomiting | Injections | Taste changes | Hair loss |
Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy
| High (> 90% Chance of CINV Without Prophylaxis) | |||
| AC combination (doxorubicin or epirubicin with cyclophosphamide) Carmustine (> 250 mg/m2) Cisplatin (≥ 50 mg/m2) Cyclophosphamide (> 1500 mg/m2) Dacarbazine |
Doxorubicin (> 60 mg/m2) Epirubicin (> 90 mg/m2) Ifosfamide (≥ 10 g/m2) Mechlorethamine Streptozocin |
||
| Moderate (30%–90% Chance of CINV Without Prophylaxis) | |||
| Amifostine (> 300 mg/m2) Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine (≤ 250 mg/m2) Cisplatin (< 50 mg/m2) Clofarabine Cyclophosphamide (≤ 1500 mg/m2) Cytarabine (> 200 mg/m2) Dactinomycin |
Daunorubicin Doxorubicin (≤ 60 mg/m2) Epirubicin (≤ 90 mg/m2) Idarubicin Ifosfamide (< 10 g/m2) Interferon (≥ 10 million IU/m2) Interleukin-2 (> 12–15 million IU/m2) Irinotecan Melphalan Methotrexate (250 to > 1000 mg/m2) Oxaliplatin Temozolomide |
||
| Low (10%–30% Chance of CINV Without Prophylaxis) | |||
| Amifostine (≤ 300 mg/m2) Cabazitaxel Cytarabine (100–200 mg/m2) Docetaxel Eribulin Etoposide 5-Fluorouracil Floxuridine Gemcitabine Interferon (> 5 to < 10 million IU/m2) Interleukin-2 (≤ 12 million IU/m2) Ixabepilone |
Liposomal doxorubicin Methotrexate (> 50 to < 250 mg/m2) Mitomycin Mitoxantrone Paclitaxel Paclitaxel-albumin Pemetrexed Pralatrexate Pentostatin Romidepsin Thiotepa Topotecan |
||
| Minimal (< 10% Chance of CINV Without Prophylaxis) | |||
| Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine |
Cytarabine (< 100 mg/m2) Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon (≤ 5 million/units/m2) Ipilimumab |
Methotrexate (≤ 50 mg/m2) Nelarabine Ofatumumab Panitumumab Pegaspargase Peginterferon Rituximab |
Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vinorelbine |
Emetogenicity of Intravenous Chemotherapeutic Agents
Abbreviation: CINV, chemotherapy-induced nausea and vomiting.
Data from Refs.[8–10]
| NCCN | ASCO | MASCC | |
|---|---|---|---|
| High | |||
|
12 mg po or IV 8 mg po days 2–4 or 8mg po day 2, 8 mg twice daily days 3 and 4a |
12 mg po or IV 8 mg po or IV; days 2–3 or days 2–4 |
20 mg (12 mg if used with an NK1 antagonist) 8 mg bid for 3-4 d (qd with NK1 antagonist) |
| Moderate | |||
|
12 mg po or IV 8 mg po or IV days 2 and 3 |
8 mg po or IV 8 mg po or IV days 2 and 3 |
8 mg 8 mg for 2–3 d |
| Low | 12 mg po or IV | 8 mg po or IV | 4-8 mg |
Corticosteroid Dosing Recommendations
All corticosteroid doses for moderate and high regimens are in combination with a 5HT3 antagonist +/- a neurokinin-1 antagonist.
Abbreviations: IV, intravenous; MASCC, Multinational Association of Supportive Care in Cancer; NK1, neurokinin-1.
aWhen given with fosaprepitant, 150 mg IV.
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The goal of this activity is to evaluate the role of corticosteroids in the treatment of CINV.
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Serotonin receptor antagonists (5HT3-RA), neurokinin-1 (NK1) receptor antagonists, and corticosteroids are the main agents used in the prevention and treatment of CINV. Additional agents available in the clinicians’ armamentarium are dopamine antagonists, cannabinoids, benzodiazepines, and miscellaneous agents, such as olanzapine. Dexamethasone is the most widely used corticosteroid in the treatment of CINV, and methylprednisolone has also been studied and used. Both corticosteroids are effective as monotherapy and in combination with other agents, either with a serotonin antagonist alone or as part of a triple-drug regimen with an NK1 antagonist. They are recommended agents in both the acute and delayed settings.[8–10]
The mechanism of action of corticosteroids in CINV remains relatively unknown. Studies in pigeons suggest that the antiemetic effect of steroids may be partially from their activity in the central nervous system.[13] Evidence also suggests that the effect may be from activation of glucocorticoid receptors in the nucleus of the solitary tract in the medulla.[14] Lastly, dexamethasone and methylprednisolone have also been shown to antagonize 5HT3A receptors in Xenopus oocytes; this antagonism may also explain the beneficial effects of corticosteroids in CINV prophylaxis and treatment.[15]
Acute CINV. The role of corticosteroids in acute CINV management is largely in combination with either a 5HT3 antagonist alone or as part of triple-drug therapy with an NK1 antagonist. In the moderately emetogenic setting, when used in combination with a 5HT3 antagonist, the optimal dexamethasone dose is 8 mg ( Table 3 ). This dose was established by the Italian Group for Antiemetic Research in a study of 587 patients receiving carboplatin, cyclophosphamide, or anthracyclines. Patients were randomized to receive 1 of 3 dexamethasone treatments in combination with ondansetron, 8 mg intravenously: 8 mg intravenously before chemotherapy plus 4 mg orally every 6 hours for 4 doses, starting at the same time of the chemotherapy; 24 mg intravenously as a single dose before chemotherapy; or 8 mg intravenously as a single dose before chemotherapy. All patients received oral dexamethasone, 4 mg twice daily from days 2 to 5. The rates of complete protection against vomiting/nausea were not significantly different among the 3 dosing arms (84.6%/66.7%; 83.6%/56.9%; 89.2%/61.0%), nor was a significant difference seen in delayed control (81.0%/46.7%; 81.3%/45.1%; 79.8%/46.1%).[16]
