Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America
Meaningful improvements in survival
Article first published online: 17 SEP 2002
Copyright © 2002 American Cancer Society
Volume 95, Issue 7, pages 1528–1538, 1 October 2002
How to Cite
Jänne, P. A., Freidlin, B., Saxman, S., Johnson, D. H., Livingston, R. B., Shepherd, F. A. and Johnson, B. E. (2002), Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer, 95: 1528–1538. doi: 10.1002/cncr.10841
- Issue published online: 17 SEP 2002
- Article first published online: 17 SEP 2002
- Manuscript Accepted: 25 APR 2002
- Manuscript Received: 8 APR 2002
- lung neoplasm;
- small cell lung carcinoma;
- limited stage;
To determine the changes in clinical trials and outcomes of patients with limited-stage small cell lung carcinoma (SCLC) treated on Phase III randomized trials initiated in North America between 1972 and1992.
Phase III trials from 1972 to 1992 for patients with limited-stage SCLC were identified. Patients with limited-stage SCLC treated during a similar time interval were also evaluated in the Surveillance, Epidemiology, and End Results (SEER) database. Trends were tested in the number of trials, in the number and gender of patients entered on trial, and in survival duration over time.
Thirty trials involving 6564 patients were eligible for analyses. Nineteen trials (61%) involving 3626 patients were initiated within the first half of this time period (1972–1981). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10–16 months) and 17.0 months (range, 11–20 months), respectively (P < 0.001). Of 26 studies available for survival analysis, 5 (19%) showed a statistically significant survival prolongation in the experimental arm compared with the control arm with a median prolongation of 3.4 months (range, 1–5.2 months). All five evaluated some aspect of thoracic radiation therapy. Over a similar time period, there was a 6.4-month increase in the median survival of limited-stage SCLC patients listed in the SEER database (P < 0.0001) and a more than doubling of the 5-year survival from 5.2% to 12.1% (P = 0.0001).
Analyses of the patients with limited-stage SCLC treated on Phase III trials in North America initiated between 1972 and 1992 and those listed in the SEER database show significant improvements in median survivals. Furthermore, the 5-year survival of patients with limited-stage SCLC listed in the SEER database has more than doubled over the last 25 years. Further research will be needed to determine the relative contribution of improved therapy, supportive care, and stage migration to this prolongation in survival. Cancer 2002;95:1528–38. © 2002 American Cancer Society.
Combined modality therapy using combination chemotherapy and thoracic radiation therapy is now the standard therapy for patients with limited-stage small cell lung carcinoma (SCLC).1, 2 The therapeutic approach for patients with early-stage SCLC has evolved from attempts at surgical resection in the 1960s,3 to thoracic radiation therapy in the 1970s,4 to chemotherapy plus thoracic radiation in the 1980s and 1990s.1 The combined modality regimens have evolved from 1–2 years of cyclophosphamide-based therapy5, 6 to four to six cycles of etoposide and cisplatin administered concurrently with early chest radiotherapy.2 This treatment regimen for patients meeting protocol entry criteria is partially successful because 25% of patients are alive and free of cancer 5 years after starting treatment. However, most patients with limited-stage SCLC treated with currently available treatments still die.
The outcome of patients with extensive-stage SCLC has improved considerablyin the past 25 years.7 Analyses of patients with extensive-stage SCLC treated on randomized Phase III trials in North America and patients identified and followed in the Surveillance, Epidemiology, and End Results (SEER) database revealed that the median of median survivals for both groups of patients had increased by 2 months between 1972 and 1990.7 Furthermore, the 5-year survival rate of patients with extensive-stage SCLC followed in the SEER database has modestly increased from 0.8% for those treated between 1973 and 1974 to 1.6% for patients treated between 1989 and 1990.
