Combination Chemotherapy With Carboplatin, Etoposide, and Vincristine as First-Line Treatment in Small-Cell Lung Cancer By U. Gatzemeier, D.K. Hossfeld, R. Neuhauss, M. Reck, W. Achterrath, and L. Lenaz Purpose: The antineoplastic activity of carboplatin and etoposide may be improved by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in small-cell lung cancer (SCLC). A phase II study with CEV was carried out. Patients and Methods: One hundred twenty-one untreated patients with SCLC (63 with limited disease [LD], 58 with extensive disease [ED]) were treated with a combination of 300 mg/m 2 intravenous (IV) on day 1, etoposide 140 mg/m 2 IV daily on days 1 to 3, and vincristine 1.4 mg/m 2 IV on days 1, 8, and 15 every 4 weeks. Results: A 90% rate overall response rate including
56%complete responses (CRs) was achieved in LD and an 83% overall response rate including 35% CRs was observed in ED. Median survival time was 13 months in limited disease and 9.5 months in extensive disease. The 24 and 36 months survival rates were 29%in LD and 9%in ED. Myelosuppression was the main form of toxicity. Conclusion: The combination of CEV is a new active and well-tolerated regimen in the treatment of SCLC. Prospective randomized studies of CEV with conventional chemotherapy are warranted. J Clin Oncol 10:818-823. © 1992 by American Society of Clinical Oncology.
T
a 92% overall response rate in extensive disease (ED). Myelosuppression was the main toxicity. 29 We attempted to improve the antineoplastic activity of carboplatin and etoposide by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in SCLC.30 The optimal schedule of CEV has been investigated in untreated patients with extensive disease in a phase I study in which an 88% overall response rate, including 33% CRs, were achieved in 20 assessable patients.3 1 A phase II study with CEV was carried out in LD, ED, and SCLC, and is the subject of this report.
HE COMBINATION of cisplatin and etoposide is one of the most active regimens in the treatment of small-cell lung cancer (SCLC)1,2 with antineoplastic activity comparable to the more frequently used cyclophosphamide, doxorubicin, and vincristine (CAV) regimen. 3-23 The major toxic effects of treatment with cisplatin and etoposide are nausea, vomiting, and nephrotoxicity, which are mainly induced by cisplatin. 3-6 Furthermore, treatment duration may be limited because of neurotoxicity (peripheral neuropathy, ototoxicity), which is related to the cumulative dose of cisplatin. 4 Carboplatin, a second-generation platinum analog, induced statistically significantly less nephro-, oto-, and neurotoxicity and vomiting when compared with cisplatin in three randomized studies.24 Carboplatin is one of the most active agents in untreated SCLC. 2 In three disease-oriented phase II studies with a total of 66 patients, a 61% overall response rate including 14% complete responses (CRs) was achieved. 25 -27 Data on the antineoplastic activity and toxicity of the combination of carboplatin and etoposide in SCLC were initially published by the Royal Marsden Hospital in 1985 and updated in 1987.28,29 In this study, 30% CR and 87% overall response rates were achieved in limited disease (LD), whereas there were no CRs but
PATIENTS AND METHODS PatientSelection Patients with histologically confirmed SCLC with bidimensionally measurable indicator lesions or assessable disease on physical examination (chest x-ray or computed tomographic [CT] scan) were enrolled. Eligibility requirements included an age > 18 to < 75 years, a life expectancy of at least 3 months, a performance status of < 2 on the World Health Organization (WHO) scale, no brain metastases, no prior chemotherapy or radiotherapy, adequate bone marrow, renal and hepatic functions, and serum electrolytes within the normal range. All patients gave informed consent to participate in this study. Staging and Follow-Up Procedures
From the Departmentof Thoracic Oncology, GrosshansdorfHospital, Department of Hematology, University Hamburg, Germany; and Bristol-Myers Squibb PharmaceuticalGroup, Princeton,NJ. Submitted January 28, 1991; acceptedDecember 19, 1991. Address reprint requests to U. Gatzemeier, MD, Department of Thoracic Oncology, GrosshansdorfHospital, Center of Pneumology and Thoracic Surgery, W-2070 Grosshansdorf,Germany. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1005-0019$3.00/0
818
The pretreatment evaluation consisted of a complete medical history, physical examination, and laboratory workup with complete hemogram (differential and platelet count), serum creatinine, bilirubin, SGOT, SGPT, alkaline phosphatase, electrolytes, and creatinine clearance. The staging procedures included bronchoscopy, x-ray, and CT scan of the chest, CT scan of the brain, CT scan and ultrasound of the abdomen, bone scan, and bone marrow biopsy. Bone lesions were measured by roentgenography.2 LD was defined as tumor confined to one hemithorax but including mediastinal involvement and ipsilateral supraclavicular
Journal of Clinical Oncology, Vol 10, No 5 (May), 1992: pp
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8 18
- 82 3
819
CEV IN SCLC Table 1. Patient Characteristics
lymph nodes. ED denoted any involvement beyond these confines 32 including pleural effusion. The size of neoplastic lesions was determined before each cycle and 4 weeks after the last cycle of chemotherapy. Complete hemogram, serum creatinine, creatinine clearance, electrolytes, and liver function tests were performed before each cycle and 4 weeks after the last cycle of chemotherapy. During chemotherapy, complete blood counts were monitored weekly. After completion of treatment, follow-up examinations were done every 3 months.
