Carboplatin

Carboplatin injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of carboplatin and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see).



There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥ 3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor < 2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.



Carboplatin injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.



Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m² IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

Carboplatin - 300 mg/m² IV on day 1 every 4 weeks for 6 cycles (alternatively see

).

Cyclophosphamide - 600 mg/m² IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see

).



Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.



Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.



The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.

Platelets	Neutrophils	Adjusted Dose* (From Prior Course)
> 100,000	> 2,000	125%
50 to 100,000	500 to 2,000	No adjustment
< 50,000	< 500	75%

  * Percentages apply to carboplatin injection as a single agent or to both carboplatin and cyclophosphamide   

     combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe

     myelosuppression. Escalations above 125% were not recommended for these studies.

Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.

Baseline Creatinine Clearance	Recommended Dose on Day 1
41 to 59 mL/min	250 mg/m2
16 to 40 mL/min	200 mg/m2

The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.



These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression.

Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient's pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (see ). The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).



A simple formula for calculating dosage, based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mLmin), has been proposed by Calvert. In these studies, GFR was measured by ⁵¹Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN DOSING Total Dose (mg) = (target AUC) × (GFR + 25)  Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

The target AUC of 4 mg/mL

min to 6 mg/mLmin using single agent carboplatin appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent carboplatin administered to previously treated patients and the likelihood of developing toxicity.

	% Actual Toxicity in Previously Treated Patients
AUC (mg/mL · min)	Gr 3 or Gr 4 Thrombocytopenia	Gr 3 or Gr 4 Leukopenia
4 to 5	16%	13%
6 to 7	33%	34%

Because renal function is often decreased in elderly patients, formula dosing of carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity.



Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin.



Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D₅W) or 0.9% Sodium Chloride Injection, USP.



When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution.  

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see

	First Line Combination Therapy* Percent	Second Line Single Agent Therapy** Percent
Bone Marrow
Thrombocytopenia <100,000/mm3 <50,000/mm3	66 33	62 35
Neutropenia <2,000 cells/mm3 <1,000 cells/mm3	96 82	67 21
Leucopenia <4,000 cells/mm3 <2,000 cells/mm3	97 71	85 26
Anemia <11 g/dL < 8 g/dL	90 14	90 21
Infections	16	5
Bleeding	8	5
Transfusions	35	44
Gastrointestinal
Nausea and vomiting	93	92
Vomiting	83	81
Other GI side effects	46	21
Neurologic
Peripheral neuropathies	15	6
Ototoxicity	12	1
Other sensory side effects	5	1
Central neurotoxicity	26	5
Renal
Serum creatinine elevations	6	10
Blood urea elevations	17	22
Hepatic
Bilirubin elevations	5	5
SGOT elevations	20	19
Alkaline phosphatase elevations	29	37
Electrolytes loss
Sodium	10	47
Potassium	16	28
calcium	16	31
Magnesium	61	43
Other side effects
Pain	44	23
Asthenia	41	11
Cardiovascular	19	6
Respiratory	10	6
Allergic	11	2
Genitourinary	10	2
Alopecia	49	2
Mucositis	8	1

Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see ).



Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences  that can be noted in the adverse experience table.

**Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single agent carboplatin.



In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single agent therapy.



Bone marrow suppression is the dose-limiting toxicity of carboplatin. Thrombocytopenia with platelet counts below 50,000/mm³ occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm³ occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm³ occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single agent therapy. By day 28, 90% of patients have platelet counts above 100,000/mm³; 74% have neutrophil counts above 2,000/mm³; 67% have leukocyte counts above 4,000/mm³.



Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia.



The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia.



Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients).



Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy.



Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer patients) and in about one-third of these patients it is severe. Carboplatin, as a single agent or in combination, is significantly less emetogenic than cisplatin; however, patients previously treated with emetogenic agents, especially cisplatin, appear to be more prone to vomiting. Nausea alone occurs in an additional 10% to 15% of patients. Both nausea and vomiting usually cease within 24 hours of treatment and are often responsive to antiemetic measures. Although no conclusive efficacy data exist with the following schedules, prolonged administration of carboplatin, either by continuous 24-hour infusion or by daily pulse doses given for 5 consecutive days, was associated with less severe vomiting than the single-dose intermittent schedule. Emesis was increased when carboplatin was used in combination with other emetogenic compounds. Other gastrointestinal effects observed frequently were pain, in 17% of the patients; diarrhea, in 6%; and constipation, also in 6%.



Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild paresthesias occurring most frequently. Carboplatin therapy produces significantly fewer and less severe neurologic side effects than does therapy with cisplatin. However, patients older than 65 years and/or previously treated with cisplatin appear to have an increased risk (10%) for peripheral neuropathies. In 70% of the patients with pre-existing cisplatin induced peripheral neurotoxicity, there was no worsening of symptoms during therapy with carboplatin. Clinical ototoxicity and other sensory abnormalities such as visual disturbances and change in taste have been reported in only 1% of the patients. Central nervous system symptoms have been reported in 5% of the patients and appear to be most often related to the use of antiemetics.



Although the overall incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may result in cumulative neurotoxicity.



Development of abnormal renal function test results is uncommon, despite the fact that carboplatin, unlike cisplatin, has usually been administered without high-volume fluid hydration and/or forced diuresis. The incidences of abnormal renal function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian cancer patients). Most of these reported abnormalities have been mild and about one-half of them were reversible.



Creatinine clearance has proven to be the most sensitive measure of kidney function in patients receiving carboplatin, and it appears to be the most useful test for correlating drug clearance and bone marrow suppression. Twenty-seven percent of the patients who had a baseline value of 60 mL/min or more demonstrated a reduction below this value during carboplatin therapy.



The incidences of abnormal liver function tests in patients with normal baseline values were reported as follows: total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian cancer patients). These abnormalities have generally been mild and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may complicate the assessment in many patients. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe abnormalities of liver function tests were reported.



The incidences of abnormally decreased serum electrolyte values reported were as follows: sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47%, 28%, 31%, and 43%, respectively, in pretreated ovarian cancer patients). Electrolyte supplementation was not routinely administered concomitantly with carboplatin, and these electrolyte abnormalities were rarely associated with symptoms.



Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions have been similar in nature and severity to those reported with other platinum-containing compounds, i.e. rash, urticaria, erythema, pruritus, and rarely bronchospasm and hypotension. Anaphylactic reactions have been reported as part of postmarketing surveillance (see ). These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.



Injection site reactions, including redness, swelling, and pain, have been reported during postmarketing surveillance. Necrosis associated with extravasation has also been reported.



Pain and asthenia were the most frequently reported miscellaneous adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely.



Malaise, anorexia, hypertension, dehydration, and stomatitis have been reported as part of postmarketing surveillance.