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Etoposide, VP-16
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100 mg/m2 IV on days 1, 2, and 3 in combination with cisplatin (100 mg/m2 IV) on day 1 every 21 days for 4 cycles. In a phase 3 trial of 1867 patients with stage IB to stage III NSCLC, cisplatin/etoposide was one of several regimens to collectively show a significant improvement in 5-year survival versus observation (44.5% vs. 40.4%) following complete resection.[34318]
50 mg/m2 IV on days 1, 2, 3, 4, and 5, and on days 29, 30, 31, 32, and 33 with cisplatin (50 mg/m2 IV) on days 1, 8, 29, and 36 plus concurrent radiotherapy for 25 days starting on day 1 has been studied. Responding patients proceeded to thoracotomy. Median overall survival ranged from 15 to 17 months. Grades 3 or 4 esophagitis and grade 4 neutropenia occurred.[34319] [51373]
50 mg/m2 IV to 100 mg/m2 IV once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer 100 mg/m2 IV once daily on days 1, 3, and 5 every 3 to 4 weeks. Etoposide injection should be administered over at least 30 to 60 minutes, while etoposide phosphate injection (Etopophos) may be infused over 5 minutes to 3.5 hours.[53552] [64884] Other doses and regimens have been used; consult the literature for specific protocols.
100 mg/m2 IV on days 1 to 5, in combination with cisplatin (20 mg/m2 IV on days 1 to 5) and bleomycin (30 units IV on days 1, 8, and 15), every 21 days for 3 cycles.[64341] [49371] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] In a randomized clinical trial, treatment with BEP resulted in a response rate of 94% of patients with disseminated germ cell tumors compared with 88% for those treated with etoposide plus cisplatin.[49371] In a randomized clinical trial of patients with favorable-prognosis germ-cell cancer, there was not a significant difference between 3 cycles of BEP and 4 cycles in terms of overall or disease-free survival.[64341]
100 mg/m2 IV on days 1 to 5 in combination with cisplatin (20 mg/m2 IV on days 1 to 5), every 21 days for 4 cycles.[64338] [49372] [49375] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] In 2 consecutive randomized trials for good-risk metastatic germ cell tumors, 92% of patients treated with CP achieved a complete response (CR), with a relapse rate of 9% after a median follow-up of 7.6 years; the median time to relapse was 10 months.[64338] In another randomized trial of patients with good-risk disseminated germ cell tumor, treatment with EP resulted in a CR rate of 93% compared with 96% in patients treated with vinblastine, bleomycin, cisplatin, cyclophosphamide, and dactinomycin (VAB-6), with a relapse rate of 11% versus 12%, respectively; patients treated with EP had less toxicity than those who received VAB-6.[49372] Treatment with EP resulted in a 90% CR rate in a third randomized controlled trial compared with 88% for patients with good-risk germ cell tumors who received carboplatin plus etoposide (EC); after a median follow-up of 22.4 months, 3% of patients receiving EP relapsed compared with 12% of those who received EC.[49375]
75 mg/m2 IV on days 1 to 5, in combination with cisplatin (20 mg/m2 IV on days 1 to 5), ifosfamide (1,200 mg/m2 IV on days 1 to 5), and mesna (240 mg/m2 IV over 15 minutes before ifosfamide, then 240 mg/m2 IV at 4 and 8 hours from the start of each ifosfamide on days 1 to 5), every 21 days for 4 cycles. Patients who received previous radiation therapy had an initial 25% dose reduction of etoposide and ifosfamide.[29305] [49539] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] Due to a high risk of febrile neutropenia, colony-stimulating factors were administered in clinical trials. In a randomized clinical trial, treatment with VIP resulted in a complete response (CR) rate of 37% in patients with advanced, disseminated germ cell tumors compared with 31% in patients treated with bleomycin, etoposide, and cisplatin (BEP); 2-year failure-free survival (64% vs. 60%) and 2-year overall survival (74% vs. 71%) were not significantly different between treatment arms. Grade 3 or higher toxicity was significantly higher in patients who received VIP.[49539]
100 mg/m2 IV once daily on days 1 and 2 in combination with methotrexate, leucovorin, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen), repeated every 2 to 3 weeks depending on toxicity. Multiple studies have been reported with cure rates ranging from 70% to 90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as 3 consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2 to 3 additional courses after complete hCG response.[33966] [33967]
100 mg/m2 IV once daily on days 1, 2, and 8 in combination with methotrexate, leucovorin, actinomycin D, and cisplatin (EMA-EP regimen), repeated every 2 to 3 weeks depending on toxicity. Studies in patients with chemorefractory high-risk gestational trophoblastic disease have shown response rates of greater than 90% with salvage treatment with EMA-EP. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity.[33965]
150 mg/m2 daily IV over 2 hours on days 1 to 5 plus cyclophosphamide 400 mg/m2 daily IV over 1 hour on days 1 to 5 and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 were given in a clinical study. Clofarabine was administered before cyclophosphamide and etoposide. In patients with a blast count greater than 30 x 109 cells/L, prophylactic steroids were given.[49907] Alternately, etoposide 100 mg/m2 daily IV over 2 hours on days 1 to 5 plus cyclophosphamide 440 mg/m2 daily IV over 1 hour on days 1 to 5, and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 has been studied. Each drug was given daily for 4 days if administered as consolidation treatment.[49910]
Carboplatin 635 mg/m2 IV on day 3 in combination with ifosfamide 3,000 mg/m2 IV on days 3, 4 and 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 IV on days 3, 4, and 5 repeated for a maximum of 3 cycles. 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. 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]
80 mg/m2 IV over 1 hour, then cytarabine 1 g/m2 IV over 6 hours, then 3 hours later, mitoxantrone 6 mg/m2 IV bolus. All should be given daily for 6 days.[49914]
Safety and efficacy have not been established.
