O ncology 1992:49(suppl 1): 11—18
D epartm ent o f 1lem atology and Medical Oncology Peter M acC allum C ancer Institute M elbourne. A ustralia
Carboplatin/Etoposide in Small Cell Lung Cancer
Keywords
Abstract
Carboplatin Etoposide Lung cancer
Carboplatin etoposide is an active combination in small cell lung cancer. In phase 11 studies, it produces results that appear equivalent to cisplatin etopo side. but it has not been compared in a randomized study. It has a better toxicity profile than cisplatin etoposide when compared in non-small cell lung cancer. The combination of carboplatin, etoposide is very well tolerated by elderly pa tients. Carboplatin etoposide lacks important non hematologic side effects, which has led to its assessment in dose escalation studies with colony-stimulat ing factors and autologous bone marrow transplantation.
Cisplatin and etoposide have been successfully used in patients with small cell lung cancer (SCLC) as initial therapy, salvage therapy, as an alternating regimen with CAV (cyclophosphamide doxorubicin vincristine), and as consolidation therapy after CAV [1 3], Carboplatin ¡platinum, diammine [1.1-cyclobutane dicarboxylato(2-)0.0']-, C BI)CA. NSC 241240. or J M -81 is a second-genera tion platinum 11 complex and an analogue of cisplatin. In preclinical experimental tumors, carboplatin is as active as cisplatin in murine P388 leukemia. B16 melanoma, colon 38 carcinoma, and other tumors [4. 5], Carboplatin is superior to cisplatin in PC6A plasmacytoma and colon CX-I xenograph but inferior to cisplatin in L12I0 leuke mia and CD8F1 mammary carcinoma [4 7]. In animal toxicity studies, the dose-limiting toxicity was myelosuppression in contrast to the renal toxicity and neurotoxicity seen with cisplatin [8,9], Clinical phase I trials with carboplatin confirmed the preclinical studies; myelosuppression. especially throm bocytopenia, was identified as the dose-limiting toxicity
[10-14], Nausea and vomiting were mild compared with that expected with cisplatin, and nephrotoxicity, neu rotoxicity. and ototoxicity were uncommon. Significant nonhematologic toxicity was not encountered until doses of 1.200 1,600 mg n r were reached [ 15]. Carboplatin has been studied in 56 patients with SCLC at a dose o f 250-400 mg n r i.v. every month [16], O f 30 previously untreated patients. 3 achieved a complete re sponse (CR) and 15 a partial response (PR) for an overall objective response rate o f 60%. Of 17 patients who had relapsed while off previous chemotherapy. 24% achieved an objective response. The median duration of objective response was 4.5 months (range. 2 9). This order of re sponse is one of the highest reported for a single agent in SCLC. Jacobs et al. [17] studied 14 previously untreated SCLC patients treated with carboplatin 400 mg n r every 28 days [17], Eleven of 14 responded, but the duration of response was only 8 weeks and the median survival was 29 weeks (range, 11 68 + ).
James 1- Bishop. MD Department of Hematology and Medical Oncology Peter MacCallum C ancer Institute 4SI Little Lonsdale St Melbourne 3000 (Australia)
« I002S. Karger AG. Basel 0030 2414 02 0407 0011 $ 2.75 0
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James F. Bishop
Carboplatin/Etoposide Combinations
Bishop
Carboplatin Etoposide in Small Cell I ung Cancer
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58%. PR 28%) of patients with LD and 75% (CR 25%, PR 50%) with ED. The relapse-free survival for patients Carboplalin's high single-agent activity in SCLC pro with CR was 58% at 18 months, with a median of 7.8 vided a rationale for its inclusion in the development of months for PR. The 18-month survival rate after CR was multidrug combinations. Smith et al. [18] reported 52 59%, with a median survival o f 10 months for those with previously untreated patients with SCLC who were given 4 PR. Carboplatin ifosfamide etoposide/vincrisline has courses ofcarboplalin 300 mg n r i.v. on day I plus etopo- been studied in SCLC patients with LD [23]. The actuarial side 100 mg n r i.v. on days 1,2. and 3. Chest radiotherapy 2-year survival was 33%. with a minimum follow-up of 18 (40 Gy) was given to all patients with limited disease (LD); months. Although more myelosuppression occurred with no prophylactic cranial irradiation was given. Carbopla- the 4-drug combinations, which are clearly active, the tu tin etoposide produced objective responses in 82% (CR mor responses to the 4-drug combinations appear similar 29%) of patients with LD and 88% o f patients with exten to those seen with carboplatin etoposide alone. The sive disease (ED). However, the median duration of re carboplatin etoposide combination has not been directly sponse in L D patients was only 7 months and 5.5 months in compared in randomized studies with cisplatin etoposide ED patients; survival al 1 year was 35% for LD and 26% in SCLC patients. However, in