The majority of patients with SCLC have extensive-stage disease and the modest increase in survival for patients with extensive-stage disease is encouraging. The increase in survival for patients with limited-stage disease is potentially much more important because it improves their chance for a cure. There are 2–10-fold more 5-year survivors of limited-stage SCLC than there are survivors with extensive-stage SCLC.8–11 Potential survival gains observed in Phase II studies for patients with limited-stage SCLC may be much more important for increasing the number of patients who are alive and free of SCLC at 5 years. Therefore, we decided to perform analyses similar to Chute et al.7 and Chen et al.12 for patients with limited-stage SCLC treated on Phase II and Phase III trials in North America during the past 25 years. We also assessed the outcomes of patients with limited-stage SCLC who were not treated as part of a clinical trial during the last 25 years using the population-based SEER database. This is not meant to be a review study of SCLC but an analysis of outcomes of patients with limited-stage SCLC treated on cooperative group Phase III clinical trials and in a population-based registry. Whenever possible, we evaluated the pilot and Phase II studies that were used in subsequent Phase III studies to generate a statistical model that would be used to determine the success of Phase II and pilot studies when taken into a Phase III trial setting.12 We incorporated the Phase II studies into this study because there are not enough Phase II studies to warrant a separate study.
MATERIALS AND METHODS
Phase III Trials
Phase III trials initiated for patients with limited-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1992, by a computer-based search of MEDLINE (using the keywords “lung neoplasm,” “carcinoma, small cell,” “limited stage,” “randomized” and “phase III”), and by direct contact with the leaders of the cooperative groups (Cancer and Leukemia Group B, Eastern Cooperative Oncology Group,Southeastern Oncology Group, North Central Cancer Treatment Group [NCCTG], Southwest Oncology Group, and the National Cancer Institute of Canada Clinical Trials Group). We evaluated the randomized trials initiated between 1972 and 1992 and completed by 1996 because this time period allowed adequate time for patient enrollment into a study, follow-up, and publication of the results of the therapeutic trials. Only trials that were published either in full form or reported as a published abstract were considered for this analysis. Trials were ineligible for analysis if they had fewer than 20 patients per treatment arm, did not separate information for limited-stage patients, or had prophylactic cranial irradiation (PCI) as the only study variable because the results of PCI have been reported as a metaanalysis.13
The lung carcinoma committee chairs from each cooperative group in North America were contacted to inform them of this analysis and to determine whether additional trials had been performed that were not known to the authors. Investigators from NCCTG declined to participate in this study by not providing missing data. Information obtained from each trial and the methods used to compute the median of median survival times were identical to our previously published reports.7, 14 Of 30 Phase III trials, 4 (13%) published articles did not have all of this information available. In these cases, the chairperson of the cooperative group or the author of the study was contacted and additional data were obtained if available and the author permitted its use. In studies where the median survival was not stated in the publication, we estimated the median survival from enlargements of the figures in the published article.
The SEER database was also evaluated to compare the median and 5-year survival information for all patients with SCLC and for patients with limited-stage SCLC versus with our analysis of patients treated on Phase III trials over the same time period. The time period between 1974 and 1996 was evaluated because the starting year corresponded most closely with the start of the cooperative group studies and 1996 corresponded most closely with the year the cooperative group trials finished their patient accrual. In this analysis, patients from the SEER database with in situ, localized, or regional disease are termed “limited-stage” to be consistent with the terminology used in the cooperative group studies.
Phase II and Pilot Trials
Phase II and pilot trials that were used subsequently as the experimental arms of Phase III trials were identified using the published Phase III clinical trials and by searching the MEDLINE database. Only studies that used the identical or a very similar treatment regimen between the Phase II/pilot trials and Phase III studies were considered for evaluation.12 Information was obtained on the dates of the Phase II studies, the number and gender of patients, the chemotherapy regimens, the chest radiotherapy treatment plan, the response rates, the median survival, and the number of deaths at the time of the Phase II analysis.
Least squares linear regression was used to evaluate time trends in the Phase III data. The two-sample t test, Wilcoxon test, and Pearson chi-square test were used to compare data for the 1973–1987 versus the 1988–1996 periods. The trend in median and 5-year survivals among patients with limited-stage SCLC in the SEER database was calculated using a least squares regression analysis. All P values corresponded to two-sided tests.
