Carboplatin/Etoposide in Small Cell Lung Cancer
Abstract
Carboplatin etoposide is an active combination in small cell lung cancer.In phase II studies. it produces results that appear equivalent to cisplatin/etopo-side, but it has not beencompared 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/eloposide lacks important nonhematologic side eflects. 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[l.l-cyclobutane dicarboxylato(2-)-0.0'1-.CBDCA.NSC 241240.or JM-8;isa second-genera-tion platinum II 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 L1210 leuke-mia and CD8FI mammary carcinoma [4-7].In animal toxicity studies, the dose-limiting toxicity was myelosup-pression 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/mwere reached[15].
Carboplatin has been studied in 56 patients with SCLC at a dose of 250-400 mg/m’i.v. every month[16].Of 30 previously untreated patients. 3 achieved a complete re-sponse (CR)and 15 a partial response (PR) for an overall objective response rate of 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/㎡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 F.Bishup.MI)
Depariment of Hematology and Medical Oncology
Peter MacCallum Cancer Institute
I8I Little Lonstale St
Melhourne 3000(Australial

1992S.Karger AG.Basel
0030 241492
0497 001152.75 0 
Carboplatin/Etoposide Combinations
Carboplatin’s high single-agent activity in SCLC pro-vided a rationale for its inclusion in the development of multidrug combinations. Smith et al. [18] reported 52 previously untreated patients with SCLC who were given 4 courses of carboplatin 300 mg/㎡’i.v.on day I plusetopo-side 100mg/m’i.v.on days 1,2.and 3.Chest radiotherapy (40 Gy) was given to all patients with limited disease(LD); no prophylactic cranial irradiation was given. Carbopla-tin etoposide produced objective responses in 82% (CR 29%) of patients with LD and 88% of patients with exten-sive disease(ED).However.the median duration of re-sponse in LD patients was only 7monthsand 5.5monthsin ED patients:survival at I year was 35% for LD and 26% for ED patients.
In an Australian study[19].carboplatin 100mg/㎡i.v. days I through 3 plus etoposide 120 mg/㎡i.v.days l through 3 was given to 94 previously untreated SCLC pa-tients. The CR rate was 40% and the PR rate was 37%.The median relapse-free survival for patients with LD was 14.6 months and 7.9 months for ED patients. The median sur-vival for LD patients was 15.3 months(range 1.1-22.1) and 8.3 months (range.0.1-22.0)for ED patients.This study reported more myelosuppression than did Smith et al. [18].World Health Organization grade 3 or 4 neu-tropenia(<1.0 x 10°/1)occurred in 63% of patients[19]. Otherwise.carboplatin/ctoposide was well tolerated;48% of patients experienced no nausea and nausea without vomiting occurred in 62% ofpatients. Both regimens pro-duced high response rates. However, in contrast to the Australian Study [19]. Smith et al. [18] reported short re-mission duration and survival in LD patients. While rea-sons for this difference are unclear. Smith et al. did not in-clude prophylactic CNS irradiation, and 29% of their pa-tients relapsed in the CNS. and the dose modifications for cytopenia were more substantial. Both studies demon-strate that carboplatin etoposide is a highly active. well-tolerated regimen in SCLC. Preliminary results of high-dose etoposide(200 mg/㎡/day x 3)and carboplatin(125 mg/㎡)in SCLC have been reported [20]. As expected. myelosuppression was severe, but results appeared similar to those previously discussed with this combination at lower doses [18,19]. A further report of etoposide/carbo-platin/vincristine suggested that high responses were achievable with minimal toxicity[21].
The eflicacy and toxicity of the 4-drug regimen etoposide/carboplatin/cyclophosphamide/vincristine were assessed in 90 previously untreated patients with SCLC [22]. Objective responses were seen in 86% (CR

