- Email: [email protected]
Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress?
Lung Cancer 20 (1998) 151 – 160
Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress? Ulrik N. Lassen a,*, Fred R. Hirsch a, Kell Østerlind b, Bengt Bergman c, Per Dombernowsky d a
Finsen Center, Department of Oncology 5074, Rigshospitalet, 9 Blegdams6ej, DK-2100 Copenhagen, Denmark b Medical Department F, Hillerød Sygehus, DK-3400 Hillerød, Denmark c Department of Pulmonary Medicine, Sahlgrenska Hospital, Gothenburg, Sweden d Department of Oncology, Herle6 Uni6ersity Hospital, DK-2730 Herle6, Denmark Received 29 October 1997; received in revised form 10 February 1998; accepted 11 February 1998
Abstract During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973–1981) were compared with 585 patients treated in the late period (1981–1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P= 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: SCLC; Extensive stage; Stage migration; Prognostic factors; Survival
1. Introduction
* Corresponding author. Tel.: + 45 35453986; fax: + 45 35453990; e-mail: [email protected]
Since the introduction of combination chemotherapy in the treatment of small-cell lung cancer (SCLC) in the 1970s many different mod-
0169-5002/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0169-5002(98)00011-7
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
152
Table 1 Main outcome measures of patients with extensive stage SCLC included in six consecutive randomised trials from 1973 to 1992 Trial (ref.)
Arm
No. patients
Regimen
CR (%)
OR (%)
MS (weeks)
1-year (%)
1973–76 [14]
A B A B A B C A B A B C A B C
53 58 76 70 89 92 88 150
LCbM LCbMV LCMV LCMV+DE LCMV LCEV (E15) LCEV (E2) LCVE/CEV LCVE/CEVc LCVM+DEV as A/PvdH LCVE/PDVdMH PTV/as arm ‘C’ JTV/as arm ‘C’ CLV/EDV/PVdH
4 9 17 23 24 23 30 28
68 67 68 72 69 66 74
25 33 40 54 28 32 48 28
10 25 27 30 15 14 22 19
25 18 18 26 30 24
70 73 62 69 64 54
46 48 38 48 49 42
20 26 16 32 28 22
1976–78 [17] 1978–81 [19]
1984–86a 1981–85 [21]
1985–92 [22]
69 68 66 76 79 77
P-value 0.01 NS B0.05
NS
NS
L, lomustine; C, cyclophosphamide; M, methotrexate; V, vincristine; D, doxorubicin; E, etoposide; P, cisplatin; Vd, vindesine; H, hexamethylmelamine; T, teniposide; J, carboplatin; NS, not significant; E2, etoposide orally day 3 – 6; E15, etoposide orally day 14–17. a Unpublished results. b Cyclophosphamide dose 700 mg/m2; other trials 1000 mg/m2. c Complete responders randomised to vincristine and either intermittent high dose C+E or continuously orally treatment with C+E.
ifications have been investigated. These include the introduction and addition of more active drugs, early and late intensification, alternating regimens, combined radio-chemotherapy and biologic response modifiers. In limited stage of disease, in particular thoracic radiotherapy has resulted in improved overall survival [1] whereas the impact of modern chemotherapy with platinum compounds and epipodophyllotoxins has not been completely clarified. However, in extensive disease overall survival has remained at a plateau in the past two decades and the need for new active drugs and new treatment strategies is striking. The initial optimism for chemotherapy is more tempered and many studies now deal with aspects of reducing toxicity without interfering with the outcome [2 – 4]. Extensive stage SCLC has been subject to many Phase II trials of intensive chemotherapy and new drugs have often been tested in patients with poor prognosis, e.g. patients with recurrent SCLC [5]. The early studies of etoposide in previously treated SCLC yielded poor objective response rates, but subsequent studies with previously un-
treated patients resulted in response rates of 70– 80% [6]. Recent Phase II trials have demonstrated that new drugs can be safely introduced to chemotherapy naive patients without compromising median survival by treating non-responders with salvage regimens of well-known activity [7]. This makes studies of new treatment strategies possible in patients with more favorable prognosis, but at the same time rises the question how to treat patients with poorer prognosis SCLC. The importance of prognostic factors in SCLC has been intensively studied and many factors have been identified including extensive stage, poor performance status, advanced age and elevated lactate dehydrogenase. Additionally, sex, the severity of symptoms and other biochemical tests have been reported as having a prognostic impact [8–12]. A recent review indicated that the intensification of the treatment of extensive stage SCLC over the past decades has led to improved response rates and survival [13]. In another study the change in outcome over time was related to stage migration due to improved staging procedures [14].
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
153
Table 2 Comparison of pretreatment characteristics of patients with limited and extensive SCLC treated in the two periods Characteristic Sex (% female) Age, median (range) Performance status (%) 0–1 2 3–4 Stage (% extensive) LDH, median (range) U/l (B450, normal) AP, median (range) U/l (B275, normal)
Period 1 (1973 – 81) (N= 963) 28 61 (23–70) 61 21 18 53 500 (180–11 120) 240 (55–3300)
Period 2 (1981 – 92) (N =1131) 35 62 (30 – 70) 60 21 19 55 479 (45 – 12 550) 232 (14 – 3940)
P-value 0.001a 0.02c NSb
NSa NSc NSc
LDH, lactate dehydrogenase; AP, alkaline phosphatase. a 2 x -test. b Mann – Whitney U-test. c One-way ANOVA.
Six randomised trials including patients with extensive stage SCLC and three trials with limited disease were performed in our institution from 1973 –1992 [15–23]: four trials including only extensive stage, and two trials included both stages of SCLC (Table 1). In order to detect a possible treatment-related improved outcome during two decades we compared the outcome of three trials of extensive stage from 1973 to 1981 with three trials including patients with extensive disease from 1981 to 1992. These two periods included a comparable number of patients with extensive disease. The first trials contained three to six drugs in sequential regimens and the latter trials contained sevent to nine drugs administered in sequential or alternating regimens. Prognostic factors were included in this analysis in order to identify possible changes in the population over time.