60 mg/m2 per day IV on 2 consecutive days in weeks 3, 7, and 11 in combination with mechlorethamine (6 mg/m2 IV on weeks 1, 5, and 9), doxorubicin (25 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vinblastine (6 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vincristine (1.4 mg/m2 (Max: 2 mg) IV on weeks 2, 4, 6, 8, 10, and 12), bleomycin (5 units/m2 IV on weeks 2, 4, 6, 8, 10, and 12) and prednisone (40 mg/m2 PO every other day for 10 weeks then tapered by 10 mg PO every other day between weeks 10 and 12). Total duration of Stanford V regimen is 12 weeks (three 4-week cycles).[40464] [40465] [36931] [40466] [40469] Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide have been reduced to 65% if ANC less than 1,000 cells/mm3 (treatment delayed if ANC less than 500 cells/mm3). Prophylactic sulfamethoxazole-trimethoprim, acyclovir, and a H2-blocker were given throughout the treatment period.[40464] G-CSF has also been used to maintain dose intensity as needed after the first dose reduction.[40465] [40469] Alternative prophylactic medications have also been used.[36931]
100 mg/m2 IV once daily on days 1 to 3 in combination with bleomycin (10 units/m2 IV on day 8), doxorubicin (25 mg/m2 IV on day 1), cyclophosphamide (650 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2 PO once daily on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials.[12501] [40572] The escalated dose BEACOPP regimen includes etoposide 200 mg/m2 IV once daily on days 1 to 3, in combination with bleomycin (10 units/m2 IV on day 8), doxorubicin (35 mg/m2 IV on day 1), cyclophosphamide (1,200 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2 PO once daily on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials.[12501] [40572]The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials.[12501] [40572] [40568] Escalated dose BEACOPP has shown significantly better freedom from treatment failure at 10 years (82% vs. 70%) and overall survival at 10 years (86% vs. 80%) compared to standard dose BEACOPP.[49830] A regimen of 4 cycles of escalated dose BEACOPP followed by 4 cycles of standard-dose BEACOPP has also been used in patients who achieve a complete response after the initial 4 cycles of escalated dose BEACOPP.[40568]
125 mg/m2 IV on days 1, 2, and 3 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1; doxorubicin 25 mg/m2 IV on days 1 and 2; vincristine 1.4 mg/m2 IV on day 8; prednisone 20 mg/m2 PO twice daily on days 1 to 7; and cyclophosphamide 600 mg/m2 IV on days 1 and 2 repeated every 3 weeks for up to 5 cycles. Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1 due to the high incidence of febrile neutropenia.[45378] At a median follow-up time of 42.1 (range, 0.1 to 80.9) months, the 3-year event-free survival rate was significantly improved in patients (median age, 15.6 years; range, 3.4 to 21.99 years) with newly diagnosed, stage IIB with bulk tumor or stage IIIB, IVA, or IVB classic Hodgkin lymphoma who received brentuximab vedotin plus AVEPC compared with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) (92.1% vs. 82.5%; hazard ratio (HR) = 0.41; 95% CI, 0.25 to 0.67) in a multicenter, randomized, phase 3 trial (n = 587). The 3-year overall survival rates were 99.3% and 98.5% in the brentuximab vedotin plus AVEPC and ABVE-PC arms, respectively.[68172]
Etoposide 100 mg/m2 IV once daily on days 1 to 3, ifosfamide 5 g/m2 IV mixed with equal dose of mesna via continuous intravenous infusion over 24 hours beginning on day 2, carboplatin AUC 5 IV on day 2 (Max: 800 mg), 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]
Etoposide 100 mg/m2/day IV on days 1, 2, and 3 in combination with carboplatin AUC 5 (Max: 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]
Etoposide 60 mg/kg IV on day -3 in combination with total body irradiation with 1320 cGy (11 fractions of 120 cGy delivered between days -7 and -4).[44348]
