Systemic therapy regimens for platinum-sensitive recurrent epithelial carcinoma of the ovary, peritoneum, or fallopian tube: Carboplatin and gemcitabine plus bevacizumab^[1]

Cycle length: 21 days. Total cycles: 6 to 10. Following completion of chemotherapy, single-agent bevacizumab maintenance therapy may be continued on an every three week schedule until disease progression or toxicity.
Drug	Dose and route	Administration	Given on days
Gemcitabine	1000 mg/m² IV	Dilute in 250 mL NS^¶ and administer over 30 minutes.	Days 1 and 8
Carboplatin	AUC* = 4 mg/mL per min IV	Dilute in 250 mL NS^¶ and administer over one hour.	Day 1
Bevacizumab	15 mg/kg IV	Dilute into a total volume of 100 mL NS.^¶ Administer first dose over 90 minutes, before carboplatin and gemcitabine. If well tolerated, the second infusion may be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 30 minutes.^Δ^[2]	Day 1
Pretreatment considerations:
Emesis risk	MODERATE on day 1; LOW on day 8.^◊ Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	There is no standard premedication regimen. Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
Vesicant/irritant properties	Carboplatin and gemcitabine are irritants. Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis	Primary prophylaxis with G-CSF is not indicated (risk of febrile neutropenia <2%).^[1] Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
Dose adjustment for baseline liver or kidney dysfunction	Each carboplatin dose should be calculated based upon kidney function by use of the Calvert formula.* A lower starting dose for gemcitabine may be needed in patients with liver impairment. 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 prior to treatment on days 1 and 8.
Assess electrolytes and liver and kidney function prior to each new cycle of treatment.
Assess changes in neurologic function, blood pressure, and risk for bleeding prior to each new cycle of treatment. Urine protein/creatinine ratio should be obtained when appropriate.
Suggested dose modifications for toxicity:
Myelotoxicity	For initiation of each new treatment cycle, ANC ≥1500/microL, Hb ≥8.5 g/dL, and platelet count ≥100,000/microL.^[1] If day 8 ANC 1000 to 1499/microL and/or platelets 75,000 to 99,999/microL, reduce gemcitabine dose by 50%. If day 8 ANC <1000/microL and/or platelets <75,000/microL, omit gemcitabine dose.^[3] For intracycle febrile neutropenia, ANC <500/microL for more than five days, ANC <100/microL for more than three days, or any platelet count <25,000/microL, reduce gemcitabine dose to 800 mg/m² for both days 1 and 8. If toxicities recur despite dose reduction, permanently delete the day 8 gemcitabine dose. Discontinue carboplatin and gemcitabine if hematologic recovery does not occur within three weeks.
Thrombotic microangiopathy	Thrombotic microangiopathy (TMA, also sometimes called thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) has been associated with gemcitabine, in individuals who have received a large or small cumulative dose.^[3] Consider the possibility of TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, kidney failure, and/or neurologic findings. Management consists of drug discontinuation and supportive care, without plasma exchange, as long as there is high confidence in a drug-induced etiology rather than TTP. Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
Nephrotoxicity	Alterations in kidney function during therapy may require a recalculation of the carboplatin dose. Refer to UpToDate topics on dosing of anticancer agents in adults.
Pulmonary toxicity	A variety of manifestations of pulmonary toxicity have been reported with gemcitabine.^[3] Discontinue gemcitabine immediately and permanently. Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
Other toxicity	For severe (grade 3 or 4) nonhematologic toxicities, gemcitabine should be held or decreased by 50% based on clinical judgement.^[1] Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious (≥grade 2) hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS, severe venous thromboembolism, and severe heart failure.^[1,2] Do not administer bevacizumab within 28 days of surgery or until wounds are fully healed.^[2] Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects and toxicity of molecularly targeted antiangiogenic agents, cardiovascular effects.
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 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; G-CSF: granulocyte colony stimulating factors; Hb: hemoglobin; 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).

¶ 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.

Δ Do not administer or mix bevacizumab with dextrose solutions.

◊ 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.

References:

Aghajanian C, Blank SV, Goff BA, et al. OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30:2039.
Bevacizumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 29, 2019).
Gemcitabine hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 29, 2019).

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Systemic therapy regimens for platinum-sensitive recurrent epithelial carcinoma of the ovary, peritoneum, or fallopian tube: Carboplatin and gemcitabine plus bevacizumab[1]

Systemic therapy regimens for platinum-sensitive recurrent epithelial carcinoma of the ovary, peritoneum, or fallopian tube: Carboplatin and gemcitabine plus bevacizumab^[1]