No. of patients Male/female ratio Age, years (median) Range WHO performance status Median Range 0 1 2 Stage of disease LD ED
Treatment Plan This study was designed as a nonrandomized phase II study. Chemotherapy consisted of carboplatin 300 mg/m2 intravenously 2 (IV) on day 1, etoposide 140 mg/im IV on days 1 to 3, vincristine 2 1.4 mg/m (maximum 2 mg) IV on days 1, 8, and 15. Carboplatin and etoposide were given as IV infusions over 30 and 60 minutes and vincristine as an IV bolus injection. Carboplatin was given without prehydration and posthydration. Low-dose antiemetics were administered prophylactically. Vincristine was withdrawn if peripheral neurotoxicity of a WHO grade 1 occurred. Cycles were repeated every 4 weeks if WBC and platelet counts were > 4 x 109/L and Ž 100 x 109/L or on recovery to these values. Six cycles of chemotherapy were planned for all responding patients. Radiotherapy All patients with LD and patients with ED without distant metastases who achieved complete remission were offered simultaneous chest and prophylactic cranial irradiation. Additionally, patients with these stages of disease who achieved a very good partial response (PR) were offered chest irradiation. Chest irradiation was administered at a tumor dose of 46 Gy, given in single doses of 2 Gy five times per week over a period of 4 to 5 weeks. The irradiation field encompassed the primary tumor and the whole mediastinum up to the jugulum. Supraclavicular regions were included in case of supraclavicular lymph node involvement. Source for radiotherapy was a linear accelerator (8 MEV photones). Brain irradiation was given in fractions of 2.5 Gy four times per week up to 30 Gy by lateral opposed fields. Treatment, Response, and Toxicity Patients were considered assessable for response and toxicity if they had received at least one cycle of chemotherapy. Tumor response and response duration were classified according to WHO criteria.33 Toxicity was evaluated by worst event for each organ 33 system using the WHO scale. CRs underwent a bronchoscopy and biopsy evaluation. Median response duration and median survival time were estimated by the Kaplan-Meier method. Survival was calculated from the first day of treatment.
patients received at least one cycle of chemotherapy and were assessed for response and toxicity. Their clinical characteristics are summarized in Table 1. Sixty-three
0 0-2 70 46 5 63 58
patients presented with LD and 58 with ED. One hundred twenty-one patients received a total of 442 cycles of chemotherapy. The median number of cycles per patient was four (range, one to six). Vincristine was withdrawn at a median total dose of 10 mg (range, 6 to 24 mg). Seven patients received only one cycle of chemotherapy because of rapid tumor progression. Fortytwo CRs (35 LD and seven locally ED) received chest and prophylactic brain irradiation. Additionally, 24 patients (22 LD and two locally ED) who achieved a good PR after six cycles of chemotherapy underwent chest irradiation. Response Rates, Response Duration,and Survival CEV induced in 121 patients, 52 (43%) CRs, and 48 (39%) PRs, an overall response rate of 83% (95% confidence interval [CI], CR 34% to 52%; CR + PR 76% to 96%; Table 2). The objective response rate was 90% in LD and 83% in ED (Table 2) (95% CI, 82% to 98% in LD; 73% to 93% in ED). CR rates were 56% in LD and 35% in ED. The 95% CI for CR was 43% to 69% in LD and 22% to 48% in ED. Twenty-four patients (22 LD and two locally ED without distant metastases) who achieved a good PR after six cycles of chemotherapy underwent subsequent chest irradiation. In eight (36%) of 22 patients with LD, the PRs were converted into CRs, resulting in a CR rate of 68% (43 of 63) in LD. Table 2. Response by Stage of Disease
RESULTS
A total of 127 consecutive patients were entered onto the study from April 1987 to August 1988. Six patients were not assessable because four patients had nonSCLC, one refused treatment during the first cycle, and one was lost to follow-up. One hundred twenty-one
121 91/30 61 23-76
CR
CR&PR
Stage
No. of Patients
No.
%
No.
%
All
121
52
43
100
83
LD
63
35
(33-43) 56
(43-69) ED
58
20
35 (22-48)
NOTE. 95%confidence limits in parentheses.
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(76-96) 57
90
(82-98) 48 83 (73-93)
820
GATZEMEIER ET AL
Median follow-up exceeded 30 months. The median remission duration was 8.5 months, 6 months in ED, and 11.5 months in LD. Median survival for all patients was 10.5 months, 14 months for LD, and 9.5 months for ED (Fig 1). Patients with chemotherapeutically induced CR have a median survival time of 18 months, CRs after chemotherapy and radiotherapy have a median survival time of 13 months. The percentage of 24- and 36-month survivors is 29% each in LD, and 9% each in ED. Sites of Relapse Thirty-five (58%) of 60 patients who achieved a CR after CEV alone or after CEV with sequential chest irradiation have relapsed so far. Twenty-three percent (eight of 35) of the patients had intrathoracic and 32% (11 of 35) extrathoracic relapses. Chest and extrathoracic relapses were observed in 45% (16 of 35) of the patients. Most patients showed multiple sites of relapses and/or brain metastases. CNS metastases were observed in 49% (17 of 35) of patients. The liver and bones were the sites of relapse in 17% (six of 35) and in 14% (five of 35) of the patients. Only six patients developed isolated CNS metastases, all of whom had received prophylactic cranial irradiation.
