Oncology I992:49(suppl 1):25 33
Ulrich Gatzemeier “ Joachim von Pawelb Reiner Laumenc D/e/iT Ä'. HossfeliL' Renate Neuhauss“ Martin Recka Luigi Lenaze
Carboplatin/Etoposide/ Vincristine Therapy in Small Cell Lung Cancer
Department of Thoracic Oncology. Grosshansdorf Hospital, Grosshansdorf: Hospital Gauting, Munich: Hospital Seltershcrg. Giessen: Department of Hematology and Oncology. University o f Hamburg. FRG Bristol-Myers Company International Group. New York, N.Y.. USA
Abstract Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC; 14% complete response. CR: and 61% CR + partial response. PR). The combination carboplatin etoposide vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 4-year survival rates are 26% in limited disease and 8% in extensive disease, with a plateau of the survival curve. This regimen is highly effective and exhibits lowtoxicity in SCLC. To evaluate the role of carboplatin in combination chemo therapy in patients with extensive SCLC. a phase III trial was performed. In this ongoing trial comparing CEV and etoposide vincristine in SCLC patients with extensive disease, CR and overall response rates are higher in the CEV arm (CR 32 vs. 17%. CR + PR 80 vs. 60%). with statistically significant difference. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use ofthe new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.
Cisplatin etoposide is one of the most active regimens in the treatment of small cell lung cancer (SCLC) [1, 2]. Retrospective analyses of phase II and III trials and results of randomized studies showed that this combination has
comparable to higher activity than the more frequently used regimen CAV (cyclophosphamide/doxorubicin/ vincristine) [3-20]. Major problems of treatment with cisplatin/etoposide are nausea, vomiting, and nephro-
Ulrich Gatzemeier. M l) Department o f Thoracic Oncology G rosshansdorf Hospital ( enter of Pneumolog) and Thoracic Surgery D-VV 2070Grosshansdorf11 RG)
< I992S. Karger AG. Basel 0030 2414 92 0497 0025 $ 2.75 0
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KeyWords Chemotherapy Small cell lung cancer Carboplatin Etoposide Vincristine
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hypotheses in patients with ED. These results, however, were obtained by retrospective comparison, and should be verified in a randomized study to define the therapeutic value of carboplatin in combination with EV. Therefore, a phase III trial was conducted to compare EV with and without carboplatin with regard to antineoplastie activity and safety at doses inducing comparable dose-limiting hematologic toxicity in previously untreated patients with extensive SCLC. We review' results of both the phase II and phase III trials here.
Patients and Methods The principal criteria lor entry in both studies were as follows: histologic diagnosis of SCLC. good World Health Organization (WHO) performance status (ai least grade 2). no evidence of CNS métastasés, and no previous treatment. Eligibility requirements in cluded: age 18-75 years, life expectancy o f at least 3 months, and ade quate bone marrow, renal, and hepatic function. For the phase II trial, patients with LD and ED were included. In the phase III trial, only patients with ED were enrolled. Staging and Follow-Up Procedures The pretreatment evaluation consisted o f complete history, physical examination, and laboratory workup with complete hemo gram (differential and platelet count), serum creatinine, serum glu tamic-oxaloacetic transaminase, serum glutamic-pyruvate trans aminase. serum alkaline phosphatase, serum bilirubin, serum elec trolytes. and creatinine clearance. The staging procedures included bronchoscopy, roentgenography, and computed tomography of the chest, brain, and abdomen, as well as ultrasound abdominal scans and radionuclide bone scans. Bone lesions were measured by roent genography. LD was defined as tum or confined to one hemithorax but included mediastinal involvement and ipsilateral supraclavicular lymph nodes. ED denoted any involvement beyond these confines including pleural effusions. Stage EDI was defined as locally ad vanced disease with cytologically positive pleural effusion, chest wall invasion, or bilateral supraclavicular lymph node involvement, but no distant métastasés. Definition o f stage ED2 was locally advanced disease with distant métastasés. The size of neoplastic lesions was de termined before each cycle and 4 weeks after the last cycle. Complete hemogram, serum creatinine, creatinine clearance, electrolytes, and liver function were obtained before each cycle and 4 weeks after the last cycle. During chemotherapy, the complete blood cell count was monitored weekly. After completion o f treatment, follow-up exami nations were done every 3 months. Treatment Response and Toxic ity Patients were considered evaluable for response and toxicity if they had received at least one treatment cycle. Tumor response and response duration were classified according to W HOcriteria. Toxic ity was evaluated by worst event for each organ system using the WHO scale. Patients who had clinical CR underwent bronchoscopy and biopsy evaluation. Median response duration and median sur vival time were calculated by the Kaplan-Meier method. Survival was calculated from the 1st day o f treatment.
Gatzemeier von Pawel; Laumen Hossfeld Neuhauss Reck Lena/
CEV in SCLC
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toxicity, which are mainly induced by cisplatin [3-6]. Furthermore, treatment duration is limited because of neurotoxicity, primarily dependent on the cumulative dose of cisplatin [4]. Carboplatin is a second-generation platinum analogue. In randomized studies it induced sta tistically significantly less nephrotoxicity, ototoxicity, and gastroenteric toxicity than did cisplatin; bone marrow suppression was the dose-limiting toxicity [21]. Carboplatin is one of the most active agents in previously untreated SCLC [2]. Summarized results of'4 disease-oriented phase II studies with a total of 76 patients showed that it induced a complete response (CR) rate of 11% and a 59% overall response [22-25]. In three studies in which all patients had previously received chemotherapy, the overall response rate was 17% and the CR rate 4% [22. 25. 26], The 59% response rate in untreated patients is similar to the re sponse rate reported for etoposide and teniposide. which were the most active agents against SCLC. The first data on the antineoplastie activity and toxicity of the carboplatin etoposide combination in SCLC were published in 1985 by the Royal Marsden Hospital [27], In this study, a 30% CR and 87% overall response rate was achieved in patients with limited disease (LD). whereas there were no CRs but a 92% overall response in patients with extensive disease (ED). In our pilot study, CEV (carboplatin etoposide vincristine) administered to pa tients with ED produced a CR rate of 37% and a partial response (PR) rate of 53%. with an overall response rate of 90%. Myelosuppression was the dose-limiting toxicity [28.29], Since these results suggested that the antineoplastic activity of CEV is comparable with that of cisplatin etoposide in SCLC. a disease-oriented, phase II study of the 3-drug combination was conducted in previously un treated patients. In addition. EV (etoposide vincristine) has been eval uated at comparable doses in 2 disease-oriented phase II studies in extensive-stage SCLC [30. 31]. In both studies, the dosage of etoposide was 600 mg n r per course. Vincris tine was administered in a dose of 2 mg i.v. on day 1 or on days 1and 8 per course [22.31]. In 66 patients, the CR rate was 20% and 71% overall remissions were achieved. Median remission duration and survival time w'ere 8 months. These results indicate that EV’s activity is com parable to the more frequently used combinations CAV [10. II. 15. 18. 32 36] and ACE (doxorubicin cyclophos phamide etoposide) [12]. Adding carboplatin to EV and reducing the dose of etoposide seems to improve the antineoplastie activity without increasing dose-limiting hematologic toxicity. The completed phase II study with CEV confirmed these
Phase II Trial
Patient Characteristics A total of 127 consecutive patients entered the study from April 1987 to August 1988. One hundred and tw'enty-one(9l male) patients were evaluable for therapeutic response and survival (table 2). Six patients had to be excluded: I w'as lost to follow-up. 4 had changes in histology to non-SCLC types (detected during repeat bronchoscopy orsurgery after inadequate response to chemotherapy), and I refused further therapy. One hundred and twenty-one patients received at least I cycle o f chemotherapy and were assessed for response and toxicity. The median performance status was 90 (range. 60 100). Sixty-eight patients presented with LD and 59 with ED. Only 13 of them had locally advanced disease (ED I ): 46 had distant métastasés (ED2). One hundred and twenty-one patients received a total of 442 cyclesofchemotherapy. The median number of cycles per patient was 4(range. 1-6). Vincristine was withdrawn from treatment at a median total dose of 10 mg (range. 6-24). Seven patients received only one cycle of chemotherapy, primarily due to rapid tumor progression or toxicity. Sixty-six patients had chest irradiation and 42 patients had prophylactic cranial irradiation.