2. Patients and methods A total of 1111 consecutive patients with extensive stage SCLC entered one of six consecutive randomized trials from 1973 to 1992 at the Finsen Institute, Herlev University Hospital and Bispebjerg Hospital, Copenhagen, Hillerød Hospital, all in Denmark, or Renstro¨mska Hospital, Gothenburg, Sweden (Table 1). All patients had a histo-
logic or cytologic diagnosis of SCLC following the WHO guidelines. Patients older than 70 years of age and patients with prior or simultaneous malignancies, except cone resected cervical cancer or treated basal cell carcinoma of the skin, were excluded. All trials had been approved by the local ethics committee. The first three trials of extensive stage SCLC from 1973 to 1981 included 526 patients (period 1), and the three latest trials from 1981 to 1992 included 585 patients (period 2), two trials with patients of all stages and one trial including patients with extensive disease only. One of the late trials, including 150 patients with extensive disease, was discontinued prematurely. This trial addressed maintenance chemotherapy in responders with two different schedules, but due to a too low randomization rate, the study was closed. The results have not been published and only survival data from these patients is included in the present analysis. Pretreatment staging procedures included physical evaluation, chest radiographs, bronchoscopy with biopsy and bilateral bone marrow aspiration and biopsy. Peritoneoscopy with liver biopsy was performed in the first period and replaced by ultrasonography with liver biopsy in the second period. Radionuclide or computed tomography (CT) of brain metastases were only performed if clinically suspected. Blood tests included complete cell counts (CBC), serum creatinine, sodium and
154
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
Table 3 Comparison of pretreatment characteristics of patients with extensive disease treated in the two periods Characteristic Sex (% female) Age, median (range) Performance status (%) 0–1 2 3–4 Distant metastases (%) Liver Bone marrow Brain LDH, median (range) U/l (B450, normal) AP, median (range) U/l (B275, normal)
Period 1 (1973 – 81) (N=526)
Period 2 (1981 – 92) (N = 585)
27 61 (23–70)
35 62 (30 – 70)
45 26 29
47 25 28
33 35 11 642 (200–11 120) 278 (70–3300)
40 33 12 634 (45 – 12 550) 278 (14 – 3940)
P-value 0.001a NSc NSb
0.01a NSa NSa NSc NSc
x 2-test. Mann – Whitney U-test. c One-way ANOVA. a
b
potassium, serum urate, lactate dehydrogenase (LDH) and alkaline phosphatase (AP). In the early period, three randomized trials of patients with limited stage SCLC were also performed [16,19,22]. The pretreatment characteristics of these patients and of the patients with limited stage in the late period were included in the comparison of prognostic factors within the two periods.
3. Statistics Construction of a database and statistical analysis were carried out using the statistical package SPSS for Windows. Patient characteristics in the two groups were compared using one-way ANOVA for continuous data, Mann – Whitney U-test for ordinal data, and a x 2-test for discrete data. All tests were two-sided with a P-value threshold of 0.05. Survival analysis was based on the Kaplan–Meier method and comparisons were made using the Kaplan – Meier log-rank test. Estimation of hazard ratios and tests for interactions between potential prognostic factors were made with Cox proportional hazard regression model with a P-value threshold of 0.01.
4. Results
4.1. Pretreatment characteristics The distribution of pretreatment characteristics between the two groups is listed in Table 2. A significant increase in the frequency of female patients (P= 0.001) and the frequency of elderly patients (P= 0.02) due to a 2% increase in patients 65–70 years of age was observed during the time periods. No differences between the two groups were observed with respect to performance status, extent of disease, elevated lactate dehydrogenase (LDH) and alkaline phosphatase (AP). Table 3 shows the distribution between the two treatment periods of pretreatment characteristics in patients with extensive disease only. In contrast to the results of the whole patient population (Table 2) the distribution of the age in patients with extensive disease was equal in the two periods. Female patients were more frequent in the late period. The detection of liver metastases significantly increased from 32 to 41% (PB0.005). No differences in the distribution of other characteristics, including other metastatic sites, were observed between the groups. A Cox regression analysis of independent prognostic factors of survival was performed. The
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
155
Table 4 Cox regression analysis of factors of independent influence on survival for 1111 patients with extensive disease, treated from 1973 to 1992 Variable
Estimate (B)
Relative risk (RR)
95% CI for RR
P-value
Period Age Sex PS Liver metastases BM metastases Brain metastases LDH AP
−0.04 0.17 −0.02 0.21 −0.02 0.14 0.30 0.28 0.17
0.96 1.19 0.98 1.23 0.98 1.15 1.35 1.33 1.19
0.85 – 1.09 1.09 – 1.30 0.86 – 1.13 1.16 – 1.31 0.85 – 1.14 1.00 – 1.32 1.10 – 1.67 1.21 – 1.45 1.09 – 1.30
0.57 0.0001 0.80 B0.0001 0.84 0.05 0.005 B0.0001 0.001
CI, confidence intervals; BM, bone marrow; LDH, lactate dehydrogenase; AP, alkaline phosphatase. Categories: Period, 1973 – 1981= 0, 1981 – 1992 = 1; age, B55=0, 55–64 =1, \64= 2; sex, male =0, female =1; PS, WHO performance status; stage, limited= 0, extensive= 1; LDH, 0–450 = 0, 450–900= 1, \900=2; AP, 0 – 275 = 0, 275 – 450=1, \450= 2.
impact of time as an independent prognostic factor in extensive stage SCLC was assessed by introducing a variable with the value 0 for period 1 (1973–1981) and the value 1 for period 2 (1981 – 1992). Young age, good performance status and normal LDH and AP were all independent factors with a significant impact on survival. Female gender and period had no prognostic impact. The presence of brain metastases was correlated with a poor prognosis, while bone marrow metastases and liver metastases had no independent influence on survival (Table 4). A separate Cox regression analysis was performed for each treatment period for patients with extensive disease. In both periods good performance status and normal LDH favored a good prognosis. Age was a significant prognostic factor only in the early period whereas elevated AP became a negative prognostic factor in the late period (Table 5).
ferences were observed between the two periods (Fig. 1, P= 0.49, log-rank test). The grade of myelosuppression in the two periods is displayed in Table 6. In the early period, grade IV leukopenia occurred in 24% of the patients and in the late period in 42% (P B 0.001). Febrile neutropenia occurred in 19 and 34% (PB 0.001). The presence of several poor prognostic factors might confound treatment-related benefits. In order to detect a possible improved outcome in patients with extensive disease, but without other poor prognostic factors, a separate analysis of patients with extensive disease, performance status 0–2, age below 65 years and normal level of LDH was made. However, median survival was equal in the two periods (354 days and 359 days, respectively) and a comparison of data from the two treatment periods could not disclose any change over time in survival or in objective response rates.