Etoposide has been given in combination with carboplatin, cyclophosphamide, and doxorubicin. In Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1 to 3 (4 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per 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]
100 mg/m2 per day IV on days 1 to 5 in combination with cisplatin 40 mg/m2 per day IV on days 1 to 5 (CVP regimen), alternating with cyclophosphamide, vincristine, and doxorubicin (CADO regimen). Two cycles of each regimen should be given as induction therapy, followed by surgery. The administration of cisplatin as a 1-hour infusion reduced the incidence of neutropenia compared to administration as a continuous infusion.[50270]
A small series of patients with recurrent desmoid tumors were treated with combination chemotherapy including a regimen of etoposide 100 mg/m2 per day IV on days 1 to 3, in combination with ifosfamide (2,500 mg/m2 per day IV with mesna on days 1 to 3), repeated every 3 to 4 weeks. Two patients received a combination of mitomycin/doxorubicin/cisplatin in sequence with etoposide/ifosfamide. Clinical benefit was reported in 6 of 7 patients and objective responses were noted in 3 patients.[27474]
120 mg/m2 per day IV over at least 30 minutes on days 1 to 3 plus cisplatin 60 mg/m2 IV over 1 hour (with hydration) on day 1 repeated every 3 weeks for up to 8 cycles (median of 6 cycles; range, 2 to 9 cycles) has been studied in 16 patients in a phase 2 study. Overall response rate was 56%.[41519]
75 mg/m2 per day IV on days 1 to 4 plus cisplatin 20 mg/m2 per day IV (with hydration) on days 1 to 4 and ifosfamide 1,200 mg/m2 per day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1 to 4 repeated every 3 weeks for 4 cycles (median of 4 cycles; range, 1 to 6 cycles) or until disease progression or unacceptable toxicity resulted in favorable overall response rates in a nonrandomized study of 28 patients (20 with thymoma). All patients received granulocyte colony-stimulating factor 5 mcg/kg/day subcutaneously on days 5 to 15 or until a postnadir white blood cell count of 10,000 cells/mm3.[41521]
75 mg/m2 per day IV on days 1 to 4 plus cisplatin 20 mg/m2 per day IV (with hydration) on days 1 to 4 and ifosfamide 1,200 mg/m2 per day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1 to 4 repeated every 3 weeks for 4 cycles or until disease progression or unacceptable toxicity (median of 4 cycles; range, 1 to 6 cycles) resulted in an overall response rate (ORR) of 32% (all partial responses; median duration of response, 11.9 months) in 28 patients with advanced thymoma or thymic carcinoma in a nonrandomized study. All patients received granulocyte colony-stimulating factor 5 mcg/kg per day subcutaneously on days 5 to 15 or until a postnadir white blood cell count of 10,000 cells/mm3. At a median follow-up of 43 months, the median overall survival (OS) time was 31.6 months and the 1- and 2-year OS rates were 89% and 70%, respectively. In the 8 patients with advanced thymic carcinoma, the ORR was 25% and the 1- and 2-year OS rates were 75% and 50%, respectively. Serious toxicity reported in this study included grade 3 or 4 thrombocytopenia (18%), leukopenia (16%), and anemia (15%).[41521]
Ifosfamide 1,800 mg/m2 per day IV for 5 days (on days 0 to 4), carboplatin 400 mg/m2 per day IV for 2 days (on day 0 to 1) and etoposide 100 mg/m2 per day IV for 5 days (on days 0 to 4), repeated every 21 days.[50019]
35 mg/m2 IV once daily on days 1 to 4 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer etoposide 50 mg/m2 IV once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Etoposide injection should be administered over at least 30 to 60 minutes, while etoposide phosphate injection (Etopophos) may be infused over 5 minutes to 3.5 hours.[64884] [53552] Other doses and regimens have been used; consult the literature for specific protocols.