Results Response. CEV induced a 43% CR rate and a 39% PR rate in 121 patients. The overall response rate was 82.7%. and the objective response rate was 84.1% in LD and 81.1% in ED (table 3). CRs were reached in 52.4% of pa tients with LD and 32.8% of patients with ED. Survival. Median follow-up now exceeds 40 months. The median remission duration is 8.5 months 6 months in ED and 11.5 months in LD patients. Median survival for all patients is 10.5 months, 13 months for LD and 9.0 months for ED (table 4; fig. 1). The median survival time in stage EDI and ED2 was not statistically significantly dif ferent (9.5 vs. 10.5 months). Patients with CR have a
Drug
Dosage scheme (q4wk). mg n r
Carboplatin day 1 i.v. infusion Etoposide days 1 3 i.v. infusion Vincristine days 1.8. and 15 i.v. bolus
300 140 1.4
Table 2. Phase II study in SCLC: patient characteristics
Patients, n Evaluable, n
127 121
oCX
M F Stage LD ED Age. years Median Range Performance status Median Range
96 31 68 59 61 23 76 90 60 100
Table 3. Phase II study of SCLC: responses
All LD ED
CR. %
Overall response. %
43 52.4 32.8
82.7 84.1 81.1
Table 4. Phase II study in SCLC: survival
All LD ED
Median survival time, months
One-year survival, %
Four-year survival. %
10.5 13.0 9.0
41.7 51.7 31.3
17.8 26.4 8.6
median survival time of 18 months and patients with PR of 9.5 months. The l- and 4-year survival rates are 51.7 and 26.4% in LDand 31.3 and 8.6% in ED. respectively (fig. 1, 2). The plateau of both curves in patients with LD and ED between 2 and 3 years' survival suggests there may be a significant increase in long-term survivors with the CEV combination.
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Treatment Schedule and Dosage Inthisnonrandom ized phase II study,chemotherapy consisted of carboplatin 300 mg n r i.v. on day I, etoposide 140 mg/m i.v. days 1 through 3, and vincristine 1.4 mg n r (maximum 2 mg) i.v. on days 1. 8, and 15 (table 1). Carboplatin and etoposide were given as intra venous infusion over 30 and 60 min and vincristine as intravenous bolus injection. Carboplatin was given without prehydration or posthydration. Low-dose antiemetics were prophylactically ad ministered. Vincristine had to be withdrawn if peripheral neurotoxic ity (WHO grade I ) occurred. We planned to repeat the cycles every 4 weeks if the leukocyte and platelet values were 4 x 10' land 100 x 10'/1, respectively. If these levels were not reached, we planned to de lay treatment. Four to six cycles of chemotherapy were planned for all patients with a CR or PR after the second cycle. Patients with pro gressive disease after the first cycle or any time thereafter and patients without remission after the second cycle of chemotherapy w'erc to be withdrawn from the study. All patients with LD who achieved a CR and those with ED without distant métastasés and CR after 6 cycles of chemotherapy received chest and prophylactic cranial irradiation. The total tumor dose was 45 and 30 Gy. given together.
Table 1. Phase II study in SCLC: treatment regimen
100
P ro gre ss
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80
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T im e (m o ) P < 0 .0 0
Table 5. Phase 11 study in SCLC: median survival time according to prognostic factors
Patients, n
Stage FI) 58 LI) 63 Karnofsky performance status < 80% 45 >80% 76 Sex M 91 F 30 Age. years 60 69
Survival time, months
9.5 14.0
Table 6. Phase II study in SCLC: median survival time according to second-line therapy
/évalue (log rank)
0.02
9.5 14.0
0.008
10.5 10.5
0.196
10.5 10.5
0.206
The most important prognostic factors (table 5) for sur vival are stage of disease and performance status. Patients with LI) and Karnofsky performance status above 80% survived significantly longer than patients with ED and Karnofsky performance status less than 80%. Sex and age did not influence the median survival time. There is no dif ference in survival between men and women and between patients younger and older than 60 years. Patients who re ceived a second-line treatment after treatment failure (table 6) also had a poor prognosis in comparison with pa tients who did not need alternative chemotherapy. These data confirmed that the best response after the first course of chemotherapy is one of the most important predictive parameters for long-term survival. Of the group of 66 pa-
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Fig. 2. Phase 11 study o f SCLC: survival according to response in patients with limited disease.
W ithout second-line therapy With second-line therapy
Patients, n
Survival lime, months
61
I4.0
60
9.5
p value (log rank)
0.02
tients who received adjuvant radiotherapy, 24 had only PRs after completing chemotherapy. In 36% of these pa tients the PR converted to a CR because of radiotherapy. The prognosis of these patients is similar to that of patients who achieved CR during chemotherapy (fig. 3). Two thirds of the patients who still had a PR despite ad juvant therapy had a very poor prognosis (fig. 4), and all died within I year. Thus, achieving a CR is the only way to achieve long-term survival in SCLC. The analysis of relapse after CR (table 7) shows that only 23% of patients had local tumor recurrence. More than three fourths of patients had distant métastasés with and without relapse of the primary site. Despite prophy lactic cranial irradiation of 30 Gy, 48% of patients with CR experienced CNS métastasés if relapse occurred. The liver and bone were the main sites of relapse. Toxicity. Myelosuppression was the major side effect (table 8). Leukopenia of WHO grades 3 and 4 was ob served in 19 and 6% of the patients, respectively. Throm bocytopenia of WHO grades 3 and 4 occurred in 12 and 3% of the patients, respectively. No anemia of these de-
Gatzemeier von Pawel Laumen Hossfeld Neuhauss/Reek, Lenaz
CFV in SCLC
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Fïg.1- Phase II study of SCLC: survival according to stage.
(lo g ra n k )
Fig. 3. Phase II study of SCL.C: survival according to radiotherapy (RT) given before or after CR was achieved.
Table 7. Phase II study in SCLC: sites o f relapse after CR
Location
Patients, %
Primary site Distant sites Primary and distant sites CNS Liver Bone
22.8 31.4 45.7 48.5 17.1 14.3
grees was observed. Median leukocyte nadir was 3.1 x I09/l (days 13-15) with recovery occurring days 21 -23 and median thrombocyte nadir was 128 x IO'Vl (days 12-14) with recovery occurring days 19-21. The main nonhematologic toxicities were nausea, vomiting, alopecia, and peripheral neuropathy (table 9). WHO grades 3 and 4 vomiting was observed in 22 and 2% of patients, respec tively. WHO grade 3 alopecia occurred in 81 % of patients. Peripheral neuropathy of WHO grades 2 and 3 was in duced in 28 and 5% of patients, respectively. This side ef fect was mostly reversible after withdrawing vincristine. No nephrotoxicity or ototoxicity was observed.
Fig. 4. Phase II study o f SCLC: survival according to CR or PR remission status after radiotherapy (RT).
Table 8. Phase II study in SCLC: hematologic toxicity
Patients, % WHO grade 0 Hemoglobin Leukopenia Thrombocytopenia
35.8 14.8 44.3
1
2
3
4
47.7 24.1 14.2
16.5 35.2 19.8
0 19.4 12.3
0 6.5 3.4
Table 9. Phase II study in SCLC: nonhematologic toxicity
Patients, % WHO grade 0 Nausea/vomiting Alopecia Obstipation Peripheral neuropathy Fever Nephrotoxicity Ototoxicity
4.2 5.2 92.7 13.6 98.1 0 0
1
2
3
33.1 2.6 3.7 53.4 0.9
38.1 11.2 0.9 28.0 0.9
22.0 81.0 2.8 5.1
4 2.5 -
—
-
-
-
-
-
-
-
-
-
Phase III Trial Patient Characteristics Since November 1988, 188 evaluable patients have been treated according to the ongoing protocol (table 10). Ninety-three patients received CEV and 95 patients EV. Distribution of sex, age. perfor mance status, and stage o f disease was well balanced between the two arms. Only patients with stage EDI and CR to chemotherapy had chest radiotherapy (50 Gy to the tumor and mediastinum).