In the highly emetogenic chemotherapy setting, before the introduction of routine combination with NK1 antagonists, when used in combination with a 5HT3 alone, the recommended dose of dexamethasone was 20 mg. A study by the Italian Group for Antiemetic Research evaluated various single intravenous doses of dexamethasone (4, 8, 12, or 20 mg) in combination with ondansetron, 8 mg intravenously in patients receiving cisplatin. Complete protection from acute vomiting and nausea was significantly superior with the 20-mg dose compared with the 4- and 8-mg doses (83.2%/71% vs. 69.2%/60.9% and 69.1%/61%), and superior, but not significantly, to the 12-mg dose (78.5%/66.9%).[17] With the introduction of the NK1 antagonists, the triple-drug combination has become the standard of care for highly emetogenic regimens. When this combination is used, the dose of the steroid is reduced to account for the interaction with CYP3A4, which increases the area under the curve of the corticosteroid by approximately 50%. The dose of dexamethasone in this triple-drug regimen is reduced to 12 mg for acute management of CINV. Corticosteroids are also an option for monotherapy in low emetogenic regimens, especially in patients who would be receiving it for hypersensitivity prophylaxis (e.g., paclitaxel; Table 3 ).
Delayed CINV. Dexamethasone is also recommended for the management of delayed CINV in both high and moderately emetogenic chemotherapy regimens. Doses are generally 8 mg once or twice daily in the delayed setting, depending on emetogenicity and concurrent antiemetics ( Table 3 ). More recent data have suggested that corticosteroids could be eliminated from the delayed setting without decreased efficacy in CINV control in some settings. Aapro et al.[18] evaluated 300 chemotherapy-naïve female patients receiving AC/EC (anthracycline and cyclophosphamide/epirubicin and cyclophosphamide)-based chemotherapy. All patients received a single injection of palonosetron, 0.25 mg intravenously in combination with dexamethasone, 8 mg intravenously on day 1 and were then randomized to either dexamethasone, 4 mg orally twice daily or placebo for days 2 and 3. The primary end point was complete response (no emesis and no rescue medication) in the overall (days 1–5) period. Overall complete response was achieved in 53.7% of the group receiving palonosetron plus dexamethasone days 1 through 3 and in 53.6% of the group receiving palonosetron plus dexamethasone on day 1. The authors concluded that a single injection of palonosetron and dexamethasone on day 1 might be a sufficient treatment option, and that reducing dexamethasone was not associated with significant reduction in antiemetic control during the 5-day period, or with an impact on patient functioning.
A similar study conducted by Celio et al.[19] evaluated 332 chemotherapy-naïve patients receiving a variety of moderately emetogenic chemotherapy regimens, with oxaliplatin-based or anthracycline-containing regimens the most common. Patients received a single 0.25-mg injection of palonosetron in combination with dexamethasone, 8 mg intravenously on day 1 and were then randomized to either 8 mg of oral dexamethasone daily or placebo for days 2 and 3. Noninferiority was shown, with overall complete response rates of 67.5% for those administered dexamethasone only on day 1, and 71.1% for those also administered dexamethasone on days 2 and 3. The authors concluded that palonosetron plus single-dose dexamethasone administered before common moderately emetogenic chemotherapy regimens protects against acute and delayed CINV, which is noninferior to that of palonosetron plus dexamethasone for 3 days, and that the major benefit of the single-day regimen occurred in patients receiving non-AC moderately emetogenic chemotherapy regimens.[19] A single-day administration of triple-drug therapy (dexamethasone, fosaprepitant, and palonosetron) was also investigated in a small single-arm study,[20] which, if proven to be similar in efficacy in randomized trials, would provide a more convenient and perhaps safe option for patients undergoing emetogenic chemotherapy.
Corticosteroids used in CINV as either monotherapy or in combination with other agents are generally very well tolerated. The most common side effects are transient elevations in glucose, insomnia, anxiety, and gastric upset. However, in most settings the duration of therapy with a corticosteroid is short and side effects can be managed, and the benefits are thought to outweigh any adverse effects. They are not completely benign, however, and, although uncommon, can decompensate diabetes, cause psychosis, or reactivate an ulcer.[21] In a survey of 60 patients receiving moderately emetogenic chemotherapy with dexamethasone for acute and delayed CINV prophylaxis, patients reported moderate to severe problems with insomnia (45%), indigestion/epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%) the week after chemotherapy.[22] A theoretical concern has also been expressed about their use in patients undergoing immunosuppressive chemotherapy because of a potential increased risk for infection and interference with the antitumor effects of chemotherapy.[21,23] Their use in the bone marrow transplant setting and in some hematologic malignancies remains provider- and institution-specific.