70 mg/m2 PO once daily on days 1 to 4 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Alternatively, administer etoposide 100 mg/m2 PO once daily on days 1 to 5 in combination with other approved chemotherapeutic agents, every 3 to 4 weeks. Round the dose to the nearest capsule strength. The recommended dose of etoposide capsules is two times the IV dose, rounded to the nearest 50 mg.[53551] Other doses and regimens have been used; consult the literature for specific protocols.
100 mg/m2 IV on days 1 to 3, in combination with cisplatin (75 mg/m2 IV on day 1) and concurrent radiation therapy, every 3 weeks for up to 4 to 6 cycles (EP); cisplatin has also been administered at a dose of 25 mg/m2 IV on days 1 to 3.[64886] [34315] An alternative cisplatin/etoposide dosing regimen for the treatment of limited-stage SCLC is etoposide 120 mg/m2 IV on days 1 to 3 in combination with cisplatin 60 mg/m2 IV on day 1, every 3 weeks for 4 cycles.[34312] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] The use of colony-stimulating factors is not recommended during concurrent EP plus radiation therapy.[64887] In an open-label, phase 3 trial comparing twice-daily radiation therapy versus once-daily radiation therapy and a backbone of concurrent EP in patients with limited-stage SCLC, treatment with EP plus twice-daily radiotherapy resulted in a median overall survival of 30 months, 2-year overall survival of 56%, and median progression-free survival of 15.4 months. Once-daily radiation therapy was not superior to twice-daily radiation.[64886]
100 mg/m2 daily IV on days 1, 2, 3 in combination with carboplatin (AUC 6 IV on day 1), every 3 weeks for up to 6 cycles. Hyperfractionated thoracic radiation therapy should be given concurrently with chemotherapy. Treatment with carboplatin and etoposide with concurrent HTRT resulted in an overall response rate of 76% to 92.5% (complete response, 40.5% to 56.5%), median time to progression of 9.5 to 10.5 months, and overall survival of 17 to 17.5 months.[50248]
100 mg/m2 IV on days 1, 2, and 3, every 3 weeks for 4 cycles. Administer in combination with carboplatin (AUC 5 IV on day 1, 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]
80 to 100 mg/m2 IV on days 1 to 3 plus carboplatin (AUC 5 to 6 IV on day 1), 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]
80 to 100 mg/m2 IV on days 1 to 3 plus carboplatin (AUC 5 to 6 IV on day 1), 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]
80 to 100 mg/m2 IV on days 1 to 3 plus cisplatin (75 to 80 mg/m2 IV on day 1), 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.[64736] [61913] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] 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]
80 to 100 mg/m2 IV on days 1 to 3 plus cisplatin (75 to 80 mg/m2 IV on day 1), 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.[64736] [61913] Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration.[28393] 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]
80 mg/m2 daily IV on days 1, 2, 3 in combination with carboplatin AUC 5 IV on day 1, every 3 to 4 weeks up to 4 courses. [50232]
Etoposide 100 mg/m2 daily IV on days 1, 2, 3 in combination with cyclophosphamide 1,000 mg/m2 IV on day 1 and doxorubicin 45 mg/m2 IV on day 1, every 3 weeks for 5 cycles.[50310] [51057]
100 mg/m2 per day IV on days 1 to 5 in combination with ifosfamide 1,800 mg/m2 per day IV on days 1 to 5 (with equal dose mesna) repeated every 3 weeks; alternating with vincristine 2 mg/m2 (maximum dose of 2 mg) on day 1 with doxorubicin 75 mg/m2 IV bolus on day 1, and cyclophosphamide 1,200 mg/m2 on day 1 repeated every 3 weeks. Dactinomycin 1.25 mg/m2 IV on day 1 was substituted for doxorubicin once a cumulative doxorubicin dose of 375 mg/m2 IV was reached.[29312]
IV: 200 mg/m2 per day.[12501][40572]
PO: 100 mg/m2 per day.
IV: 200 mg/m2 per day.[12501][40572]
PO: 100 mg/m2 per day.