a randomized study of for ED patients. etoposide with either cisplatin or carboplatin in nonIn an Australian study [19], carboplatin 100 mg n r i.v. SCLC. there were no significant differences in overall re days I through 3 plus etoposide 120 mg n r i.v. days 1 sponse. time to progression, or survival [24]. The cisplatin through 3 was given to 94 previously untreated SCLC pa combination was significantly more toxic and was asso tients. The CR rate was 40% and the PR rate was 37%. The ciated with more leukopenia, nausea and vomiting, diar median relapse-free survival for patients with LD was 14.6 rhea. and renal dysfunction than w;as carboplatin etopo months and 7.9 months for ED patients. The median sur side. This toxicity comparison is consistent with carbopla vival for LD patients was 15.3 months (range 1.1-22.1) tin as a single agent compared with cisplatin in ovarian and 8.3 months (range, 0.1 22.0) for ED patients. This cancer or carboplatin cyclophosphamide compared with study reported more myelosuppression than did Smith et cisplatin cyclophosphamide in the same disease [25. 26]. al. [18], World Health Organization grade 3 or 4 neu tropenia ( < 1.0 x 10“ I) occurred in 63% of patients [19], Otherwise, carboplatin etoposide was well tolerated; 48% Carboplatin/Etoposide in the Elderly of patients experienced no nausea and nausea without vomiting occurred in 62% of patients. Both regimens pro The median age of patients in many SCLC studies is duced high response rates. However, in contrast to the approximately 67 years. The improved tolerance to carbo Australian Study [19], Smith el al. [18] reported short re platin etoposide compared with cisplatin/etoposide or mission duration and survival in LD patients. While rea CAV suggests that standard-dose carboplatin combina sons for this difference are unclear. Smith et al. did not in tions may be particularly useful in the elderly. We studied clude prophylactic CNS irradiation, and 29% of their pa the outcome in 26 of 179 patients treated in Australia with tients relapsed in the CNS. and the dose modifications for carboplatin etoposide combinations who were aged 70 or cytopenia were more substantial. Both studies demon older. Overall, 69% o f patients younger than 70 years ob strate that carboplatin, etoposide is a highly active, well- tained an objective response compared with 88% of pa tolerated regimen in SCLC. Preliminary results of high- tients aged 70 years or older (p = 0.07). Patients younger dose etoposide (200 mg nr day x 3) and carboplatin (125 than 70 years with LD had significantly longer relapse-free mg n r) in SCLC have been reported [20]. As expected, survival than did older patients. The nonhematologic tox myelosuppression was severe, but results appeared similar icity was similar for all patients irrespective of age. Patients to those previously discussed with this combination at aged 70 years or older had significantly more neutropenia lower doses [18. 19], A further report of etoposide carbo (p = 0.01 )and thrombocytopenia (p = 0.01) than did pa platin vincristine suggested that high responses were tients younger than 70 years. However, the duration of cy achievable with minimal toxicity [21]. topenia was short, and none of the elderly patients had in The efficacy and toxicity of the 4-drug regimen fective or bleeding sequelae. etoposide carboplatin / cyclophosphamide / vincristine An analysis of carboplatin/etoposide dose delivery re were assessed in 90 previously untreated patients with vealed that the dose, dose intensity, and duration of SCLC [22]. Objective responses were seen in 86% (CR therapy were similar in both age groups. When other prog
Etoposide Schedule In most cisplatin etoposide combinations, etoposide was given as a short intravenous infusion for 3 or 5 days. Cavalli et al. [28] showed that etoposide is schedule-depen dent in SCLC. with the best results obtained with etopo side given over 3 days. Slevin et al. [29] demonstrated in SCLC that 500 mg, n r over 24 h is inferior to etoposide 500 m g/nr divided over 5 days. Etoposide has recently pro duced potentially exciting results in SCLC when used as continuous oral therapy. In 17 SCLC patients previously treated with intravenous etoposide. an oral dose of 50 mg n r day x 21 produced objective responses in 47% [30]. In 20 untreated, poor-prognosis SCLC patients, oral etopo side 50 mg twice daily over 11 days produced objective res ponses in 85% [31]. High-dose etoposide 1.2 g /n r over 3 days for 2 cycles without bone marrow rescue has been used in previously untreated patients with extensive SCLC [32, 33]. The median survival in 13 patients was only 7.5 months. These results suggest that etoposide is scheduledependent. with prolonged schedules worthy of further study. However, the optimal dose and schedule of etopo side in combination with carboplatin remains to be estab lished.
