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Carboplatin
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NOTE: The Society of Gynecologic Oncology (SGO) has issued a statement detailing platinum dosing and sparing recommendations to overcome challenges of limited drug availability. This statement and disease-specific recommendations can be found at https://www.sgo.org/chemotherapy-drug-shortage/.
Carboplatin Dosing with the Calvert equation:[25916]
NOTE: For all equations, AUC (area under the plasma concentration vs. time curve) is expressed in mg/ml x min and GFR (glomerular filtration rate) in ml/min.
The GFR should be calculated using creatinine clearance determined by actual measurements or estimated by using the Cockroft-Gault or Jeliffe methods. It should be noted that these methods of determining creatinine clearance may not be as accurate, especially in patients with renal dysfunction or patients with low body weight, as the (51)Cr-EDTA method used in the original study. Currently, (51)Cr-EDTA is not available in the United States. The following are general recommendations for target AUC; however, exact dosing guidelines have not been established and may vary depending upon the disease state and protocol.
NOTE: By the end of 2010, all clinical laboratories in the US will use the standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine. Compared to older methods of measuring serum creatinine, the IDMS method may underestimate serum creatinine when values are relatively low (e.g. about 0.7 mg/dl). This could result in an overestimation of GFR in patients with normal renal function and when using the Calvert formula for carboplatin dosing (see below), may result in a higher than desired dose and increased drug-related toxicity. If a patient's GFR is calculated based on a serum creatinine measured using the IDMS method, the FDA recommends that physicians consider capping the dose of carboplatin for desired exposure to avoid potential overdosing. Based on the Calvert formula, maximum doses can be calculated as follows:
Target AUC = 6, the maximum dose is 6 x 150 = 900 mg
Target AUC = 5, the maximum dose is 5 x 150 = 750 mg
Target AUC = 4, the maximum dose is 4 x 150 = 600 mg
Maximum dose recommendations are based on a maximum estimated GFR = 125 ml/min. Higher estimated GFR values should not be used.[42067]
Adults: The total carboplatin dose in mg for adults may be calculated using the Calvert equation:[25916]
Total dose (mg) = target AUC x (GFR + 25)
Children: The following equation should be used to calculate carboplatin dosage (mg/m2) in children. This equation accounts for differences in the renal elimination of carboplatin between adults and children:[25916]
Total dose (mg/m2) = target AUC x [(0.93 x GFR) + 15]
For patients with previously untreated ovarian cancer, administer carboplatin 300 mg/m2 IV on day 1 in combination with cyclophosphamide (600 mg/m2 IV on day 1), repeated every 4 weeks for 6 cycles. For patients with recurrent ovarian cancer, administer single-agent carboplatin 360 mg/m2 IV (or AUC 5 to 6) on day 1, repeated every 4 weeks. Dosage adjustments should be made according to the lowest post-treatment platelet or neutrophil value as assessed by weekly blood counts.[29203]
200 to 650 mg/m2 intraperitoneally every 4 to 6 weeks has been studied. In 1 trial, 350 mg/m2 intraperitoneally with cyclophosphamide IV every 3 to 4 weeks resulted in similar response and survival rates as carboplatin 350 mg/m2 IV and cyclophosphamide IV with less myelotoxicity.[25918]
AUC 5 to 7.5 IV on day 1 in combination with paclitaxel (175 to 185 mg/m2 IV over 3 hours on day 1), every 3 weeks for 6 cycles. In clinical trials, carboplatin combined with paclitaxel has been shown to be less toxic and produce similar efficacy to cisplatin combined with paclitaxel as first-line treatment of patients with advanced ovarian cancer.[13626][40931][40932] Additionally, carboplatin AUC 6 IV on day 1 in combination with paclitaxel (80 mg/m2 IV on days 1, 8, and 15), every 3 weeks for 6 cycles has been given. This dose-dense combination was compared to conventional carboplatin/paclitaxel in 631 patients with advanced ovarian cancer. Progression-free survival, the primary endpoint, was significantly higher in the dose-dense arm (28 months vs. 17.2 months, p = 0.0015).[40935]
AUC 5 IV on day 1, immediately preceded by docetaxel (75 mg/m2 IV over 1 hour on day 1), repeated every 3 weeks for 6 cycles. In a phase III trial of 1077 patients, carboplatin combined with docetaxel was compared to carboplatin combined with paclitaxel. No significant differences in response rate, progression-free survival, or overall survival were observed between the 2 groups. Grades 2 to 4 neurosensory toxicity were significantly greater in the paclitaxel containing regimen (30% vs. 11%, p < 0.001) and grades 3 to 4 neutropenia were significantly higher in the docetaxel containing regimen (94% vs. 84%, p < 0.001).[33942]
Carboplatin AUC 6 IV in combination with paclitaxel (200 mg/m2) IV on day 1 given every 21 days produced an overall survival of 12.3 months in a phase 3 comparison of 4 chemotherapy doublets in advanced NSCLC.[34305] In another similar 4-arm phase 3 comparison, carboplatin AUC 6 IV on day 1 in combination with paclitaxel 225 mg/m2 IV on day 1 given every 21 days, produced an overall survival of 7.8 months, which was similar to the reference regimen of cisplatin and paclitaxel.[41098]
AUC 6 IV in combination with docetaxel (75 mg/m2 IV) on day 1 given every 21 days for 4 to 6 cycles. In a phase 3 trial of 1,203 patients with unresectable locally advanced or metastatic NSCLC, docetaxel and platinum combinations (cisplatin or carboplatin) were compared with cisplatin/vinorelbine. No difference was observed between docetaxel/carboplatin and cisplatin/vinorelbine in overall survival, the primary endpoint. Grade 3 and 4 anemia and nausea/vomiting were significantly lower in both docetaxel containing arms. In addition, hospitalizations and treatment discontinuation secondary to toxicity were higher with cisplatin/vinorelbine.[44411] A separate phase 3 trial conducted in 422 patients with inoperable, locally advanced or metastatic NSCLC compared docetaxel/carboplatin to mitomycin C/cisplatin plus either ifosfamide or vinblastine. The primary endpoint, 1-year overall survival, was not significantly different between the treatment arms. Grade 3 and 4 neutropenia, infection, and mucositis were all significantly higher with docetaxel/carboplatin, while quality of life scores were significantly better.[34309]
AUC 5 IV on day 1 in combination with gemcitabine 1,200 mg/m2 IV on days 1 and 8, every 21 days for 6 cycles.[34307] Alternatively, carboplatin AUC 5 IV on day 1 with gemcitabine 1,000 mg/m2 IV on days 1, 8 and 15, repeated every 28 days for 4 cycles[34308] or, carboplatin AUC 5 IV day 1 with gemcitabine 1,000 mg/m2 IV on days 1 and 8, repeated every 21 days for 4 cycles, have also been studied.[42689]