median thrombocyte nadir was 128 x 109/L. Recovery of leukocytes and thrombocytes was usually complete by days 21 to 23 and 19 to 21. The main nonhematologic toxicities were nausea, vomiting, alopecia, and peripheral neuropathy. Vomiting of WHO grades 3 and 4 was observed in 22% and 2% of patients, respectively, and alopecia of grade 3 occurred in 81% of patients. Peripheral neuropathy of WHO grades 2 and 3 was induced in 28% and 4% of patients, respectively. This side effect was reversible after vincristine withdrawal. No nephrotoxicity or ototoxicity was observed. DISCUSSION One part of the current investigative strategies for SCLC is the design of more active and/or less toxic regimens using existing antineoplastic agents. Earlier studies had shown that the combination of cisplatin and etoposide is highly active as first-line and salvage treatment in SCLC.3 -8,28,34 Carboplatin and etoposide was
investigated in LD SCLC in two trials, and in ED SCLC in four. 29,35-37 The data of these studies suggest that
carboplatin and etoposide might be less active than cisplatin and etoposide in both LD and ED, especially 37 3 8 29 30 34 regarding CR rates and median survival times. - , , , -
37 The use of carboplatin and etoposide at higher dosages showed comparable antineoplastic activity, but more 29 35 36 severe myelosuppression than at lower dosages. , ,
Toxicity Myelosuppression was the major side effect experienced by patients (Table 3). Leukopenia of WHO grades 3 and 4 was observed in 19% and in 7% of patients; thrombocytopenia grades 3 and 4 occurred in 12% and in 9% of patients. No severe anemia was observed. Median leukocyte nadir was 3.1 x 109/L and
The addition of ifosfamide, 38,39 ifosfamide and vincristine, 40 and cyclophosphamide and vincristine4 1 to carboplatin and etoposide resulted in improved CR rates with comparable or higher overall response rates and median survival times (Table 4).29,35-41 However, these combinations induced leukopenia and thrombocytopenia of WHO
1001 80 60 C) 40 is
- -limited
20
extensive U
U.~~
0
0
I 5
I 10
I 15
I 20
I 25
Time (Months)
i
I
30
35
40 Fig 1. CEV in SCLC; survival according to stage.
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821
CEV IN SCLC Table 3. Worst Toxicities With Assessable Patients According to WHO Scale WHO Grades 0
Leukocytes Thrombocytes Hemoglobin Neurotoxicity (peripheral) Fever Nausea/vomiting Obstipation Alopecia
1
2
3
4
No.
%
No.
%
No.
%
No.
%
No.
%
18 54 43 17 119 5 112 6
15 45 36 14 98 4 93 5
29 17 58 65 1 40 5 4
24 14 48 54 1 33 4 3
43 24 20 34 1 46 1 13
36 20 17 28 1 38 1 11
23 15 0 5 0 27 3 98
19 12 0 4 0 22 2 81
8 11
7 9
0 3 0 0
2
age of long-term survivors. The antineoplastic activity of CEV is similar to that of the other carboplatin containing three- and four-drug regimens. However, the hematologic toxicity of CEV was minimal compared with these combinations. Leukopenia of grades 3 and 4 occurred in 19% and 7% of patients; thrombocytopenia of grades 3 and 4 was observed in 12% and 9% of patients. CEV results in similar CR rates, overall response rates, median survival times, and percentage of 24-month survivors as compared with the more frequently used combinations of cisplatin and etoposide, CAV, or CAV alternating with cisplatin and etoposide in LD and in ED (Table 5). The antineoplastic activity of
grades 3 and 4 in 74% to 100% and 57% to 85% of the patients, respectively. 38,40,41 Life-threatening leukopenia and thrombocytopenia occurred in 43% to 81% and in 16% to 50% of the patients, respectively, and infections of WHO grades 3 and 4 were observed with a frequency between 7% and 37%.38,40,41 To avoid life-threatening hematologic toxicities, we added only vincristine as the third drug to carboplatin and etoposide because of its low myelosuppressive potential and its activity in SCLC. In the present study, CEV induced higher CR and overall response rates in LD and ED patients than carboplatin and etoposide, and a similar median survival time and a higher percent-
Table 4. SCLC. Phase II Studies With Carboplatin Containing Regimens CR + PR
CR Chemotherapy
Stage of Disease
No. of Patients
No. of Studies
Carboplatin/ifosfamide
ED
30
1
Carboplotin/etoposide
ED
157
4
LD
63
2
ED
30
2
Carboplatin/etoposide/ifosfamide
Carboplotin/etoposide/ifosfamide/ vincristine Carboplatin/etoposide/cyclophosphamide/vincristine
CEV
LD
18
1
LD
30
1
ED
50
1
LD
40
1
ED
58
1
LD
63
1
-
Survivor % at 24 Months
No.
%
No.
%
MS (months)
1
3
19
63
8
nr
Le Chevalier et a1
8-12
nr
10-15
nr
8-9
nr
Smith aeta1 3 Bishop et al Evans et al36 et a137 Luikort et Smith et al129 35 Bishop et a1 Smith et al03
19
nr
Hornedo et a39 3 Smith et aPl
14
37
Thatcher et al40
9,6
5
13
30
9,5
9
Own data
14
29
Own data
(3-6) 20 13 (8-18)
(45-81) 100 65 (57-73)
22 35 (23-47) 30 9 (13-47) 13 72 (51-93) 16 50 (32-68) 11 22 (10-34) 60 24 (45-75) 20 35 (22-48) 35 56 (43-69)
50 79 (69-89) 27 90 (78-102) 17 94 (83-105) 23 77 (62-92) 76 38 (64-88) 83 33 (71-95) 48 83 (73-93) 57 90 (82-98)
NOTE. There were > 14 patients per study. 95% confidence limits are in parentheses. Abbreviations: MS, median survival; nr, not reported.
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Authors 42
29
Bishop et a141 Bishop aeta14
822
GATZEMEIER ET AL Table 5. SCLC Studies With Carboplatin/Etoposide/Vincristine and More Frequently Used Regimens Chemotherapy
CEV
Cisplatin/etoposide
CAV
CAV alternating with cisplatin/etoposide
NOTE. There were
2
Stage of Disease
No. of Patients
No. of Studies
LD
63
1
ED
58
1
LD
45
2
ED
330
7
LD
387
7
ED
1137
14
LD
152
1
ED
290
2
CR%
CR + PR%
56 (43-69) 35 (22-48) 56 (41-71) 26 (21-31) 49 (45-53) 15 (13-17) 52 (44-60) 29 (24-34)
90 (82-98) 83 (73-93) 89 (80-98) 70 (65-75) 73 (69-77) 59 (56-62) 82 (76-88) 69 (64-74)
MS (months)
Survivors (%) at 24 Months
Reference
14
29
Own data
9,5
9
Own data
15-17
23-30
3,4
9-15
5-10
3-8
11-16
15-23
6-11
0-8
12-14,16 38-40 8-18,42
15
20
41
9-10
nr
8,9
14 patients per study. 95% confidence limits are in parentheses.