Phase III Trials
Forty-three North American cooperative group and institutional Phase III trials were initiated between 1972 and 1992 and completed by 1996 and comprised 7305 patients with limited-stage SCLC. Thirteen trials did not meet the criteria for our study and were excluded.15–27 Seven trials had fewer than 20 patients per arm and were statistically unreliable,15–21 one trial did not have information separately for limited-stage patients,27 and in five trials PCI was the only study variable.22–26 Thirty Phase III studies involving 6564 patients were available for analysis. The results of these 30 trials are listed in Table 1. Four trials are included in the analysis of the trials but are excluded from the survival trend analyses as the randomization in these studies was based on response to initial therapy and took place 1.5–9 months after initiation of treatment.37, 45, 48, 54 The survival of the patients treated on these four trials is skewed artificially as only patients responding to initial therapy are entered on study and evaluated for survival. Therefore, 26 Phase III studies involving 5245 patients were available for survival trend analyses. A summary of characteristics of the 30 trials is shown in Table 2.
|First author||Study yrs||No. of patients per arm||Gender M/F||Regimen||No. of responders CR/PR||Median survival (mos)||No. of deaths||P|
|Maurer28||1972-1976||15||NA||C + TI +/−PCI +/−C (maint)||4/4||11.1||98||NS|
|Maurer28||1972-1976||41||NA||CM + TI +/−PCI +/−CM (maint)||14/7||9.0|
|Maurer28||1972-1976||12||NA||CMV +TI +/−PCI +/−CMV (maint)||6/1||9.3|
|Maurer28||1972-1976||47||NA||CM(HD)V + TI +/−PCI +/− CM (HD) V (maint)||22/7||9.3|
|Seydel29||1975-1979||56||NA||TI +PCI +CC1||29/14||11.1||48|
|Eagan30||1976-1978||31||22/9||V1OCA × 8 +TI||13/NA||15.5||55||NS|
|Eagan30||1976-1978||31||23/8||V1OCAP × 8 +TI||12/NA||16.9|
|McCracken31||1976-1979||63||NA||COMF × 2 +TI +PCI AC/COMF (maint)||1/22||11.5||56||0.803|
|McCracken31||1976-1979||70||NA||CHO × 2 +TI +PCI COMF/AC (maint)||7/14||11.1||54|
|McCracken31||1976-1979||72||NA||COMF × 2+ BCG +TI +PCI COMF/AC (maint)||6/17||9.5||60|
|McCracken31||1976-1979||72||NA||CHO × 2+ BCG +TI +PCI AC/COMF (maint)||6/25||10.8||53|
|Perez32||1976-1980||33||28/5||TI +PCI CAD × 8 (if progression)||7/10||11||15||NS|
|Perez32||1976-1980||37||26/11||CAD × 2 TI +PCI CAD × 8||12/6||7.6||23|
|Aisner33||1977-1980||21||16/5||CAE +/− PCI||13/5||16.0||NA||0.18|
|Aisner33||1977-1980||23||14/9||CAE COMP1/CAE +/−PCI||15/6||12.0|
|Daniels34||1977-1980||28||22/6||P1OCC1 × 2 TI + PCI P1OCC1 VAM (if progression)||12/5||10.0||0.47|
|Daniels34||1977-1980||28||19/9||VAM × 3 TI + PCI P1OCC1/VAM||8/10||16.0|
|Maurer35||1977-1981||157||113/44||MAC1C × 2 TI + PCI MAC1C × 2 +/− BCG||81/30||12.0||129||NS|
|Maurer35||1977-1981||150||109/41||CC1 V/AV (alt) × 1 TI + PCI CC1 V/AV (alt) × 1 +/− BCG||69/35||11.5||120|
|Bunn6||1977-1986||49||36/13||CMC1/VAP1 (alt) × 4 + PCI||21/19||11.6||43||0.035|
|Bunn6||1977-1986||47||28/19||CMC1/VAP1 (alt) × 4 + T1 + PCI||38/8||15.0||39|