AUC 6 IV on day 1 in combination with nanoparticle albumin-bound (nab) paclitaxel (100 mg/m2 IV over 30 minutes on days 1, 8, and 15), repeated every 21 days; administer carboplatin immediately after the nab-paclitaxel infusion on day 1.[30742] Nab-paclitaxel plus carboplatin was noninferior to paclitaxel plus carboplatin in patients with previously untreated non-resectable stage IIIB or stage IV non-small cell lung cancer (NSCLC) in a multicenter, randomized, phase 3 trial (n = 1,052). The primary endpoint of overall response rate (ORR) assessed by independent radiologic review was significantly improved with nab-paclitaxel/carboplatin compared with solvent-based (sb) paclitaxel plus carboplatin (33% vs. 25%); all responding patients in the nab-paclitaxel arm had a partial response (PR) while 1 patient in the sb-paclitaxel arm achieved a complete response. In a subgroup analysis, the ORR was significantly improved with nab-paclitaxel plus carboplatin in patients with squamous cell histology (41% vs. 24%) but not nonsquamous cell histology (26% vs. 25%). Median progression-free survival (6.3 months vs. 5.8 months) and overall survival (12.1 months vs. 11.2 months) were nonsignificantly improved with nab-paclitaxel/carboplatin.[42820]
AUC 5 IV in combination with pemetrexed (500 mg/m2 IV) on day 1, repeated every 3 weeks for 4 cycles. In a phase 3 trial, 436 patients were randomized to pemetrexed/carboplatin or gemcitabine/carboplatin. No significant differences were observed for the primary endpoint, health-related quality of life, or the secondary endpoint, overall survival. Grade 3 or 4 toxicities were significantly worse in the gemcitabine/carboplatin arm.[42689]
AUC 5 IV on day 1 and pemetrexed (500 mg/m2 IV on day 1) repeated every 21 days for 4 cycles in combination with pembrolizumab (200 mg IV on day 1 every 3 weeks OR 400 mg IV on day 1 every 6 weeks). Administer pembrolizumab prior to pemetrexed and chemotherapy when given on the same day. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. In a multicenter double-blind clinical trial (KEYNOTE-189), patients with previously untreated metastatic, EGFR- and ALK-negative, nonsquamous NSCLC, regardless of PD-L1 status, were randomized to treatment with pemetrexed plus either cisplatin or carboplatin, in combination with either pembrolizumab (n = 410) or placebo (n = 206). After a median follow-up of 31 months, the median overall survival (22 months vs. 10.6 months), progression-free survival (9 months vs. 4.9 months), and overall response rate (48.3% vs. 19.9%) were significantly improved in the pembrolizumab arm. The median duration of response was 12.5 months for patients who received pembrolizumab plus pemetrexed/platinum chemotherapy compared with 7.1 months in those receiving placebo plus pemetrexed/platinum chemotherapy.[57889] [28376] [66703]
AUC 6 IV on day 1 with either paclitaxel (200 mg/m2 IV on day 1) or nab-paclitaxel (100 mg/m2 IV on days 1, 8, and 15) repeated every 3 weeks for 4 cycles in combination with pembrolizumab (200 mg IV on day 1 every 3 weeks OR 400 mg IV on day 1 every 6 weeks). Administer pembrolizumab prior to chemotherapy when given on the same day. Following completion of platinum-based therapy, pembrolizumab may be continued as maintenance therapy until disease progression or unacceptable toxicity, for up to 24 months. In a multicenter, randomized, double-blind clinical trial (KEYNOTE-407), treatment with pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel (n = 278) significantly improved median overall survival (17.2 months vs. 11.6 months) and progression-free survival (6.4 months vs. 4.8 months) compared with placebo plus carboplatin and paclitaxel/nab-paclitaxel (n = 281) in patients with metastatic squamous NSCLC. The overall response rate was also significantly improved in the pembrolizumab arm (58% vs. 35%), for a median duration of 7.2 months and 4.9 months, respectively.[57889] [66530]
AUC 6 IV on day 1, preceded by bevacizumab (15 mg/kg IV over 90 minutes) and paclitaxel (200 mg/m2 IV over 3 hours), every 3 weeks for 6 cycles of chemotherapy. After completion of chemotherapy, continue bevacizumab (15 mg/kg IV), on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is well tolerated, the second infusion may be given over 60 minutes; if the 60-minute infusion is well tolerated, subsequent infusions may be given over 30 minutes. In a randomized, open-label clinical trial (n = 878), median overall survival was significantly longer in chemotherapy-naive patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC treated with bevacizumab/paclitaxel/carboplatin (BCP) compared with paclitaxel/carboplatin (CP) alone (12.3 months vs. 10.3 months); investigator-assessed progression-free survival (PFS) was also longer in the bevacizumab arm. In an exploratory analysis, the impact of bevacizumab was not significant in women, patients age 65 years and older, or in patients with weight loss of 5% or more at study entry.[60402]
AUC 6 IV on day 1, every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer in combination with paclitaxel (200 mg/m2 IV, or 175 mg/m2 IV in Asian patients, every 3 weeks for up to 4 to 6 cycles), bevacizumab (15 mg/kg IV until disease progression or unacceptable toxicity), and atezolizumab (840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity). Administer atezolizumab prior to bevacizumab and chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label, phase 3 clinical trial (IMpower150), treatment with atezolizumab plus bevacizumab/paclitaxel/carboplatin (ABCP) significantly improved overall survival in patients with metastatic nonsquamous NSCLC compared with BCP without atezolizumab (19.2 months vs. 14.7 months); overall survival with atezolizumab/paclitaxel/carboplatin was not significantly different from BCP. Progression-free survival was also significantly improved in the ABCP arm compared with BCP (8.5 months vs. 7 months). The objective response rate was 55% (complete response [CR], 4%) versus 42% (CR, 1%), respectively, for a median duration of 10.8 months and 6.5 months, respectively.[60793] [63819]
AUC 6 IV on day 1, every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer in combination with nab-paclitaxel (100 mg/m2 IV on days 1, 8, and 15) and atezolizumab (840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity). Administer atezolizumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. First-line treatment of EGFR- and ALK-negative metastatic NSCLC with atezolizumab plus nab-paclitaxel and carboplatin significantly improved median overall survival (18.6 months vs. 13.9 months) and median progression-free survival (7.2 months vs. 6.5 months) compared with nab-paclitaxel and carboplatin alone in a multicenter, randomized, open-label trial (IMpower130). The overall response rate was 46% (complete response [CR], 5%) in the atezolizumab arm compared with 32% (CR, 1%) in the control arm, for a median duration of 10.8 months versus 7.8 months, respectively.[60793] [66441]
70 mg/m2/day IV on days 1 through 4 in combination with 5-fluorouracil (5-FU) (600 mg/m2/day continuous IV infusion on days 1 through 4). Chemotherapy cycles were started on days 1, 22, and 43 and were administered concurrently with radiotherapy (RT). In a phase III trial, 226 patients with stage III or IV squamous cell carcinoma of the oropharynx (no evidence of distant metastasis) were randomized to receive RT alone or concomitantly with carboplatin/5-FU. Overall survival at 5 years was significantly improved in the chemoradiotherapy arm (22.4% vs. 15.8%, p = 0.05). The 5-year specific disease free survival rate (26.6% vs. 14.6%, p = 0.01) and locoregional control rate (47.6% vs. 24.7%, p = 0.002) were also significantly improved with chemoradiotherapy. Hematologic and skin toxicities were more common in chemoradiotherapy arm. In addition, grades 3 and 4 mucositis and poor nutritional status occurred more frequently with concomitant therapy. There were no significant differences in late toxic effects between the arms when assessed at 5 years.[43174][43119]