CEV seems promising in ED because 78% of patients had extrathoracic disease, which is generally considered an unfavorable prognostic factor for response and survival. 32
The percentage of 24-month survivors after CEV is high (29% of patients with LD and 9% of patients with ED) and in the upper range as observed thus far. CEV given in the dosages used in this study induced markedly less life-threatening leukopenia than CAV or CAV alternating with cisplatin and etoposide. After CAV at higher dosages and after CAV alternating with cisplatin and etoposide was given, leukopenia of grade 4 was observed in 40% to 70% of the patients, 9,10 ,13, 19,20 and
after CEV was given, in 7% of the patients. The rate of peripheral neuropathies is relatively high after CEV but comparable to CAV with weekly administered vincristine. 21 The nephrotoxicity occurring after cisplatincontaining regimens was not observed in our study. 4-6 In conclusion, the activity of CEV in SCLC is comparable to or higher than that of the more frequently used chemotherapies regarding CR and overall response rates. The high proportion of long-term survivors observed in this study is gratifying. The encouraging results of our study warrant a direct comparison of the efficacy of this combination with conventional chemotherapy in prospective randomized studies.
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8. Roth BJ, Johnson DH, Greco FA, et al: A phase III trial of etoposide (E) and cisplatin (P) versus cyclophosphamide (C), doxorubicin (A), and vincristine (V) versus alternation of the two therapies for patients (Pts) with extensive small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 8:225, 1989 (abstr 875) 9. Evans WK, Feld R, Murray N, et al: Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. Ann Int Med 107:451-458, 1987 10. Lowenbraun S, Birch R, Buchanan R, et al: Combination chemotherapy in small cell lung cancer carcinoma. Cancer 54:23442350, 1984 11. Johnson HDH, Einhorn LH, Birch R, et al: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 5:1731-1738, 1987 12. Bunn PA, Greco FA, Einhorn L: Cyclophosphamide, doxorubicin, and etoposide as first-line therapy in the treatment of small-cell lung cancer. Semin Oncol 13:45-53, 1986 (suppl 3) 13. Hong WK, Nicaise C, Lawson R, et al: Etoposide combined with cyclophosphamide plus vincristine and with high-dose cyclo-
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823
CEV IN SCLC phosphamide 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 7:450-456, 1989 14. Jackson DV, Case LD: Small-cell lung cancer: A 10-year perspective. Semin Oncol 13:63-74, 1986 (suppl 3) 15. Livingston RB, Schulman S, Mira JG, et al: Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: A Southwest Oncology Cancer Group study. Cancer Treat Rep 70:1395-1401, 1986 16. Messeih AA, Schweitzer JM, Lipton A, et al: Addition of etoposide to cyclophosphamide, doxorubicin, and vincristine for remission induction and survival in patients with small cell lung cancer. Cancer Treat Rep 71:61-66, 1987 17. Feld R, Evans WK, De Boer G, et al: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol 2:294-304, 1984 18. Livingston RB, Moore TN, Heilbrunn L, et al: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Int Med 88:194-199, 1978 19. Figueredo AT, Hryniuk WM, Strautmanis I, et al: Cotrimoxacole prophylaxis during high-dose chemotherapy of smallcell lung cancer. J Clin Oncol 3:54-64, 1985 20. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2:1200-1208, 1984 21. Niederle N, Krischke W, Schulz U, et al: Untersuchungen zur kurzzeitigen Induktions- und zyklischen Erhaltungstherapie beim inoperablen kleinzelligen Bronchialkarzinom. Klin Wschr 60:829-838, 1982 22. Feld R, Evans WK, Coy P, et al: Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 5:1401-1409, 1987 23. Holoye PY, Samuels ML, Lanzotti VJ, et al: Combination chemotherapy and radiation therapy for small cell carcinoma. JAMA 237:1221-1224, 1977 24. Rozencweig M, Martin A, Beltangady M, et al: Comparison of carboplatin and cisplatin given as first-line single-agent chemotherapy for stage III-IV ovarian cancer: A meta analysis of three randomized trials, in Bunn PA, Canetta R, Ozols RF, et al (eds): Carboplatin (JM-8)-Current Perspectives and Future Directions. Philadelphia, PA, Saunders, 1990, pp 175-186 25. Smith IE, Harland SJ, Robinson BA, et al: Carboplatin: A very active new cisplatin analog in the treatment of small cell lung cancer. Cancer Treat Rep 69:43-46, 1985 26. Jacobs RH, Bitran JD, Deutsch M, et al: Phase II study of carboplatin in previously untreated patients with metastatic small cell lung carcinoma. Cancer Treat Rep 71:311-312, 1987 27. Pallar6s C, L6pez ULpez JJ, Paredes AL, et al: First-line carboplatin (CBDCA) 24 hours infusion on patients (PTS) with disseminated oat cell carcinoma of the lung. Proc Eur Conf Clin Oncol 4:7, 1987 (abstr 26)
28. Smith IE, Evans BD: Carboplatin (JM8) as a single-agent and in combination in the treatment of small cell lung cancer. Cancer Treat Rev 12:73-75, 1985 (suppl A) 29. Smith IE, Evans BD, Gore ME, et al: Carboplatin (paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. J Clin Oncol 5:185-189, 1987 30. Dombernowsky P, Hansen HH, Sorensen PG, et al: Vincristine (NSC-67574) in the treatment of small-cell anaplastic carcinoma of the lung. Cancer Treat Rep 60:239-242, 1976 31. Gatzemeier U, Achterrath W, Heckmayr M, et al: Pilot study with carboplatin/vincristine (VCR)/etoposide as first line therapy in extensive small cell lung cancer. Proc ECCO 4:17, 1987 (abstr 67) 32. Havemann K, Wolf M, Holle R, et al: Alternating versus sequential chemotherapy in small-cell lung cancer. Cancer 59:10721082, 1987 33. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981 34. Evans WK, Osoba D, Feld R, et al: Etoposide (VP-16) and cisplatin: An effective treatment for relapse in small-cell lung cancer. J Clin Oncol 3:65-71, 1985 35. Bishop JF, Raghavan D, Stuart-Harris R, et al: Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer. J Clin Oncol 5:1574-1578, 1987 36. Evans WK, Eisenhauer E, Hughes P, et al: VP-16 and carboplatin in previously untreated patients with extensive small cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group. Br J Cancer 58:464-468, 1988 37. Luikart SD, Goutsou M, Mitchell ED, et al: Phase II trial of high dose etoposide (VP-16) and carboplatin (CBDCA) in extensive small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 9:251, 1990 (abstr 970) 38. Smith IE, Perren TJ, Ashley SA, et al: Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small-cell lung cancer. J Clin Oncol 8:899-905, 1990 39. Hornedo J, Lianes P, Cruchaga S, et al: Ifosfamide, carboplatin, and VP 16 in untreated extensive stage (ED) small-cell lung cancer (SCLC). European Society of Medical Oncology, Abstracts of the 13th Congress, October 30 to November 1, 1988, Lugano, Switzerland, C 91, abstr. 362 (P) 40. Thatcher N, Lind M, Stout R, et al: Carboplatin, ifosfamide, and etoposide with mid-course vincristine and thoracic radiotherapy for limited stage small cell carcinoma of the bronchus. Br J Cancer 60:98-101, 1989 41. Bishop JF, Kefford R, Raghavan D, et al: Etoposide, carboplatin, cyclophosphamide, and vincristine in previously untreated patients with small-cell lung cancer. Cancer Chemother Pharmacol 25:367-370, 1990 42. Le Chevalier T, Thomas F, Subirana R, et al: A phase II study of the combination of carboplatin and ifosfamide in previously untreated metastatic small cell carcinoma. Cancer 67:29802983, 1991
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56%complete responses (CRs) was achieved in LD and an 83% overall response rate including 35% CRs was observed in ED. Median survival time was 13 months in limited disease and 9.5 months in extensive disease. The 24 and 36 months survival rates were 29%in LD and 9%in ED. Myelosuppression was the main form of toxicity. Conclusion: The combination of CEV is a new active and well-tolerated regimen in the treatment of SCLC. Prospective randomized studies of CEV with conventional chemotherapy are warranted. J Clin Oncol 10:818-823. © 1992 by American Society of Clinical Oncology.
T
a 92% overall response rate in extensive disease (ED). Myelosuppression was the main toxicity. 29 We attempted to improve the antineoplastic activity of carboplatin and etoposide by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in SCLC.30 The optimal schedule of CEV has been investigated in untreated patients with extensive disease in a phase I study in which an 88% overall response rate, including 33% CRs, were achieved in 20 assessable patients.3 1 A phase II study with CEV was carried out in LD, ED, and SCLC, and is the subject of this report.
HE COMBINATION of cisplatin and etoposide is one of the most active regimens in the treatment of small-cell lung cancer (SCLC)1,2 with antineoplastic activity comparable to the more frequently used cyclophosphamide, doxorubicin, and vincristine (CAV) regimen. 3-23 The major toxic effects of treatment with cisplatin and etoposide are nausea, vomiting, and nephrotoxicity, which are mainly induced by cisplatin. 3-6 Furthermore, treatment duration may be limited because of neurotoxicity (peripheral neuropathy, ototoxicity), which is related to the cumulative dose of cisplatin. 4 Carboplatin, a second-generation platinum analog, induced statistically significantly less nephro-, oto-, and neurotoxicity and vomiting when compared with cisplatin in three randomized studies.24 Carboplatin is one of the most active agents in untreated SCLC. 2 In three disease-oriented phase II studies with a total of 66 patients, a 61% overall response rate including 14% complete responses (CRs) was achieved. 25 -27 Data on the antineoplastic activity and toxicity of the combination of carboplatin and etoposide in SCLC were initially published by the Royal Marsden Hospital in 1985 and updated in 1987.28,29 In this study, 30% CR and 87% overall response rates were achieved in limited disease (LD), whereas there were no CRs but
PATIENTS AND METHODS PatientSelection Patients with histologically confirmed SCLC with bidimensionally measurable indicator lesions or assessable disease on physical examination (chest x-ray or computed tomographic [CT] scan) were enrolled. Eligibility requirements included an age > 18 to < 75 years, a life expectancy of at least 3 months, a performance status of < 2 on the World Health Organization (WHO) scale, no brain metastases, no prior chemotherapy or radiotherapy, adequate bone marrow, renal and hepatic functions, and serum electrolytes within the normal range. All patients gave informed consent to participate in this study. Staging and Follow-Up Procedures
From the Departmentof Thoracic Oncology, GrosshansdorfHospital, Department of Hematology, University Hamburg, Germany; and Bristol-Myers Squibb PharmaceuticalGroup, Princeton,NJ. Submitted January 28, 1991; acceptedDecember 19, 1991. Address reprint requests to U. Gatzemeier, MD, Department of Thoracic Oncology, GrosshansdorfHospital, Center of Pneumology and Thoracic Surgery, W-2070 Grosshansdorf,Germany. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1005-0019$3.00/0
818
The pretreatment evaluation consisted of a complete medical history, physical examination, and laboratory workup with complete hemogram (differential and platelet count), serum creatinine, bilirubin, SGOT, SGPT, alkaline phosphatase, electrolytes, and creatinine clearance. The staging procedures included bronchoscopy, x-ray, and CT scan of the chest, CT scan of the brain, CT scan and ultrasound of the abdomen, bone scan, and bone marrow biopsy. Bone lesions were measured by roentgenography.2 LD was defined as tumor confined to one hemithorax but including mediastinal involvement and ipsilateral supraclavicular
Journal of Clinical Oncology, Vol 10, No 5 (May), 1992: pp
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8 18
- 82 3
819
CEV IN SCLC Table 1. Patient Characteristics
lymph nodes. ED denoted any involvement beyond these confines 32 including pleural effusion. The size of neoplastic lesions was determined before each cycle and 4 weeks after the last cycle of chemotherapy. Complete hemogram, serum creatinine, creatinine clearance, electrolytes, and liver function tests were performed before each cycle and 4 weeks after the last cycle of chemotherapy. During chemotherapy, complete blood counts were monitored weekly. After completion of treatment, follow-up examinations were done every 3 months.