|Perez36||1978-1983||142||NA||CAV + PCI E/HMM × 3||48/21||11.3||NA||0.03|
|Perez36||1978-1983||149||NA||CAV + TI + PCI E/HMM × 3||68/19||13.8|
|Kies37||1979-1982||40||24/16||VMV1AC (CR) + TI + PCI CE × 4 VMV1AC||NA||12||NA||NS|
|Kies37||1979-1982||53||31/22||VMV1AC (CR) + CE × 4 + PCI VMV1AC||NA||12|
|Kies37||1979-1982||93||65/28||VMV1AC (PR/NR) + WVTI + PCI CE × 4 VMV1AC||NA||11.8|
|Kies37||1979-1982||98||72/26||VMV1AC (PR/NR) + RVTI + PCI CE × 4 VMV1AC||NA||10.6|
|Jackson38||1979-1983||46||NA||VAC × 3 + TI + PCI VAC (maint)||24/10||13.6||NA||NS|
|Jackson38||1979-1983||38||NA||EVAC × 3 + TI + PCI EVAC (maint)||19/11||15.0|
|Hong39||1979-1983||43||30/13||CAV × 4 TI (if PR) PCI||18/11||12.7||39||0.384|
|Hong39||1979-1983||47||25/22||CEV × 4 TI (if PR) PCI||18/13||13.4||43|
|Hong39||1979-1983||26||16/10||C (HD)/V × 4 TI (if PR) PCI||8/5||9.5||25|
|Einhorn40; Bunn41||1979-1983||41||NA||CAV +/− TI + PCI||10/13||13.4||37||NS|
|Einhorn40 Bunn41||1979-1983||39||NA||CAE +/− TI + PCI||10/15||11.1||37|
|Jett42||1979-1986||113||70/43||CAV + TI + PCI||64/9||12.4||102||0.13|
|Jett42||1979-1986||118||68/50||CAVE + TI + PCI||75/7||15.1||101|
|Messeih43||1980-1982||26||NA||CAV × 4 PCI + TI (if PR) CAV||9/8||10.8||NA||0.25|
|Messeih43||1980-1982||23||NA||CAVE × 4 PCI + TI (if PR) CAVE||12/9||12||NA|
|Perry5||1981-1984||129||85/44||CEV × 6 + PCI CEV/CAV (alt)||46/36||13.6||118||0.0099c|
|Perry5||1981-1984||125||81/44||CEV × 6 + TI + PCI CEV/CAV (alt)||59/36||13.1||104|
|Perry5||1981-1984||145||91/54||CEV × 3 TI + PCI + CEV × 3 CEV/CAV (alt)||82/36||14.6||113|
|Feld44||1981-1984||146||96/50||CAV × 3 EP × 3 + PCI RT (T)||65/49||13.7||129||0.56|
|Feld44||1981-1984||154||98/56||CAV/EP (alt) × 3 + PCI RT (T)||79/46||14.2||134|
|Creech45||1981-1985||102||67/35||CC1M (CR/PR) TI + PCI CC1M/AV1 (maint)||16/2||15.0||101||0.0021|
|Creech45||1981-1985||105||58/47||CC1M (CR/PR) AV1 PCI CC1M/AV1 (maint)||10/2||13.5||101|
|Creech45||1981-1985||48||32/16||CC1M (NR/LP) TI AV1 (maint)||12/8||14.0||48|
|Creech45||1981-1985||60||33/27||CC1M (NR/LP) AV1 AV1 (maint)||6/12||11.2||60|
|Johnson46||1982-1985||230||163/67||CAV × 6 +/− PE × 2||70/47||12.8||202||0.92|
|Johnson46||1982-1985||156||107/49||CAV × 6 + TI +/− PE × 2||52/24||14.4||131|
|Goodman47||1982-1984||194||114/80||EVAC × 6 TI + PCI EVAC × 6||93/56||15.1||174||0.58|
|Goodman47||1982-1984||194||133/61||EP/VAC (alt) × 3 TI + PCI EP/VAC × 3 (alt)||105/47||16.5||173|
|Carlson48||24||12/12||P1OC1C/V1AM (CR/PR) +/− P1OC1C/V1AM||NA||18.9||NA||0.91|
|Carlson48||24||11/13||P1OC1C/V1AM (CR/PR) TI||NA||20.3|
|Lipton49||1983-1986||29||20/10||CAVE × 3 TI + PCI CAVE||NA||11||17||0.51|
|Lipton49||1983-1986||32||21/8||CAVE × 3 + RA233 TI + PCI CAVE + RA233||NA||14||21|
|Murray50||1985-1988||153||100/53||CAV/EP × 3 + TI (cycle 6) PCI||85/39||16||NA||0.008|
|Murray50||1985-1988||155||92/63||CAV/EP × 3 + TI (cycle 2) PCI||99/32||21.2|
|Maurer51||1986-1992||169||108/61||ACE × 3 PCE × 2 + TI + PCI ACE × 3||100/49||18.6||138||0.1242|
|Maurer51||1986-1992||178||117/61||ACE × 3 PCE × 2 + TI + PCI + Warfarin ACE × 3||109/50||21.4||137|