300 mg/m2 IV on day 1 in combination with 5-fluorouracil (5-FU) (1,000 mg/m2/day continuous IV infusion over 96 hours on days 1 through 4); repeated every 4 weeks. In a phase III trial, 277 patients were randomized to receive carboplatin-5-FU, cisplatin-5-FU, or methotrexate (MTX). An increase in overall response rate was achieved with carboplatin-5-FU versus MTX, which was of borderline statistical significance (21% vs. 10%, p = 0.05). The overall response rate was numerically lower with carboplatin/5-FU compared to cisplatin-5-FU (21% vs. 32%).[43120]
AUC 5 IV on day 1, in combination with fluorouracil (1,000 mg/m2 per day IV infusion over days 1 to 4), every 3 weeks for up to 6 cycles. Administer with cetuximab (400 mg/m2 IV as an initial loading dose on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks). Complete cetuximab administration 1 hour prior to chemotherapy and continue until disease progression or unacceptable toxicity. In a phase 3 trial, 442 patients were randomized to receive a platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab. Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab to chemotherapy compared with chemotherapy alone (10.1 months vs. 7.4 months). However, sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.[35055]
100 mg/m2 IV weekly in combination with paclitaxel (40 to 45 mg/m2 IV weekly). Chemotherapy was administered weekly prior to radiation therapy. In a clinical trial, 62 patients were administered carboplatin-paclitaxel concomitantly with radiation therapy. An overall survival of 33 months was achieved. A complete response (CR) occurred in 75% of patients; among patients with a CR, an overall survival of 49 months was achieved. At a follow-up of 30 months, a local control rate of 63% was observed.[43182]
Carboplatin AUC 5 IV on day 1 in combination with etoposide (120 mg/m2/day IV on days 1 through 3) and bleomycin (30 international units on day 2), repeated every 21 days for 4 cycles has been used. In a randomized trial, the combination of carboplatin (AUC 5), etoposide, and bleomycin (CEB) was compared with the standard regimen of bleomycin, etoposide, and cisplatin (BEP) in patients with good-prognosis, metastatic testicular cancer. The combination containing carboplatin resulted in a significantly lower response rate than the cisplatin-containing regimen (87.3% vs. 94.4%, respectively).[25919]
Single dose carboplatin IV (AUC 7 if measured by EDTA; 90% of that dose if measured by 24-hour urinary creatinine clearance) after resection. In a phase III trial of patients with stage I seminoma, no difference in relapse-free rates were observed between single dose carboplatin and adjuvant radiotherapy amongst the 1,447 patients who met the minimum follow-up requirement of 5 years. Contralateral germ-cell tumors occurred in only 2 patients randomized to receive carboplatin as compared to 15 patients randomized to receive radiotherapy.[49358]
Carboplatin AUC 5 IV on day 2 (Max: 800 mg), ifosfamide 5 g/m2 IV mixed with equal dose of mesna via continuous intravenous infusion over 24 hours beginning on day 2, and etoposide 100 mg/m2/day on days 1 through 3, every 2 weeks (ICE regimen) for 3 cycles, was developed to treated relapsed NHL and allow for adequate stem cell collection prior to transplant.[29307] Alternative dosage regimens have been used, including some in the outpatient setting.[51026]
Ifosfamide 0 to 10 g/m2 IV in 4 divided doses on days -6 to -3, in combination with carboplatin 1,500 to 2,000 mg/m2 IV in 3 divided doses on days -6 to -4 (1,500 mg/m2) or in 4 divided doses on days -6 to -3 (more than 1,500 mg/m2), and etoposide 1,200 to 2,400 mg/m2 IV in 4 divided doses on days -6 to -3. Ifosfamide was administered on days -6 to -3 as a 22-hour infusion and mesna (each dose was 20% of the total dose/day of ifosfamide) was administered before the start of ifosfamide and every 6 hours after, including 2 doses after the final ifosfamide infusion. Each carboplatin dose was administered as a 1 hour infusion. Etoposide was administered undiluted through a central line.[50463]
Etoposide 100 mg/m2/day IV on days 1 to 3 in combination with carboplatin AUC 5 (Max dose: 800 mg) IV on day 2 and ifosfamide 5 g/m2 mixed with an equal dose of mesna administered via continuous IV infusion for 24 hours beginning day 2. Filgrastim was administered at 10 mcg/kg/day starting on day 5 until completion of leukapheresis.[29307]
350 mg/m2 IV on day 1 in combination with teniposide 50 mg/m2/day IV on days 1, 2, and 3, every 28 days. Treatment has been studied up to a maximum of 10 cycles.[50299]
175 mg/m2 IV once weekly on weeks 1 through 4 and 7 through 10 in combination with vincristine 1.5 mg/m2 IV (Max dose: 2 mg) once weekly on weeks 1 through 10 as induction therapy.[58630][50300] Begin maintenance therapy on week 12 with carboplatin 175 mg/m2 IV once weekly for 4 weeks and vincristine 1.5 mg/m2 (Max dose: 2 mg) IV once weekly for 3 weeks repeated every 6 weeks for 8 cycles. Do not start maintenance therapy or the next cycle of maintenance therapy until the ANC is more than 1,000 cells/mm3 and the platelet count is more than 100,000 cells/mm3.[58630]
AUC 5 IV on day 1, every 28 days for 6 cycles.[50316] Alternately, carboplatin 350 to 400 mg/m2 IV on day 1, every 21 days for up to 8 cycles, has also been studied.[50317]
AUC of 6 IV over 30 minutes on day 1 following paclitaxel 225 mg/m2 IV over 3 hours repeated every 21 days (CP regimen) for 6 cycles was compared with methotrexate 30 mg/m2 on days 1, 15, and 22, vinblastine 3 mg/m2 IV on days 2, 15, and 22, doxorubicin 30 mg/m2 on day 2, and cisplatin 70 mg/m2 on day 2 (MVAC regimen) in a randomized, phase III trial. In this study, the median overall survival (OS) times were 13.8 and 15.4 months with CP and MVAC, respectively (p = 0.75) in 85 patients (median follow-up of 32.5 months). This study was halted due to slow patient accrual and was therefore underpowered to detect a difference in the primary endpoint of OS. The progression-free survival time was 5.2 months in the CP arm and 8.7 months in the MVAC arm (p = 0.24). Grade 3 or higher toxicity reported less often with CP compared with MVAC included neutropenia (29% vs. 67%), anemia (5% vs. 38%), thrombocytopenia (10% vs. 21%), fatigue (10% vs. 24%), and dyspnea (2% vs. 14%); grade 3 sensory neuropathy occurred more often with CP (15% vs. 2%). Additionally, worst degree toxicity of grade 4 or higher occurred in fewer patients in the CP arm (15% vs. 33%) and there was 1 treatment-related death in each study arm.[47217]
AUC 5 IV on day 1 every 3 weeks for 4 cycles in combination with paclitaxel (80 mg/m2 IV once weekly for 12 weeks) and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks); administer pembrolizumab prior to chemotherapy when given on the same day. Alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After completion of 12 weeks (4 cycles) of pembrolizumab, paclitaxel, and carboplatin, continue neoadjuvant therapy with 4 cycles of doxorubicin (60 mg/m2 IV every 3 weeks) plus cyclophosphamide (600 mg/m2 IV every 3 weeks) and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks), followed by surgery; administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with high-risk (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement), early stage triple-negative breast cancer were randomized to neoadjuvant treatment with pembrolizumab or placebo in combination with carboplatin and paclitaxel, followed by anthracycline and cyclophosphamide in a phase 3 clinical trial (KEYNOTE-522); after definitive surgery, patients received adjuvant pembrolizumab or placebo. Treatment with pembrolizumab plus chemotherapy significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy. The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.[66036] [57889]