IV: 200 mg/m2 per day.[12501][40572]
IV: 150 mg/m2 per day.[49907]
IV: 120 mg/m2 per day.[49848]
Specific guidelines for dosage adjustments in hepatic impairment are not provided by the manufacturer. However, biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination and the unbound (free) fraction of etoposide significantly correlates with increased bilirubin in cancer patients.[61465][53551][53552]
Dosage adjustments based on bilirubin levels have been suggested as follows:
Etoposide is available as an injectable or a liquid-filled, soft gelatin capsule formulation. Etopophos (etoposide phosphate) is an IV prodrug that is converted to etoposide by dephosphorylation. Etoposide works by causing induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals. These actions lead to cell cycle arrest, mostly at the G2 stage of the cell cycle, and cell death. Etoposide capsules are indicated for the first-line treatment of small-cell lung cancer (SCLC) in combination with other chemotherapeutic agents.[53551] IV etoposide and etoposide phosphate are indicated for the first-line treatment of SCLC in combination with other chemotherapeutic agents and for the treatment of refractory testicular tumors as part of combination therapy.[53552][64884] Etoposide was approved by the FDA in 1983.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Emetic Risk
IV Doses: Low
Oral Doses: Minimal/Low
Extravasation Risk
Etoposide Phosphate for Injection
Reconstitution:
Dilution:
Intravenous Infusion:
Etoposide Injection
Dilution:
Intravenous Infusion:
Fever has infrequently been reported in patients treated with both IV and oral etoposide; both fever and infection have also been reported in neutropenic patients.[53551] [64884] [53552] Postmarketing experience indicates that elderly patients may be more sensitive to the infectious complications of etoposide treatment.[53551] [64884]
Bone marrow suppression is a dose-related and dose-limiting toxicity of etoposide, with myelosuppression-related fatalities reported. Leukopenia with white blood cell counts (WBC) less than 4,000 cells/mm3 occurred in 60% to 91% of patients from multiple databases who received etoposide oral or IV monotherapy (n = 2,081); grade 4 leukopenia (less than 1,000 cells/mm3) occurred in 3% to 17% of patients. Thrombocytopenia with platelet counts below 100,000 cells/mm3 occurred in 22% to 41% of patients receiving etoposide monotherapy in these databases; grade 3 or 4 thrombocytopenia (less than 50,000 cells/mm3) occurred in 1% to 20% of patients. Anemia also occurred in 33% or fewer database patients.[53551] [64884] In clinical studies where etoposide phosphate was administered as monotherapy (n = 206) or in combination with cisplatin (n = 60) for various malignancies, neutropenia was the most common adverse reaction.[53552] Granulocyte nadirs typically occur 7 to 14 days after administration and platelet nadirs occur 9 to 16 days after administration. Bone marrow recovery is usually complete by day 20 and is not cumulative. Myelosuppression was more common in elderly patients in postmarketing experience with etoposide. Grade 3 or 4 leukopenia and granulocytopenia were more frequent among elderly patients (age 65 or older) compared to younger patients in various clinical trials.[53551] [64884]
Nausea and vomiting are the major gastrointestinal toxicities associated with etoposide treatment, occurring in 31% to 43% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53552] [64884] [53551] Both are generally mild-to-moderate in severity, requiring treatment discontinuation in 1% of patients. GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]
Diarrhea (1% to 13%) and abdominal pain (2% or less) have been reported in patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53551] [64884] Constipation has also been infrequently reported.[53552] [53551] [64884] GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]
Anorexia has been reported in 10% to 13% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[53551] [64884] Dysphagia and dysgeusia have also been infrequently reported with etoposide treatment.[53552] [53551] [64884] GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53551] [64884]
Stomatitis has been reported in 1% to 6% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081); mucositis/esophagitis has been reported as mild to severe. GI toxicities are slightly more frequent after oral administration compared to IV administration. Postmarketing experience with etoposide indicates that elderly patients may be more sensitive to GI toxicities.[53552] [53551] [64884]
Transient hypotension has been reported in 1% to 2% of patients following the rapid IV administration of etoposide; delayed hypotension has not been noted. Administer etoposide by slow IV infusion over 30 to 60 minutes to prevent hypotension. If hypotension occurs, stop the infusion and give fluids or other supportive therapy as necessary; restart the infusion at a slower rate when therapy is resumed.[64884]
New primary malignancy, specifically acute leukemia with or without a preleukemic phase, has been reported rarely in patients treated with IV or oral etoposide alone or in combination with other chemotherapy agents. The risk of development of a preleukemic or leukemic syndrome is unclear.[61465] [53551] Secondary leukemias have occurred with long-term use of IV etoposide phosphate.[53552]