|Maksymiuk52||1987-1990||64||NA||PE × 2 CAV × 4 + TI + PCI +/− rIFNγ||48/11||20.0||NA||0.007|
|Maksymiuk52||1987-1990||66||NA||EP × 2 CAV × 4 + TI + PCI +/− rIFNγ||40/17||13.0|
|Maksymiuk52||1987-1990||65||NA||E(24 h)P × 2 CAV × 4 + TI + PCI +/− rIFNγ||44/12||17.3|
|Maksymiuk52||1987-1990||64||NA||E(24 h)P(24 h) × 2 CAV × 4 + TI + PCI +/− rIFNγ||44/14||20.1|
|Bunn53||1989-1991||108||65/43||PE + TI||47/45||17||85||0.15|
|Bunn53||1989-1991||107||61/46||PE + TI + GM-CSF||39/40||14||90|
|Turrisi2||1989-1992||206||122/84||PE × 4 + TI PCI||91/70||19||175||0.04|
|Turrisi2||1989-1992||211||122/89||PE × 4 + BID TI PCI||110/61||23||160|
|Bonner54||1990-1996||132||77/55||EP × 3 TI + EP × 2 EP × 1 PCI||24.6||NA||0.49|
|Bonner54||1990-1996||130||74/56||EP × 3 BID TI + EP × 2 EP × 1 PCI||23.0|
|Wood55||1992-1995||33||NA||PE/CAV (alt) × 3 + TI||25/6||17.3||NA||0.56|
|Wood55||1992-1995||35||NA||PE/CAV (alt) × 3 + TI + MA||24/6||17.3|
|No. of studies||19||11|
|No. of patients||3626 (55%)||2938 (45%)|
|Women||34%||37.5%||P = 0.025|
|Median no. of patients enrolled||116||308|
|Median no. of patients per arm||47||103||P = 0.047|
Of the 26 studies used for the survival trend analysis, 6 (23%) studies examined questions regarding radiation therapy, 14 (54%) evaluated different chemotherapy regimens, and 6 (23%) evaluated the addition of a biologic modifier to the treatment regimen. Of the four trials excluded from the survival trend analysis, three evaluated radiation therapy (one compared the addition of radiation therapy with the addition of chemotherapy different from the induction regimen, one compared the addition of radiation therapy with chemotherapy, and one compared daily with twice daily radiation therapy) and one evaluated chemotherapy sequencing and the size of the radiation field. Twenty (77%) studies had two arms, two (8%) studies had three arms, and four (15%) studies had four arms.
Twenty-eight of the 30 (93%) studies had information on the staging systems used to evaluate potential sites of metastatic disease and to select patients for study entry. Twenty-seven (96%) studies required a bone marrow examination. A computed tomographic scan (CT) of the head was required in 13 of 28 (46%) studies and it was optional in 9 of 28 (32%) studies. In studies initiated between 1972 and 1981, a CT scan of the head was required in 4 of 17 (24%) studies and it was optional in 6 of 17 (35%) studies compared with 10 of 12 (82%) and 2 of 12 (18%) studies initiated between 1982 and 1992, respectively. Magnetic nuclear resonance imaging scan (MRI) of the brain was not required in any of the studies but was optional in 2 of 28 (7%) of the studies. Six of 28 (22%) studies, all initiated between 1972 and 1981, used brain radionuclide scans to examine patients for central nervous systemmetastases. CT scans of the chest and abdomen were required in 6 of 28 (21%) and in 5 of 28 (18%) studies, respectively. All of these studies took place in the later time period (1982–1992).