AUC 5 IV on day 1 every 3 weeks for 4 cycles in combination with paclitaxel (80 mg/m2 IV once weekly for 12 weeks) and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks); administer pembrolizumab prior to chemotherapy when given on the same day. Alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After completion of 12 weeks (4 cycles) of pembrolizumab, paclitaxel, and carboplatin, continue neoadjuvant therapy with 4 cycles of epirubicin (90 mg/m2 IV every 3 weeks) plus cyclophosphamide (600 mg/m2 IV every 3 weeks) and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks), followed by surgery; administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Do not administer adjuvant pembrolizumab monotherapy to patients with disease progression or unacceptable toxicity related to neoadjuvant treatment with pembrolizumab plus chemotherapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with high-risk (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement), early stage triple-negative breast cancer were randomized to neoadjuvant treatment with pembrolizumab or placebo in combination with carboplatin and paclitaxel, followed by anthracycline and cyclophosphamide in a phase 3 clinical trial (KEYNOTE-522); after definitive surgery, patients received adjuvant pembrolizumab or placebo. Treatment with pembrolizumab plus chemotherapy significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy. The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.[66036]
Carboplatin AUC 6 IV with docetaxel (75 mg/m2 IV) on day 1 repeated every 3 weeks for a total of 6 cycles plus trastuzumab (8 mg/kg IV infusion on week 1, followed by 6 mg/kg IV infusion every 3 weeks for a total of 52 weeks) (TCH regimen). Interim analysis of a phase 3 trial comparing the TCH regimen versus doxorubicin, cyclophosphamide, docetaxel, and trastuzumab showed similar efficacy. The incidence of cardiac toxicity is significantly less with TCH.[33126]
Carboplatin AUC 6 IV on day 1 in combination with paclitaxel 175 mg/m2 IV over 3 hours on day 1, every 3 weeks for 6 cycles has been studied.[50012] [50011]
AUC 6 IV in combination with paclitaxel 175 mg/m2 IV beginning in week 1 repeated every 3 weeks for 6 cycles. Alternatively, carboplatin AUC 2 IV and paclitaxel 80 mg/m2 IV may be administered weekly for 3 weeks with a 1 week rest to complete 6 4-week cycles. Give both regimens with trastuzumab (4 mg/kg IV on week 1 then 2 mg/kg IV once/week starting week 2), continue trastuzumab until disease progression or unacceptable toxicity. A phase 3 trial of 196 patients with previously untreated HER2-overexpressing metastatic breast cancer examined trastuzumab and paclitaxel +/- carboplatin. The primary endpoint, overall response rate, was significantly increased with the addition of carboplatin (52% vs. 36%). Progression-free survival was also significantly better in the carboplatin arm (10.7 months vs. 7.1 months). Grade 4 neutropenia (36% vs. 12%) and grade 3 thrombocytopenia (9% vs. 1%) occurred more frequently in the carboplatin arm.[34295] A comparison of 2 parallel phase 2 studies revealed an increase in overall response rate, median time to disease progression, and overall survival with weekly administration of carboplatin/paclitaxel versus every 3 week administration.[34296]
AUC 2 IV on days 1 and 8, every 21 days in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8, every 21 days) and pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression); the number of cycles of gemcitabine plus carboplatin was not specified.[66122] [66123] [57889] Administer pembrolizumab prior to chemotherapy when given on the same day. In a multicenter, double-blind clinical trial (KEYNOTE-355), patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting were randomized to treatment with either pembrolizumab or placebo in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin regardless of tumor PD-L1 expression. The addition of pembrolizumab to chemotherapy significantly improved the median progression-free survival (9.7 months vs. 5.6 months) compared with placebo plus chemotherapy in the subgroup of patients with a CPS of 10 or more. The objective response rate was 53% compared with 40%, respectively (complete response, 17% vs. 13%) for a median duration of 19.3 months in the pembrolizumab arm and 7.3 months in the placebo arm.[57889] [66123]
Carboplatin 635 mg/m2 IV on day 3 in combination with ifosfamide 3,000 mg/m2/day IV on days 3, 4, 5 (each dose mixed with mesna 600 mg/m2 IV, followed by mesna 600 mg/m2 IV over 15 minutes at 3, 6, 9, and 12 hours after the start of ifosfamide) and etoposide 100 mg/m2/day IV on days 3, 4, 5, repeated each cycle. Rituximab 375 mg/m2 IV was given on days 1 and 3 of cycles 1 and 2, and on day 3 only of cycle 3. Treatment was given up to a maximum of 3 cycles. Colony-stimulating factors were initiated on day 6 of each cycle and intrathecal chemotherapy was also given as appropriate. Overall response rate was 60% and overall survival at 2 to 3 years was 37.5%.[44193]
Ifosfamide 1,800 mg/m2/day IV for 5 days (on days 0, 1, 2, 3, 4), carboplatin 400 mg/m2/day IV for 2 days (on day 0, 1) and etoposide 100 mg/m2/day IV for 5 days (on days 0, 1, 2, 3, 4), repeated every 21 days.[50019]
Carboplatin has been given in combination with etoposide, cyclophosphamide, and doxorubicin, in the following fashion. In Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). All cycles given at 3 week intervals. Patients with favorable biologic features received 4 cycles; if incomplete response after 4 cycles, patients given an additional 4 cycles. Patients with unfavorable biologic features received 8 cycles. Infants younger than 60 days of age received granulocyte colony-stimulating factor after each cycle.[49848]
AUC of 6 IV over 30 minutes following paclitaxel 225 mg/m2 IV over 3 hours on day 1 repeated every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 42.9% (complete response rate, 14.3%; median duration of response, 16.9 months) in 21 patients with invasive, recurrent, or metastatic thymoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 60% that would warrant further study of this regimen. At a median follow-up of 59.4 months, the median progression-free survival time was 16.7 months and the median overall survival time was not reached. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.[47361]
AUC of 6 IV over 30 minutes following paclitaxel 225 mg/m2 IV over 3 hours on day 1 administered every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 21.7% (all partial responses; median duration of response, 4.5 months) in 23 patients with invasive, recurrent, or metastatic thymic carcinoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 45% that would warrant further study of this regimen. At a median follow-up of 63.8 months, the median progression-free survival and overall survival times were 5 and 20 months, respectively. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.[47361]