4.2. Outcome Patients treated in the late period had a higher complete response rate. In the early period CR was 20% compared to 25% in the late period (P = 0.05). However, no difference in overall response rates was observed (66 vs 65%, P = 0.9). Also 1-year survival (20.5 vs 25.6%), 2-year survival (4.5 vs 6.9%) and 5-year survival rates (2.5 vs 2.4%) were comparable and no statistical dif-
5. Discussion A recent review [13] has focused on the outcome of extensive stage SCLC over the last decade. Studies from single institutions and cooperative groups included in the latter review showed an increase in objective response rates and it was suggested that more aggressive treatment
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
156
Table 5 Cox regression analysis of factors with independent influence on survival in patients with extensive disease, treated 1973 – 1981 and 1981–1992 Variable
Estimate (B)
Relative risk (RR)
95% CI for RR
P-value
1973–1981 Age PS Liver mets. BM Brain LDH AP
0.21 0.22 −0.19 0.18 0.28 0.36 0.10
1.24 1.24 0.83 1.19 1.32 1.43 1.11
1.09 – 1.41 1.13 – 1.37 0.66 – 1.03 0.96 – 1.47 1.01 – 1.73 1.02 – 2.02 0.97 – 1.26
0.001 B0.0001 0.08 0.10 0.04 0.0001 0.12
1981–1992 Age PS Liver mets. BM Brain LDH AP
0.14 0.20 0.12 0.13 0.28 0.25 0.23
1.15 1.23 1.13 1.14 1.32 1.28 1.25
1.02 – 1.30 1.13 – 1.33 0.92 – 1.39 0.95 – 1.37 1.01 – 1.73 1.13 – 1.45 1.12 – 1.41
0.03 B0.0001 0.23 0.17 0.04 0.0001 0.0001
CI, confidence intervals; liver mets., liver metastases. Categories: age, B55= 0, 55 – 64 = 1, \64= 2; sex, male =0, female = 1; PS, WHO performance status; stage, limited = 0, extensive= 1; LDH, 0 – 450= 0, 450 – 900=1, \900= 2; AP, 0 – 275= 0, 275 – 450=1, \450=2.
had led to improved outcome. However, a majority of the reviewed studies were Phase II studies including few patients. Furthermore, response rates in general are higher in most Phase II studies. In the present analysis of 1111 patients with extensive disease treated in our own cooperative group the rate of complete remission significantly increased, but survival and overall response rates remained unchanged. The outcome was similar to the results of other large Phase III trials [24 – 27]. The patients included in our randomized trials were unselected except from an upper age limit of 70 years. Female gender was more frequent in the late period, but gender had no prognostic impact in extensive stage SCLC. The frequency of extensive disease was equal in the two periods (53 and 55%, respectively). This was less frequent than reported in most studies from the United States. The reason for this is not clear, but perhaps reflects differences in staging procedures. The staging procedures used followed the general recommendations. However, bilateral bone marrow biopsy and aspiration (BM) was used as a standard to detect bone marrow involvement whereas radionuclide bone scan was not used. Bone scan
seems to be superior to unilateral BM [28]. Bilateral BM has not been compared with bone scan, but these modalities are regarded as complimentary. Furthermore, thoracic CT was not performed routinely in either periods, because radiotherapy was not applied in patients with limited disease. Stage migration was not observed even though the frequency of liver metastases increased over time. This was probably due to the introduction of ultrasonography as a replacement of peritoneoscopy in the early 1980s [29]. Ultrasonography and abdominal CT-scan are considered more sensitive than peritoneoscopy [30] and this could lead to the assumption that extensive stage was under-diagnosed in the early trials. However, the frequency of patients with extensive stage SCLC did not change. A possible explanation could be that more patients in the early period in fact did have advanced disease, but were classified as having limited stage. However, this would result in an inferior survival of both stages in this period. A stage migration due to improved staging procedures would then lead to an improved survival over time both in limited and extensive stage of disease. This was not the case as
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
157
Fig. 1. Kaplan – Meier plot of overall survival of the two groups, extensive stage only; (- - -) early period 1973 – 1981, N= 508, median survival 208 days (95% CI, 191–225 days); (——) late period 1981 – 1992, N= 623, median survival 215 days (95% CI, 194–236 days); P =0.49, log-rank test.
the outcome of patients with extensive disease was equal in both treatment periods. In a study of prognostic factors in 411 patients treated from 1973–1987, a change over time was observed in the prognostic importance of distant metastatic sites [14]. In the early era brain metastases were associated with a shortened survival, but not in the recent era. On the other hand, liver metastases were a negative prognostic factor only in the recent era. In our series, the change of diagnostic procedures apparently did not lead to stage migration. In the Cox regression analysis of patients with extensive disease the presence of brain metastases was associated with a poor survival in both periods. Brain scans were only performed in patients with clinical suspected brain metastases and patients with symptoms have a poorer prognosis than patients with subclinical brain metastases.
The improved detection of liver metastases with ultrasonography had no prognostic impact. Dose intensity in the present study was evaluated only by comparison of hematological toxicity in the two periods. According to this the grade of myelosuppression has increased but a complete comparison of delivered doses was not performed. However, it seems that the regimens have been more aggressive in the 1980s than in the 1970s (Table 6). This is indicated by the steep initial slopes of the survival curves from the late period (Fig. 1) which relates to early toxic deaths. The introduction of four-drug chemotherapy, including vincristine, led to a clear improvement in response rates and survival in SCLC [15]. The present data indicate that the addition of more than four drugs led to no further benefits in extensive disease and neither did the introduction of alternating schedules of different combinations.
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
158
Table 6 WHO grade IV leukopenia and febrile neutropenia in the trials from 1973 to 1992 Trial
Regimen
Grade IV leukopenia (%)
Febrile neutropenia (%)
Ref. [15] Arm A Arm B
LCaM LCaMV
13 9
6 2
Ref. [18] Arm A Arm B
LCMV LCMV+DE
23 22
13 9
Ref. [20] Arm A Arm B Arm C
LCMV LCEV (E15) LCEV (E2)
25 19 51
22 27 40
Ref. [21] Arm A Arm B Arm C
LCVM+DEV as A/PvdH LCVE/PDVdMH
34 29 78
25 21 69
Ref. [23] Arm A Arm B Arm C
PTV/as arm ‘C’ JTV/as arm ‘C’ CLV/EDV/PVdH
37 31 45
30 32 28
Grade IV leukopenia was more frequent in the late period ([15,18,20] versus [21,23], PB0.001) and febrile neutropenia was more frequent in the late period [15,18,20] versus ([21,23], PB0.001). The trial from 1984 to 86 was not included in this analysis, because it was discontinued prematurely and complete toxicity data have not been assessed. L, lomustine; C, cyclophosphamide; M, methotrexate; V, vincristine; D, doxorubicin; E, etoposide; P, cisplatin; Vd, vindesine; H, hexamethylmelamine; T, teniposide; J, carboplatin E2, etoposide orally day 3–6; E15, etoposide orally days 14 – 17. a Cyclophosphamide dose 700 mg/m2; other trials 1000 mg/m2. b Complete responders randomised to vincristine and either intermittent high dose C+E or continuously orally treatment with C+E.