No. of patients Male/female ratio Age, years (median) Range WHO performance status Median Range 0 1 2 Stage of disease LD ED
Treatment Plan This study was designed as a nonrandomized phase II study. Chemotherapy consisted of carboplatin 300 mg/m2 intravenously 2 (IV) on day 1, etoposide 140 mg/im IV on days 1 to 3, vincristine 2 1.4 mg/m (maximum 2 mg) IV on days 1, 8, and 15. Carboplatin and etoposide were given as IV infusions over 30 and 60 minutes and vincristine as an IV bolus injection. Carboplatin was given without prehydration and posthydration. Low-dose antiemetics were administered prophylactically. Vincristine was withdrawn if peripheral neurotoxicity of a WHO grade 1 occurred. Cycles were repeated every 4 weeks if WBC and platelet counts were > 4 x 109/L and Ž 100 x 109/L or on recovery to these values. Six cycles of chemotherapy were planned for all responding patients. Radiotherapy All patients with LD and patients with ED without distant metastases who achieved complete remission were offered simultaneous chest and prophylactic cranial irradiation. Additionally, patients with these stages of disease who achieved a very good partial response (PR) were offered chest irradiation. Chest irradiation was administered at a tumor dose of 46 Gy, given in single doses of 2 Gy five times per week over a period of 4 to 5 weeks. The irradiation field encompassed the primary tumor and the whole mediastinum up to the jugulum. Supraclavicular regions were included in case of supraclavicular lymph node involvement. Source for radiotherapy was a linear accelerator (8 MEV photones). Brain irradiation was given in fractions of 2.5 Gy four times per week up to 30 Gy by lateral opposed fields. Treatment, Response, and Toxicity Patients were considered assessable for response and toxicity if they had received at least one cycle of chemotherapy. Tumor response and response duration were classified according to WHO criteria.33 Toxicity was evaluated by worst event for each organ 33 system using the WHO scale. CRs underwent a bronchoscopy and biopsy evaluation. Median response duration and median survival time were estimated by the Kaplan-Meier method. Survival was calculated from the first day of treatment.
patients received at least one cycle of chemotherapy and were assessed for response and toxicity. Their clinical characteristics are summarized in Table 1. Sixty-three
0 0-2 70 46 5 63 58
patients presented with LD and 58 with ED. One hundred twenty-one patients received a total of 442 cycles of chemotherapy. The median number of cycles per patient was four (range, one to six). Vincristine was withdrawn at a median total dose of 10 mg (range, 6 to 24 mg). Seven patients received only one cycle of chemotherapy because of rapid tumor progression. Fortytwo CRs (35 LD and seven locally ED) received chest and prophylactic brain irradiation. Additionally, 24 patients (22 LD and two locally ED) who achieved a good PR after six cycles of chemotherapy underwent chest irradiation. Response Rates, Response Duration,and Survival CEV induced in 121 patients, 52 (43%) CRs, and 48 (39%) PRs, an overall response rate of 83% (95% confidence interval [CI], CR 34% to 52%; CR + PR 76% to 96%; Table 2). The objective response rate was 90% in LD and 83% in ED (Table 2) (95% CI, 82% to 98% in LD; 73% to 93% in ED). CR rates were 56% in LD and 35% in ED. The 95% CI for CR was 43% to 69% in LD and 22% to 48% in ED. Twenty-four patients (22 LD and two locally ED without distant metastases) who achieved a good PR after six cycles of chemotherapy underwent subsequent chest irradiation. In eight (36%) of 22 patients with LD, the PRs were converted into CRs, resulting in a CR rate of 68% (43 of 63) in LD. Table 2. Response by Stage of Disease
RESULTS
A total of 127 consecutive patients were entered onto the study from April 1987 to August 1988. Six patients were not assessable because four patients had nonSCLC, one refused treatment during the first cycle, and one was lost to follow-up. One hundred twenty-one
121 91/30 61 23-76
CR
CR&PR
Stage
No. of Patients
No.
%
No.
%
All
121
52
43
100
83
LD
63
35
(33-43) 56
(43-69) ED
58
20
35 (22-48)
NOTE. 95%confidence limits in parentheses.