AUC 6 IV on day 1 in combination with etoposide 100 mg/m2/day IV on days 1, 2, 3, every 3 weeks for 6 courses. Hyperfractionated thoracic radiation therapy should be given concurrently with chemotherapy.[50248]
AUC 5 IV on day 1, every 3 weeks for 4 cycles. Administer in combination with etoposide (100 mg/m2 IV on days 1, 2, and 3, every 3 weeks for 4 cycles) and atezolizumab (840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks). Administer atezolizumab prior to chemotherapy when given on the same day. In a randomized, double-blind, phase 3 clinical trial (IMpower133), the addition of atezolizumab to carboplatin plus etoposide significantly improved overall survival (12.3 months vs. 10.3 months) and progression-free survival (5.2 months vs. 4.3 months) compared with placebo plus carboplatin/etoposide. Survival at 1 year was 51.7% versus 38.2%, respectively. Treatment was well-tolerated, with 56.5% of patients in the atezolizumab arm experiencing grade 3 or 4 adverse reactions compared with 56.1% of those in the placebo arm. Immune-related adverse reactions occurred in 39.9% versus 24.5% of patients, respectively.[63611] [60793]
AUC 5 to 6 IV on day 1 plus etoposide (80 to 100 mg/m2 IV on days 1 to 3), following administration of durvalumab (1,500 mg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]
AUC 5 to 6 IV on day 1 plus etoposide (80 to 100 mg/m2 IV on days 1 to 3), following administration of durvalumab (20 mg/kg IV over 60 minutes on day 1), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.[64736] [61913]
AUC 5 IV on day 1 in combination with etoposide 80 mg/m2/day IV on days 1, 2, 3 per cycle every 3 to 4 weeks up to 4 courses.[50232]
AUC 7 IV on day 1 in combination with paclitaxel 175 mg/m2 IV on day 1, every 3 weeks for 5 cycles.[25767]
AUC 4 IV on day 1 in combination with irinotecan (enzyme-inducing antiepileptic drug: 340 mg/m2 IV on days 1 and 15; non-enzyme-inducing antiepileptic drug: 125 mg/m2 IV on days 1 and 15) and bevacizumab 10 mg/kg IV on days 1 and 15, every 28 days for up to 12 cycles.[50297]
AUC 5 IV over 30 minutes on day 1; 30 minutes prior to carboplatin infusion on day 1, administer pemetrexed 500 mg/m2 IV over 10 minutes. Repeat every 21 days for up to 6 cycles, until disease progression or unacceptable toxicity. Premedicate pemetrexed with dexamethasone 4 mg by mouth twice daily for 3 days, beginning the day before pemetrexed administration to reduce cutaneous reactions. Additionally, supplement with folic acid (400 to 1,000 mcg by mouth daily) and vitamin B12 (1 mg IM every 3 months) beginning 7 days prior to the first dose of pemetrexed and continuing for 21 days after the last dose to reduce the severity and frequency of hematologic and GI toxicities; after the first dose, vitamin B12 may be given on the same day as pemetrexed. Do not substitute oral for IM vitamin B12.[59790] [60907] [20638] [60908] [60909]
AUC 4.5 IV on day 1, in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8) and atezolizumab (1,200 mg IV over 60 minutes on day 1), every 21 days for up to 6 cycles. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.[65902]
AUC 4.5 or 5 IV over 1 hour on day 1, in combination with gemcitabine (1,000 mg/m2 IV over 30 minutes on day 1 and 8), every 21 days for 4 cycles. In a randomized, phase 3 clinical trial, treatment with gemcitabine plus either cisplatin or carboplatin significantly improved disease-free survival in patients with locally advanced UTUC when initiated within 90 days after radical nephroureterectomy compared with surveillance. Based on recommendations from the independent data monitoring committee, study enrollment was ended early and patients still within the 90-day window from nephroureterectomy were offered chemotherapy.[66092]
AUC 5 on day 1 plus dostarlimab 500 mg IV on day 1 and paclitaxel 175 mg/m2 on day 1 repeated every 3 weeks for 6 doses; administer dostarlimab prior to chemotherapy on day 1 of each cycle. Starting 3 weeks after the sixth dose, give single-agent dostarlimab 1,000 mg IV every 6 weeks until disease progression or for up to 3 years.[66619] At a median follow-up time of approximately 25 months, the 24-month investigator-assessed progression-free survival rates were significantly higher the dostarlimab plus carboplatin and paclitaxel arm compared with the placebo plus carboplatin and paclitaxel arm in patients with primary advanced or recurrent endometrial cancer in the overall study population (36.1% vs. 18.1%) and in a subpopulation of 118 patients with dMMR/MSI-H tumors (61.4% vs. 15.7%) in a randomized, double-blind, phase 3 (RUBY) trial. At the time of this interim analysis, the 24-month overall survival rates were also significantly improved in patients who received dostarlimab compared with placebo in the overall (71.3% vs. 56%) and dMMR/MSI-H subgroup (83.3% vs. 58.7%) populations. In the overall population, 54.7% of patients had endometrioid carcinoma-type endometrial cancer, 47.8% of patients had recurrent disease, and 82.6% had not received external pelvic radiation.[69254]
AUC 5 or 6 IV on day 1 in combination with paclitaxel 175 mg/m2 IV on day 1 and durvalumab 1,120 mg (if patient weighs 30 kg or more) or 15 mg/kg (if patient weighs less than 30 kg) IV on day 1 and every 21 days for 6 cycles. Administer durvalumab prior to chemotherapy when given on the same day. After completion of 6 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg (if patient weighs 30 kg or more) or 20 mg/kg (if patient weighs less than 30 kg) IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Patients with advanced or recurrent endometrial cancer were randomized to treatment with durvalumab or placebo plus carboplatin/paclitaxel in a multicenter, randomized, double-blind clinical trial (DUO-E); enrolled patients were required to have known mismatch repair gene status. The primary outcome of progression-free survival (PFS) was significantly improved in the durvalumab arm compared with placebo in the intent-to-treat population (10.2 months vs. 9.6 months); however, based on an exploratory analysis by MMR status (not reached vs. 7 months), the PFS improvement in the overall population was primarily attributed to patients with dMMR tumors.[70771] [61913]
AUC 5 IV and paclitaxel 175 mg/m2 IV on day 1 every 3 weeks for 6 cycles, in combination with pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression or for up to 24 months in patients without disease progression. Administer pembrolizumab prior to chemotherapy when given on the same day. Treatment with pembrolizumab plus carboplatin and paclitaxel significantly improved progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer compared with placebo plus carboplatin and paclitaxel in a multicenter, randomized, double-blind clinical trial (KEYNOTE-868) in both the mismatch repair deficient (dMMR) (not reached vs. 6.5 months) and mismatch repair proficient (pMMR) (11.1 months vs. 8.5 months) cohorts.[57889] [70798]
Dosage adjustments based on hematologic parameters (based on trials of patients with ovarian cancer treated with carboplatin alone or in combination):
Neutrophils
Platelets
Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.[29203] [42067]
No dosage adjustments are needed in patients with hepatic impairment.