Accordingly, the introduction of more aggressive chemotherapy with epipodophyllotoxins and platinum compounds resulted in a modest increase in complete response, but no change in overall response rates.
6. Conclusion Although long-term survival can be observed in all stages of SCLC, the prognosis in patients with extensive SCLC remains poor. In a recent randomized trial from our own group, the median survival of extensive stage SCLC was 37 weeks with the best treatment regimen [23]. The median survival of patients with extensive stage SCLC and poor prognostic factors such as poor performance status, age over 65 years and ele-
vated LDH, is below 8 weeks and intensive treatment does not seem feasible in these patients. In a randomised study of patients with extensive SCLC and poor prognosis, no survival benefit was obtained with four-drug chemotherapy compared to a less intensive two-drug combination [2]. Less intensive treatment is preferable for these patients aiming at tumor reduction as best palliation. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.
Acknowledgements This study was supported by The Foundation for the Support of Medical Cancer Treatment.
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
References [1] Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. New Engl J Med 1992;327:1618–24. [2] Girling DJ, Hopwood P, Lallemand G, et al. Randomised trial of four-drug 6s less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Br J Cancer 1996;73:406 – 13. [3] Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577–80. [4] Girling DJ, Thatcher N, Clark PI, et al. Comparison of oral etoposide and standard multidrug intravenous chemotherapy for small cell lung cancer: a stopped multicentre randomised trial. Lancet 1996;348:563–6. [5] Grant SC, Gralla RJ, Kris MG, et al. Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: The case for studies in previously treated patients. J Clin Oncol 1992;10:484–98. [6] Bork E, Ersbøll J, Dombernowsky P, et al. Teniposide and etoposide in previously untreated small cell lung cancer: A randomized study. J Clin Oncol 1991;9:1627– 31. [7] Ettinger DS, Finkelstein DM, Abeloff MD. Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: An Eastern Cooperative Oncology Group randomized study. J Natl Cancer Inst 1992;84:1077–84. [8] Sagman U, Feld R, DeBoer G, et al. Small cell carcinoma of the lung — Derivation of a prognostic index (Abstr). Clin Invest 1986;27:189. [9] Souhami RL, Bradbury I, Geddes DM, et al. Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res 1985;45:2878 – 82. [10] Østerlind K, Hansen HH, Hansen M, et al. Long-term disease-free survival in small-cell carcinoma of the lung: A study of clinical determinants. J Clin Oncol 1986;4:1307– 13. [11] Wolf M, Holle R, Hans K, et al. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): The role of sex as a predictor for survival. Br J Cancer 1991;63:986 – 92. [12] Lassen U, Østerlind K, Hansen M, et al. Long-term survival in small-cell lung cancer: Posttreatment characteristics in patients surviving 5 to 18 + years—An analysis of 1714 consecutive patients. J Clin Oncol 1995;13:1215 – 20. [13] Aisner J. Extensive-disease small-cell lung cancer: The thrill of victory; The agony of defeat. J Clin Oncol 1996;14:658 – 65. [14] Dearing MP, Steinberg SM, Phelps R, et al. Outcome of patients with small-cell lung cancer: Effect of changes in staging procedures and imaging technology on prognostic factors over 14 years. J Clin Oncol 1990;8:1042–9.
159
[15] Hansen HH, Dombernowsky P, Hansen M. Chemotherapy of advanced small-cell anaplastic carcinoma: Superiority of four drug combination. Ann Intern Med 1978;89:177 – 81. [16] Hansen HH, Dombernowsky P, Hirsch FR. Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic cranial irradiation in patients receiving combination chemotherapy. Cancer 1980;46:279 – 84. [17] Hansen M, Hansen HH, Dombernowsky P. Long-term survival in small cell carcinoma of the lung. J Am Med Assoc 1980;244:247 – 50. [18] Østerlind K, So¨renson S, Hansen HH, et al. Continuous 6ersus alternating combination chemotherapy for advanced small cell carcinoma of the lung. Cancer Res 1983;43:6085 – 9. [19] Østerlind K, Hansen HH, Hansen HS, et al. Chemotherapy 6ersus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. Br J Cancer 1986;54:7 – 17. [20] Hirsch FR, Hansen HH, Hansen M, et al. The superiority of combination chemotherapy including etoposide based on in vivo small-cell lung cancer: A randomized trial of 288 consecutive patients. J Clin Oncol 1987;5:585 – 91. [21] Pedersen AG, Østerlind K, Vindeløv LL. Alternating or continuous chemotherapy of small cell lung cancer. A three armed randomized trial (Abstr). Proc Am Soc Clin Oncol 1987;6:187. [22] Østerlind K, Hansen M, Hirsch FR. Combination chemotherapy of limited small cell lung cancer. A controlled trial on 222 patients comparing two alternating regimens. Ann Oncol 1991;2:41 – 6. [23] Lassen U, Kristjansen PEG, Østerlind K, et al. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up. Ann Oncol 1996;7:365 – 71. [24] Bleehen NM, Fayers PM, Girling DJ, et al. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 1989;59:584 – 90. [25] Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regiments in extensive small-cell-lung cancer: a Phase II trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282 – 91. [26] Giaccone G, Dalesio O, Mcvie JG, et al. Maintenance chemotherapy in small cell lung cancer: Long-term results of a randomized trial. J Clin Oncol 1993;11:1230 – 40. [27] Souhami RL, Rudd R, Elvira MRD, et al. Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: A Cancer Research Campaign Trial. J Clin Oncol 1994;12:1806 – 13. [28] Levitan N, Byrne RE, Bromer RH, et al. The value of bone scan and bone marrow biopsy staging small cell lung cancer. Cancer 1985;56:652 – 4.
160
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
[29] Hansen SW, Jensen F, Pedersen NT, et al. Detection of liver metastases in small-cell lung cancer: A comparison of peritoneoscopy with liver biopsy and ultrasonography with fine-needle aspiration. J Clin Oncol 1987;5:255–9.
.
[30] Hirsch FR, Østerlind K, Jensen LI, et al. The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer. Ann Oncol 1992;3:469 – 74.
Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress? Ulrik N. Lassen a,*, Fred R. Hirsch a, Kell Østerlind b, Bengt Bergman c, Per Dombernowsky d a
Finsen Center, Department of Oncology 5074, Rigshospitalet, 9 Blegdams6ej, DK-2100 Copenhagen, Denmark b Medical Department F, Hillerød Sygehus, DK-3400 Hillerød, Denmark c Department of Pulmonary Medicine, Sahlgrenska Hospital, Gothenburg, Sweden d Department of Oncology, Herle6 Uni6ersity Hospital, DK-2730 Herle6, Denmark Received 29 October 1997; received in revised form 10 February 1998; accepted 11 February 1998
Abstract During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973–1981) were compared with 585 patients treated in the late period (1981–1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P= 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: SCLC; Extensive stage; Stage migration; Prognostic factors; Survival
1. Introduction
* Corresponding author. Tel.: + 45 35453986; fax: + 45 35453990; e-mail: [email protected]
Since the introduction of combination chemotherapy in the treatment of small-cell lung cancer (SCLC) in the 1970s many different mod-
0169-5002/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0169-5002(98)00011-7
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
152
Table 1 Main outcome measures of patients with extensive stage SCLC included in six consecutive randomised trials from 1973 to 1992 Trial (ref.)
Arm
No. patients
Regimen
CR (%)
OR (%)
MS (weeks)
1-year (%)
1973–76 [14]
A B A B A B C A B A B C A B C
53 58 76 70 89 92 88 150
LCbM LCbMV LCMV LCMV+DE LCMV LCEV (E15) LCEV (E2) LCVE/CEV LCVE/CEVc LCVM+DEV as A/PvdH LCVE/PDVdMH PTV/as arm ‘C’ JTV/as arm ‘C’ CLV/EDV/PVdH
4 9 17 23 24 23 30 28
68 67 68 72 69 66 74
25 33 40 54 28 32 48 28
10 25 27 30 15 14 22 19
25 18 18 26 30 24
70 73 62 69 64 54
46 48 38 48 49 42
20 26 16 32 28 22
1976–78 [17] 1978–81 [19]
1984–86a 1981–85 [21]
1985–92 [22]
69 68 66 76 79 77
P-value 0.01 NS B0.05
NS
NS
L, lomustine; C, cyclophosphamide; M, methotrexate; V, vincristine; D, doxorubicin; E, etoposide; P, cisplatin; Vd, vindesine; H, hexamethylmelamine; T, teniposide; J, carboplatin; NS, not significant; E2, etoposide orally day 3 – 6; E15, etoposide orally day 14–17. a Unpublished results. b Cyclophosphamide dose 700 mg/m2; other trials 1000 mg/m2. c Complete responders randomised to vincristine and either intermittent high dose C+E or continuously orally treatment with C+E.
ifications have been investigated. These include the introduction and addition of more active drugs, early and late intensification, alternating regimens, combined radio-chemotherapy and biologic response modifiers. In limited stage of disease, in particular thoracic radiotherapy has resulted in improved overall survival [1] whereas the impact of modern chemotherapy with platinum compounds and epipodophyllotoxins has not been completely clarified. However, in extensive disease overall survival has remained at a plateau in the past two decades and the need for new active drugs and new treatment strategies is striking. The initial optimism for chemotherapy is more tempered and many studies now deal with aspects of reducing toxicity without interfering with the outcome [2 – 4]. Extensive stage SCLC has been subject to many Phase II trials of intensive chemotherapy and new drugs have often been tested in patients with poor prognosis, e.g. patients with recurrent SCLC [5]. The early studies of etoposide in previously treated SCLC yielded poor objective response rates, but subsequent studies with previously un-
treated patients resulted in response rates of 70– 80% [6]. Recent Phase II trials have demonstrated that new drugs can be safely introduced to chemotherapy naive patients without compromising median survival by treating non-responders with salvage regimens of well-known activity [7]. This makes studies of new treatment strategies possible in patients with more favorable prognosis, but at the same time rises the question how to treat patients with poorer prognosis SCLC. The importance of prognostic factors in SCLC has been intensively studied and many factors have been identified including extensive stage, poor performance status, advanced age and elevated lactate dehydrogenase. Additionally, sex, the severity of symptoms and other biochemical tests have been reported as having a prognostic impact [8–12]. A recent review indicated that the intensification of the treatment of extensive stage SCLC over the past decades has led to improved response rates and survival [13]. In another study the change in outcome over time was related to stage migration due to improved staging procedures [14].
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
153
Table 2 Comparison of pretreatment characteristics of patients with limited and extensive SCLC treated in the two periods Characteristic Sex (% female) Age, median (range) Performance status (%) 0–1 2 3–4 Stage (% extensive) LDH, median (range) U/l (B450, normal) AP, median (range) U/l (B275, normal)
Period 1 (1973 – 81) (N= 963) 28 61 (23–70) 61 21 18 53 500 (180–11 120) 240 (55–3300)
Period 2 (1981 – 92) (N =1131) 35 62 (30 – 70) 60 21 19 55 479 (45 – 12 550) 232 (14 – 3940)
P-value 0.001a 0.02c NSb
NSa NSc NSc
LDH, lactate dehydrogenase; AP, alkaline phosphatase. a 2 x -test. b Mann – Whitney U-test. c One-way ANOVA.
Six randomised trials including patients with extensive stage SCLC and three trials with limited disease were performed in our institution from 1973 –1992 [15–23]: four trials including only extensive stage, and two trials included both stages of SCLC (Table 1). In order to detect a possible treatment-related improved outcome during two decades we compared the outcome of three trials of extensive stage from 1973 to 1981 with three trials including patients with extensive disease from 1981 to 1992. These two periods included a comparable number of patients with extensive disease. The first trials contained three to six drugs in sequential regimens and the latter trials contained sevent to nine drugs administered in sequential or alternating regimens. Prognostic factors were included in this analysis in order to identify possible changes in the population over time.