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(76-96) 57
90
(82-98) 48 83 (73-93)
820
GATZEMEIER ET AL
Median follow-up exceeded 30 months. The median remission duration was 8.5 months, 6 months in ED, and 11.5 months in LD. Median survival for all patients was 10.5 months, 14 months for LD, and 9.5 months for ED (Fig 1). Patients with chemotherapeutically induced CR have a median survival time of 18 months, CRs after chemotherapy and radiotherapy have a median survival time of 13 months. The percentage of 24- and 36-month survivors is 29% each in LD, and 9% each in ED. Sites of Relapse Thirty-five (58%) of 60 patients who achieved a CR after CEV alone or after CEV with sequential chest irradiation have relapsed so far. Twenty-three percent (eight of 35) of the patients had intrathoracic and 32% (11 of 35) extrathoracic relapses. Chest and extrathoracic relapses were observed in 45% (16 of 35) of the patients. Most patients showed multiple sites of relapses and/or brain metastases. CNS metastases were observed in 49% (17 of 35) of patients. The liver and bones were the sites of relapse in 17% (six of 35) and in 14% (five of 35) of the patients. Only six patients developed isolated CNS metastases, all of whom had received prophylactic cranial irradiation.
median thrombocyte nadir was 128 x 109/L. Recovery of leukocytes and thrombocytes was usually complete by days 21 to 23 and 19 to 21. The main nonhematologic toxicities were nausea, vomiting, alopecia, and peripheral neuropathy. Vomiting of WHO grades 3 and 4 was observed in 22% and 2% of patients, respectively, and alopecia of grade 3 occurred in 81% of patients. Peripheral neuropathy of WHO grades 2 and 3 was induced in 28% and 4% of patients, respectively. This side effect was reversible after vincristine withdrawal. No nephrotoxicity or ototoxicity was observed. DISCUSSION One part of the current investigative strategies for SCLC is the design of more active and/or less toxic regimens using existing antineoplastic agents. Earlier studies had shown that the combination of cisplatin and etoposide is highly active as first-line and salvage treatment in SCLC.3 -8,28,34 Carboplatin and etoposide was
investigated in LD SCLC in two trials, and in ED SCLC in four. 29,35-37 The data of these studies suggest that
carboplatin and etoposide might be less active than cisplatin and etoposide in both LD and ED, especially 37 3 8 29 30 34 regarding CR rates and median survival times. - , , , -
37 The use of carboplatin and etoposide at higher dosages showed comparable antineoplastic activity, but more 29 35 36 severe myelosuppression than at lower dosages. , ,
Toxicity Myelosuppression was the major side effect experienced by patients (Table 3). Leukopenia of WHO grades 3 and 4 was observed in 19% and in 7% of patients; thrombocytopenia grades 3 and 4 occurred in 12% and in 9% of patients. No severe anemia was observed. Median leukocyte nadir was 3.1 x 109/L and
The addition of ifosfamide, 38,39 ifosfamide and vincristine, 40 and cyclophosphamide and vincristine4 1 to carboplatin and etoposide resulted in improved CR rates with comparable or higher overall response rates and median survival times (Table 4).29,35-41 However, these combinations induced leukopenia and thrombocytopenia of WHO
1001 80 60 C) 40 is
- -limited
20
extensive U
U.~~
0
0
I 5
I 10
I 15
I 20
I 25
Time (Months)
i
I
30
35
40 Fig 1. CEV in SCLC; survival according to stage.
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821
CEV IN SCLC Table 3. Worst Toxicities With Assessable Patients According to WHO Scale WHO Grades 0
Leukocytes Thrombocytes Hemoglobin Neurotoxicity (peripheral) Fever Nausea/vomiting Obstipation Alopecia
1
2
3
4
No.
%
No.
%
No.
%
No.
%
No.
%
18 54 43 17 119 5 112 6
15 45 36 14 98 4 93 5
29 17 58 65 1 40 5 4
24 14 48 54 1 33 4 3
43 24 20 34 1 46 1 13
36 20 17 28 1 38 1 11
23 15 0 5 0 27 3 98
19 12 0 4 0 22 2 81
8 11
7 9
0 3 0 0
2
age of long-term survivors. The antineoplastic activity of CEV is similar to that of the other carboplatin containing three- and four-drug regimens. However, the hematologic toxicity of CEV was minimal compared with these combinations. Leukopenia of grades 3 and 4 occurred in 19% and 7% of patients; thrombocytopenia of grades 3 and 4 was observed in 12% and 9% of patients. CEV results in similar CR rates, overall response rates, median survival times, and percentage of 24-month survivors as compared with the more frequently used combinations of cisplatin and etoposide, CAV, or CAV alternating with cisplatin and etoposide in LD and in ED (Table 5). The antineoplastic activity of
grades 3 and 4 in 74% to 100% and 57% to 85% of the patients, respectively. 38,40,41 Life-threatening leukopenia and thrombocytopenia occurred in 43% to 81% and in 16% to 50% of the patients, respectively, and infections of WHO grades 3 and 4 were observed with a frequency between 7% and 37%.38,40,41 To avoid life-threatening hematologic toxicities, we added only vincristine as the third drug to carboplatin and etoposide because of its low myelosuppressive potential and its activity in SCLC. In the present study, CEV induced higher CR and overall response rates in LD and ED patients than carboplatin and etoposide, and a similar median survival time and a higher percent-
Table 4. SCLC. Phase II Studies With Carboplatin Containing Regimens CR + PR
CR Chemotherapy
Stage of Disease
No. of Patients
No. of Studies
Carboplatin/ifosfamide
ED
30
1
Carboplotin/etoposide
ED
157
4
LD
63
2
ED
30
2
Carboplatin/etoposide/ifosfamide
Carboplotin/etoposide/ifosfamide/ vincristine Carboplatin/etoposide/cyclophosphamide/vincristine
CEV
LD
18
1
LD
30
1
ED
50
1
LD
40
1
ED
58
1
LD
63
1
-
Survivor % at 24 Months
No.
%
No.