58%.PR 28%) of patients with LD and 75% (CR 25%. PR 50%)with ED.The relapse-free survival for patients with CR was 58% at 18 months. with a median of 7.8 months for PR. The 18-month survival rate after CR was 59%. with a median survival of 10 menths for those with PR. Carboplatin ifosfamide ctoposide vincristine has been studied in SCLC patients with LD[23].The actuarial 2-year survival was 33%. with a minimum follow-up of 18 months. Although more myelosuppression occurred with the 4-drug combinations,which are clearly active.the tu-mor responses to the 4-drug combinations appear similar to those seen with carboplatin/etoposide alone. The carboplatin/etoposide combination has not been directly compared in randomized studies with cisplatin/etoposide in SCLC patients. However, in a randomized study of etoposide with either cisplatin or carboplatin in non-SCLC.there were no significant diflerences in overall re-sponse. time to progression. or survival[24]. The cisplatin combination was significantly more toxic and was asso-ciated with more leukopenia.nausea and vomiting,diar-rhea,and renal dysfunction than was carboplatin/etopo-side.This toxicity comparison is consistent with carbopla-tin as a single agent compared with cisplatin in ovarian cancer or carboplatin cyclophosphamide compared with cisplatin cyclophosphamide in the same disease[25.26].
Carboplatin/Etoposide in the Elderly
The median age of patients in many SCLC studies is approximately 67 years.The improved tolerance to carbo-platin/etoposide compared with cisplatin ctoposide or CAV suggests that standard-dose carboplatin combina-tions may beparticularly useful in the elderly.We studied the outcome in 26 of 179 patients treated in Australia wwith carboplatin/etoposide combinations who were aged 70 or older. Overall.69% of patients younger than 70 years ob-tained an objective response compared with 88% of pa-tients aged 70 years or older(p =0.07).Patients younger than 70 years with LD had significantly longer relapse-free survival than did older patients. The nonhematologic tox-icity was similar for all patients irrespective of age.Patients aged 70 years or older had significantly more neutropenia (p = 0.01)and thrombocytopenia(p= 0.01)than did pa-tients younger than 70 years.However,the duration of cy-topenia was short. and none of the elderly patients had in-fective or blecding sequelae.
An analysis of carboplatin/etoposide dose delivery re-vealed that the dose. dose intensity. and duration of therapy were similar in both age groups.When other prog-
12

Bishop

Carboplatin/Etoposide in Small Cell Lung
Cancer 
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 findingisin contrast to otherlarger analyses of prognostic factors using doxorubi-cin-based regimens,which suggest that age is a significant prognostic factor [27]. These data suggest that carbopla-tin/etoposide may be an eflective. less toxic alternative to cisplatin/etoposide in older patients.
Etoposide Schedule
In most cisplatin/etoposide combinations, etoposide was given as a short intravenous infusion for 3 or 5 days. Cavalliet al.[28]showed that ctoposide 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 500mg/㎡over 24 his inferior to etoposide 500 mg/m'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 50mg ㎡/day x 21 produced objective responses in 47%[30].In 20 untreated,poor-prognosis SCLC patients,oral etopo-side 50 mg twice daily over I I days produced objective res-ponses in 85% [31]. High-dose etoposide 1.2g㎡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 schedule-dependent.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 myelo-suppressed patient, including autologous bone marrow rescue, optimal platelet and antibiotic support, andcol-ony-stimulating factors. These developments and the disappointing 2-year results with conventional-dose chemotherapy have led to considerable interest in high-dose,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 Spitzeret 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 Souhamiet 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 Humblet et al. [49]. escalated doses of cyclophos-phamide carmustine etoposide were used.The CR ratein-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 cis-platin's unacceptable nonhematologic toxicity.Dose-response relationships of carboplatin have been identified in preclinical animal tumors and human xenographs[50. 51].These studies provide a rationale for the use of high-dose carboplatin. Ozols et al.[52]administered 800mg/㎡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 0.6x 10°land platelet nadir of 6.5 x 10°lafter the first cycle.However. patients were able to receive a further 4 cycles of 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 1,600mg/㎡The median duration of severe granulocytopenia (<0.5 x 10°/l)ranged from I day for the 800-mg mdosc to 76 days for the 1.600-mg/㎡ dose.One patient died while neutropenic. A fall in hemoglobin was also noted in some patients. Two of'9 patients at the 800-mg/㎡and4of 6at the 1.600-mg/㎡dose experienced a fall in glomerular filtration rate (GFR) between 25 and 50%.Nausea and vomitingdid not appear to be dose related but neuropathy and ototoxicity occurred orly at doses of 1.200 mg/m'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- 
port. As a single agent with ABMT. the maximum tolcrat-ed dose of carboplatin is 2.000 mg/㎡ when given as a 4-day 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 2.400mg/㎡.Ofpatients treated with this regimen.the one patient with SCLC responded. Thus, carboplatin can be cscalated 5-6 times the usual phase Il 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].lt is not yet clear from these early phase studies what individual contribution carboplatin and etoposide have made and whether tumor efficacy has been substantially improved. These approaches provide future opportunities for carbo-platin/etoposide in SCLC.
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 GFR. Egorin et al.[56.57]developed and prospectively validated simple formulas to relate thrombocytopenia and creatinine clearance.
Calvertet al.[58]showed that carboplatin plasma clear-ance was linearly related to GFR. Using GFR, a target area under the curve (AUC) for carboplatin could be cal-culated and achieved. Based on GFR calculations. the same AUC was achieved with doses(in mg/m')that varied up to 330%.Dosing of carboplatin using AUC rather than body surface area is a rational method of studying toxici-ties for dillerent 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]. Gra-nulocyte-macrophage colony-stimulating factor (GM-CSF) induces the development of neutrophils.mononu-clear phagocytes,and cosinophil colonies in semisolid