NOTE: Recommendations are only available for the initial course of treatment for ovarian cancer with carboplatin as a single agent or with cyclophosphamide. Subsequent adjustments should be done base on the toxicity of the previous course.
CrCl >= 60 ml/min: no dosage adjustment needed.
CrCl 41—59 ml/min: give 250 mg/m2 on day 1 of the initial course for ovarian cancer.
CrCl 16—40 ml/min: give 200 mg/m2 on day 1 of the initial course for ovarian cancer.
CrCl <= 15 ml/min: Data too limited to permit a recommendation.
Intermittent hemodialysis
Multiple reports document the use of carboplatin in patients who are receiving concurrent hemodialysis. Most of the reports indicate that carboplatin is removed by hemodialysis. Studies indicate that anuric patients may receive carboplatin at initial doses not exceeding 150 mg/m2 IV followed by dialysis within 24—48 hours of treatment (written communication, Bristol-Myers Squibb Oncology/Immunology Division, September 1999).
† Off-label indication
Carboplatin (CBDCA) is a platinum compound related to cisplatin. Carboplatin is formed by replacing the chloride leaving groups of cisplatin with 1, 1-cyclobutanedicarboxylato ligand, which increases the stability of the leaving groups. On a molar basis, carboplatin is 45 times less cytotoxic than cisplatin. Carboplatin has a more favorable adverse effect profile than cisplatin, which has led to the investigation of the replacement of cisplatin with carboplatin in many regimens. Carboplatin and cisplatin seem to be equally effective in ovarian, non-small cell and small cell lung cancers. Comparative trials are ongoing in these cancers and others to determine if there is an advantage of carboplatin over cisplatin. Most tumors that are resistant to cisplatin will be resistant to carboplatin. Currently, there does not seem to be a role for carboplatin in place of cisplatin in the routine management of testicular or head and neck cancers. Due to its myelosuppressive effects, carboplatin has been used in bone marrow ablation protocols and in the treatment of relapsed leukemias. The FDA approved carboplatin for the treatment of ovarian cancer in March 1989.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Emetic Risk
Extravasation Risk
Reconstitution of vials:
Further dilution for infusion:
Intermittent infusion:
Continuous infusion:
Intraperitoneal Administration:
NOTE: Carboplatin is not approved by the FDA for intraperitoneal administration.
Bone marrow suppression is the dose-limiting toxicity of carboplatin and may be more severe in patients with impaired kidney function, prior therapy especially cisplatin-containing regimens, and/or who are receiving other myelosuppressive chemotherapy or radiotherapy. Myelosuppression also occurs after intraperitoneal administration of carboplatin. Thrombocytopenia (defined as < 100,000 cells/mm3; severe, < 50,000 cells/mm3), neutropenia (defined as < 2000 cells/mm3; severe, < 1000 cells/mm3), leukopenia (defined as < 4000 cells/mm3; severe, < 2000 cells/mm3), and anemia (defined as < 11 grams/dL; severe, < 8 grams/dL) have been reported. Following single-agent carboplatin, nadirs typically occur at about day 21 and most counts recover by day 28. Drug-related death has been reported in less than 1% of patients who developed infectious or hemorrhagic complications with carboplatin therapy. Neutropenic fever has been reported. Hematologic adverse effects that occurred in 1893 patients who received single-agent carboplatin for various cancer types include severe thrombocytopenia (25%), neutropenia (16%), leukopenia (15%); anemia was also reported (71%). In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), thrombocytopenia (combination arm, 66%; single-agent arm, 62%), neutropenia (combination arm, 96%; single-agent arm, 67%), leukopenia (combination arm, 97%; single-agent arm, 85%), and anemia (combination arm, 90%; single-agent arm, 90%) were reported. Additionally, severe thrombocytopenia (combination arm, 33%; single-agent arm, 35%), neutropenia (combination arm, 82%; single-agent arm, 21%), leukopenia (combination arm, 71%; single-agent arm, 26%), and anemia (combination arm, 14%; single-agent arm, 21%) were reported in this analysis. Monitor blood counts between courses of therapy. Treatment cycles may need to be delayed for severe myelosuppression; the carboplatin dosage may be increased or decreased based on nadir platelet and neutrophil counts.[52338]
Gastrointestinal (GI) system adverse events that occurred in 1893 patients who received single-agent carboplatin for various cancer types include vomiting (65%), nausea (10%-15%), GI pain (17%), diarrhea (6%), and constipation (6%). Patients who had received prior chemotherapy, particularly cisplatin, or receive carboplatin in combination with other chemotherapy were more likely to experience emesis. Nausea and vomiting usually resolves within 24 hours and these symptoms often respond well to antiemetic therapy. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), nausea and vomiting (combination arm, 93%; single-agent arm, 92%), vomiting (combination arm, 83%; single-agent arm, 81%), mucositis (combination arm,8 %; single-agent arm, 1%), and other GI side effects (combination arm, 46%; single-agent arm, 21%) were reported. In postmarketing surveillance, stomatitis and anorexia were reported in patients who received carboplatin.[52338]
Electrolyte changes that occurred in 1893 patients who received single-agent carboplatin for various cancer types include abnormally decreased sodium (hyponatremia) (29%), magnesium (hypomagnesemia) (29%), calcium (hypocalcemia) (22%), and potassium (hypokalemia) (20%). These electrolyte abnormalities were usually asymptomatic. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), hyponatremia (combination arm, 10%; single-agent arm, 47%), hypomagnesemia (combination arm, 61%; single-agent arm, 43%), hypocalcemia (combination arm, 16%; single-agent arm, 31%), and hypokalemia (combination arm, 16%; single-agent arm, 28%) were reported.[52338]
