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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -3 مورد

Systemic therapy regimens for non-small cell lung cancer: Pembrolizumab, paclitaxel, and carboplatin[1]

Systemic therapy regimens for non-small cell lung cancer: Pembrolizumab, paclitaxel, and carboplatin[1]
Cycle length: Every 21 days.
Duration of therapy: Maximum of four cycles, followed by maintenance therapy with pembrolizumab alone every three weeks.*
Drug Dose and route Administration Given on days
Pembrolizumab 200 mg Dilute in NS or D5W to a final concentration between 1 to 10 mg/mL and infuse over 30 minutes through an 0.2- to 5-micron sterile, nonpyrogenic, low-protein-binding inline or add-on filter. Day 1
PaclitaxelΔ 200 mg/m2 IV Dilute in NS or D5W to a final concentration of 0.3 to 1.2 mg/mL and administer over one to three hours via 0.22 micron in-line filter; use non-PVC container and tubing set. Day 1
Carboplatin AUC◊ = 6 mg/mL per min IV Dilute in 250 mL NS or D5W and administer over 30 minutes. Day 1
Pretreatment considerations:
Emesis risk
  • MODERATE; (MINIMAL with pembrolizumab monotherapy).§
  • Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Immune status
  • Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as pembrolizumab in patients with an underlying autoimmune disorder. Pembrolizumab should be used with extreme caution in such individuals.
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 for pembrolizumab.
  • Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
Vesicant/irritant properties
  • Paclitaxel can cause significant tissue damage; avoid extravasation. Carboplatin is an irritant.
  • Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis
  • The incidence of grade 3 through 5 neutropenia was approximately 15% in the pembrolizumab-plus-chemotherapy arm versus 17% in the chemotherapy-only arm.[1] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to existing guidelines.
  • 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.
Thyroid function tests
  • Assess baseline thyroid function tests (TSH, FT4) every one to two cycles.
Regulatory issues
  • An FDA-approved patient medication guide, which is available with the US Prescribing Information,[2] must be dispensed with pembrolizumab.
Monitoring parameters:
  • CBC with differential and platelet count before each treatment.
  • Assess electrolytes (including glucose), liver, and kidney tests every three weeks prior to each new cycle of treatment. Thyroid function prior to initiation of therapy and every one to two cycles during treatment, and/or as clinically indicated.
  • Assess changes in neurologic function prior to each treatment cycle.
  • Monitor for infusion reactions, fatigue, colitis, hepatotoxicity, hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism, nephrotoxicity, pneumonitis, hyperglycemia, and skin rash. Many other clinically relevant immune-mediated toxicities have been observed, which may involve any organ system or tissue, and may be severe or fatal.
  • While immune-mediated toxicities generally occur during treatment with pembrolizumab, adverse reactions, including infusion-related reactions, may also develop weeks to months after therapy discontinuation.
  • Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
Suggested dose modifications for toxicity:¥
Myelotoxicity
  • During the initial phase of combined therapy, treatment with pembrolizumab, paclitaxel, and carboplatin should be delayed until the ANC is >1500/microL and platelet count is >100,000/microL.[3,4] If a patient developed 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. The carboplatin dose should be decreased by 25% in patients whose platelet count nadir is <50,000/microL of whose neutrophil nadir is <500.[4]
  • Consider discontinuing paclitaxel and carboplatin therapy if a patient qualifies for a third dose reduction. Dose reductions should be maintained for subsequent cycles.[1]
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 dosing of anticancer agents in adults; chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
Neurotoxicity¥
  • For patients who develop severe neuropathy (grade 3 or 4) for a week or longer, the dose of paclitaxel should be reduced by 20% for subsequent courses.[3]
Pembrolizumab immune-related toxicity
  • No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.[1,2,6]
  • All patients should be closely monitored and evaluated for immune-mediated adverse effects at least every three weeks during therapy.
  • In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Based on the type and severity of the reaction, withhold treatment and administer systemic glucocorticoids. Upon resolution to ≤grade 1, initiate glucocorticoid taper. Immune-mediated adverse reactions that do not resolve with systemic glucocorticoids may be managed with other systemic immunosuppressants (based on limited data). Discontinue pembrolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, AST/ALT elevation >8 times ULN, total bilirubin elevation >3 times ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 times ULN for hepatitis with hepatic tumor involvement, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, or if there is an inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[2]
  • Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for pembrolizumab,[2] from ASCO,[6] from the MASCC,[7] from the NCCN,[8] and from the SITC.[9]
  • Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
If there is a change in body weight of at least 10%, doses should be recalculated.
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 antineoplastic therapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ALT: alanine aminotransferase; ANC: absolute neutrophil count; ASCO: American Society of Clinical Oncology; AST: aspartate aminotransferase; AUC: area under the concentration × time curve; CBC: complete blood count; D5W: 5% dextrose in water; FDA: US Food and Drug Administration; FT4: free thyroxine; GFR: glomerular filtration rate; IV: intravenous; MASCC: Multinational Association of Supportive Care in Cancer; NCCN: National Comprehensive Cancer Network; NS: normal saline; PD-1: programmed cell death protein 1; PVC: polyvinyl chloride; SITC: Society for Immunotherapy of Cancer; TSH: thyroid-stimulating hormone; ULN: upper limit of normal.

* Patients who had radiographic disease progression but were clinically stable could continue to receive treatment at the discretion of an investigator until disease progression was confirmed by imaging performed at least 28 days after the imaging assessment that first showed disease progression.

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

Δ 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.

◊ AUC is converted to a patient-specific carboplatin dose (in mg) according to kidney 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 of chemotherapy-induced nausea and vomiting in adults.

¥ In the original protocol, treatment-related toxicity, except for peripheral neuropathy, had to return to ≤grade 1 before initiating a subsequent cycle. If toxic effects were clearly attributed to one component of the treatment, that component alone could be discontinued. Dose adjustments in the study may differ slightly from those recommended by the manufacturer. The manufacturer's recommendations can be found in the United States Prescribing Information.[2-4]

References:
  1. Paz-Arez L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018; 379:2040.
  2. Pembrolizumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on September 24, 2019).
  3. Paclitaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on January 8, 2019).
  4. Carboplatin injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on January 8, 2019).
  5. Langer CJ, 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.
  6. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021; 39:4073.
  7. MASCC 2020 clinical practice recommendations for the management of immune-mediated adverse events from checkpoint inhibitors. (Available online at link.springer.com/journal/520/topicalCollection/AC_c9dc4afd8c5d6799b830394e9758cad9, accessed on January 26, 2021).
  8. NCCN guidelines for management of immunotherapy-related toxicities. (Available online at nccn.org, accessed on June 21, 2021).
  9. SITC cancer immunotherapy guidelines. (Available online at sitcancer.org/research/cancer-immunotherapy-guidelines, accessed on March 10, 2022).
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