marrow culturesystems. GM-CSF has been usedclinically to accelerate hematopoietic recovery following chemo-therapy with or without ABMT [66-69].When used with chemotherapyalone.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 mg/㎡/day x3 and etoposide 120 mg/mday x 3 for 6 cycles with GM-CSF given at 15. 10. and 5 ug kg on days 4-11 and at 15μg/kg on days 4-18.4-25.8-15.and 8-21.For GM-CSF 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 ofGM-CSF had significantly more throm-bocytopenia. Duration of neutropenia and thrombo-cytopenia significantly increased with increasing numbers of chemnotherapy 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 μg kg and double-dose carboplatin 200mg/㎡/day x 3 and etoposide 240 mg/㎡/dayx3. These courses were associated with granulocytopenia less than 0.5 x 10'I for more than 6 days in all patients by course 3. These data suggest that the optimal GM-CSF doseand schedule are 5 μgkgondays4-Iland that multi-ple 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 bladdercancer[71].As not-ed 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-poietie 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-3and erythropoietin. These studies should de-termine if high-dose chemotherapy with these factors can improve clinical outcome.
14

Bishop

Carboplatin/Etoposide in Small Cell Lung
Cancer 
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
References

in SCLC.The combinationis very well tolerated byelderly patients with lungcancer. Carboplatin/ctoposide'slack 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 eflicacy but will require rigorous clinical assessment.
1 Sierocki JS.Hilaris BS.Hopfan S.Martini V. Barton D. Gobey RB.Wittes RE:Cisdi-chlorodiammeplatinum (Il)and VP 16-213: An active induction regimen for small cell car-cinoma of the lung. Cancer Treat Rep 1979:63:9-10.
2 Evans WK.Osobe D. Feld R. Shepherd FA. Bagos MJ.DeBoer G.etal:Etoposide(VP-16) and cisplatin: An ellective treatment for re. lapse in small cell lung cancer.J Clin Oncol 1985:3:65-71.
3 Evans WK. Feld R. Murray N. Willan A. Coy P.Osoha D.Shepherd FA.Clark DA. Levitt M.MacDonald A:Superiority of alter-nating non-cross resistant chemotherapy inex-tensive small cell lung cancer.Ann Intern Med 1987:107:451-458.
4 Bradner WT.Rose WC.Hultalen JB:Antitu-mor activity ofplatinum analogs. in Prestayko AW.Crooke ST.Carter SK (eds):Cisplatin-Current Status and New Developments.New York.Academic Press.1980.pp 171-182.
5 Wolpert-Defelippes MK:Antitumour activity of cisplatin analogs.in Prestayko AW.Crooke ST.Carter SK(eds):Cisplatin-Current Sta-tus and New Developments.New York.Ac-ademic Press.1980.pp 193-212.
6 Wilkinson R.Cox PJ.Jones M. Harrap K R: Selection of potential second generation plati-num compounds.Biochimie 1978:60:851-857.
7 Lelieveld P: Preclinical studies on toxicity. antitumour activity and pharmacokinetics of cisplatin and three recently developed deriva-tives. Eur J Cancer Clin Oncol 1984:20: 1087-1104
8 Harrap K R. Jones M. Wilkinson CR.Clink HM.Sparrow S.Mitchley B.Clark S.Vessey A:Antitumor.toxic and biochemical proper-ties of cisplatin and eight other platinum com-plexes.in Prestayko AW.Crooke ST.Carter SK (eds):Cisplatin-Current Status and New Developments.New York. Academic Press. 1980.p193.
9 Rose WC.Schurig JE.Bradner WT.Huftalen JB:Antitumour activity and toxicity of cisdi-amminedichloroplatinum Il analogs.Cancer Treat Rep 1982:66:135-146.