Intensive Therapy In recent years, a number of successful support stra tegies have been developed for the severely myelosuppressed patient, including autologous bone marrow rescue, optimal platelet and antibiotic support, and col ony-stimulating factors. These developments and the disappointing 2-year results with conventional-dose chemotherapy have led to considerable interest in highdose, intensive therapy in SCLC. High-dose chemother apy with autologous bone marrow transplantation (ABMT) following relapse from initial therapy in SCLC has produced poor results. Single case reports [34-36] of
patients in this setting noted responses of short duration. In two larger series by Spitzer et al. [37] and Pico et al. [38], only a few patients achieved CR of short duration with few longer-term survivors. Over 200 patients have received high-dose chemo therapy with ABMT as intensification in single-arm stu dies following initial standard-dose chemotherapy [39-48]. In general, the results have been disappointing, with median relapse-free survival and survival similar to those of standard chemotherapy approaches. The largest studies, by Souhami et al. [47] and Smith et al. [43], report ed median relapse-free survivals of only 9-41 weeks. In a randomized study of intensive chemotherapy and ABMT by Humblel et al. [49], escalated doses of cyclophos phamide carmustine etoposide were used. TheCR rate in creased from 38 to 79% with the intensive postinduction therapy. Relapse-free survival, but not survival, was sig nificantly increased overall and in the LD subset with in tensive therapy. This improvement is modest but may be extended by current studies incorporating other drugs such as carboplatin. The ability to escalate cisplatin dose is limited by cisplatin’s unacceptable nonhematologic toxicity. Doseresponse relationships of carboplatin have been identified in preclinical animal tumors and human xenographs [50. 51]. These studies provide a rationale for the use of highdose carboplatin. Ozols et al. [52] administered 800 mg n r every 35 days to 30 previously treated patients with ova rian cancer. As expected, myelosuppression was the major toxicity, with a median leukocyte nadir of 0.6 x 109/l and platelet nadir of 6.5 x 109/l after the first cycle. However, patients were able to receive a further 4 cycles o f similar chemotherapy. This study showed that repeated cycles of double-dose carboplatin were feasible, but that this dose of carboplatin did not overcome established cisplatin re sistance. Gore et al. [15] studied high-dose carboplatin in patients receiving doses of 800, 1,200, or 1,600 m g/nr. The median duration of severe granulocytopenia (< 0 .5 x I09 I) ranged from I day for the 800-ntg/nr dose to 76 days for the 1.600-mg n r dose. One patient died while neutropenic. A fall in hemoglobin was also noted in some patients. Two of 9 patients at the 800-mg n r and 4 of 6 al the 1.600-rng n r dose experienced a fall in glomerular filtration rate (G FR ) between 25 and 50%. Nausea and vomiting did not appear to be dose related but neuropathy and ototoxicity occurred only at doses of 1.200 m g/nr and above. Five of 7 patients with SCLC achieved an objective response. These studies illustrate the expected toxicity of high-dose carboplatin given as a single agent without sup
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nostic factors were taken into account, multivariate re gression analysis showed that age dichotomized at 70 was not a significant prognostic factor for survival in patients treated with this combination. This finding is in contrast to other larger analyses o f prognostic factors using doxorubi cin-based regimens, which suggest that age is a significant prognostic factor [27], These data suggest that carboplatin etoposide may be an effective, less toxic alternative to cisplatin etoposide in older patients.
Carboplatin Dosing Although carboplatin is not nephrotoxic, the optimal dose of carboplatin at escalated doses requires renal func tion assessment. The thrombocytopenia experienced with standard-dose carboplatin was more pronounced in pa tients with reduced G FR . Egorin el al. [56. 57] developed and prospectively validated simple formulas to relate thrombocytopenia and creatinine clearance. Calvert et al. [58] showed that carboplatin plasma clear ance was linearly related to G FR . Using G FR , a target area under the curve (AUC) for carboplatin could be cal culated and achieved. Based on G FR calculations, the same AUC was achieved with doses (in mg n r) that varied up to 330%. Dosing ofcarboplatin using AUC rather than body surface area is a rational method of studying toxici des for different carboplatin doses. This method is yet to be applied consistently to high-dose carboplatin etoposide regimens but should help to make toxicity more predict able.
Hematopoietic Growth Factors The hematopoietic growth factors or CSFs are glyco protein hormones that stimulate proliferation and dif ferentiation of hematopoietic stem cells [59-65], G ra nulocyte-macrophage colony-stimulating factor (GMCSF) induces the development o f neutrophils, m ononu clear phagocytes, and eosinophil colonies in semisolid
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marrow culture systems. GM -CSF has been used clinically to accelerate hematopoietic recovery following chemo therapy with or without ABMT [66-69], When used with chemotherapy alone, GM-CSF did not reduce the number of febrile episodes but did shorten the neutropenia dura tion. especially following ABMT [69], The optimal dose and schedule of GM -CSF were studied in 47 SCLC pa tients receiving carboplatin/etoposide [70]. Forty-one pa tients were studied with carboplatin 100 m g / i r r / d a y x 3 and etoposide 120 m g/nr day x 3 for 6 cycles with GMCSF given at 15. 10. and 5 pg/kg on days 4- 11 and at 15 pg/kg on days 4 18. 4-25. 8-15. and 8-21. For GMCSF schedules starting on day 4, duration and dose of GM -CSF did not influence the duration or depth of neu tropenia. GM -CSF schedules starting on day 8 were asso ciated with a significantly longer duration of neutropenia than those beginning on day 4. Patients given prolonged administration ofG M -CSF had significantly more throm bocytopenia. Duration of neutropenia and throm bo cytopenia significantly increased with increasing numbers of chemotherapy cycles. Dyspnea and hypotension with the first GM -CSF dose were significantly more common with day-4 schedules. An additional 6 patients in this study received GM -CSF 10 pg/kg and double-dose carboplatin 200 m g/nr day x 3 and etoposide 240 mg n r day x 3. These courses were associated with granulocytopenia less than 0.5 x 10‘M for more than 6 days in all patients by course 3. These data suggest that the optimal GM -CSF dose and schedule are 5 pg/kg on days 4 - 11 and thatmultiple double doses of carboplatin and etoposide are achiev able but with substantial neutropenia. Further, carbopla tin etoposide should be administered only for 3 courses. Granulocyte colony-stimulating factor (G-CSF) con vincingly reduced neutropenia and mucositis following chemotherapy in patients with bladder cancer [71]. Asnotcd in a preliminary report of a randomized trial [72] of G-CSF in patients receiving chemotherapy for SCLC. G-CSF reduced the duration of neutropenia, incidence of febrile neutropenia episodes, and days hospitalized. There are currently many ongoing studies of hemato poietic growth factors with carboplatin with or without etoposide in lung cancer. Studies are being planned and carried out with combinations of growth factors such as interleukin-3 and erythropoietin. These studies should de termine if high-dose chemotherapy with these factors can improve clinical outcome.