2. Patients and methods A total of 1111 consecutive patients with extensive stage SCLC entered one of six consecutive randomized trials from 1973 to 1992 at the Finsen Institute, Herlev University Hospital and Bispebjerg Hospital, Copenhagen, Hillerød Hospital, all in Denmark, or Renstro¨mska Hospital, Gothenburg, Sweden (Table 1). All patients had a histo-
logic or cytologic diagnosis of SCLC following the WHO guidelines. Patients older than 70 years of age and patients with prior or simultaneous malignancies, except cone resected cervical cancer or treated basal cell carcinoma of the skin, were excluded. All trials had been approved by the local ethics committee. The first three trials of extensive stage SCLC from 1973 to 1981 included 526 patients (period 1), and the three latest trials from 1981 to 1992 included 585 patients (period 2), two trials with patients of all stages and one trial including patients with extensive disease only. One of the late trials, including 150 patients with extensive disease, was discontinued prematurely. This trial addressed maintenance chemotherapy in responders with two different schedules, but due to a too low randomization rate, the study was closed. The results have not been published and only survival data from these patients is included in the present analysis. Pretreatment staging procedures included physical evaluation, chest radiographs, bronchoscopy with biopsy and bilateral bone marrow aspiration and biopsy. Peritoneoscopy with liver biopsy was performed in the first period and replaced by ultrasonography with liver biopsy in the second period. Radionuclide or computed tomography (CT) of brain metastases were only performed if clinically suspected. Blood tests included complete cell counts (CBC), serum creatinine, sodium and
154
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
Table 3 Comparison of pretreatment characteristics of patients with extensive disease treated in the two periods Characteristic Sex (% female) Age, median (range) Performance status (%) 0–1 2 3–4 Distant metastases (%) Liver Bone marrow Brain LDH, median (range) U/l (B450, normal) AP, median (range) U/l (B275, normal)
Period 1 (1973 – 81) (N=526)
Period 2 (1981 – 92) (N = 585)
27 61 (23–70)
35 62 (30 – 70)
45 26 29
47 25 28
33 35 11 642 (200–11 120) 278 (70–3300)
40 33 12 634 (45 – 12 550) 278 (14 – 3940)
P-value 0.001a NSc NSb
0.01a NSa NSa NSc NSc
x 2-test. Mann – Whitney U-test. c One-way ANOVA. a
b
potassium, serum urate, lactate dehydrogenase (LDH) and alkaline phosphatase (AP). In the early period, three randomized trials of patients with limited stage SCLC were also performed [16,19,22]. The pretreatment characteristics of these patients and of the patients with limited stage in the late period were included in the comparison of prognostic factors within the two periods.
3. Statistics Construction of a database and statistical analysis were carried out using the statistical package SPSS for Windows. Patient characteristics in the two groups were compared using one-way ANOVA for continuous data, Mann – Whitney U-test for ordinal data, and a x 2-test for discrete data. All tests were two-sided with a P-value threshold of 0.05. Survival analysis was based on the Kaplan–Meier method and comparisons were made using the Kaplan – Meier log-rank test. Estimation of hazard ratios and tests for interactions between potential prognostic factors were made with Cox proportional hazard regression model with a P-value threshold of 0.01.
4. Results
4.1. Pretreatment characteristics The distribution of pretreatment characteristics between the two groups is listed in Table 2. A significant increase in the frequency of female patients (P= 0.001) and the frequency of elderly patients (P= 0.02) due to a 2% increase in patients 65–70 years of age was observed during the time periods. No differences between the two groups were observed with respect to performance status, extent of disease, elevated lactate dehydrogenase (LDH) and alkaline phosphatase (AP). Table 3 shows the distribution between the two treatment periods of pretreatment characteristics in patients with extensive disease only. In contrast to the results of the whole patient population (Table 2) the distribution of the age in patients with extensive disease was equal in the two periods. Female patients were more frequent in the late period. The detection of liver metastases significantly increased from 32 to 41% (PB0.005). No differences in the distribution of other characteristics, including other metastatic sites, were observed between the groups. A Cox regression analysis of independent prognostic factors of survival was performed. The
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
155
Table 4 Cox regression analysis of factors of independent influence on survival for 1111 patients with extensive disease, treated from 1973 to 1992 Variable
Estimate (B)
Relative risk (RR)
95% CI for RR
P-value
Period Age Sex PS Liver metastases BM metastases Brain metastases LDH AP
−0.04 0.17 −0.02 0.21 −0.02 0.14 0.30 0.28 0.17
0.96 1.19 0.98 1.23 0.98 1.15 1.35 1.33 1.19
0.85 – 1.09 1.09 – 1.30 0.86 – 1.13 1.16 – 1.31 0.85 – 1.14 1.00 – 1.32 1.10 – 1.67 1.21 – 1.45 1.09 – 1.30
0.57 0.0001 0.80 B0.0001 0.84 0.05 0.005 B0.0001 0.001
CI, confidence intervals; BM, bone marrow; LDH, lactate dehydrogenase; AP, alkaline phosphatase. Categories: Period, 1973 – 1981= 0, 1981 – 1992 = 1; age, B55=0, 55–64 =1, \64= 2; sex, male =0, female =1; PS, WHO performance status; stage, limited= 0, extensive= 1; LDH, 0–450 = 0, 450–900= 1, \900=2; AP, 0 – 275 = 0, 275 – 450=1, \450= 2.
impact of time as an independent prognostic factor in extensive stage SCLC was assessed by introducing a variable with the value 0 for period 1 (1973–1981) and the value 1 for period 2 (1981 – 1992). Young age, good performance status and normal LDH and AP were all independent factors with a significant impact on survival. Female gender and period had no prognostic impact. The presence of brain metastases was correlated with a poor prognosis, while bone marrow metastases and liver metastases had no independent influence on survival (Table 4). A separate Cox regression analysis was performed for each treatment period for patients with extensive disease. In both periods good performance status and normal LDH favored a good prognosis. Age was a significant prognostic factor only in the early period whereas elevated AP became a negative prognostic factor in the late period (Table 5).
ferences were observed between the two periods (Fig. 1, P= 0.49, log-rank test). The grade of myelosuppression in the two periods is displayed in Table 6. In the early period, grade IV leukopenia occurred in 24% of the patients and in the late period in 42% (P B 0.001). Febrile neutropenia occurred in 19 and 34% (PB 0.001). The presence of several poor prognostic factors might confound treatment-related benefits. In order to detect a possible improved outcome in patients with extensive disease, but without other poor prognostic factors, a separate analysis of patients with extensive disease, performance status 0–2, age below 65 years and normal level of LDH was made. However, median survival was equal in the two periods (354 days and 359 days, respectively) and a comparison of data from the two treatment periods could not disclose any change over time in survival or in objective response rates.