10 Calvert AH.Harland SJ.Newell DR.Siddik ZH.Jones AC.McElwain TJ. Raju S.Wilt-shaw E.Smith IE. Baker JM.Peckam MJ. Harrap K R:Early clinical studies with cis-diammine-1.1-cyclobutane dicarboxylate pla-tinum Il. Cancer Chemother Pharmacol 198219:140-147.
Hl Joss RA. Kaplan S.Goldhirsch A. Sessa C. Brunner K W.Cavalli F: A phase I tria1of cis-diammine-I.l-cyclobutane dicarboxylate pla-tinum Il tcarhoplatin.CBDCA.JM-8)with a single dose every live-week schedule.Invest New Drugs 1984:2:297-304.
12 Koeller JM.TrumpDL..Tutsch KD.Earhartt RH.Davis TE. Tormey DC: Phase I clinical trial and pharmacokinetics of carboplatin by single monthly 30 minute infusion.Cancer 1986:57:222-225.
13 Van Echo DA. Egorin MJ. Whitacre MY. Olman EA.Aisner J:Phase I clinical and pharmacologic trial of carhoplatin daily for 5 days.Cancer Treat Rep 1984:68:1103-1114.
14 Roseneweig M.Nicaise C.Beer M.Crespeigne N.Van Rijmenant M.I.enazL.Kenis Y:Phase I study of carboplatin (CBDCA)given on a 5 day intravenous schedule. J Clin Oncol 1983:1:621-626.
15 Gore ME. Calvert AH.Smith IE: High dose carhoplatin in the treatment of lung cancer and mesothelioma:AphaseIdose escalationstudy. Eur J Cancer 1987:23:1391-1397.
16 Smith IE. Harland SJ. Robinson BA.Evans BD.Goodhart LC.Calvert AH.Yarnold J. Glees JP.Baker J.Ford HT: Carboplatin: A very active new cisplatin analog in the treat-ment of small cell lung cancer.Cancer Treat Rep 1985:69:43 46.
17 Jacobs RH.Bitran JD.Deutsch M.Hollman PC.Sinkule J.Purl S.Golomh HM:Phase Il study of carboplatin in previously untreated patients with metastatic small cell lung cancer. Cancer Treat Rep 1987:71:311-312
18 Smith IE. Evans BD.Gore ME. Repetto L. Yarnold JR. Fod HT: Carboplatin (parapla-tin:JMX) and ctoposide (VPI6)as lirst-line combination therapy for small cell lungcancer. J Clin Oncol 1987:5:185-189.
19 Bishop JF. Raghavan D. Stuart-Harris R. Morstyn G.Aroney R.Keflord R. Yuen K. Lee J.Gianoutsos P.Olver IN:Carboplatin