Carboplatin/Etoposide in Small Cell Lung Cancer
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port. As a single agent with ABM T. the maximum tolerat ed dose of carboplatin is 2.000 m g/nr when given as a 4day continuous infusion or 5 times the usual phase II dose [53]. The dose-limiting toxicity was reversible cholestatic hepatitis, renal dysfunction, and moderate ototoxicity at 2.400 m g/nr. Of patients treated with this regimen, the one patient with SCLC’ responded. Thus, carboplatin can be escalated 5-6 times the usual phase II dose with autologous bone marrow support. Carboplatin with and without etoposide has now been used in combination in a number of high-dose programs with autologous bone marrow rescue in SCLC. germ cell tumors, breast cancer, and melanoma [47.54.55], It is not yet clear from these early phase studies what individual contribution carboplatin and etoposide have made and whether tum or efficacy has been substantially improved. These approaches provide future opportunities for carbo platin etoposide in SCLC.
Conclusions Carboplatin/etoposide is an active combination in SCLC and has a better toxicity profile than does cisplatin etoposide. An efficacy study comparing carboplatin/ etoposide with cisplatin etoposide has not been reported
in SCLC. The combinationis very well tolerated by elderly patients with lung cancer. Carboplatin etoposide's lack of important nonhematopoietic toxicity has resulted in preli minary studies of high-dose therapy with CSF or ABMT. These studies hold the promise of improved efficacy but will require rigorous clinical assessment.
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50 Harrap K R. Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Treat Rev 1985:12:21 33. 5 1 Rose W C. Schurig J E. Preclinical antitumour and toxicologic profile of carboplatin. Cancer Treat Rev 1985:12:1 19. 52 Ozols RF. Ostetega Y. Curt G. Young RC: High dose carboplatin in refractory ovarian cancer patients. J Clin Oncol 1987;5:197-201. 53 Elder JP. Shea TC. Henncr WD. Elias AD. Teicher BA, Weissman !.. WheclerCA. Ayash L.SehmybcrSM. Deary J.Schimpper LE. Fur E. Amman KH: High-dose combination alky lating agent therapy with carboplatin and au tologous bone marrow transplantation in solid tumors: in Bunn PA. Jr. C'anetta R. Ozols R I-', et al (eds): Carboplatin (JM-8): Current Per spectives and Future Directions. Philadelphia. Saunders. 1990. pp 353 .360. 54 Jones RB. Shapall EJ. Ross M. Coniglio D. Alphonti ML. Peters WP: High dose carbo platin. cyclophosphamide and BCNU with au tologous bone marrow support, excessive hepatic toxicity. Cancer Chemother Pharma col 1990;26:155-156. 55 Antman K. Edcr JP. Elias A. Ayash L. Shea TC. Weissman L. Critchlow .1. Schrybar SM. BeggC. Teicher BA: High dose thiotepa alone and in combination regimens with bone mar row support. Semin Oncol 1990:17(suppl 3): 33 38. 56 Egorin M J. Van Echo DA. Tipping SJ.OIman EA. Whitacrc MY.Thompson BW. Aisner J: Pharmacokinetics and dosage reduction of cisdiamminc ( l.l-cyclobutanedicarboxylato) platinum in patients with impaired renal func tion. Cancer Res 1984:44:5432-5438. 57 Egorin MJ. Van Echo DA. Olman F.A. Whitacrc MY. Forrest A. Aisner J: Prospec tive validation of a pharmacologically based dosing scheme for the eisdiamminediehloroplatinum (II) analogue diamminecyclobu.anc-dicarbo.xylatoplatinum. Cancer Res 1985;45:6502-6506. 58 Calvert AH. Newell DR. Gumbrell LA. O'RcillyS. Barncll M. Boxall FE.Siddik ZH. Johnson IR. Gore M E. Wiltshaw E: Carbo platin dosage: Prospective-evaluation ofasamplel'ormula based on renal function. J Clin On col 1989:7:1748 1756. 59 Clark SC. Kamen R: The human hematopoi etic colony-stimulating factors. Science 1987; 236:1229-1237. 60 Golde DW. Gasson JC: Cytokines: Myeloid growth factors: in Gallin Jl. Goldstein IM. Snyder man R (eds): Inflammation: BasicPrinciples and Clinical Correlates. New York. Raven, 1988. pp 253 261. 61 Golde DW. Gasson JC: Hormones that sti mulate the growth of blood cells. Sci Am 1988;259:34-42. 62 Metcalf D: The granulocyte-macrophage co lony-stimulating factors. Science 1985:229: 16-22.