Extravasation resulting in an injection site reaction including local soft tissue toxicity, swelling, pain, and cellulitis has been reported in postmarketing experience with IV etoposide and etoposide phosphate. Rarely, extravasation has been associated with skin necrosis and venous induration.[64884] [53552]
Rash, urticaria, and/or pruritus have infrequently been reported in patients receiving IV or oral etoposide at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash consistent with peri-vasculitis has been reported. Additionally, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and skin hyperpigmentation occurred infrequently with IV or oral etoposide monotherapy with several different dose schedules for treatment of a wide variety of malignancies; there was a single report of radiation recall dermatitis.[64884] [53551] Pigmentation, radiation recall reaction, SJS, and TEN also occurred in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552]
Seizures, occasionally associated with allergic reactions, have been infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[53551] [64884] Seizures also occurred in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552]
Asthenia, fatigue, and malaise were reported infrequently in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies. Grade 3 or 4 asthenia was more frequent in elderly patients (age 65 years or more) compared to younger patients in 5 monotherapy studies of etoposide phosphate in patients with a variety of tumor types.[64884] [53551]
Transient cortical blindness and optic neuritis were infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[64884] [53551] [53552]
Interstitial pneumonitis/pulmonary fibrosis occurred infrequently in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies.[64884] [53551] [53552]
Metabolic acidosis has been reported in patients who received IV or oral etoposide monotherapy for the treatment of a wide variety of malignancies at doses higher than the recommended dose.[64884] [53551]
Anaphylactoid reactions characterized by chills, fever, sinus tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported in 0.7% to 2% of patients who received IV etoposide and in less than 1% of the patients who received oral etoposide in clinical trials; reactions have occurred during the initial infusion of etoposide. Reactions typically respond to stopping the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as necessary; however, these reactions can be fatal. Hypertension and/or flushing have also been reported; blood pressure usually normalizes within a few hours after stopping the infusion. Sometimes, facial/tongue swelling (angioedema), cough, diaphoresis, cyanosis, throat irritation/tightness, laryngospasm, back pain, and/or loss of consciousness have occurred in association with allergic reactions; rarely, an apparent hypersensitivity-associated apnea has been reported.[64884] [53551] Anaphylactoid reactions have also been reported with IV etoposide phosphate. Permanently discontinue etoposide phosphate in patients who develop a severe hypersensitivity reaction.[53552]
Hepatotoxicity has been reported with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies, generally in patients receiving higher than the recommended dose.[64884] [53551] Hepatotoxicity was also reported in patients with a variety of malignancies treated with etoposide phosphate monotherapy in clinical trials.[53552] Hepatic adverse reactions occurred in 3% or fewer patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[64884] [53551]
Reversible cases of acute renal failure (unspecified) have been reported with administration of high-dose etoposide phosphate (2,220 mg/m2) with total body irradiation used for stem cell transplantation. The etoposide phosphate formulation contains dextran 40, which has been associated with acute renal failure when administered in high doses.[53552] Elevated BUN was reported more often in elderly patients treated with etoposide or etoposide phosphate in combination with cisplatin.[53551] [64884]
Reversible alopecia, sometimes progressing to total baldness, was observed in 8% to 66% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081). Postmarketing experience suggests that elderly patients may experience more alopecia compared to younger patients.[64884] [53551]
Somnolence/drowsiness was infrequently reported in patients treated with IV or oral etoposide monotherapy using several different dose schedules for treatment of a wide variety of malignancies. Somnolence was reported more often in elderly patients treated with etoposide or etoposide phosphate in combination with cisplatin.[53551] [64884]
Peripheral neuropathy was reported in 1% to 2% of patients treated with IV or oral etoposide monotherapy in multiple databases from clinical trials (n = 2,081).[64884] [53551]
Bone marrow suppression (e.g., neutropenia, thrombocytopenia) is a dose-limiting toxicity with etoposide therapy and has resulted in severe infection, bleeding, and death. The use of etoposide requires an experienced clinician knowledgeable in administering chemotherapy. Obtain complete blood cell counts prior to each cycle of therapy with etoposide and more frequently as clinically indicated. After administration of etoposide, granulocyte nadirs generally occur in 7 to 14 days and platelet nadirs within 9 to 16 days; bone marrow recovery is usually complete by day 20.[53552] [64884] [53551] Do not administer a new course of therapy until the ANC has recovered above 500 cells/mm3 and the platelet count above 50,000 cells/mm3.[64884] [53551]