%
MS (months)
1
3
19
63
8
nr
Le Chevalier et a1
8-12
nr
10-15
nr
8-9
nr
Smith aeta1 3 Bishop et al Evans et al36 et a137 Luikort et Smith et al129 35 Bishop et a1 Smith et al03
19
nr
Hornedo et a39 3 Smith et aPl
14
37
Thatcher et al40
9,6
5
13
30
9,5
9
Own data
14
29
Own data
(3-6) 20 13 (8-18)
(45-81) 100 65 (57-73)
22 35 (23-47) 30 9 (13-47) 13 72 (51-93) 16 50 (32-68) 11 22 (10-34) 60 24 (45-75) 20 35 (22-48) 35 56 (43-69)
50 79 (69-89) 27 90 (78-102) 17 94 (83-105) 23 77 (62-92) 76 38 (64-88) 83 33 (71-95) 48 83 (73-93) 57 90 (82-98)
NOTE. There were > 14 patients per study. 95% confidence limits are in parentheses. Abbreviations: MS, median survival; nr, not reported.
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Authors 42
29
Bishop et a141 Bishop aeta14
822
GATZEMEIER ET AL Table 5. SCLC Studies With Carboplatin/Etoposide/Vincristine and More Frequently Used Regimens Chemotherapy
CEV
Cisplatin/etoposide
CAV
CAV alternating with cisplatin/etoposide
NOTE. There were
2
Stage of Disease
No. of Patients
No. of Studies
LD
63
1
ED
58
1
LD
45
2
ED
330
7
LD
387
7
ED
1137
14
LD
152
1
ED
290
2
CR%
CR + PR%
56 (43-69) 35 (22-48) 56 (41-71) 26 (21-31) 49 (45-53) 15 (13-17) 52 (44-60) 29 (24-34)
90 (82-98) 83 (73-93) 89 (80-98) 70 (65-75) 73 (69-77) 59 (56-62) 82 (76-88) 69 (64-74)
MS (months)
Survivors (%) at 24 Months
Reference
14
29
Own data
9,5
9
Own data
15-17
23-30
3,4
9-15
5-10
3-8
11-16
15-23
6-11
0-8
12-14,16 38-40 8-18,42
15
20
41
9-10
nr
8,9
14 patients per study. 95% confidence limits are in parentheses.
CEV seems promising in ED because 78% of patients had extrathoracic disease, which is generally considered an unfavorable prognostic factor for response and survival. 32
The percentage of 24-month survivors after CEV is high (29% of patients with LD and 9% of patients with ED) and in the upper range as observed thus far. CEV given in the dosages used in this study induced markedly less life-threatening leukopenia than CAV or CAV alternating with cisplatin and etoposide. After CAV at higher dosages and after CAV alternating with cisplatin and etoposide was given, leukopenia of grade 4 was observed in 40% to 70% of the patients, 9,10 ,13, 19,20 and
after CEV was given, in 7% of the patients. The rate of peripheral neuropathies is relatively high after CEV but comparable to CAV with weekly administered vincristine. 21 The nephrotoxicity occurring after cisplatincontaining regimens was not observed in our study. 4-6 In conclusion, the activity of CEV in SCLC is comparable to or higher than that of the more frequently used chemotherapies regarding CR and overall response rates. The high proportion of long-term survivors observed in this study is gratifying. The encouraging results of our study warrant a direct comparison of the efficacy of this combination with conventional chemotherapy in prospective randomized studies.
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823
CEV IN SCLC phosphamide 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 7:450-456, 1989 14. Jackson DV, Case LD: Small-cell lung cancer: A 10-year perspective. Semin Oncol 13:63-74, 1986 (suppl 3) 15. Livingston RB, Schulman S, Mira JG, et al: Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: A Southwest Oncology Cancer Group study. Cancer Treat Rep 70:1395-1401, 1986 16. Messeih AA, Schweitzer JM, Lipton A, et al: Addition of etoposide to cyclophosphamide, doxorubicin, and vincristine for remission induction and survival in patients with small cell lung cancer. Cancer Treat Rep 71:61-66, 1987 17. Feld R, Evans WK, De Boer G, et al: Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol 2:294-304, 1984 18. Livingston RB, Moore TN, Heilbrunn L, et al: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Int Med 88:194-199, 1978 19. Figueredo AT, Hryniuk WM, Strautmanis I, et al: Cotrimoxacole prophylaxis during high-dose chemotherapy of smallcell lung cancer. J Clin Oncol 3:54-64, 1985 20. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2:1200-1208, 1984 21. Niederle N, Krischke W, Schulz U, et al: Untersuchungen zur kurzzeitigen Induktions- und zyklischen Erhaltungstherapie beim inoperablen kleinzelligen Bronchialkarzinom. Klin Wschr 60:829-838, 1982 22. Feld R, Evans WK, Coy P, et al: Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 5:1401-1409, 1987 23. Holoye PY, Samuels ML, Lanzotti VJ, et al: Combination chemotherapy and radiation therapy for small cell carcinoma. JAMA 237:1221-1224, 1977 24. Rozencweig M, Martin A, Beltangady M, et al: Comparison of carboplatin and cisplatin given as first-line single-agent chemotherapy for stage III-IV ovarian cancer: A meta analysis of three randomized trials, in Bunn PA, Canetta R, Ozols RF, et al (eds): Carboplatin (JM-8)-Current Perspectives and Future Directions. Philadelphia, PA, Saunders, 1990, pp 175-186 25. Smith IE, Harland SJ, Robinson BA, et al: Carboplatin: A very active new cisplatin analog in the treatment of small cell lung cancer. Cancer Treat Rep 69:43-46, 1985 26. Jacobs RH, Bitran JD, Deutsch M, et al: Phase II study of carboplatin in previously untreated patients with metastatic small cell lung carcinoma. Cancer Treat Rep 71:311-312, 1987 27. Pallar6s C, L6pez ULpez JJ, Paredes AL, et al: First-line carboplatin (CBDCA) 24 hours infusion on patients (PTS) with disseminated oat cell carcinoma of the lung. Proc Eur Conf Clin Oncol 4:7, 1987 (abstr 26)
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