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Treatment Schedule and Dosage Patients with extensive-stage SCLC were allocated by central ran domization to receive either CEV or EV. Dosage and schedule are shown in figure 5. Chemotherapy was repeated every 4 weeks up to 6 cycles. Vincristine was withdrawn if WHO grade 1 peripheral neu rotoxicity occurred.
Carboplalin 3 0 0 mg rn7 day 1 Etoposido 140 m g m? days 1 3 Vincristino 1 4 m g m? days 1. 8, 15
Etoposido 3 0 0 mg m7 days 1 3 Vincristine 1.4 mg m 7 days 1. 8
I O N
Up to 6 cycles (q4wk)
Fig. 5. Phase III study of SC'LC: CEV versus EV treatment re
gimen. Fig. 6. Phase III study of SCLC: overall survival according to CEV or EV treatment regimen.
Table 12. Phase III study in SCLC: hematologic toxicides (WHO grade of myelosuppression)
Evaluable (as of April 1991) Sex M F Age. years Median Range Performance status Median Range Stage Extensive I Extensive II
CEV
EV
93
95
70 23
65 30
57 37-74
62 18-75
80 60 100
80 60 100
39 56
33 65
Table 11. Phase III studv in SCLC: responses
Regimen
CR, %
CR + PR. %
CEV (n = 93) EV (n = 95)
32.3* 17.9*
80.7* 60.0*
* CEV versus EV significantly different: p = 0.002.
30
p value
Patients. %
Patients, n
Leukocytes 2 3 4 Platelets 2 3 4 Hemoglobin 2 3 4
CEV
EV
32.3 18.3 10.8
21.1 15.8 5.3
0.01
15.1 15.1 7.5
4.2 2.1 2.1
0.001
21.5 5.4 2.2
11.6 5.3 0
0.02
Table 13. Phase III study in SCLC: nonhematologic toxicity (W H O grade >2)
Patients, %
Nausea vomiting Alopecia Peripheral neuropathy Obstipation Fever Nephrotoxicity Ototoxicity
Gatzemeier von Pawel Laumen Hossfcld Neuhauss Reck Lena/
CEV in SCLC
CEV
EV
12.0 71.0 2.2 3.3 1.1 0 0
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Table 10. Phase III study in SCLC: patient characteristics
Discussion One part of current investigative strategies for SCLC is the design of more active, less toxic regimens using exist ing antincoplastic agents. Earlier studies had shown that the combination ofcisplatin and etoposide is highly active as first-line treatment and salvage therapy in SCLC [3-8. 37. 38]. The cisplatin analogue carboplatin was used with etoposide in LD patients in two trials, and in ED patients in four trials [39-42]. The summarized data of these studies suggest that carboplatin/etoposide may be less active than cisplatin etoposide in LD and ED. especially with regard to CR rates and median survival times. Preliminary results in ED with high-dose carboplatin etoposide indicate an antineoplastic activity similar to that attained with the same regimen at lower dosages, but severe myelosuppres sion [42]. In further phase II studies, ifosfamide. ifosfamide/ vincristine, and cyclophosphamide vincristine were add ed to carboplatin/etoposide [43-46]. In comparison to carboplatin etoposide, an increase of CR rates with com parable to higher overall response rates and median sur vival times was achieved in LD and ED patients [39-47]. The combinations carboplatin/etoposide/ifosfamide with or without vincristine and carboplatin/etoposide/cyclophosphamide/vincristine induced WHO grades 3 and
4 leukopenia and thrombocytopenia in 74-100% and 57-85% of patients, respectively [43, 45. 46], Lifethreatening leukopenia and thrombocytopenia occurred in 43 and 3 1% of the patients, respectively. WHO grades 3 and 4 infections were seen with a frequency of up to 36% [43.46], To avoid life-threatening hematologic toxicities, we added only vincristine to carboplatin etoposide because of its low myelosuppressive potential and its relatively high activity against SCLC. In the complete phase II study. CEV induced higher CR and overall response rates in LD and ED patients than did carboplatin/etoposide. The CR and overall response rates and median survival times were similar to those of the other carboplatincontaining 3- and 4-drug regimens. Compared with these combinations, the hematologic toxicity of CEV was mini mal. WHO grades 3 and 4 leukopenia occurred in 19 and 7% of patients, respectively, and thrombocytopenia of these degrees was observed in 12 and 9% of patients. Comparison of the CEV treatment results with those of the more frequently used combinations like CA V, or CA V alternating with cisplatin etoposide. and cisplatin/etoposideshows the following: In LDand ED patients, CEV in duced similar CR and overall response rates and median survival times. In ED patients. CEV achieved higher CRs and overall responses than did CAV. Its remission-induc ing activity, with regard to CRs and overall responses, is comparable to that of cisplatin/etoposide and to alternat ing treatment with CAV and cisplatin/etoposide. Dura tion of median survival times appears similar to the other regimens mentioned. The very high 1- and 4-year survival rates in LD and ED patients in the phase II trial are re markable. The activity of CEV seems particularly remark able in ED because 78% of patients were in stage 2. which is considered an unfavorable prognostic factor for re sponse and survival [48]. These encouraging survival data (especially in ED pa tients) were confirmed in the ongoing phase 111 trial, which compared CEV to EV alone. According to remission and survival data, there is now a clear indication that CEV is superiorto the EV regimen. CEV induced significantly less life-threatening leukopenia than did CAV or CAV alter nating with cisplatin etoposide. After CAV at higher doses and after CAV alternating with cisplatin/etoposide. grade 4 leukopenia was observed in 40-70% of patients [9-13. 20. 34. 49] and in 7% of patients after CEV. The incidence of peripheral neuropathies is relatively high after CEV but comparable to CAV. Nephrotoxicity after cisplatin-containing regimens was not observed in our study [12.13.33.34],
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Results Response. The remission rate of the randomized trial comparing CEV with EV is shown in table 11. The overall response rate with CEV is 80.7% compared with 60% with EV. This dillerence is statistically significant (p = 0.002). The response data of the CE V-treated group are exactly in accordance with the results of the phase 11 trial. Survival. Because the trial is ongoing, median survival data are preliminary. Figure 6 shows the survival curves for the 188 evaluable patients. The median survival time for CEV is 9.5 months compared with 8.5 months for EV. Although this is not a statistically significant difference, there is a clear trend for better survival with the 3-drug combination. Toxicity. In both arms, myelosuppression was the ma jor side effect (table 12). There were statistically significant differences in leukopenia and thrombocytopenia between CEV and EV. with more pronounced toxicity in thecarboplatin-containing regimen. Nonheniatologic toxicity was not a major problem. There were no differences in nausea and vomiting, alopecia, and peripheral neuropathy be tween the CEV and EV regimens (table 13).
Conclusion The activity of CEV in SCLC is at least comparable to that of the more frequently used chemotherapies with re gard to CR and overall response rates. The high propor tion of long-term survivors in the phase II trial deserves emphasis. Although these data await confirmation in the ongoing phase 111 trial, they currently show that the ad
dition of carboplatin to EV in ED patients led to a higher response rate and a slight increase in survival. On the basis of the very encouraging long-term survival rate in the phase II trial, we are going to initiate a doseescalating trial with prevention of myelosuppression (us ing growth factors) to intensify the initial treatment of LD patients with SCLC.
1 Klastersky J: Therapy of small cell lung cancer: Anything new'.’ Fur .1Cancer Clin Oncol 1988; 24: i 07- f 12. 2 AisncrJ. AbramsJ:Cisplatinforsmallcell lung cancer. Semin Oncol !989:!6(suppl 6):2 9. 3 Wolf M. Havemann K. Hollc R. et al: Cisplatin etoposide versus ifosfamide etoposide combination chemotherapy in small-cell lung cancer: A multicenter German randomized trial. J Clin Oncol 1987:5:1880-1889. 4 Boni C. Cocconi G. Bisagni G. et al: Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer. A phase II trial. Cancer 1989:63:638-642. 5 Wilke H. Achterralh W. Schmoll H-J, et al: T.toposideand split-dose cisplatin in small-cell lung cancer. Am J Clin Oncol 1988:11(5): 572-578. 6 Fvans WK. Shepherd FA. Feld R.elal: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985:3: 1471-1477. 7 Ihde DC. Johnson BF„ Mulshine JL. et al: Randomized trial of high dose versus standard dose etoposide and cisplatin (VP 16 Plat) in ex tensive stage small cell lung cancer (SCLC) (abstract 7 ¡4). Proc Am SocClin Oncol 1987:6: 181. 8 Roth BJ. Johnson DH. Greco FA. ct al: A phase 111 tria Iof etoposide ( E) and cisplatin (P) versus cyclophosphamide (C). doxorubicin (Aland vincristine) V) versus alternation of the two therapies for patients (Pts) with extensive small cell lung cancer (SCLC) (abstract 875). Proc Am SocClin Oncol 1989:8:225. 9 Evans WK. Feld R. Murray N.et al: Superior ity of alternating non-cross-resistant chemo therapy in extensive small cell lungcancer. Ann Intern Med 1987: !07:451-458. 10 Lowcnbraun S. Birch R. Buchanan R. et al. and the Southeastern Cancer Study Group: Combination chemotherapy in small cell lung carcinoma. Cancer 1984:54:2344 2350.