4.2. Outcome Patients treated in the late period had a higher complete response rate. In the early period CR was 20% compared to 25% in the late period (P = 0.05). However, no difference in overall response rates was observed (66 vs 65%, P = 0.9). Also 1-year survival (20.5 vs 25.6%), 2-year survival (4.5 vs 6.9%) and 5-year survival rates (2.5 vs 2.4%) were comparable and no statistical dif-
5. Discussion A recent review [13] has focused on the outcome of extensive stage SCLC over the last decade. Studies from single institutions and cooperative groups included in the latter review showed an increase in objective response rates and it was suggested that more aggressive treatment
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
156
Table 5 Cox regression analysis of factors with independent influence on survival in patients with extensive disease, treated 1973 – 1981 and 1981–1992 Variable
Estimate (B)
Relative risk (RR)
95% CI for RR
P-value
1973–1981 Age PS Liver mets. BM Brain LDH AP
0.21 0.22 −0.19 0.18 0.28 0.36 0.10
1.24 1.24 0.83 1.19 1.32 1.43 1.11
1.09 – 1.41 1.13 – 1.37 0.66 – 1.03 0.96 – 1.47 1.01 – 1.73 1.02 – 2.02 0.97 – 1.26
0.001 B0.0001 0.08 0.10 0.04 0.0001 0.12
1981–1992 Age PS Liver mets. BM Brain LDH AP
0.14 0.20 0.12 0.13 0.28 0.25 0.23
1.15 1.23 1.13 1.14 1.32 1.28 1.25
1.02 – 1.30 1.13 – 1.33 0.92 – 1.39 0.95 – 1.37 1.01 – 1.73 1.13 – 1.45 1.12 – 1.41
0.03 B0.0001 0.23 0.17 0.04 0.0001 0.0001
CI, confidence intervals; liver mets., liver metastases. Categories: age, B55= 0, 55 – 64 = 1, \64= 2; sex, male =0, female = 1; PS, WHO performance status; stage, limited = 0, extensive= 1; LDH, 0 – 450= 0, 450 – 900=1, \900= 2; AP, 0 – 275= 0, 275 – 450=1, \450=2.
had led to improved outcome. However, a majority of the reviewed studies were Phase II studies including few patients. Furthermore, response rates in general are higher in most Phase II studies. In the present analysis of 1111 patients with extensive disease treated in our own cooperative group the rate of complete remission significantly increased, but survival and overall response rates remained unchanged. The outcome was similar to the results of other large Phase III trials [24 – 27]. The patients included in our randomized trials were unselected except from an upper age limit of 70 years. Female gender was more frequent in the late period, but gender had no prognostic impact in extensive stage SCLC. The frequency of extensive disease was equal in the two periods (53 and 55%, respectively). This was less frequent than reported in most studies from the United States. The reason for this is not clear, but perhaps reflects differences in staging procedures. The staging procedures used followed the general recommendations. However, bilateral bone marrow biopsy and aspiration (BM) was used as a standard to detect bone marrow involvement whereas radionuclide bone scan was not used. Bone scan
seems to be superior to unilateral BM [28]. Bilateral BM has not been compared with bone scan, but these modalities are regarded as complimentary. Furthermore, thoracic CT was not performed routinely in either periods, because radiotherapy was not applied in patients with limited disease. Stage migration was not observed even though the frequency of liver metastases increased over time. This was probably due to the introduction of ultrasonography as a replacement of peritoneoscopy in the early 1980s [29]. Ultrasonography and abdominal CT-scan are considered more sensitive than peritoneoscopy [30] and this could lead to the assumption that extensive stage was under-diagnosed in the early trials. However, the frequency of patients with extensive stage SCLC did not change. A possible explanation could be that more patients in the early period in fact did have advanced disease, but were classified as having limited stage. However, this would result in an inferior survival of both stages in this period. A stage migration due to improved staging procedures would then lead to an improved survival over time both in limited and extensive stage of disease. This was not the case as
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
157
Fig. 1. Kaplan – Meier plot of overall survival of the two groups, extensive stage only; (- - -) early period 1973 – 1981, N= 508, median survival 208 days (95% CI, 191–225 days); (——) late period 1981 – 1992, N= 623, median survival 215 days (95% CI, 194–236 days); P =0.49, log-rank test.
the outcome of patients with extensive disease was equal in both treatment periods. In a study of prognostic factors in 411 patients treated from 1973–1987, a change over time was observed in the prognostic importance of distant metastatic sites [14]. In the early era brain metastases were associated with a shortened survival, but not in the recent era. On the other hand, liver metastases were a negative prognostic factor only in the recent era. In our series, the change of diagnostic procedures apparently did not lead to stage migration. In the Cox regression analysis of patients with extensive disease the presence of brain metastases was associated with a poor survival in both periods. Brain scans were only performed in patients with clinical suspected brain metastases and patients with symptoms have a poorer prognosis than patients with subclinical brain metastases.
The improved detection of liver metastases with ultrasonography had no prognostic impact. Dose intensity in the present study was evaluated only by comparison of hematological toxicity in the two periods. According to this the grade of myelosuppression has increased but a complete comparison of delivered doses was not performed. However, it seems that the regimens have been more aggressive in the 1980s than in the 1970s (Table 6). This is indicated by the steep initial slopes of the survival curves from the late period (Fig. 1) which relates to early toxic deaths. The introduction of four-drug chemotherapy, including vincristine, led to a clear improvement in response rates and survival in SCLC [15]. The present data indicate that the addition of more than four drugs led to no further benefits in extensive disease and neither did the introduction of alternating schedules of different combinations.
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
158
Table 6 WHO grade IV leukopenia and febrile neutropenia in the trials from 1973 to 1992 Trial
Regimen
Grade IV leukopenia (%)
Febrile neutropenia (%)
Ref. [15] Arm A Arm B
LCaM LCaMV
13 9
6 2
Ref. [18] Arm A Arm B
LCMV LCMV+DE
23 22
13 9
Ref. [20] Arm A Arm B Arm C
LCMV LCEV (E15) LCEV (E2)
25 19 51
22 27 40
Ref. [21] Arm A Arm B Arm C
LCVM+DEV as A/PvdH LCVE/PDVdMH
34 29 78
25 21 69
Ref. [23] Arm A Arm B Arm C
PTV/as arm ‘C’ JTV/as arm ‘C’ CLV/EDV/PVdH
37 31 45
30 32 28
Grade IV leukopenia was more frequent in the late period ([15,18,20] versus [21,23], PB0.001) and febrile neutropenia was more frequent in the late period [15,18,20] versus ([21,23], PB0.001). The trial from 1984 to 86 was not included in this analysis, because it was discontinued prematurely and complete toxicity data have not been assessed. L, lomustine; C, cyclophosphamide; M, methotrexate; V, vincristine; D, doxorubicin; E, etoposide; P, cisplatin; Vd, vindesine; H, hexamethylmelamine; T, teniposide; J, carboplatin E2, etoposide orally day 3–6; E15, etoposide orally days 14 – 17. a Cyclophosphamide dose 700 mg/m2; other trials 1000 mg/m2. b Complete responders randomised to vincristine and either intermittent high dose C+E or continuously orally treatment with C+E.