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Carboplatin Etoposide in Small Cell Lung Cancer
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28 Cavalli F. Sontag RW. Jungi F. Senn HJ. Brunner K W: VP 16-213. Monotherapy for re mission induction of small cell lung cancer: A randomized trial using three dosage schedules. Cancer Treat Rep 1978;62:473-475. 29 Slevin ML. Clark PL. Joel SP. Malik S. Os borne R.I. Gregory WM. Lowe DG. Rc/nck R ll. Wriglcy PFM: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. .1Clin Oncol 1989:7:1333 134«. 3« Johnson D ll. Slrupp .1. Greco FA. Mande KR. Ilainsworth JD: Prolonged administra tion of oral etoposide in previously treated small cell lung cancer patients (abstract). Proc Am Soe Clin Oncol 1990:9:227. 31 Clark PL. Cottier B. Joel SP. Thompson PL. Slevin M L: Prolonged administration ofsinglc agent oral etoposide in patients with untreated small cell lung cancer (abstract). Proc Am Soe Clin Oncol 1990:9:226. 32 Wolf SN. Johnson DH. Hände KR. Ilains worth J D. Greco FA: High dose etoposide as a single agent chemotherapy for small cell car cinoma of the lung. Cancer Treat Rep 1983: 67:957 958. 33 Greco FA. Johnson DH. Mande K R. Porter I !.. Ilainsworth JD. Wolf SN: High dose etoposide (VP-16) in small cell lung cancer. Semin Oncol 1985:12
D epartm ent o f 1lem atology and Medical Oncology Peter M acC allum C ancer Institute M elbourne. A ustralia
Carboplatin/Etoposide in Small Cell Lung Cancer
Keywords
Abstract
Carboplatin Etoposide Lung cancer
Carboplatin etoposide is an active combination in small cell lung cancer. In phase 11 studies, it produces results that appear equivalent to cisplatin etopo side. but it has not been compared in a randomized study. It has a better toxicity profile than cisplatin etoposide when compared in non-small cell lung cancer. The combination of carboplatin, etoposide is very well tolerated by elderly pa tients. Carboplatin etoposide lacks important non hematologic side effects, which has led to its assessment in dose escalation studies with colony-stimulat ing factors and autologous bone marrow transplantation.
Cisplatin and etoposide have been successfully used in patients with small cell lung cancer (SCLC) as initial therapy, salvage therapy, as an alternating regimen with CAV (cyclophosphamide doxorubicin vincristine), and as consolidation therapy after CAV [1 3], Carboplatin ¡platinum, diammine [1.1-cyclobutane dicarboxylato(2-)0.0']-, C BI)CA. NSC 241240. or J M -81 is a second-genera tion platinum 11 complex and an analogue of cisplatin. In preclinical experimental tumors, carboplatin is as active as cisplatin in murine P388 leukemia. B16 melanoma, colon 38 carcinoma, and other tumors [4. 5], Carboplatin is superior to cisplatin in PC6A plasmacytoma and colon CX-I xenograph but inferior to cisplatin in L12I0 leuke mia and CD8F1 mammary carcinoma [4 7]. In animal toxicity studies, the dose-limiting toxicity was myelosuppression in contrast to the renal toxicity and neurotoxicity seen with cisplatin [8,9], Clinical phase I trials with carboplatin confirmed the preclinical studies; myelosuppression. especially throm bocytopenia, was identified as the dose-limiting toxicity
[10-14], Nausea and vomiting were mild compared with that expected with cisplatin, and nephrotoxicity, neu rotoxicity. and ototoxicity were uncommon. Significant nonhematologic toxicity was not encountered until doses of 1.200 1,600 mg n r were reached [ 15]. Carboplatin has been studied in 56 patients with SCLC at a dose o f 250-400 mg n r i.v. every month [16], O f 30 previously untreated patients. 3 achieved a complete re sponse (CR) and 15 a partial response (PR) for an overall objective response rate o f 60%. Of 17 patients who had relapsed while off previous chemotherapy. 24% achieved an objective response. The median duration of objective response was 4.5 months (range. 2 9). This order of re sponse is one of the highest reported for a single agent in SCLC. Jacobs et al. [17] studied 14 previously untreated SCLC patients treated with carboplatin 400 mg n r every 28 days [17], Eleven of 14 responded, but the duration of response was only 8 weeks and the median survival was 29 weeks (range, 11 68 + ).