11 Johnson D ll. Einhorn LIE Birch R .etal.and the Southeastern Cancer Study Group: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxo rubicin and vincristine for extensive-stage small-cell lungcancer: A phase 111 trial of the Southeastern Cancer Study Group. J Clin On col 1987;5:1731-1738. 12 Bunn PA. Greco FA. Einhorn L: Cyclophos phamide. doxorubicin and etoposide as firstline therapy in the treatment of small-cell lung cancer. Semin Oncol 1986:13:45- 53. 13 I long W K. Nicaise C. Lawson R. et al: Etopo side combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol. 1989:7: 450— 456. 14 Jackson DV. Case LD. Small-cell lungcancer: A 10-ycar perspective. Semin Oncol. 1986:13 (suppl 3):63 74. 15 Livingston RB. Schulman S. Mira JG. et al: Combined alkvlatorsand multiple-site irradia tion for extensive small cell lung cancer: A Southwest Oncology Group Study. Cancer Treat Rep 1986:70:1395-1401. 16 Messeih A A. Schweitzer J M. Lipton A. et al: Addition of etoposide to cyclophosphamide, doxorubicin and vincristine for remission in duction and survival in patients with small cell lungcancer. Cancer Treat Rep 1987:71:61 66. 17 Feld R. Evans WK. De Boer G. et al: Com bined modality induction therapy without maintenance chemotherapy for small cell car cinoma of the lung. J Clin Oncol 1984:2: 294-304. IS Livingston R B. MooreTN. Heilbrunn L.elal: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Intern Med 1978:88:194-199. 19 Dombernowsky P. Hansen H FI. Sorensen PG. ct al: Vincristine (NSC-67574) in the treatment of small cell anaplastic carcinoma of the lung. Cancer Treat Rep 1976:60:239 242.
20 Johnson DH. Einhorn LH. Birch R. et al. and The Southeastern Cancer Study Group: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxo rubicin. and vincristine for extensive-stage small-cell lung cancer: A phase II trial of the Southeastern Cancer Study Group. J Clin On col 1987:5:1731 1738. 2 1 Rozeneweig M. Martin A. Bcltangady M. el al: Randomized trials of carboplatin versus cisplalir in advanced ovarian cancer: in Bunn PA Jr. Canetta R. Ozols R F. ct al (eds): Carbopla tin (JM-8): Current Perspectives and Future Directions. Philadelphia. Saunders. 1990. pp 175-186. 22 Smith IE. Harland SJ. Robinson BA. et al: Carboplatin: A very active new cisplatin an alog in the treatment of small cell lung cancer. Cancer Treat Rep 1985:69:43-46. 23 Jacobs R 11. Bitran JD , Dcutsch M.etal: Phase II study of carboplatin in previously untreated patients with metastatic small cell lung car cinoma. CanccrTreat Rep 1987:71:311 312. 24 Pallarés C, Lopez Lopez JJ. Paredes A. et al: First line carboplatin (CBDCA) 24 hours in fusion on patients (PTS) with disseminated oat cell carcinoma of the lung (abstract 26). Proc F.CCO 1987:4:7. 25 Tainura T. Saij GN. Shinkai T. el al: Phase II study of carboplatin in small cell lung cancer. Jpn JClin Oncol 1988:18:27-32. 26 Ogawa M. Inuyana Y. Kato T. ct al: Phase II study of carboplatin (abstract). Proc Am Soc Clin Oncol 1987:6:20. 27 Smith IE. Evans BD: Carboplatin (JM8) as a single agent and in combination in the treat ment of small cell lung cancer. Cancer Treat Rev. I985:l2(suppl a):73-75. 28 Neuhauss R. Achterralh W. Gatzemeier U. el al: C’arboplatinum vincristine and etoposide as first line therapy in small-cell lung cancer (SCLC) (abstract 5 34-M 008). .1 Cancer Res Clin Oncol 1988:114(suppl):S155. 29 GatzemeierU,Achterralh W. HcckmayrM.ct al: Pilot study with carboplatin vincristine (VCR) etoposide as first line therapy in exten sive small cell lung cancer (abstract 67). Proc ECCO 1987:4:17.
32
Gat/emeier von Pavvel I.aumen Hossfeld Neuhauss Reck Lcnaz
CF.V in SCLC
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References
30 Morgan DAL. Gilson D. Fletcher J: Vincris tine and eloposidc: An effective chemotherapy regimen with reduced toxicity in extensive small-cell lung cancer. EurJ Cancer Clin Oncol 19X7:23:619-621. 31 Von Pawel J. Wilke H. Vallée D: Phase-IIStudie mit Etoposide Vincristine beim klein zelligen Bronchialkarzinom (extensive dis ease). Pneumologie 1990:44(suppl):582— 583. 32 Feld R, Evans WK. Coy P. et al: Canadian multicenter randomized trial comparing se quential and alternating administration of two non-cross-resistant chemotherapy combina tions in patients with limited small-cell car cinoma of the lung. J Clin Oncol 19X7:5: 1401-1409. 33 Niederle N. Krischkc W. Schulz U. et al: Un tersuchungen zur kurzzeitigen Induktions und zyklischen Erhaltungstherapie beim in operablen kleinzelligen Bronchialkarzinom. Klin Wochenschr 1982:60:829-83X. 34 Figuercdo AT. Hryniuk WM. Strautmanis I. et al: Co-trimoxazolc prophylaxis during high dose chemotherapy of small-cell lung cancer. J Clin Oncol 1985:3:54-64. 35 Holoye PY. Samuels M L. Lanzotti VJ. et al: Combination chemotherapy and radiation therapy for small cell carcinoma. JAMA 1977; 237:1221-1224. 36 Contis RL: Clinical trials of cyclophospha mide. etoposide, and vincristine in the treat ment of small-cell lung cancer. Semin Oncol 1986; 13(suppl 3):40 44.
37 Evans W K. Osoba D. Feld R. el al: Etoposide (VP-16) and cisplatin: An effective treatment for relapse in small-cell lung cancer. J Clin On col 1985:3:65 71. 38 Miller AB. Hoogslraten B. Staquct M. et al: Reporting results of cancer treatment. Cancer 19X1:47:207-214. 39 Smith IE. Evans BD. Gore M E. ct al: Carboplatin (Paraplatin: .IMS) and etoposide (VP16) as first-line combination therapy for smallcell lung cancer. J Clin Oncol 1987:5:185—189. 40 Bishop JF , Raghavan D. Stuart-Harris R. et al: Carboplatin (CBDCA. JM-X) and VP-16213 in previously untreated patients with small-cell lung cancer. J Clin Oncol 1987:5: 1574 1578. 41 Evans WK. Eiscnhauer E, Hughes P. el al: VP-16 and carboplatin in previously untreated patients with extensive smallcell lung cancer: A study of the National Cancer Institute of Canada clinical trials group. Br J Cancer 1988:58:464-468. 42 LuikartSD. Mitchell EP. Van Echo D A.ctal. for the Cancer and Leukemia Group B (CALGB): Phase I II trial of etoposide (VP16) and carboplatin (CBDCA) in untreated ex tensive small cell lung cancer (SCLC) (ab stract). Proc Am Soc Clin Oncol 1988:7:195. 43 Smith IE. Pcrren T J. Yarnold J R: Carboplatin (Cp), VPI6 (V) and ifosfamide (I) intensive chemotherapy (CT) for small cell lung car cinoma (SCLC). A phase II study (abstract 6.1.18). Lung Cancer 1988:4(suppl): 104.