Survival Time of Patients
The median survival of patients treated in the Phase III studies is shown in Table 1. Nineteen trials included data on the number of patients who had died at the time of analysis (median percent of patients deceased per trial at the time of data analysis beforepublication, 85; range, 54–97%). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10–16 months) and 17.0 months (range, 11–20 months), respectively (P < 0.001; Fig. 1). The increase in median survival remained significant after adjusting for the change in the proportion of female patients during these two time periods.
Of the 26 Phase III trials, 5 (19%) showed a statistically significant difference in survival time when the patient cohort received the experimental therapy compared with the control group (absolute differences in the experimental arm compared with the control arm: 1, 2.5, 3.4, 4, and 5 months; median, 3.4 months).2, 5, 6, 36, 50 A sixth study showed a significant survival prolongation in the control arm compared with only one of the three experimental arms.52 All five of the studies with a significant survival prolongation in the experimental arms compared with the control arm(s) evaluated some aspect of radiation therapy. Three of the studies compared chemotherapy alone with a combination of chemotherapy and thoracic radiation therapy,5, 6, 36 one study compared early versus late thoracic radiation therapy,50 and one study compared daily versus twice daily thoracic radiation therapy.2 Only one other study available for survival trend analysis evaluated the addition of thoracic radiation therapy to chemotherapy.46 Although not statistically different, the median survival in this study was greater for those patients who received thoracic radiation compared with those treated with chemotherapy alone (Table 1). However, the randomization in this study was terminated prematurely due to significant toxicities in the combined modality arm. As a result, the final number of patients randomized to that arm (n = 147) was less than the projected statistical estimate (n = 166), which may account for the survival findings. Of the 26 studies, 20 (76%) showed no survival benefit in the experimental arm(s) compared with the control arm (Table 1).
Phase II and Pilot Trials
We identified nine Phase II trials that led subsequently to a Phase III study. We excluded five Phase II trials because we found differences between the Phase II and Phase III studies in the chemotherapy drugs used,17, 56 the chemotherapy drug schedule,57 the Phase II study did not include thoracic radiation although it was administered in the subsequent Phase III trial,58 or the Phase II study did not report results separately for limited-stage patients.59 Table 3 compares the number of patients, the response rate, and the median survival between the Phase II and Phase III trials. All four of the Phase II studies were performed in the later time period (1982–1992). The median response rates in the Phase II studies (median, 90.5%; range, 85–96%) were slightly better than in the Phase III studies (median, 86%; range, 77–89%). In one of four studies, the median survival was longer in the Phase II study than in the Phase III study.60 However, in three of the four studies, the median survival was actually longer in the Phase III study than in the Phase II study.61–63 These four Phase II trials and their corresponding Phase III studies are insufficient to construct a statistically reliable model to determine the success of the Phase III studies based on the Phase II results. To generate such a model, approximately 10 Phase II studies with corresponding Phase III studies will be required.
|Authors Phase II/Phase III||No. of patients||Regimena||Phase II response rate CR/PR(%)||Phase III response rate CR/PR (%)||Phase II median survival (mos)||Phase III median survival (mos)|
|Goodman et al.60 Goodman et al.47||71||EVAC × 6 TI + PCI EVAC × 6||76/12||48/29||21.2||15.1|
|Murray et al.41/Murray et al.50||76||CAV/EP × 3 + TI (cycle 2) PCI||76/17||64/21||18.0||21.2|
|Aisner et al.52/Maurer et al.51||61||ACE × 3 PCE × 2 + TI + PCI + Warfarin ACE × 3||57/28||61/28||18.0||21.4|
|Turrisi et al.63/Turrisi et al.2||40||PE × 4 + BID TI PCI||78/18||56/31||20.0||23.0|
Information on the median and 5-year survival times of patients with limited-stage SCLC is available in the SEER population database. SEER survival data are recorded from the time of diagnosis, rather than from the initiation of therapy as has been done in the studies reported in the current study. Therefore, the data on median survival are not directly comparable to the survival data from the Phase III cooperative group studies. In the SEER database, the median survival of patients with limited-stage SCLC increased from a median of 9.1 months between 1973 and 1974 to 15.5 months in patients diagnosed between 1995 and 1996 (P < 0.0001 for trend; Fig. 2a). There has also been more than a doubling in the 5-year survival rate from 5.2% between 1975 and 1976 to 12.1% between 1991 and 1992 (P = 0.0001; Fig. 2b).
