Chemotherapy regimens for advanced non-small cell lung cancer: Paclitaxel, carboplatin, and bevacizumab^[1]

Cycle length: Every 21 days for a maximum of six cycles, followed by maintenance therapy with bevacizumab every three weeks.
Drug	Dose and route	Administration	Given on days
Paclitaxel	200 mg/m² IV	Dilute in 250 mL NS* (final concentration of 0.3 to 1.2 mg/mL) and administer over three hours.^¶	Day 1
Carboplatin	AUC^Δ = 6 mg/mL per min IV	Dilute in 250 mL NS* and administer over 30 minutes (administer 60 minutes after the completion of the paclitaxel infusion).	Day 1
Bevacizumab	15 mg/kg IV	Dilute into a total volume of 100 mL of NS.* The first dose should be administered over 90 minutes one hour after carboplatin. If well tolerated, the second infusion may be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 10 to 30 minutes.^[2]	Day 1
Pretreatment considerations:
Emesis risk	MODERATE (MINIMAL when bevacizumab is given as maintenance).^◊ Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration. There is no standard premedication regimen for bevacizumab. Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
Vesicant/irritant properties	Paclitaxel can cause significant tissue damage and carboplatin is an irritant; avoid extravasation. Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis	Primary prophylaxis with hematopoietic growth factors is not recommended (risk of febrile neutropenia is approximately 5%^[1]). Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
Dose adjustment for baseline liver or kidney dysfunction	Each carboplatin dose should be calculated based upon kidney function by use of the Calvert formula.^Δ A lower starting dose of paclitaxel may be needed in patients with liver impairment. Bevacizumab does not require dosage adjustments for liver or kidney dysfunction.^[2] Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and dosing of anticancer agents in adults.
Monitoring parameters:
CBC with differential weekly during treatment.
Serum electrolytes and liver and kidney function tests prior to each treatment cycle.
Assess changes in neurologic function, blood pressure, urine protein concentration, and risk for bleeding prior to each treatment cycle.
Suggested dose modifications for toxicity:
Myelotoxicity	Treatment with paclitaxel and carboplatin should be delayed until the ANC is >2000/microL and platelet count is >100,000/microL.^[3,4] If a patient develops severe neutropenia (<500/microL) for a week or longer, or febrile neutropenia during the prior course, then the paclitaxel and carboplatin doses should be reduced by 20 to 25% for subsequent courses.^[5] An alternative to dose reduction is the institution of hematopoietic growth factor support. Both the carboplatin and paclitaxel doses should be decreased by 25% in patients whose platelet count nadir is <50,000/microL for longer than five days.^[4]
Kidney/hepatic toxicity	Alterations in kidney function during therapy may require a recalculation of the carboplatin dose. Paclitaxel dose may need to be adjusted for hepatic impairment on day 1 of each cycle. Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and dosing of anticancer agents in adults.
Neurotoxicity	For patients who develop severe peripheral neuropathy (grade 3 or 4) for a week or longer, the dose of paclitaxel should be reduced by 20% for subsequent courses.^[4]
Other toxicity	Assess changes in blood pressure, urine protein concentration, and risk for bleeding prior to each treatment. Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS.^[2] Do not administer within 28 days of surgery.
If there is a change in body weight of at least 10%, doses should be recalculated.
Dose reductions may also be indicated if there are other grade 2 or higher nonhematologic toxicities. The dose reduction is at the discretion of the clinician, as formal guidelines are not available.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ANC: absolute neutrophil count; AUC: area under the concentration × time curve; CBC: complete blood count; GFR: glomerular filtration rate; IV: intravenous; NCCN: National Comprehensive Cancer Network; NS: normal saline; RPLS: reversible posterior leukoencephalopathy syndrome.

* Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).

¶ Paclitaxel can be administered in NS, D5W, or NS/D5W* at varying concentrations between 0.3 to 1.2 mg/mL. Use glass or polypropylene bottles or polypropylene or polyolefin plastic bags, and administer through polyethylene-lined administration sets with a microporous membrane 0.22 microns or less.

Δ AUC is converted to a patient-specific carboplatin dose (in mg) according to renal function by using the Calvert formula. The Calvert formula is total dose (mg) = (target AUC) × (GFR + 25). If using measured serum creatinine, limit the maximal GFR for the calculation to 125 mL/min. Refer to UpToDate topics on dosing of anticancer agents in adults.

◊ Consensus-based guidelines from the NCCN classify higher carboplatin doses (AUC ≥4) as highly emetogenic; by contrast, the American Society of Clinical Oncology and the Multinational Association for Supportive Care in Cancer guidelines consider all carboplatin doses to be moderately emetogenic. Although many institutions classify carboplatin-containing regimens as moderately emetogenic, a benefit for adding a neurokinin 1 receptor antagonist on day 1 has been shown in many studies; additional prophylaxis beyond day 1 for delayed emesis is not needed for most patients. Refer to UpToDate topics on prevention and treatment of chemotherapy-induced nausea and vomiting in adults.

References:

Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542.
Bevacizumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 29, 2019).
Carboplatin injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 29, 2019).
Paclitaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 29, 2019).
Langer CT, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995; 13:1860.

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Chemotherapy regimens for advanced non-small cell lung cancer: Paclitaxel, carboplatin, and bevacizumab[1]

Chemotherapy regimens for advanced non-small cell lung cancer: Paclitaxel, carboplatin, and bevacizumab^[1]