44 HorncdoJ. Lianes P. Cruchaga S. ct al: Ifoslamidc. carboplatin and VP 16 in untreated ex tensive stage (F.D) small cell lung cancer (SCLC) (abstract 362 P). ESMO. Abstracts of the 13th Congress. Lugano. October 30 November I, 1988. 45 Bishop J F: Carboplatin in lung cancer. Lung Cancer 1988:5:8 14. 46 Thatcher N. Lind M. Stout R. ct al: Carbopla tin. ifosfamidc and etoposide with mid-course vincristine and thoracic radiotherapy for 'lim ited' stage small cell carcinoma of the bron chus. Br J Cancer 1989:60:98 101. 47 Le Chevalier T, Subirana R. Ruffie P. et al: Carboplatin + ifosfamidc in untreated meta static small cell carcinoma (SCLC) (abstract 922). Proc Am Soc Clin Oncol 1989:8:237. 48 Havemann K. Wolf M. Nolle R. et al: Alter nating versus sequential chemotherapy in small cell lung cancer. Cancer 1987:59: 1072-10X2. 49 Perez C A. F.inhorn L. Oldham R K. et al. for the Southeastern Cancer Study Group. Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagcnt chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 1984:2:1200 1208.
Discussion
Dr. Gatzemeier: Only a very small group of patients with extensive disease survived, but they all had good perfor mance status and only one metastatic site. Dr. Ultra: You achieved good results with the CEV reg imen. Why did you add vincristine to the carboplatin/ etoposide regimen?
Dr. Gatzemeier: Of all the drugs available for small cell lung cancer, the vinca alkaloids are very active. We added vincristine because of its low myelosuppressive potential. Dr. Saijo: What is the difference between ED I and ED II? Dr. Gatzemeier: There is no difference in survival between these two groups. Some trials, however, divide this disease stage into two groups. ED I patients have locally ad vanced, extensive disease with bulky disease in mediastinal lymph nodes, chest wall invasion, and no further distant métastasés. In contrast, all ED II patients have distant métastasés.
33
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Dr. Yoneda: In your study, what type of patients survived in the long term?
Ulrich Gatzemeier “ Joachim von Pawelb Reiner Laumenc D/e/iT Ä'. HossfeliL' Renate Neuhauss“ Martin Recka Luigi Lenaze
Carboplatin/Etoposide/ Vincristine Therapy in Small Cell Lung Cancer
Department of Thoracic Oncology. Grosshansdorf Hospital, Grosshansdorf: Hospital Gauting, Munich: Hospital Seltershcrg. Giessen: Department of Hematology and Oncology. University o f Hamburg. FRG Bristol-Myers Company International Group. New York, N.Y.. USA
Abstract Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC; 14% complete response. CR: and 61% CR + partial response. PR). The combination carboplatin etoposide vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 4-year survival rates are 26% in limited disease and 8% in extensive disease, with a plateau of the survival curve. This regimen is highly effective and exhibits lowtoxicity in SCLC. To evaluate the role of carboplatin in combination chemo therapy in patients with extensive SCLC. a phase III trial was performed. In this ongoing trial comparing CEV and etoposide vincristine in SCLC patients with extensive disease, CR and overall response rates are higher in the CEV arm (CR 32 vs. 17%. CR + PR 80 vs. 60%). with statistically significant difference. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use ofthe new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.
Cisplatin etoposide is one of the most active regimens in the treatment of small cell lung cancer (SCLC) [1, 2]. Retrospective analyses of phase II and III trials and results of randomized studies showed that this combination has
comparable to higher activity than the more frequently used regimen CAV (cyclophosphamide/doxorubicin/ vincristine) [3-20]. Major problems of treatment with cisplatin/etoposide are nausea, vomiting, and nephro-
Ulrich Gatzemeier. M l) Department o f Thoracic Oncology G rosshansdorf Hospital ( enter of Pneumolog) and Thoracic Surgery D-VV 2070Grosshansdorf11 RG)
< I992S. Karger AG. Basel 0030 2414 92 0497 0025 $ 2.75 0
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KeyWords Chemotherapy Small cell lung cancer Carboplatin Etoposide Vincristine
26
hypotheses in patients with ED. These results, however, were obtained by retrospective comparison, and should be verified in a randomized study to define the therapeutic value of carboplatin in combination with EV. Therefore, a phase III trial was conducted to compare EV with and without carboplatin with regard to antineoplastie activity and safety at doses inducing comparable dose-limiting hematologic toxicity in previously untreated patients with extensive SCLC. We review' results of both the phase II and phase III trials here.
Patients and Methods The principal criteria lor entry in both studies were as follows: histologic diagnosis of SCLC. good World Health Organization (WHO) performance status (ai least grade 2). no evidence of CNS métastasés, and no previous treatment. Eligibility requirements in cluded: age 18-75 years, life expectancy o f at least 3 months, and ade quate bone marrow, renal, and hepatic function. For the phase II trial, patients with LD and ED were included. In the phase III trial, only patients with ED were enrolled. Staging and Follow-Up Procedures The pretreatment evaluation consisted o f complete history, physical examination, and laboratory workup with complete hemo gram (differential and platelet count), serum creatinine, serum glu tamic-oxaloacetic transaminase, serum glutamic-pyruvate trans aminase. serum alkaline phosphatase, serum bilirubin, serum elec trolytes. and creatinine clearance. The staging procedures included bronchoscopy, roentgenography, and computed tomography of the chest, brain, and abdomen, as well as ultrasound abdominal scans and radionuclide bone scans. Bone lesions were measured by roent genography. LD was defined as tum or confined to one hemithorax but included mediastinal involvement and ipsilateral supraclavicular lymph nodes. ED denoted any involvement beyond these confines including pleural effusions. Stage EDI was defined as locally ad vanced disease with cytologically positive pleural effusion, chest wall invasion, or bilateral supraclavicular lymph node involvement, but no distant métastasés. Definition o f stage ED2 was locally advanced disease with distant métastasés. The size of neoplastic lesions was de termined before each cycle and 4 weeks after the last cycle. Complete hemogram, serum creatinine, creatinine clearance, electrolytes, and liver function were obtained before each cycle and 4 weeks after the last cycle. During chemotherapy, the complete blood cell count was monitored weekly. After completion o f treatment, follow-up exami nations were done every 3 months. Treatment Response and Toxic ity Patients were considered evaluable for response and toxicity if they had received at least one treatment cycle. Tumor response and response duration were classified according to W HOcriteria. Toxic ity was evaluated by worst event for each organ system using the WHO scale. Patients who had clinical CR underwent bronchoscopy and biopsy evaluation. Median response duration and median sur vival time were calculated by the Kaplan-Meier method. Survival was calculated from the 1st day o f treatment.