Serious hypersensitivity reactions or anaphylaxis (e.g., rash (unspecified), urticaria, erythema, pruritus, and rarely bronchospasm and hypotension) were reported in 2% of patients who received single-agent carboplatin for various cancer types (n = 1893). Allergic reactions were reported in 11% of women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (n = 393) and 2% of women with ovarian cancer who received single-agent carboplatin as second-line therapy (n = 553). In postmarketing surveillance, anaphylactoid reactions were reported in patients who received carboplatin. Patients with prior exposure to platinum or platinum-containing compounds, including cisplatin, may be at increased risk for anaphylactoid reactions. Hypersensitivity usually develops after >= 6 courses of carboplatin. Manage severe reactions with epinephrine, corticosteroid, and antihistamine therapy.[52338]
Ototoxicity and other sensory abnormalities such as visual impairment (visual disturbance) and dysgeusia (change in taste) were reported in 1% of patients who received single-agent carboplatin for various cancer types (n = 1893). Hearing loss has occurred in pediatric patients who received higher than recommended carboplatin in combination with other ototoxic drugs. Additionally, reversible or partially reversible loss of vision has occurred with higher than recommended carboplatin doses. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), ototoxicity (combination arm, 12%; single-agent arm, 1%) and other sensory side effects (combination arm, 5%; single-agent arm, 1%) were reported.[52338]
Increased alkaline phosphatase levels (24%), elevated hepatic enzymes including increased AST levels (15%), and hyperbilirubinemia (5%) were reported in patients who received single-agent carboplatin for various cancer types (n = 1893). Most hepatic adverse effects were mild and were reversible in about half the cases. Severe hepatic enzyme abnormalities have been reported with high-dose carboplatin use in patients receiving a bone marrow transplant. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), increased alkaline phosphatase levels (combination arm, 29%; single-agent arm, 37%), increased AST levels (combination arm, 20%; single-agent arm, 19%), and hyperbilirubinemia (combination arm, 5%; single-agent arm, 5%) were reported.[52338]
New primary malignancy has been reported in patients who received carboplatin-containing combination chemotherapy.[52338] In the treatment of ovarian cancer, platinum-based therapy has been associated with an increased risk of new malignancy, primarily acute myelogenous leukemia, myelodysplastic syndromes, acute lymphocytic leukemia and chronic myelogenous leukemia. The risk of new malignancy increases with cumulative carboplatin doses higher than 2,000 mg. However, in evaluating the risks versus benefits of platinum-based chemotherapy in the treatment of ovarian cancer, the survival benefits exceed the risk of new malignancy.[25494]
Alopecia occurred in 3% of patients who received single-agent carboplatin for various cancer types (n = 1893). Additionally, alopecia was reported in 49% of women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (n = 393) and 2% of women with ovarian cancer who received single-agent carboplatin as second-line therapy (n = 553). In postmarketing surveillance, injection site reaction (e.g., redness, swelling, and pain) and tissue necrosis associated with extravasation have been reported in patients who received carboplatin.[52338]
Increased serum creatinine (Scr) (6%) and blood urea nitrogen (BUN) (14%) levels were reported in patients who received single-agent carboplatin for various cancer types (n = 1893). Most renal adverse effects were mild and were reversible in about half the cases. A reduction in creatinine clearance (CrCl) was observed in 27% of carboplatin-treated patients who had a baseline CrCl of 60 mL/min or higher. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), increased SCr (combination arm, 6%; single-agent arm, 10%) and BUN (combination arm, 17%; single-agent arm, 22%) levels were reported. Cancer-associated hemolytic-uremic syndrome occurred rarely in patients who received carboplatin. Consider lower initial doses of single-agent carboplatin in patients with a baseline CrCl less than 60 ml/min; subsequent doses may be adjusted based on individual patient tolerance (e.g., degree of myelosuppression with therapy).[52338]
Cardiovascular toxicity was reported in 19% of women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (n = 393) and 6% of women with ovarian cancer who received single-agent carboplatin as second-line therapy (n = 553). Fatal cardiovascular events, including heart failure, thromboembolism, and cerebrovascular accidents (stroke), were reported in less than 1% of patients who received single-agent carboplatin for various cancer types (n = 1893); these events did not appear to be associated with chemotherapy use. In postmarketing surveillance, hypertension was reported in patients who received carboplatin.[52338]
In postmarketing surveillance, dehydration was reported in patients who received carboplatin.[52338]
Infectious or hemorrhagic complications with carboplatin therapy occurred in 5% of patients who received single-agent carboplatin for various cancer types (n = 1893); drug-related death has been reported in less than 1% of these patients. In women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (combination arm; n = 393) or single-agent carboplatin as second-line therapy (n = 553), bleeding (combination arm, 8%; single-agent arm, 5%) and transfusions (combination arm, 35%; single-agent arm, 44%) were reported. In this study, infection was reported in 16% of women who received carboplatin plus cyclophosphamide and 5% of women who received single-agent carboplatin as second-line therapy.[52338]
Asthenia was reported in 41% of women with ovarian cancer who received carboplatin plus cyclophosphamide as first-line therapy in 2 randomized studies (n = 393) and 11% of women with ovarian cancer who received single-agent carboplatin as second-line therapy (n = 553).[52338]
Carboplatin is contraindicated in patients who exhibit platinum compound hypersensitivity. For example, patients who have worked with platinum in the electronics industry can develop sensitivity to platinum. There is an increased incidence of hypersensitivity reactions in patients previously exposed to platinum therapy. Serious hypersensitivity reactions or anaphylaxis may occur within minutes of carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been utilized to treat these reactions.