James 1- Bishop. MD Department of Hematology and Medical Oncology Peter MacCallum C ancer Institute 4SI Little Lonsdale St Melbourne 3000 (Australia)
« I002S. Karger AG. Basel 0030 2414 02 0407 0011 $ 2.75 0
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James F. Bishop
Carboplatin/Etoposide Combinations
Bishop
Carboplatin Etoposide in Small Cell I ung Cancer
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58%. PR 28%) of patients with LD and 75% (CR 25%, PR 50%) with ED. The relapse-free survival for patients Carboplalin's high single-agent activity in SCLC pro with CR was 58% at 18 months, with a median of 7.8 vided a rationale for its inclusion in the development of months for PR. The 18-month survival rate after CR was multidrug combinations. Smith et al. [18] reported 52 59%, with a median survival o f 10 months for those with previously untreated patients with SCLC who were given 4 PR. Carboplatin ifosfamide etoposide/vincrisline has courses ofcarboplalin 300 mg n r i.v. on day I plus etopo- been studied in SCLC patients with LD [23]. The actuarial side 100 mg n r i.v. on days 1,2. and 3. Chest radiotherapy 2-year survival was 33%. with a minimum follow-up of 18 (40 Gy) was given to all patients with limited disease (LD); months. Although more myelosuppression occurred with no prophylactic cranial irradiation was given. Carbopla- the 4-drug combinations, which are clearly active, the tu tin etoposide produced objective responses in 82% (CR mor responses to the 4-drug combinations appear similar 29%) of patients with LD and 88% o f patients with exten to those seen with carboplatin etoposide alone. The sive disease (ED). However, the median duration of re carboplatin etoposide combination has not been directly sponse in L D patients was only 7 months and 5.5 months in compared in randomized studies with cisplatin etoposide ED patients; survival al 1 year was 35% for LD and 26% in SCLC patients. However, in a randomized study of for ED patients. etoposide with either cisplatin or carboplatin in nonIn an Australian study [19], carboplatin 100 mg n r i.v. SCLC. there were no significant differences in overall re days I through 3 plus etoposide 120 mg n r i.v. days 1 sponse. time to progression, or survival [24]. The cisplatin through 3 was given to 94 previously untreated SCLC pa combination was significantly more toxic and was asso tients. The CR rate was 40% and the PR rate was 37%. The ciated with more leukopenia, nausea and vomiting, diar median relapse-free survival for patients with LD was 14.6 rhea. and renal dysfunction than w;as carboplatin etopo months and 7.9 months for ED patients. The median sur side. This toxicity comparison is consistent with carbopla vival for LD patients was 15.3 months (range 1.1-22.1) tin as a single agent compared with cisplatin in ovarian and 8.3 months (range, 0.1 22.0) for ED patients. This cancer or carboplatin cyclophosphamide compared with study reported more myelosuppression than did Smith et cisplatin cyclophosphamide in the same disease [25. 26]. al. [18], World Health Organization grade 3 or 4 neu tropenia ( < 1.0 x 10“ I) occurred in 63% of patients [19], Otherwise, carboplatin etoposide was well tolerated; 48% Carboplatin/Etoposide in the Elderly of patients experienced no nausea and nausea without vomiting occurred in 62% of patients. Both regimens pro The median age of patients in many SCLC studies is duced high response rates. However, in contrast to the approximately 67 years. The improved tolerance to carbo Australian Study [19], Smith el al. [18] reported short re platin etoposide compared with cisplatin/etoposide or mission duration and survival in LD patients. While rea CAV suggests that standard-dose carboplatin combina sons for this difference are unclear. Smith et al. did not in tions may be particularly useful in the elderly. We studied clude prophylactic CNS irradiation, and 29% of their pa the outcome in 26 of 179 patients treated in Australia with tients relapsed in the CNS. and the dose modifications for carboplatin etoposide combinations who were aged 70 or cytopenia were more substantial. Both studies demon older. Overall, 69% o f patients younger than 70 years ob strate that carboplatin, etoposide is a highly active, well- tained an objective response compared with 88% of pa tolerated regimen in SCLC. Preliminary results of high- tients aged 70 years or older (p = 0.07). Patients younger dose etoposide (200 mg nr day x 3) and carboplatin (125 than 70 years with LD had significantly longer relapse-free mg n r) in SCLC have been reported [20]. As expected, survival than did older patients. The nonhematologic tox myelosuppression was severe, but results appeared similar icity was similar for all patients irrespective of age. Patients to those previously discussed with this combination at aged 70 years or older had significantly more neutropenia lower doses [18. 19], A further report of etoposide carbo (p = 0.01 )and thrombocytopenia (p = 0.01) than did pa platin vincristine suggested that high responses were tients younger than 70 years. However, the duration of cy achievable with minimal toxicity [21]. topenia was short, and none of the elderly patients had in The efficacy and toxicity of the 4-drug regimen fective or bleeding sequelae. etoposide carboplatin / cyclophosphamide / vincristine An analysis of carboplatin/etoposide dose delivery re were assessed in 90 previously untreated patients with vealed that the dose, dose intensity, and duration of SCLC [22]. Objective responses were seen in 86% (CR therapy were similar in both age groups. When other prog