Gatzemeier von Pawel; Laumen Hossfeld Neuhauss Reck Lena/
CEV in SCLC
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toxicity, which are mainly induced by cisplatin [3-6]. Furthermore, treatment duration is limited because of neurotoxicity, primarily dependent on the cumulative dose of cisplatin [4]. Carboplatin is a second-generation platinum analogue. In randomized studies it induced sta tistically significantly less nephrotoxicity, ototoxicity, and gastroenteric toxicity than did cisplatin; bone marrow suppression was the dose-limiting toxicity [21]. Carboplatin is one of the most active agents in previously untreated SCLC [2]. Summarized results of'4 disease-oriented phase II studies with a total of 76 patients showed that it induced a complete response (CR) rate of 11% and a 59% overall response [22-25]. In three studies in which all patients had previously received chemotherapy, the overall response rate was 17% and the CR rate 4% [22. 25. 26], The 59% response rate in untreated patients is similar to the re sponse rate reported for etoposide and teniposide. which were the most active agents against SCLC. The first data on the antineoplastie activity and toxicity of the carboplatin etoposide combination in SCLC were published in 1985 by the Royal Marsden Hospital [27], In this study, a 30% CR and 87% overall response rate was achieved in patients with limited disease (LD). whereas there were no CRs but a 92% overall response in patients with extensive disease (ED). In our pilot study, CEV (carboplatin etoposide vincristine) administered to pa tients with ED produced a CR rate of 37% and a partial response (PR) rate of 53%. with an overall response rate of 90%. Myelosuppression was the dose-limiting toxicity [28.29], Since these results suggested that the antineoplastic activity of CEV is comparable with that of cisplatin etoposide in SCLC. a disease-oriented, phase II study of the 3-drug combination was conducted in previously un treated patients. In addition. EV (etoposide vincristine) has been eval uated at comparable doses in 2 disease-oriented phase II studies in extensive-stage SCLC [30. 31]. In both studies, the dosage of etoposide was 600 mg n r per course. Vincris tine was administered in a dose of 2 mg i.v. on day 1 or on days 1and 8 per course [22.31]. In 66 patients, the CR rate was 20% and 71% overall remissions were achieved. Median remission duration and survival time w'ere 8 months. These results indicate that EV’s activity is com parable to the more frequently used combinations CAV [10. II. 15. 18. 32 36] and ACE (doxorubicin cyclophos phamide etoposide) [12]. Adding carboplatin to EV and reducing the dose of etoposide seems to improve the antineoplastie activity without increasing dose-limiting hematologic toxicity. The completed phase II study with CEV confirmed these
Phase II Trial
Patient Characteristics A total of 127 consecutive patients entered the study from April 1987 to August 1988. One hundred and tw'enty-one(9l male) patients were evaluable for therapeutic response and survival (table 2). Six patients had to be excluded: I w'as lost to follow-up. 4 had changes in histology to non-SCLC types (detected during repeat bronchoscopy orsurgery after inadequate response to chemotherapy), and I refused further therapy. One hundred and twenty-one patients received at least I cycle o f chemotherapy and were assessed for response and toxicity. The median performance status was 90 (range. 60 100). Sixty-eight patients presented with LD and 59 with ED. Only 13 of them had locally advanced disease (ED I ): 46 had distant métastasés (ED2). One hundred and twenty-one patients received a total of 442 cyclesofchemotherapy. The median number of cycles per patient was 4(range. 1-6). Vincristine was withdrawn from treatment at a median total dose of 10 mg (range. 6-24). Seven patients received only one cycle of chemotherapy, primarily due to rapid tumor progression or toxicity. Sixty-six patients had chest irradiation and 42 patients had prophylactic cranial irradiation.
Results Response. CEV induced a 43% CR rate and a 39% PR rate in 121 patients. The overall response rate was 82.7%. and the objective response rate was 84.1% in LD and 81.1% in ED (table 3). CRs were reached in 52.4% of pa tients with LD and 32.8% of patients with ED. Survival. Median follow-up now exceeds 40 months. The median remission duration is 8.5 months 6 months in ED and 11.5 months in LD patients. Median survival for all patients is 10.5 months, 13 months for LD and 9.0 months for ED (table 4; fig. 1). The median survival time in stage EDI and ED2 was not statistically significantly dif ferent (9.5 vs. 10.5 months). Patients with CR have a
Drug
Dosage scheme (q4wk). mg n r
Carboplatin day 1 i.v. infusion Etoposide days 1 3 i.v. infusion Vincristine days 1.8. and 15 i.v. bolus
300 140 1.4
Table 2. Phase II study in SCLC: patient characteristics
Patients, n Evaluable, n
127 121
oCX
M F Stage LD ED Age. years Median Range Performance status Median Range
96 31 68 59 61 23 76 90 60 100
Table 3. Phase II study of SCLC: responses
All LD ED
CR. %
Overall response. %
43 52.4 32.8
82.7 84.1 81.1
Table 4. Phase II study in SCLC: survival
All LD ED
Median survival time, months
One-year survival, %
Four-year survival. %
10.5 13.0 9.0
41.7 51.7 31.3
17.8 26.4 8.6
median survival time of 18 months and patients with PR of 9.5 months. The l- and 4-year survival rates are 51.7 and 26.4% in LDand 31.3 and 8.6% in ED. respectively (fig. 1, 2). The plateau of both curves in patients with LD and ED between 2 and 3 years' survival suggests there may be a significant increase in long-term survivors with the CEV combination.
27
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Treatment Schedule and Dosage Inthisnonrandom ized phase II study,chemotherapy consisted of carboplatin 300 mg n r i.v. on day I, etoposide 140 mg/m i.v. days 1 through 3, and vincristine 1.4 mg n r (maximum 2 mg) i.v. on days 1. 8, and 15 (table 1). Carboplatin and etoposide were given as intra venous infusion over 30 and 60 min and vincristine as intravenous bolus injection. Carboplatin was given without prehydration or posthydration. Low-dose antiemetics were prophylactically ad ministered. Vincristine had to be withdrawn if peripheral neurotoxic ity (WHO grade I ) occurred. We planned to repeat the cycles every 4 weeks if the leukocyte and platelet values were 4 x 10' land 100 x 10'/1, respectively. If these levels were not reached, we planned to de lay treatment. Four to six cycles of chemotherapy were planned for all patients with a CR or PR after the second cycle. Patients with pro gressive disease after the first cycle or any time thereafter and patients without remission after the second cycle of chemotherapy w'erc to be withdrawn from the study. All patients with LD who achieved a CR and those with ED without distant métastasés and CR after 6 cycles of chemotherapy received chest and prophylactic cranial irradiation. The total tumor dose was 45 and 30 Gy. given together.
Table 1. Phase II study in SCLC: treatment regimen
100
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Table 5. Phase 11 study in SCLC: median survival time according to prognostic factors
Patients, n
Stage FI) 58 LI) 63 Karnofsky performance status < 80% 45 >80% 76 Sex M 91 F 30 Age. years 60 69
Survival time, months
9.5 14.0
Table 6. Phase II study in SCLC: median survival time according to second-line therapy
/évalue (log rank)
0.02
9.5 14.0
0.008
10.5 10.5
0.196
10.5 10.5
0.206
The most important prognostic factors (table 5) for sur vival are stage of disease and performance status. Patients with LI) and Karnofsky performance status above 80% survived significantly longer than patients with ED and Karnofsky performance status less than 80%. Sex and age did not influence the median survival time. There is no dif ference in survival between men and women and between patients younger and older than 60 years. Patients who re ceived a second-line treatment after treatment failure (table 6) also had a poor prognosis in comparison with pa tients who did not need alternative chemotherapy. These data confirmed that the best response after the first course of chemotherapy is one of the most important predictive parameters for long-term survival. Of the group of 66 pa-
28
Fig. 2. Phase 11 study o f SCLC: survival according to response in patients with limited disease.
W ithout second-line therapy With second-line therapy
Patients, n
Survival lime, months
61
I4.0
60
9.5
p value (log rank)
0.02
tients who received adjuvant radiotherapy, 24 had only PRs after completing chemotherapy. In 36% of these pa tients the PR converted to a CR because of radiotherapy. The prognosis of these patients is similar to that of patients who achieved CR during chemotherapy (fig. 3). Two thirds of the patients who still had a PR despite ad juvant therapy had a very poor prognosis (fig. 4), and all died within I year. Thus, achieving a CR is the only way to achieve long-term survival in SCLC. The analysis of relapse after CR (table 7) shows that only 23% of patients had local tumor recurrence. More than three fourths of patients had distant métastasés with and without relapse of the primary site. Despite prophy lactic cranial irradiation of 30 Gy, 48% of patients with CR experienced CNS métastasés if relapse occurred. The liver and bone were the main sites of relapse. Toxicity. Myelosuppression was the major side effect (table 8). Leukopenia of WHO grades 3 and 4 was ob served in 19 and 6% of the patients, respectively. Throm bocytopenia of WHO grades 3 and 4 occurred in 12 and 3% of the patients, respectively. No anemia of these de-
Gatzemeier von Pawel Laumen Hossfeld Neuhauss/Reek, Lenaz
CFV in SCLC
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Fïg.1- Phase II study of SCLC: survival according to stage.
(lo g ra n k )
Fig. 3. Phase II study of SCL.C: survival according to radiotherapy (RT) given before or after CR was achieved.