Accordingly, the introduction of more aggressive chemotherapy with epipodophyllotoxins and platinum compounds resulted in a modest increase in complete response, but no change in overall response rates.
6. Conclusion Although long-term survival can be observed in all stages of SCLC, the prognosis in patients with extensive SCLC remains poor. In a recent randomized trial from our own group, the median survival of extensive stage SCLC was 37 weeks with the best treatment regimen [23]. The median survival of patients with extensive stage SCLC and poor prognostic factors such as poor performance status, age over 65 years and ele-
vated LDH, is below 8 weeks and intensive treatment does not seem feasible in these patients. In a randomised study of patients with extensive SCLC and poor prognosis, no survival benefit was obtained with four-drug chemotherapy compared to a less intensive two-drug combination [2]. Less intensive treatment is preferable for these patients aiming at tumor reduction as best palliation. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.
Acknowledgements This study was supported by The Foundation for the Support of Medical Cancer Treatment.
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
References [1] Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. New Engl J Med 1992;327:1618–24. [2] Girling DJ, Hopwood P, Lallemand G, et al. Randomised trial of four-drug 6s less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Br J Cancer 1996;73:406 – 13. [3] Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577–80. [4] Girling DJ, Thatcher N, Clark PI, et al. Comparison of oral etoposide and standard multidrug intravenous chemotherapy for small cell lung cancer: a stopped multicentre randomised trial. Lancet 1996;348:563–6. [5] Grant SC, Gralla RJ, Kris MG, et al. Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: The case for studies in previously treated patients. J Clin Oncol 1992;10:484–98. [6] Bork E, Ersbøll J, Dombernowsky P, et al. Teniposide and etoposide in previously untreated small cell lung cancer: A randomized study. J Clin Oncol 1991;9:1627– 31. [7] Ettinger DS, Finkelstein DM, Abeloff MD. Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: An Eastern Cooperative Oncology Group randomized study. J Natl Cancer Inst 1992;84:1077–84. [8] Sagman U, Feld R, DeBoer G, et al. Small cell carcinoma of the lung — Derivation of a prognostic index (Abstr). Clin Invest 1986;27:189. [9] Souhami RL, Bradbury I, Geddes DM, et al. Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res 1985;45:2878 – 82. [10] Østerlind K, Hansen HH, Hansen M, et al. Long-term disease-free survival in small-cell carcinoma of the lung: A study of clinical determinants. J Clin Oncol 1986;4:1307– 13. [11] Wolf M, Holle R, Hans K, et al. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): The role of sex as a predictor for survival. Br J Cancer 1991;63:986 – 92. [12] Lassen U, Østerlind K, Hansen M, et al. Long-term survival in small-cell lung cancer: Posttreatment characteristics in patients surviving 5 to 18 + years—An analysis of 1714 consecutive patients. J Clin Oncol 1995;13:1215 – 20. [13] Aisner J. Extensive-disease small-cell lung cancer: The thrill of victory; The agony of defeat. J Clin Oncol 1996;14:658 – 65. [14] Dearing MP, Steinberg SM, Phelps R, et al. Outcome of patients with small-cell lung cancer: Effect of changes in staging procedures and imaging technology on prognostic factors over 14 years. J Clin Oncol 1990;8:1042–9.
159
[15] Hansen HH, Dombernowsky P, Hansen M. Chemotherapy of advanced small-cell anaplastic carcinoma: Superiority of four drug combination. Ann Intern Med 1978;89:177 – 81. [16] Hansen HH, Dombernowsky P, Hirsch FR. Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic cranial irradiation in patients receiving combination chemotherapy. Cancer 1980;46:279 – 84. [17] Hansen M, Hansen HH, Dombernowsky P. Long-term survival in small cell carcinoma of the lung. J Am Med Assoc 1980;244:247 – 50. [18] Østerlind K, So¨renson S, Hansen HH, et al. Continuous 6ersus alternating combination chemotherapy for advanced small cell carcinoma of the lung. Cancer Res 1983;43:6085 – 9. [19] Østerlind K, Hansen HH, Hansen HS, et al. Chemotherapy 6ersus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. Br J Cancer 1986;54:7 – 17. [20] Hirsch FR, Hansen HH, Hansen M, et al. The superiority of combination chemotherapy including etoposide based on in vivo small-cell lung cancer: A randomized trial of 288 consecutive patients. J Clin Oncol 1987;5:585 – 91. [21] Pedersen AG, Østerlind K, Vindeløv LL. Alternating or continuous chemotherapy of small cell lung cancer. A three armed randomized trial (Abstr). Proc Am Soc Clin Oncol 1987;6:187. [22] Østerlind K, Hansen M, Hirsch FR. Combination chemotherapy of limited small cell lung cancer. A controlled trial on 222 patients comparing two alternating regimens. Ann Oncol 1991;2:41 – 6. [23] Lassen U, Kristjansen PEG, Østerlind K, et al. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up. Ann Oncol 1996;7:365 – 71. [24] Bleehen NM, Fayers PM, Girling DJ, et al. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 1989;59:584 – 90. [25] Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regiments in extensive small-cell-lung cancer: a Phase II trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282 – 91. [26] Giaccone G, Dalesio O, Mcvie JG, et al. Maintenance chemotherapy in small cell lung cancer: Long-term results of a randomized trial. J Clin Oncol 1993;11:1230 – 40. [27] Souhami RL, Rudd R, Elvira MRD, et al. Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: A Cancer Research Campaign Trial. J Clin Oncol 1994;12:1806 – 13. [28] Levitan N, Byrne RE, Bromer RH, et al. The value of bone scan and bone marrow biopsy staging small cell lung cancer. Cancer 1985;56:652 – 4.
160
U.N. Lassen et al. / Lung Cancer 20 (1998) 151–160
[29] Hansen SW, Jensen F, Pedersen NT, et al. Detection of liver metastases in small-cell lung cancer: A comparison of peritoneoscopy with liver biopsy and ultrasonography with fine-needle aspiration. J Clin Oncol 1987;5:255–9.
.
[30] Hirsch FR, Østerlind K, Jensen LI, et al. The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer. Ann Oncol 1992;3:469 – 74.