Closely monitor patients during IV infusions for signs and symptoms of extravasation. Extravasation has been reported in postmarketing surveillance of both etoposide and etoposide phosphate and may result in skin necrosis, venous induration, swelling, pain, and cellulitis. If dermal contact occurs, immediately and thoroughly wash areas of skin contact with soap and water and flush mucosa with water.[53552] [64884]
Closely monitor patients with hypoalbuminemia for etoposide-associated toxicities, as they may be at increased risk. Lower levels of albumin are associated with higher free fractions of etoposide.[64884] [53551]
New primary malignancy, specifically acute leukemia, has been reported rarely in patients who received etoposide in combination with other antineoplastic agents.[61465] [53551] New primary leukemias have also occurred following long-term use of etoposide phosphate.[53552]
Geriatric patients (aged 65 years and older) may be at increased risk for etoposide-associated toxicity. Because elderly patients are more likely to have decreased renal function and etoposide and its metabolites are primarily excreted by the kidney, consider monitoring renal function in these patients during therapy. In postmarketing surveillance, myelosuppression, gastrointestinal effects, infectious complications, and alopecia have been reported more often in geriatric patients who received etoposide. In a clinical study, severe leukopenia, anorexia, mucositis, dehydration, somnolence, and elevated BUN levels occurred in more geriatric patients who received etoposide or etoposide phosphate in combination with cisplatin compared with younger patients. In pooled results from 5 lung cancer trials, geriatric patients who received single-agent etoposide phosphate experienced a higher incidence of severe leukopenia, granulocytopenia, and asthenia compared with younger patients.[53551] [64884]
Use etoposide solution for injection with caution in infants as it contains polysorbate 80. In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80.[64884]
Infusion-related reactions and hypersensitivity reactions including rash, urticaria, pruritus, and anaphylaxis can occur with intravenous administration of etoposide or etoposide phosphate.[53552] [64884] Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role of concentration or rate of infusion in the development of anaphylactic-like reactions is uncertain.[64884] If hypersensitivity reactions occur, immediately interrupt the etoposide infusion and institute supportive management. Permanently discontinue etoposide or etoposide phosphate in patients who experience a severe hypersensitivity reaction.[53552] [64884]
Etoposide may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking etoposide. If a woman becomes pregnant during therapy with etoposide, she should be informed of the potential risk to the fetus. Intrauterine death and fetal toxicity (e.g., reduced fetal weight, skeletal abnormalities, cranial abnormalities, exencephaly, encephalocele, and anophthalmia) occurred in rats and mice when etoposide was administered during organogenesis; doses given in these studies were much less than the recommended human dose.[61465] [53552] [53551]
Counsel patients about the reproductive risk and contraception requirements during etoposide treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after the last etoposide dose. Women who become pregnant while receiving etoposide should be apprised of the potential hazard to the fetus. Due to the potential for male-mediated teratogenicity, males with female sexual partners of reproductive potential should use effective contraception during treatment with etoposide and for at least 4 months after the last dose. Infertility may occur with etoposide use. In females, etoposide may cause amenorrhea and premature menopause; recovery of menses and ovulation is related to age at treatment. In males, etoposide may cause oligospermia, azoospermia, and permanent loss of fertility; sperm counts have returned to normal several years after the end of therapy in some cases.[53552]
It is not known if etoposide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during etoposide or etoposide phosphate therapy.[53552] [53551] [61465]
Etoposide is a topoisomerase inhibitor that is a semisynthetic derivative of podophyllotoxin. Two different dose-dependent responses are seen at the G2 portion of the cell cycle in mammalian cells, leading to cell cycle arrest and cell death. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed; at low concentrations (0.3 mcg/mL to 10 mcg/mL), cells are inhibited from entering prophase. Etoposide does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.[53552][53551][64884] Etoposide has also been shown to cause metaphase arrest in chick fibroblasts.[53551][64884] Etoposide phosphate is a prodrug that is converted to its active moiety, etoposide, by dephosphorylation.[53552]