Table 7. Phase II study in SCLC: sites o f relapse after CR
Location
Patients, %
Primary site Distant sites Primary and distant sites CNS Liver Bone
22.8 31.4 45.7 48.5 17.1 14.3
grees was observed. Median leukocyte nadir was 3.1 x I09/l (days 13-15) with recovery occurring days 21 -23 and median thrombocyte nadir was 128 x IO'Vl (days 12-14) with recovery occurring days 19-21. The main nonhematologic toxicities were nausea, vomiting, alopecia, and peripheral neuropathy (table 9). WHO grades 3 and 4 vomiting was observed in 22 and 2% of patients, respec tively. WHO grade 3 alopecia occurred in 81 % of patients. Peripheral neuropathy of WHO grades 2 and 3 was in duced in 28 and 5% of patients, respectively. This side ef fect was mostly reversible after withdrawing vincristine. No nephrotoxicity or ototoxicity was observed.
Fig. 4. Phase II study o f SCLC: survival according to CR or PR remission status after radiotherapy (RT).
Table 8. Phase II study in SCLC: hematologic toxicity
Patients, % WHO grade 0 Hemoglobin Leukopenia Thrombocytopenia
35.8 14.8 44.3
1
2
3
4
47.7 24.1 14.2
16.5 35.2 19.8
0 19.4 12.3
0 6.5 3.4
Table 9. Phase II study in SCLC: nonhematologic toxicity
Patients, % WHO grade 0 Nausea/vomiting Alopecia Obstipation Peripheral neuropathy Fever Nephrotoxicity Ototoxicity
4.2 5.2 92.7 13.6 98.1 0 0
1
2
3
33.1 2.6 3.7 53.4 0.9
38.1 11.2 0.9 28.0 0.9
22.0 81.0 2.8 5.1
4 2.5 -
—
-
-
-
-
-
-
-
-
-
Phase III Trial Patient Characteristics Since November 1988, 188 evaluable patients have been treated according to the ongoing protocol (table 10). Ninety-three patients received CEV and 95 patients EV. Distribution of sex, age. perfor mance status, and stage o f disease was well balanced between the two arms. Only patients with stage EDI and CR to chemotherapy had chest radiotherapy (50 Gy to the tumor and mediastinum).
29
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Treatment Schedule and Dosage Patients with extensive-stage SCLC were allocated by central ran domization to receive either CEV or EV. Dosage and schedule are shown in figure 5. Chemotherapy was repeated every 4 weeks up to 6 cycles. Vincristine was withdrawn if WHO grade 1 peripheral neu rotoxicity occurred.
Carboplalin 3 0 0 mg rn7 day 1 Etoposido 140 m g m? days 1 3 Vincristino 1 4 m g m? days 1. 8, 15
Etoposido 3 0 0 mg m7 days 1 3 Vincristine 1.4 mg m 7 days 1. 8
I O N
Up to 6 cycles (q4wk)
Fig. 5. Phase III study of SC'LC: CEV versus EV treatment re
gimen. Fig. 6. Phase III study of SCLC: overall survival according to CEV or EV treatment regimen.
Table 12. Phase III study in SCLC: hematologic toxicides (WHO grade of myelosuppression)
Evaluable (as of April 1991) Sex M F Age. years Median Range Performance status Median Range Stage Extensive I Extensive II
CEV
EV
93
95
70 23
65 30
57 37-74
62 18-75
80 60 100
80 60 100
39 56
33 65
Table 11. Phase III studv in SCLC: responses
Regimen
CR, %
CR + PR. %
CEV (n = 93) EV (n = 95)
32.3* 17.9*
80.7* 60.0*
* CEV versus EV significantly different: p = 0.002.
30
p value
Patients. %
Patients, n
Leukocytes 2 3 4 Platelets 2 3 4 Hemoglobin 2 3 4
CEV
EV
32.3 18.3 10.8
21.1 15.8 5.3
0.01
15.1 15.1 7.5
4.2 2.1 2.1
0.001
21.5 5.4 2.2
11.6 5.3 0
0.02
Table 13. Phase III study in SCLC: nonhematologic toxicity (W H O grade >2)
Patients, %
Nausea vomiting Alopecia Peripheral neuropathy Obstipation Fever Nephrotoxicity Ototoxicity
Gatzemeier von Pawel Laumen Hossfcld Neuhauss Reck Lena/
CEV in SCLC
CEV
EV
12.0 71.0 2.2 3.3 1.1 0 0
8.4 62.0 2.1 0 0 0 0 Downloaded by: Kings's College London 137.73.144.138 - 11/15/2017 10:08:02 AM
Table 10. Phase III study in SCLC: patient characteristics
Discussion One part of current investigative strategies for SCLC is the design of more active, less toxic regimens using exist ing antincoplastic agents. Earlier studies had shown that the combination ofcisplatin and etoposide is highly active as first-line treatment and salvage therapy in SCLC [3-8. 37. 38]. The cisplatin analogue carboplatin was used with etoposide in LD patients in two trials, and in ED patients in four trials [39-42]. The summarized data of these studies suggest that carboplatin/etoposide may be less active than cisplatin etoposide in LD and ED. especially with regard to CR rates and median survival times. Preliminary results in ED with high-dose carboplatin etoposide indicate an antineoplastic activity similar to that attained with the same regimen at lower dosages, but severe myelosuppres sion [42]. In further phase II studies, ifosfamide. ifosfamide/ vincristine, and cyclophosphamide vincristine were add ed to carboplatin/etoposide [43-46]. In comparison to carboplatin etoposide, an increase of CR rates with com parable to higher overall response rates and median sur vival times was achieved in LD and ED patients [39-47]. The combinations carboplatin/etoposide/ifosfamide with or without vincristine and carboplatin/etoposide/cyclophosphamide/vincristine induced WHO grades 3 and
4 leukopenia and thrombocytopenia in 74-100% and 57-85% of patients, respectively [43, 45. 46], Lifethreatening leukopenia and thrombocytopenia occurred in 43 and 3 1% of the patients, respectively. WHO grades 3 and 4 infections were seen with a frequency of up to 36% [43.46], To avoid life-threatening hematologic toxicities, we added only vincristine to carboplatin etoposide because of its low myelosuppressive potential and its relatively high activity against SCLC. In the complete phase II study. CEV induced higher CR and overall response rates in LD and ED patients than did carboplatin/etoposide. The CR and overall response rates and median survival times were similar to those of the other carboplatincontaining 3- and 4-drug regimens. Compared with these combinations, the hematologic toxicity of CEV was mini mal. WHO grades 3 and 4 leukopenia occurred in 19 and 7% of patients, respectively, and thrombocytopenia of these degrees was observed in 12 and 9% of patients. Comparison of the CEV treatment results with those of the more frequently used combinations like CA V, or CA V alternating with cisplatin etoposide. and cisplatin/etoposideshows the following: In LDand ED patients, CEV in duced similar CR and overall response rates and median survival times. In ED patients. CEV achieved higher CRs and overall responses than did CAV. Its remission-induc ing activity, with regard to CRs and overall responses, is comparable to that of cisplatin/etoposide and to alternat ing treatment with CAV and cisplatin/etoposide. Dura tion of median survival times appears similar to the other regimens mentioned. The very high 1- and 4-year survival rates in LD and ED patients in the phase II trial are re markable. The activity of CEV seems particularly remark able in ED because 78% of patients were in stage 2. which is considered an unfavorable prognostic factor for re sponse and survival [48]. These encouraging survival data (especially in ED pa tients) were confirmed in the ongoing phase 111 trial, which compared CEV to EV alone. According to remission and survival data, there is now a clear indication that CEV is superiorto the EV regimen. CEV induced significantly less life-threatening leukopenia than did CAV or CAV alter nating with cisplatin etoposide. After CAV at higher doses and after CAV alternating with cisplatin/etoposide. grade 4 leukopenia was observed in 40-70% of patients [9-13. 20. 34. 49] and in 7% of patients after CEV. The incidence of peripheral neuropathies is relatively high after CEV but comparable to CAV. Nephrotoxicity after cisplatin-containing regimens was not observed in our study [12.13.33.34],
31
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Results Response. The remission rate of the randomized trial comparing CEV with EV is shown in table 11. The overall response rate with CEV is 80.7% compared with 60% with EV. This dillerence is statistically significant (p = 0.002). The response data of the CE V-treated group are exactly in accordance with the results of the phase 11 trial. Survival. Because the trial is ongoing, median survival data are preliminary. Figure 6 shows the survival curves for the 188 evaluable patients. The median survival time for CEV is 9.5 months compared with 8.5 months for EV. Although this is not a statistically significant difference, there is a clear trend for better survival with the 3-drug combination. Toxicity. In both arms, myelosuppression was the ma jor side effect (table 12). There were statistically significant differences in leukopenia and thrombocytopenia between CEV and EV. with more pronounced toxicity in thecarboplatin-containing regimen. Nonheniatologic toxicity was not a major problem. There were no differences in nausea and vomiting, alopecia, and peripheral neuropathy be tween the CEV and EV regimens (table 13).