The median and 5-year survivals of all patients with SCLC were also evaluated in the SEER database because of the potential for stage migration. Between 1973 and 1981, 43% of patients listed in the SEER database were classified as having limited disease. Between 1982 and 1992, this value decreased to 35%. Between 1973 and 1974, 12.3% of patients with lung carcinoma listed in the SEER database were classified as having SCLC. This number increased slightly to 15% between 1995 and 1996. The median survival of all patients with SCLC increased from a median of 7.3 months between 1973 and 1974 to 9.5 months between 1995 and 1996 (P < 0.001; Fig. 3a). Similarly, there was a statistically significant increase in the 5-year survival of all patients with SCLC from 3.0 % between 1973 and 1974 to 5.1 % between 1991 and 1992 (P < 0.001; Fig. 3b).
Analyses of Phase III therapeutic trials for limited-stage SCLC during the past 25 years show significant improvements in patient outcomes. The median of median survivals in Phase III studies increased by 5 months from 12.0 months in the initial time period evaluated (1972–1981) to 17.0 months in the later time period (1982–1992). This improvement is not limited to patients fitting the criteria for entry into clinical trials as it closely parallels the 6.4-month increase in the median survival observed in the SEER database over a similar time period. The potential explanations for the prolongation in survival include improvements in the treatment modalities of SCLC, improvements in supportive care during the same time period, and more sensitive staging techniques so that fewer patients who have less severe disease are identified as having limited disease. However, the increase in the median and 5-year survival times for all patients with SCLC makes these findings unlikely due to stage migration alone. In addition, the survival trend for limited-stage SCLC patients continues to increase in a linear fashion even in the later time period (1982–1992). During this period more sensitive staging techniques were employed. Over the same time period, the proportion of SCLC patients in the SEER database diagnosed with limited-stage disease decreased as did the number of all SCLC patients in other population registries.64 One possibility for these findings, as reflected in the studies from the later time period (1982–1992), is the introduction of routine CT scans of the chest and abdomen as well as CT and MRI scans of the head. The percentage of patients with limited-stage SCLC available for clinical studies may further decrease with the advent of more sensitive staging studies such as positron emission tomography scans, which may lead to longer survival.65, 66
The concordance in survival is similar to previous findings among patients with extensive-stage SCLC and advanced-stage nonsmall cell lung carcinoma (NSCLC).In the Phase III studies and in the SEER database, a 2-month and a 2-week prolongation in median survival was observed, respectively.7, 14 The similar increases in survivals among patients with three types or stages of lung carcinoma suggest that the outcomes of patients have improved to a similar extent whether they were treated on a clinical trial in North America or in one of the SEER tumor registries in 11 different states.
Two small studies have evaluated this specific issue in patients with SCLC. Cottin et al.67 evaluated the characteristics of 57 patients (of 178 total [31%]) excluded from three SCLC clinical trials. In one of these studies, they found that the median survival for 37 SCLC patients (4 limited, 33 extensive) excluded from that study was 6 months compared with 9 months in 73 patients (20 limited, 53 extensive) treated on study (P = 0.01). In contrast, Quoix et al.68 evaluated the outcomes of 171 patients (60 limited, 111 extensive) treated off protocol compared with 44 patients (21 limited, 23 extensive) treated on six clinical trials. They found no difference in the median survivals of limited-stage disease patients (12 months for patients on protocol vs. 13 months for patients off protocol; P = NS) but found a worse survival for patients with extensive-stage SCLC (7.5 months vs. 3.5 months, respectively; P < 0.05). Although we did not analyze individual patient data, our results on outcomes of patients with both stages of SCLC do not agree with these findings and show similar outcomes for patients treated on a Phase III clinical trial and in a population-based registry.