(CBDCA.JM-X)and etoposide (VP16-213)in previously untreated patients with small cell lung cancer.J Clin Oncol 1987:5:1574-1578.
20 Luikart SD.Mitchell EP.Van Echo DA.Pro-pert K.ModeasC.Perry MC.Green M:Phase I ll tnal of etoposide(VP-16)and carboplatin (CBDCA) in untreated extensive small cell lung cancer (SCLC)(ahstract).Proc Am Soc Clin Oncol 1988:7:195.
21 Gatzemeier U. Hossfeld DK. Achterrath W. Lenaz L: Carboplatin (C)vincristine (V) cloposide(E)as first line treatment in small cell lung cancer (SCLC)(abstract).Proc Am Soc Clin Oncol 1988:7:201.
22 Bishop JF.Kefford R.Raghavan D.Zalcberg J.Stuart-Harris R. Ball D. Olver IN.Fried-lander M.Bull C.Yuen K:Etoposide.carbo-platin.cyclophosphamide and vincristine in previously untreated patients with small cell lung cancer.Cancer Chemother Pharmacol 1990:25:367-370.
23 Thatcher N.Lind M.Stout R.Payne C.Carroll KB. Cambell C. Moussalli H: Carboplatin. ilosfanide and etoposide with mid-course vin-cristine and thoracic radiotherapy for limited stagesmall cell carcinoma of the bronchus.BrJ Cancer 1989:60:98-101.
24 Klastersky T.Sculier JP.Lacroix H.Dabouis G.Bereau G.Lihert P.Richez M.RavezP. Vandermoten G. Thiriaux J: A randomized study comparing cisplatin or carboplatin with eloposide in patients with advanced non-small cell lung cancer.European Organization for Research and Treatment of Cancer Protocol 07861.JClin Oncol1990:8:1556-1562.
25 Wiltshire E: Ovarian trials at the Royal Marsden.Cancer Treat Rev 1985:12(suppl A):67-71
26 Alberis D.Green S.Hannigan E.O'Toole R. Mason-Liddil N.Surwit E.Stock-Novack D. Goldherg R.Maivlya V.Nahnas W: Improved ellicacy of carboplatin cyclophosphamide (CPA) ss cisplatin (CisP)CPA. Preliminary report of a phase Ill randomized trial in stages III-IV suhoptimal ovarian cancer(OVCA) (abstract).Proc Am Soc Clin Oncol 1989:8: 151.
27 Albain KS. Crowley JJ. Le Blane M. Living-ston RB:Determinants of improved outcome in small cell lung cancer:An analysis of the 2580 patient Southwest Oncology Group data hase.J Clin Oncol |990:8:1563-1574. 
28 Cavalli F.Sontag RW.Jungi F.Senn HJ. Brunner K W: VP16-213.Monotherapy forre-mission induction of small cell lung cancer:A randomized trial using three dosage schedules. Cancer Treat Rep 1978:62:473-475.
29 Slevin MI..Clark PL. Joel SP. Malik S.Os-horne RJ.Gregory WM.Lowe DG.Reznek RH. Wrigley PFM:A randomized trial t0 evaluate the eflect of schedule on the activity of etoposideinsmallcelllungcancer.JClin Oncol 1989:7:1333-1340.
30 Johnson DHl.Strupp J.Greco FA.Hande KR.Hainsworth 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 ML:Prolonged administration of single agent oral etoposide in patients with untreated small cell lung cancer (abstract). Proc Am Soc Clin Oncol 1990:9:226.
32 Woll SN.Johnson DH.Hande KR.Hains-worth JD.Greco FA:Highdoseetoposide asa single agent chemotherapy for small cell car-cinoma of the lung.Cancer Treat Rep 1983: 67:957-958.
33 Gireco FA.Johnson DH.Hande KR.Porter LL. Hainsworth JD.Wolf SN:High dose etoposide(VP-16) in small cell lung cancer. Semin Oncol 1985:12(suppl 2):42-44.
34 BucknerCD.Rudolph RH.Fefer A.Clift R A. Epstein RB.Funk DD.Neiman PE.Slighter SJ.Storb R. Thomas ED:High dose cyclo-phosphamide for malignant disease: Toxicity. tumor response and ellects of stored autolo-gous marrow.Cancer 1972:29:357-365.
35 Gale RP.Graze PR.Wells J.Ho W.Hershko C.Lowenberg B. Feig S. Cline MJ: Autolo-gous hone marrow transplantation in patients with cancer.Exp Hematol 1979:7(suppl): 351-359
36 Douer D.Champlin RE.Ho WG.Sarna GP. WellsJH.Graze PR.Cline MJ.Gale RP:High dose combined modality therapy and autolo gous bone marrow transplantation in resistant cancer.Am J Med 1981:71:973-976.
37 Spitzer G.Dickie K A. I.itam M.Verma DS. Zander A. Lanzotti V. Valdivieso M. MeCredie K B.Samuels ML:High dose com-bination chemotherapy with autologous hone marrow transplantation in adult solid tumour. Cancer 1980:45:3075-2085.
38 Pico JL.. Beaujean F.Debre M.Carde P.L.c Chevalier T.Hayat M: High dose chemo-therapy(HDC)with autologous bone marrow transplantation (ABMT) in small cell car-cinoma of the lung (SCCL.) in relapse tab-stract).Proc Am Soc Clin Oncol 1983:2:206.
39 Harada M.Yoshida T.Funada I. Ishino C. KodoH.Mori T.Matsue K.Shiobara S.Oda-ka K.Ohtake S.Teshima H.Kondo K.Yama-mura M. Nakao S.Ueda M. Nakamura S. Hattori K: Combined modality therapy and autologous bone marrow transplantation in the treatment of advanced non-Hodgkin's Iymphoma and solid tumour: The Kanazawa experience. Transplant Proc 1982:14:733-737.
16