Contraindications to carboplatin include patients with severe bone marrow suppression and significant bleeding; patients with acute leukemia may require treatment with carboplatin despite severe bone marrow suppression. Carboplatin-induced bone marrow suppression is dose-related and is dose limiting. Complete blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. Single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered. When used in combination with other myelosuppressive chemotherapy agents, the dose and administration of carboplatin must be carefully reviewed and adjusted to minimize additive effects. Carboplatin should be used cautiously in patients with coagulopathy, reduced renal function, or in those who have received previous cisplatin or myelosuppressive therapy such as chemotherapy or radiation therapy; these patients may require reduced dosages (i.e., lower target AUC values). Carboplatin is a radiation sensitizer and patients may experience severe myelosuppression or other toxicities with concurrent use. Patients with preexisting bone marrow suppression should be allowed to recover their counts prior to carboplatin administration. Severe thrombocytopenia (< 50,000/mm3) or neutropenia (< 500/mm3) following carboplatin treatment indicates the need for a dose reduction for subsequent courses. Anemia is cumulative; transfusions or use of red blood cell growth factors may be needed during carboplatin therapy, especially during prolonged treatment. Patients with an active infection should be treated prior to receiving carboplatin when possible. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.
Due to extensive renal elimination, carboplatin dosage should be adjusted in patients with renal impairment or renal failure, including anuria, to avoid excessive myelosuppressive effects. Patients on dialysis have received carboplatin but at reduced doses. Previous therapy with nephrotoxic agents such as cisplatin or aminoglycosides may increase the incidence of nephrotoxicity. Hydration prior to treatment may lessen the nephrotoxic effects in patients with renal impairment or in those who are receiving nephrotoxic agents concurrently. Hydration should be given with high-dose carboplatin to decrease nephrotoxicity.
Carboplatin should be used with caution in patients with hearing impairment. Children are at increased risk of clinically apparent hearing loss, especially when receiving high-dose carboplatin. Concomitant use of other ototoxic agents (e.g., aminoglycosides) should be avoided.
Patients over the age of 65 years and patients previously treated with cisplatin tend to be at increased risk of developing peripheral neuropathy during carboplatin therapy. Preexisting peripheral neuropathy due to cisplatin does not worsen in about 70% of patients receiving carboplatin.[46283]
Carboplatin is classified as FDA pregnancy risk category D. Carboplatin is embryotoxic and teratogenic in animal models. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with carboplatin.[46283]
It is not known if carboplatin is excreted in breast milk. Women should stop breast-feeding while receiving carboplatin due to the potential harm to the infant.[46283]
Carboplatin therapy requires an experienced clinician in the management of cancer chemotherapy. Carboplatin administration requires a specialized care setting adequate for the appropriate management of carboplatin therapy and complications.[29203]
Geriatric patients treated with cisplatin tend to be at increased risk of developing peripheral neuropathy during carboplatin therapy. Preexisting peripheral neuropathy due to cisplatin does not worsen in about 70% of patients receiving carboplatin. Poor performance status may increase the risk of other toxicities, such as bone marrow suppression.[46283]
Vomiting occurs frequently with carboplatin therapy; ensure that patients are premedicated with appropriate antiemetic therapy prior to initiating therapy with carboplatin.[60747]
Carboplatin cytotoxic activity is similar to cisplatin as it binds with DNA to form intrastrand crosslinks and adducts that cause changes in the conformation of the DNA and affect DNA replication. Carboplatin readily crosses the cell membrane. Once inside the cell, the ring structure of carboplatin is hydroxylated by water to form the active moiety. This reaction occurs more slowly than the activation of cisplatin. Therefore, 4—6 times the amount of carboplatin is required to produce the same cytotoxic effects as cisplatin. Once in the active form, carboplatin functions similarly to cisplatin and binds with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links. Carboplatin forms irreversible covalent bonds which inhibit DNA replication, RNA transcription, and protein synthesis. Intrastrand crosslinks at the N7 position of guanine are the predominant binding sites. The maximal DNA crosslinks occur 18 hours after exposure to carboplatin compared to 6—12 hours for cisplatin. Carboplatin crosslinks have a slower removal rate than do cisplatin-induced crosslinks. This slower rate of onset and removal of carboplatin crosslinks is thought to be due to a slow rate of monofunctional adduct formation and/or a slower rate of conversion of monoadducts to crosslinks.[25915] While considered cell cycle non-specific, carboplatin cytotoxicity is increased with exposure during the S-phase and with increased infusion rates (24 hours versus 1 hour). Carboplatin causes cell cycle arrest in the G2-phase and then induces programmed cell death or apoptosis.
Revision Date: 06/26/2024, 02:43:52 PMCarboplatin is primarily administered by IV infusion. The pharmacokinetics of carboplatin and cisplatin differ greatly. Very little protein binding occurs. Carboplatin distributes well into ascites and pleural fluid. CSF concentrations are approximately 30% of plasma concentrations. Carboplatin is not metabolized but undergoes spontaneous hydrolysis to form the active compound. The excretion of carboplatin is biphasic with half-lives of 90 and 180 minutes Carboplatin is excreted primarily by the kidneys via tubular filtration and secretion. Sixty-five percent of a dose can be recovered in the urine in the first 24 hours.
The exposure to carboplatin or AUC is associated with myelosuppressive and cytotoxic effects. In general, carboplatin AUC of 4—7 is associated with acceptable myelosuppressive effects and efficacy. A carboplatin AUC of > 7 is associated with an increased incidence of severe myelosuppression with no added efficacy. Carboplatin bolus doses of 400—600 mg/m2 are associated with an AUC of 6—8 mg/mL x min in previously untreated patients with normal creatinine clearance. Several equations have been developed to individualize carboplatin dosing. The Calvert equation is the simplest equation and was approved by the FDA in 1995 for dosing of carboplatin. In the determination of this equation, creatinine clearance was determined using [23509]Cr-EDTA, which is thought to more accurately reflect glomerular filtration rate in patients with altered renal function than does a measured or a calculated creatinine clearance.[25916] Currently, [23509]Cr-EDTA is not available in the United States and creatinine clearance is determined using measured or calculated methods, which may not be as accurate. The Egorin equations use creatinine clearance and a relationship with platelet nadir to determine the carboplatin dosage. These equations also differentiate between previously treated and untreated patients to take into account the cumulative bone marrow toxicity of carboplatin.[25917] The dosing of carboplatin in many disease states is now almost entirely based upon AUC and not body surface area.
An IV dose of carboplatin distributes widely throughout the body tissues, and distribution is equal to the total body water.
Dosages should be reduced in patients with renal dysfunction. Hemodialysis removes carboplatin at a rate 25% that of the kidney. Dosages should be adjusted based upon the length of dialysis. Peritoneal dialysis does not remove carboplatin.
The pharmacokinetics of carboplatin in children and adults are similar.
Carboplatin is classified as FDA pregnancy risk category D. Carboplatin is embryotoxic and teratogenic in animal models. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with carboplatin.[46283]
It is not known if carboplatin is excreted in breast milk. Women should stop breast-feeding while receiving carboplatin due to the potential harm to the infant.[46283]
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