Etoposide Schedule In most cisplatin etoposide combinations, etoposide was given as a short intravenous infusion for 3 or 5 days. Cavalli et al. [28] showed that etoposide is schedule-depen dent in SCLC. with the best results obtained with etopo side given over 3 days. Slevin et al. [29] demonstrated in SCLC that 500 mg, n r over 24 h is inferior to etoposide 500 m g/nr divided over 5 days. Etoposide has recently pro duced potentially exciting results in SCLC when used as continuous oral therapy. In 17 SCLC patients previously treated with intravenous etoposide. an oral dose of 50 mg n r day x 21 produced objective responses in 47% [30]. In 20 untreated, poor-prognosis SCLC patients, oral etopo side 50 mg twice daily over 11 days produced objective res ponses in 85% [31]. High-dose etoposide 1.2 g /n r over 3 days for 2 cycles without bone marrow rescue has been used in previously untreated patients with extensive SCLC [32, 33]. The median survival in 13 patients was only 7.5 months. These results suggest that etoposide is scheduledependent. with prolonged schedules worthy of further study. However, the optimal dose and schedule of etopo side in combination with carboplatin remains to be estab lished.
Intensive Therapy In recent years, a number of successful support stra tegies have been developed for the severely myelosuppressed patient, including autologous bone marrow rescue, optimal platelet and antibiotic support, and col ony-stimulating factors. These developments and the disappointing 2-year results with conventional-dose chemotherapy have led to considerable interest in highdose, intensive therapy in SCLC. High-dose chemother apy with autologous bone marrow transplantation (ABMT) following relapse from initial therapy in SCLC has produced poor results. Single case reports [34-36] of
patients in this setting noted responses of short duration. In two larger series by Spitzer et al. [37] and Pico et al. [38], only a few patients achieved CR of short duration with few longer-term survivors. Over 200 patients have received high-dose chemo therapy with ABMT as intensification in single-arm stu dies following initial standard-dose chemotherapy [39-48]. In general, the results have been disappointing, with median relapse-free survival and survival similar to those of standard chemotherapy approaches. The largest studies, by Souhami et al. [47] and Smith et al. [43], report ed median relapse-free survivals of only 9-41 weeks. In a randomized study of intensive chemotherapy and ABMT by Humblel et al. [49], escalated doses of cyclophos phamide carmustine etoposide were used. TheCR rate in creased from 38 to 79% with the intensive postinduction therapy. Relapse-free survival, but not survival, was sig nificantly increased overall and in the LD subset with in tensive therapy. This improvement is modest but may be extended by current studies incorporating other drugs such as carboplatin. The ability to escalate cisplatin dose is limited by cisplatin’s unacceptable nonhematologic toxicity. Doseresponse relationships of carboplatin have been identified in preclinical animal tumors and human xenographs [50. 51]. These studies provide a rationale for the use of highdose carboplatin. Ozols et al. [52] administered 800 mg n r every 35 days to 30 previously treated patients with ova rian cancer. As expected, myelosuppression was the major toxicity, with a median leukocyte nadir of 0.6 x 109/l and platelet nadir of 6.5 x 109/l after the first cycle. However, patients were able to receive a further 4 cycles o f similar chemotherapy. This study showed that repeated cycles of double-dose carboplatin were feasible, but that this dose of carboplatin did not overcome established cisplatin re sistance. Gore et al. [15] studied high-dose carboplatin in patients receiving doses of 800, 1,200, or 1,600 m g/nr. The median duration of severe granulocytopenia (< 0 .5 x I09 I) ranged from I day for the 800-ntg/nr dose to 76 days for the 1.600-mg n r dose. One patient died while neutropenic. A fall in hemoglobin was also noted in some patients. Two of 9 patients at the 800-mg n r and 4 of 6 al the 1.600-rng n r dose experienced a fall in glomerular filtration rate (G FR ) between 25 and 50%. Nausea and vomiting did not appear to be dose related but neuropathy and ototoxicity occurred only at doses of 1.200 m g/nr and above. Five of 7 patients with SCLC achieved an objective response. These studies illustrate the expected toxicity of high-dose carboplatin given as a single agent without sup
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nostic factors were taken into account, multivariate re gression analysis showed that age dichotomized at 70 was not a significant prognostic factor for survival in patients treated with this combination. This finding is in contrast to other larger analyses o f prognostic factors using doxorubi cin-based regimens, which suggest that age is a significant prognostic factor [27], These data suggest that carboplatin etoposide may be an effective, less toxic alternative to cisplatin etoposide in older patients.