40 Stewart P.Buchner CD.Thomas ED.Bagley C.Bensinger W.Clift RA.Appelhaum FR. Sanders J:Intensive chemoradiotherapy with autologous hone marrow transplantation of small cell carcinoma of the lung.Cancer Treat Rep 1983:67:1055-1059.
41 Stahel RA.Takvorian RW.Skarin AT.Canel-losGP:Autologous bone marrow transplanta-tion following high dose chemotherapy with eyclophosphamide.BCNUand VP-16insmall cell carcinoma of the lung:A review of current literature.Eur J Clin Oncol 1984:20: 1233-1238
42 Cunningham D.Banham SW.Hutcheon AH. Dorward A.Ahmedzai S.Tansey P.Soukop M.Stevenson RD.Stack BR.Kaye SB:High dose cyclophosphamide and VP16 as late dos-age intensification therapy for small cell car-cinoma of the lung. Cancer Chemother Phar-macol 1985:15:303-306.
43 Smith IE.Evans BD.Harland SJ.Rohinson BA.Yarnold JR.Glees JG.Ford HT:High dose cyclophosphamide with autologous bone marrow rescue after conventional chemo-therapy in the treatment of small cell lung can-cer.Cancer Chemother Pharmacol 1985:14: 120-124
44 Scullier JP. Klastenky J. Stryckmans P.and the ADATC Lung Cancer Working Party: Late intensilication in small cell lung cancer:A phase I study of high doses of cyclophospha-mideandetoposide with autologous hone mar-row transplantation.J Clin Oncol 1985.3: 184-191
45 Dickie K A.Spitzer G:Evaluation of the use of high dose cytoreduction with autologous hone marrow rescue in variousmalignancies. Trans-plantation 1986:41:4-20.
46 Ihde DC.Deisseroth AB.Lichter AS.Bunn PA. Carney DN. Cohen MH. Veach SR. Makuch R W.Johnston-Early A.Abrams RA: Late intensive combined modality therapy Tol-lowed by autologous hone marrow infusion in estensive-stage small cell lung cancer.J Clin Oncol 1986:4:1443-1454.
47 Souhami RL. Hajichristou HT.Miles DW. Earl HM.Harper PG.Ash CM.Goldstone AH.Spiro SG.Gaddes DM.Tobias JS:Inten-sive chemotherapy with autologous hone mar-row transplantation of small cell lung cancer. Cancer Chemother Pharmacol 1989:24: 321-325.
48 Marangolo M.Rosti Gi.Amadori D.L.coni M. Ardizzone A.FiorentiniG.Cruciani G.Tieng hi A. Ravaioli A. Sebastiani L.:High dose ctoposide and autologous hone marrow trauns plantationas intensification treatment in small cell lung cancer: A pilot study.Bone Marrow Transpl:nt 1989:4:405 40X
49 Humblet Y.Symann M. Bosly A.Delanois L. Francis C.Machiels J.Beauduin M.Doven C. Weynants P.Longueville J:Late intensifica-tion chemotherapy withautologousbone mar-row transplantation in selected small cell car-cinoma of the lung:Arandomizedstudy.JClin Oncol 1987:5:1864-1873.
Bishop