Revision Date: 11/14/2024, 02:25:00 AMEtoposide is administered orally or intravenously (IV); etoposide phosphate is administered IV and is completely converted to etoposide in plasma. Etoposide is highly protein-bound (97%), primarily to albumin; the unbound fraction may increase in patients with low serum albumin (hypoalbuminemia) and elevated bilirubin levels (hyperbilirubinemia). Patients with higher unbound fractions may be at increased risk for etoposide-related adverse effects; in one study, phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo. Etoposide has poor cerebral spinal fluid (CSF) penetration; although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. The mean steady-state volume of distribution is 18 to 29 liters (7 to 17 liters/m2). Etoposide disposition is a biphasic process after IV administration, with a distribution half-life of 1.5 hours and terminal elimination half-life of 4 to 11 hours, independent of dose; total body clearance ranges from 33 to 48 mL/min (16 to 36 mL/min/m2). Total body clearance correlates with creatinine clearance, serum albumin levels, and nonrenal clearance. Etoposide is metabolized in the liver by the opening of the lactone ring, O-demethylation, and conjugation (glucuronidation and sulfation); O-demethylation of the dimethoxyphenol ring occurs through the CYP3A4 isoenzyme pathway to produce the active catechol metabolite. After IV administration of radiolabeled etoposide (dose range, 100 to 124 mg/m2), the mean recovery of radioactivity in the urine was 56% of the dose at 120 hours (unchanged drug, 45%; 8% or less of the dose was excreted as metabolites). Biliary excretion of unchanged drug and metabolites is an important route of etoposide elimination; fecal recovery of radioactivity was 44% of the dose at 120 hours.[53551][53552][64884]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5
O-demethylation of the dimethoxyphenol ring via cytochrome CYP3A4 is a major pathway of etoposide metabolism, with CYP3A5 also contributing at clinically relevant free etoposide concentrations; CYP2E1 and CYP1A2 may have a minor role in etoposide metabolism, but the relevance is unknown. In vitro, etoposide may also be a substrate of P-glycoprotein (P-gp).[60075][34509][57989]
There is no evidence of a first-pass effect with oral etoposide administration; a correlation does not exist between the absolute oral bioavailability of etoposide capsules and nonrenal clearance. Significant intra- and intersubject variability exists in Cmax values after either IV or oral administration of etoposide, resulting in variable bioavailability of 25% to 75% (mean, 50%) following an oral dose; however, Cmax and AUC values for oral etoposide consistently fall in the same range as the Cmax and AUC values for an IV dose of one-half the size of the oral dose. The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m2.[53551]
With IV administration, AUC and Cmax values increase linearly with dose of etoposide in the range of 100 to 600 mg/m2. Additionally, there is no accumulation in the plasma when etoposide is administered as 100 mg/m2 daily for 4 to 5 days.[53552][64884] There is marked intra- and inter-subject variability following IV etoposide administration.[64884] Etoposide phosphate is rapidly and completely converted to etoposide in plasma, and has similar pharmacokinetics and pharmacodynamics as etoposide. The pharmacokinetics of etoposide and etoposide phosphate were compared in 2 randomized crossover studies. In the first (n = 41), patients with a variety of malignancies were given etoposide phosphate or etoposide 150 mg/m2 IV over 3.5 hours. The mean AUC values were 168.3 +/- 48.2 micrograms (mcg) x hr/mL and 156.7 +/- 43.4 mcg x hr/mL, respectively; the Cmax values were 20 +/- 3.7 mcg/mL for etoposide phosphate and 19.6 +/- 4.2 mcg/mL for etoposide. Bioavailability of etoposide from etoposide phosphate was 107% (90% CI, 105% to 110%) for AUC and 103% (90% CI, 99% to 106%) for Cmax. In the second study, the mean AUC after a 1 hour infusion of etoposide phosphate or etoposide (dose-normalized to 100 mg/m2) was 96.1 +/- 22.6 mcg x hr/mL and 86 +/- 25.8 mcg x hr/mL, with Cmax values of 20.1 +/- 4.1 mcg/mL and 19 +/- 5.1 mcg/mL, respectively. Bioavailability of etoposide from etoposide phosphate was 113% (90% CI, 107% to 119%) for AUC and 107% (90% CI, 101% to 113%) for Cmax. There were no statistically significant differences in AUC or Cmax or in pharmacodynamic parameters (hematologic toxicity).[61467]
Patients with renal impairment have a reduced total body clearance, increased AUC, and lower volume of distribution at steady state.[64884][53551]
In children, an inverse relationship exists between plasma albumin levels and etoposide renal clearance. Over a dose range of 80 to 600 mg/m2, the mean renal clearance is 7 to 10 mL/min/m2 (35% of total body clearance); the effect of renal disease on etoposide clearance in children is not known. Elevated ALT is associated with reduced total body clearance of etoposide in children.[53551] [64884]
Age does not have a clinically significant effect on the pharmacokinetics of etoposide.[53552][64884][53551]
Gender does not have a clinically significant effect on the pharmacokinetics of etoposide.[53552][64884][53551]
Etoposide may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking etoposide. If a woman becomes pregnant during therapy with etoposide, she should be informed of the potential risk to the fetus. Intrauterine death and fetal toxicity (e.g., reduced fetal weight, skeletal abnormalities, cranial abnormalities, exencephaly, encephalocele, and anophthalmia) occurred in rats and mice when etoposide was administered during organogenesis; doses given in these studies were much less than the recommended human dose.[61465] [53552] [53551]
It is not known if etoposide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during etoposide or etoposide phosphate therapy.[53552] [53551] [61465]
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