The number of Phase III trials that showed a statistically significant improvement in survival in this analysis (5 of 26 studies [19%]) is similar to the number of studies showing improvement for extensive-stage SCLC (5 of 21 studies [24%]) and advanced-stage NSCLC (5 of 33 studies [15%]).7, 14 Most of the Phase III clinical trials for all three diseases have shown no statistically significant survival improvement in the experimental arms compared with the control arms. These findings should be considered when planning future randomized Phase III studies. The need for adequate sample size in designing a clinical trial cannot be overstated. The observed differences in median survival times between experimental and control arms in patients with limited-stage SCLC have been modest. Only one of the five positive trials had a difference of more than 4 months, indicating that in the future, survival improvements in excess of 4 months may be unlikely.2 This information should be considered in designing future trials for patients with limited-stage SCLC. For example, a sample size of 1000 patients is required for a trial with 90% power to detect a 4-month improvement in median survival, a 24% increase, assuming a median survival of 17 months in the control arm. Given the decrease in the number of patients with SCLC and especially those with limited-stage disease, careful selection of future studies with the greatest likelihood of success is warranted. A statistical model to aid in the selection of chemotherapy regimens for Phase III clinical studies based on Phase II and pilot studies in extensive-stage SCLC was developed recently.12, 69, 70 For limited-stage SCLC, only four Phase II studies were identified retrospectively (Table 3), which is insufficient to generate an accurate model.60–63 Due to the inherent differences in the treatments and outcomes of patients with limited-stage SCLC compared with extensive-stage SCLC, the model generated from studies of extensive-stage SCLC is not applicable to limited-stage SCLC studies.
The only clinical studies that have shown a statistically significant prolongation in survival in the experimental arms have evaluated questions involving a combination of radiation therapy and chemotherapy. No studies involving chemotherapy, given either before radiation therapy, concurrently with radiation therapy, or in maintenance therapy, have shown superiority over the control arm. These findings are of importance when planning future studies in SCLC and should prompt the need to perform additional Phase II clinical trials before proceeding with large Phase III studies. Median survival rather than response rate is likely to be a better predictor of the success of a Phase II trial when taken into a Phase III setting as has been determined for extensive-stage SCLC.12 However, for limited-stage SCLC, a minimum of 2–3 years of follow-up is needed to assess median survival in a Phase II trial. Information generated from patients with extensive-stage SCLC, the statistical model based on Phase II and pilot studies, and the current study will be useful in planning future Phase III trials in SCLC utilizing data obtained from Phase II studies and incorporating the projected cost-benefits of new agents into the standard treatment regimens.
- 26A randomized phase III study of prophylactic cranial irradiation versus observation in patients with small cell lung cancer achieving a complete response: final report of an incomplete trial by the Eastern Cooperative Ongology Group and Radiation Therapy Oncology Group (E3589/R92-01) [abstract]. Proc Am Soc Clin Oncol. 1996; 15: 376., , .
- 27A comparison of standard with intensive combination chemotherapy in small cell lung cancer-mature results: an Eastern Cooperative Oncology Group trial (ECOG) [abstract]. Proc Am Soc Clin Oncol. 1997; 16: 481a., , , .
- 28A randomized combined modality trial in small cell carcinoma of the lung. Comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer. 1980; 45: 30–39., , , et al.
- 32Thoracic and elective brain irradiation with concomitant or delayed multiagent chemotherpy in the treatment of localized small cell carcinoma of the lung: a randomized prospective study by the Southeastern Cancer Study Group. Cancer. 1981; 47: 2407–2413., , , et al.
- 37Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group study. J Clin Oncol. 1987; 5: 592–600., , , et al.
- 39Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol. 1989; 7: 450–456., , , et al.
- 40Cytoxan, Adriamycin, etoposide versus cytoxan, Adriamycin, vincristine in the treatment of small cell lung cancer (SCLC) [abstract]. Proc Am Soc Clin Oncol. 1987; 6: 168., , , .
- 45Combination chemotherapy with or without consolidation radiation therapy (RT) for regional small cell carcinoma of the lung [abstract]. Proc Am Soc Clin Oncol 1988; 7: 196., , .
- 47Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol. 1990; 8: 39–47., , , et al.
- 63Limited small cell lung cancer (LSCLC): concurrent bid thoracic radiotherapy (TRT) with platinum-etoposide (PE): an ECOG Study [abstract]. Proc Am Soc Clin Oncol. 1990; 9: 230., , , , , .