Conclusion The activity of CEV in SCLC is at least comparable to that of the more frequently used chemotherapies with re gard to CR and overall response rates. The high propor tion of long-term survivors in the phase II trial deserves emphasis. Although these data await confirmation in the ongoing phase 111 trial, they currently show that the ad
dition of carboplatin to EV in ED patients led to a higher response rate and a slight increase in survival. On the basis of the very encouraging long-term survival rate in the phase II trial, we are going to initiate a doseescalating trial with prevention of myelosuppression (us ing growth factors) to intensify the initial treatment of LD patients with SCLC.
1 Klastersky J: Therapy of small cell lung cancer: Anything new'.’ Fur .1Cancer Clin Oncol 1988; 24: i 07- f 12. 2 AisncrJ. AbramsJ:Cisplatinforsmallcell lung cancer. Semin Oncol !989:!6(suppl 6):2 9. 3 Wolf M. Havemann K. Hollc R. et al: Cisplatin etoposide versus ifosfamide etoposide combination chemotherapy in small-cell lung cancer: A multicenter German randomized trial. J Clin Oncol 1987:5:1880-1889. 4 Boni C. Cocconi G. Bisagni G. et al: Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer. A phase II trial. Cancer 1989:63:638-642. 5 Wilke H. Achterralh W. Schmoll H-J, et al: T.toposideand split-dose cisplatin in small-cell lung cancer. Am J Clin Oncol 1988:11(5): 572-578. 6 Fvans WK. Shepherd FA. Feld R.elal: VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985:3: 1471-1477. 7 Ihde DC. Johnson BF„ Mulshine JL. et al: Randomized trial of high dose versus standard dose etoposide and cisplatin (VP 16 Plat) in ex tensive stage small cell lung cancer (SCLC) (abstract 7 ¡4). Proc Am SocClin Oncol 1987:6: 181. 8 Roth BJ. Johnson DH. Greco FA. ct al: A phase 111 tria Iof etoposide ( E) and cisplatin (P) versus cyclophosphamide (C). doxorubicin (Aland vincristine) V) versus alternation of the two therapies for patients (Pts) with extensive small cell lung cancer (SCLC) (abstract 875). Proc Am SocClin Oncol 1989:8:225. 9 Evans WK. Feld R. Murray N.et al: Superior ity of alternating non-cross-resistant chemo therapy in extensive small cell lungcancer. Ann Intern Med 1987: !07:451-458. 10 Lowcnbraun S. Birch R. Buchanan R. et al. and the Southeastern Cancer Study Group: Combination chemotherapy in small cell lung carcinoma. Cancer 1984:54:2344 2350.
11 Johnson D ll. Einhorn LIE Birch R .etal.and the Southeastern Cancer Study Group: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxo rubicin and vincristine for extensive-stage small-cell lungcancer: A phase 111 trial of the Southeastern Cancer Study Group. J Clin On col 1987;5:1731-1738. 12 Bunn PA. Greco FA. Einhorn L: Cyclophos phamide. doxorubicin and etoposide as firstline therapy in the treatment of small-cell lung cancer. Semin Oncol 1986:13:45- 53. 13 I long W K. Nicaise C. Lawson R. et al: Etopo side combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol. 1989:7: 450— 456. 14 Jackson DV. Case LD. Small-cell lungcancer: A 10-ycar perspective. Semin Oncol. 1986:13 (suppl 3):63 74. 15 Livingston RB. Schulman S. Mira JG. et al: Combined alkvlatorsand multiple-site irradia tion for extensive small cell lung cancer: A Southwest Oncology Group Study. Cancer Treat Rep 1986:70:1395-1401. 16 Messeih A A. Schweitzer J M. Lipton A. et al: Addition of etoposide to cyclophosphamide, doxorubicin and vincristine for remission in duction and survival in patients with small cell lungcancer. Cancer Treat Rep 1987:71:61 66. 17 Feld R. Evans WK. De Boer G. et al: Com bined modality induction therapy without maintenance chemotherapy for small cell car cinoma of the lung. J Clin Oncol 1984:2: 294-304. IS Livingston R B. MooreTN. Heilbrunn L.elal: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Intern Med 1978:88:194-199. 19 Dombernowsky P. Hansen H FI. Sorensen PG. ct al: Vincristine (NSC-67574) in the treatment of small cell anaplastic carcinoma of the lung. Cancer Treat Rep 1976:60:239 242.
20 Johnson DH. Einhorn LH. Birch R. et al. and The Southeastern Cancer Study Group: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxo rubicin. and vincristine for extensive-stage small-cell lung cancer: A phase II trial of the Southeastern Cancer Study Group. J Clin On col 1987:5:1731 1738. 2 1 Rozeneweig M. Martin A. Bcltangady M. el al: Randomized trials of carboplatin versus cisplalir in advanced ovarian cancer: in Bunn PA Jr. Canetta R. Ozols R F. ct al (eds): Carbopla tin (JM-8): Current Perspectives and Future Directions. Philadelphia. Saunders. 1990. pp 175-186. 22 Smith IE. Harland SJ. Robinson BA. et al: Carboplatin: A very active new cisplatin an alog in the treatment of small cell lung cancer. Cancer Treat Rep 1985:69:43-46. 23 Jacobs R 11. Bitran JD , Dcutsch M.etal: Phase II study of carboplatin in previously untreated patients with metastatic small cell lung car cinoma. CanccrTreat Rep 1987:71:311 312. 24 Pallarés C, Lopez Lopez JJ. Paredes A. et al: First line carboplatin (CBDCA) 24 hours in fusion on patients (PTS) with disseminated oat cell carcinoma of the lung (abstract 26). Proc F.CCO 1987:4:7. 25 Tainura T. Saij GN. Shinkai T. el al: Phase II study of carboplatin in small cell lung cancer. Jpn JClin Oncol 1988:18:27-32. 26 Ogawa M. Inuyana Y. Kato T. ct al: Phase II study of carboplatin (abstract). Proc Am Soc Clin Oncol 1987:6:20. 27 Smith IE. Evans BD: Carboplatin (JM8) as a single agent and in combination in the treat ment of small cell lung cancer. Cancer Treat Rev. I985:l2(suppl a):73-75. 28 Neuhauss R. Achterralh W. Gatzemeier U. el al: C’arboplatinum vincristine and etoposide as first line therapy in small-cell lung cancer (SCLC) (abstract 5 34-M 008). .1 Cancer Res Clin Oncol 1988:114(suppl):S155. 29 GatzemeierU,Achterralh W. HcckmayrM.ct al: Pilot study with carboplatin vincristine (VCR) etoposide as first line therapy in exten sive small cell lung cancer (abstract 67). Proc ECCO 1987:4:17.
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CF.V in SCLC
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Discussion
Dr. Gatzemeier: Only a very small group of patients with extensive disease survived, but they all had good perfor mance status and only one metastatic site. Dr. Ultra: You achieved good results with the CEV reg imen. Why did you add vincristine to the carboplatin/ etoposide regimen?
Dr. Gatzemeier: Of all the drugs available for small cell lung cancer, the vinca alkaloids are very active. We added vincristine because of its low myelosuppressive potential. Dr. Saijo: What is the difference between ED I and ED II? Dr. Gatzemeier: There is no difference in survival between these two groups. Some trials, however, divide this disease stage into two groups. ED I patients have locally ad vanced, extensive disease with bulky disease in mediastinal lymph nodes, chest wall invasion, and no further distant métastasés. In contrast, all ED II patients have distant métastasés.
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Dr. Yoneda: In your study, what type of patients survived in the long term?