50 Harrap KR. Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Treat Rev 1985:12:21-33.
51 Rose WC.Schurig JE.Prechinical antitumour and toxicologie prolile of carhoplatin.Cancer Treat Rev 1985:12:1-19.
52 Orols 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.Henner WD. Elias AD). Techer BA.Weissman L.Wheeler CA.Ayash L.Schmyber SM.Deary J.Schimpper LE.Fur E.Antman KH:High-dose comhination alky-lat ng agent therapy with carboplatin and au-tologous hone marrow transplantation in solid tumors:in Bunn PA.Jr.Canetta R.Ozob RF. 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 carho-platin.cyclophosphamide and BCNU withau-tologous bone marrow support. excessive hepatic toxicity.Cancer Chemother Pharma-col1990:26:155-156.
55 Antman K. Eder JP. Elias A. Ayash L.Shea TC.Weissman L. Critchlow J. Schrybar SM. BeggC.Teicher BA:High dose thiotepa alone and in comhination regimens with bone mar-row support. Semin Oncol 1990:17(suppl 3): 33-38
56 Egorin MJ.Van Fcho DA.Tipping SJ.Olman EA.Whitacre MY.Thompson BW.Aisner J: Pharmacokineties and dosage reduction of cisdiammine (l.l-cyclobutanedicarboxylato) platinum in patients with impaired renalfunc-tion.Cancer Res 1984:44:5432-5438.
57 Egorin MJ. Van Echo DA.Olman EA. Whitacre MY.Forrest A.Aisner J:Prospec-tive validation of a pharmacologically hased dosing scheme for the cisdiamminedichlo-roplatinum (ll) analogue diamminecyclo-hurane-dicarboxylatoplatinum.Cancer Res 1985:45-6502-6506.
58 Calvert AH. Newell DR. Gumbrell LA. O'Reilly S.Barnell M.Boxall FE.Siddik ZH. Johnson IR. Gore ME. Wiltshaw E:Carbo-platindosage:Prospectiveevaluation ofa sam-pleformula based on renalfunction.J Clin On-col1989:7:1748-1756.
59 Clark SC.Kamen R:The human hematopoi-etic colony-stimulating factors.Science 1987: 236:1229-1237.
60 Gelde DW.Gasson JC:Cytokines:Myeloid growth factors:in Gallin Jl.Goldstein IM. Snyderman R (eds): Inflammation: Basie Principles and Clinical Correlates.New York. Raen.1988.pp 253-261.
6l 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.
Carboplatin/Etoposide in Small Cell L.ung
Cancer 
63 Morstyn G. Burgess AW: Hemopoietic growth factors: A review. Cancer Res 1988. 48:5624-5637.
64 Sachs L: The molecular control of blood cell development.Science 1987:238:1374-1379.
65 SieffCA:Hematopoetic growth factors.J Clin Invest 1987:79:1549-1557.
66 Antmann KS.Griflin JD.Elias A.Socinski MA.Ryan L.Cannistra SA.Octte D.Whitley M.Frei E III. Schnipper L.E:Eflect of recom-binant human granulocyte-macroophage co-lony stimulating factor on chemotherapy in-duced myelosuppression. N Engl J Med 1988:319:593-598.
67 Girandt SJ.Peters WP.Atwater SK. Kurt/-berg J. Borowitz MJ.Jones RB. Shapall EJ. Bast RC Jr.Gilbert CJ.Oette DH:Eflect of recombinant granulocyte-macrophage colony stimulating factor on hematoporetic recon-stitution after high-dose chemotherapy and autologous bone marrow transplantation.N Engl J Med 1988:318:869-876.

68 Nemunaitis J.Singer JW.BucknerCD.Hill R. Storb R.Thomas ED.ApplebaumFR:Use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous mar-row transplantation for lymphoid malignan-cies.Blood 1988:72:834-836.
69 Sheridan W.Morstyn G.Green M.Boyd A. Wolr M. Dodds A. MeGrath K. Maher D. Souza L.Alton K.Vincent M.Fox R: Phase Il study of granulocyte colony stimulating factor in autologous hone marrow transplantation (abstract).Proc Am Soc Clin Oncol 1989:8: 178.
70 Bishop JF.Morstyn G.Stuart-Harris R.Mat-thews JP.Green M.Zalcherg J.Raghavan D. Fox R.Yuen K.Zimet A.Kefford R:Dose and schedule 1 of granulocyte macrophage colony stimulating factor(GM-CSF)carhoplatin and etoposide in small cell-lung cancer (SCLC) (abstract).Proc Am Soc Clin Oncol 1991:10: 240.