Carboplatin Dosing Although carboplatin is not nephrotoxic, the optimal dose of carboplatin at escalated doses requires renal func tion assessment. The thrombocytopenia experienced with standard-dose carboplatin was more pronounced in pa tients with reduced G FR . Egorin el al. [56. 57] developed and prospectively validated simple formulas to relate thrombocytopenia and creatinine clearance. Calvert et al. [58] showed that carboplatin plasma clear ance was linearly related to G FR . Using G FR , a target area under the curve (AUC) for carboplatin could be cal culated and achieved. Based on G FR calculations, the same AUC was achieved with doses (in mg n r) that varied up to 330%. Dosing ofcarboplatin using AUC rather than body surface area is a rational method of studying toxici des for different carboplatin doses. This method is yet to be applied consistently to high-dose carboplatin etoposide regimens but should help to make toxicity more predict able.
Hematopoietic Growth Factors The hematopoietic growth factors or CSFs are glyco protein hormones that stimulate proliferation and dif ferentiation of hematopoietic stem cells [59-65], G ra nulocyte-macrophage colony-stimulating factor (GMCSF) induces the development o f neutrophils, m ononu clear phagocytes, and eosinophil colonies in semisolid
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Bishop
marrow culture systems. GM -CSF has been used clinically to accelerate hematopoietic recovery following chemo therapy with or without ABMT [66-69], When used with chemotherapy alone, GM-CSF did not reduce the number of febrile episodes but did shorten the neutropenia dura tion. especially following ABMT [69], The optimal dose and schedule of GM -CSF were studied in 47 SCLC pa tients receiving carboplatin/etoposide [70]. Forty-one pa tients were studied with carboplatin 100 m g / i r r / d a y x 3 and etoposide 120 m g/nr day x 3 for 6 cycles with GMCSF given at 15. 10. and 5 pg/kg on days 4- 11 and at 15 pg/kg on days 4 18. 4-25. 8-15. and 8-21. For GMCSF schedules starting on day 4, duration and dose of GM -CSF did not influence the duration or depth of neu tropenia. GM -CSF schedules starting on day 8 were asso ciated with a significantly longer duration of neutropenia than those beginning on day 4. Patients given prolonged administration ofG M -CSF had significantly more throm bocytopenia. Duration of neutropenia and throm bo cytopenia significantly increased with increasing numbers of chemotherapy cycles. Dyspnea and hypotension with the first GM -CSF dose were significantly more common with day-4 schedules. An additional 6 patients in this study received GM -CSF 10 pg/kg and double-dose carboplatin 200 m g/nr day x 3 and etoposide 240 mg n r day x 3. These courses were associated with granulocytopenia less than 0.5 x 10‘M for more than 6 days in all patients by course 3. These data suggest that the optimal GM -CSF dose and schedule are 5 pg/kg on days 4 - 11 and thatmultiple double doses of carboplatin and etoposide are achiev able but with substantial neutropenia. Further, carbopla tin etoposide should be administered only for 3 courses. Granulocyte colony-stimulating factor (G-CSF) con vincingly reduced neutropenia and mucositis following chemotherapy in patients with bladder cancer [71]. Asnotcd in a preliminary report of a randomized trial [72] of G-CSF in patients receiving chemotherapy for SCLC. G-CSF reduced the duration of neutropenia, incidence of febrile neutropenia episodes, and days hospitalized. There are currently many ongoing studies of hemato poietic growth factors with carboplatin with or without etoposide in lung cancer. Studies are being planned and carried out with combinations of growth factors such as interleukin-3 and erythropoietin. These studies should de termine if high-dose chemotherapy with these factors can improve clinical outcome.
Carboplatin/Etoposide in Small Cell Lung Cancer
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port. As a single agent with ABM T. the maximum tolerat ed dose of carboplatin is 2.000 m g/nr when given as a 4day continuous infusion or 5 times the usual phase II dose [53]. The dose-limiting toxicity was reversible cholestatic hepatitis, renal dysfunction, and moderate ototoxicity at 2.400 m g/nr. Of patients treated with this regimen, the one patient with SCLC’ responded. Thus, carboplatin can be escalated 5-6 times the usual phase II dose with autologous bone marrow support. Carboplatin with and without etoposide has now been used in combination in a number of high-dose programs with autologous bone marrow rescue in SCLC. germ cell tumors, breast cancer, and melanoma [47.54.55], It is not yet clear from these early phase studies what individual contribution carboplatin and etoposide have made and whether tum or efficacy has been substantially improved. These approaches provide future opportunities for carbo platin etoposide in SCLC.
Conclusions Carboplatin/etoposide is an active combination in SCLC and has a better toxicity profile than does cisplatin etoposide. An efficacy study comparing carboplatin/ etoposide with cisplatin etoposide has not been reported
in SCLC. The combinationis very well tolerated by elderly patients with lung cancer. Carboplatin etoposide's lack of important nonhematopoietic toxicity has resulted in preli minary studies of high-dose therapy with CSF or ABMT. These studies hold the promise of improved efficacy but will require rigorous clinical assessment.
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