71 Giabcilore JL.Jakuhowski A.Scher H.Stern-hergC. Wong G. Grous J. Yagoda A. Fain K. Moore MA.Clarkson B.et al: Elfect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med 1988:318: 1414-1422.
72 Crawford J.Ozen H.Johnson D:Giranulocyte colony stimulating factor:Prevention of che-motherapy induced febrile neutropenia in pa-tients with small cell lung cancer (abstract). Proc Am Soe Clin Oncol 1990:9:229.
Discussion
Dr. Ariyoshi: I think it is important to use growth factors to increase hematopoietic stem cells. What do you think is the difference between G-CSF and GM-CSF in chemotherapy?
Dr.Bishop:This is a diflicult question, since no comparative studies are available at this time.My impression is that GM-CSF hassome toxicity,mainlyrelated to rashand myalgia.At higher doses,we have seen pericarditis.We have reported what we call the first-dose effect of GM-CSF. This is a hy-poxemic episode associated with hypotension,which is often mild and usually not of any clinical importance.This effect. however.will go unrecognized if one is not aware of it.For instance.elderly patients with smallcell lungcancer may sim-ply collapse. Therefore, a patient needs to lie down for about 30 min after the first dose of GM-CSF.These effects, which are not particularly worrisome.are less than those seen with interferon and other similar drugs. In general. GM-CSF is well tolerated.at least at the doses we have used.and does not cause discontinuation of treatment.
G-CSF, on the other hand, has a better toxicity profile. The major toxicity seems to be some mild bone pain.which we presume is related to marrow expansion or some other mechanism.

Dr.Kumnito: The appearance of grade 4 leukocytopenia or neutropenia is no longer a contraindication for entering a study.since the patient's neutrophil count will rise rapidly af-terG-CSF orGM-CSF hasbeen administered.When do you stop GM-CSF in your current platinum/etoposide dose es-calation study?
Dr. Bishop:I do not think we can assume that growth factors will eliminate neutropenia. Clearly, phase I studies with col-ony-stimulating lactors show a biphasic curve.Almost every-one who receives myelosuppressive chemotherapy has a sig-nificant degree of neutropenia. The curve often shifts to the left.may occurearlier.and may be shorter and sharper.There is an initial rise.then a substantial drop.and then a rise again in neutrophils. It is difficul to design a study around thesc factors.InourGM-CSF study withchemotherapy doseesca-lation. we decided to stop therapy when grade4 neutropenia lasted more than 7 days.We could extend this period further. if we could accept 2-3 weeks of neutropenia.as we do in pa-tients with acute leukemia.My bias is to reduce the cytopenic periodtoabout9days.Atthistime.lam not sure that we have actuallyachieved much withthe colony-stimulating factorsin terms of high-dose chemotherapy.The combination of fac-tors.particularly interleukin 3.may offer more protection against cytopenia. 
Dr.Johnson:The durations of both neutropenia and throm-bocytopenia appear to increase with increasing courses of treatment administered with GM-CSF. In the study of CAE plus G-CSF, the duration of neutropenia decreased with subsequent courses of G-CSF. In fact. the greatest duration of neutropenia was 3daysin the first cycle versus 6 days in the placebo arm.Thereafter.the duration of neutropenia(<500 neutrophils) was I day or less. In the placebo group,neu-tropenia consistently lasted 6 days throughout all six therapy cycles. Thrombocytopenia neither increased nor decreased. This may have to do with the toxicity profile of CAE com-pared with that of platinum-containing regimens.which may have more impact on megakaryocytes.
In a small number of patients that we have treated with GM-CSF.we were not able to detect megakaryocyte marrow precursors in posttreatment marrow, suggesting a shifting of precursor cells away from platelet activity. We have not seen this in marrow of patients treated with G-CSF.
Dr. Bishop: Was there a substantial dose reduction across the courses in the CAE study?

Dr.Johnson:There were no differences in the amount of drug administered to each group. Patients in the G-CSF group who had a neutropenic episode were crossed over to open-label G-CSF. and the dose was reduced. Those in the placebo group were crossed over to open-label G-CSF,but the dose was not reduced. Nevertheless, of the 200 patients in the trial.approximately 50 were able to complete six cy-cles on time and according to study design. Nearly 40 of these patients were on the blinded G-CSF arm, and the re-maining were on the placebo arm at the end of the trial.The attrition from the placebo arm was substantial.
Dr. Bishop: Was that more substantial than what you would have expected from previous data?
Dr.Johnson:There is no doubt that we saw a greater inci-dence of fever and neutropenia in this trial than predicted. We had expected a 20% incidence of fever and neutro-penia with the doses and courses outlined. but we saw a 60%incidence.
18

Bishop

Carboplatin/Etoposide in Small Cell Lung
Cancer