1Department of Medicine, Indiana University Medical Center, Indianapolis, IN; 2The Hoosier Oncology Group, Indianapolis, IN; 3The Walther Cancer Institute, Indianapolis, IN; 4Michiana Oncology Associates, South Bend, IN; 5The Division of Biostatistics, Indiana University, Indianapolis, IN, USA
Received 6 April 2001; revised 18 June 2001; accepted 19 June 2001.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We performed this phase III study to determine whether the addition of 3 months of oral etoposide in non-progressing patients with extensive small-cell lung cancer (SCLC) treated with four cycles of etoposide plus ifosfamide plus cisplatin (VIP) improves progression-free survival (PFS) or overall survival.
Patients and methods
Patients with extensive SCLC with a Karnofsky performance score (KPS) 50, adequate renal function and bone marrow reserve were eligible. Patients with CNS metastasis were eligible and received concurrent whole-brain radiotherapy. All patients received etoposide 75 mg/m2, ifosfamide 1.2 g/m2 and cisplatin 20 mg/m2 intravenously on days 14 every 3 weeks for four cycles. Non-progressing patients were randomized to oral etoposide 50 mg/m2 for 21 consecutive days every 4 weeks for three courses versus no further therapy until progression.
Results
From September 1993 to June 1998, 233 patients were entered and treated with VIP with 144 non-progressing patients subsequently randomized to oral etoposide (n = 72) or observation (n = 72). Minimum follow up for all patients is 2 years. Toxicity with oral etoposide was mild. There was an improvement in median PFS favoring the maintenance arm of 8.23 versus 6.5 months (P = 0.0018). There was a trend towards an improvement in median (12.2 versus 11.2 months), 1-year (51.4% versus 40.3%), 2-year (16.7% versus 6.9%) and 3-year (9.1% versus 1.9%) survival (P = 0.0704) favoring the maintenance arm.
Conclusions
Three months of oral etoposide in non-progressing patients with extensive SCLC was associated with a significant improvement in PFS and a trend towards improved overall survival.
Key words: lung cancer, maintenance, small cell, VIP
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Another strategy to improve these results has been the use of maintenance therapy in non-progressing patients following induction therapy. At Indiana University, daily oral etoposide was found to be an active drug in refractory testicular cancer. Furthermore, responses were seen in patients who progressed during intravenous EP [5]. Maintenance oral etoposide has demonstrated encouraging results following salvage therapy in patients with germ-cell tumors, with a lower than expected relapse rate in a phase II trial [6]. Oral etoposide, with dosing based on 50% bioavailability [7], has equal efficacy and toxicity to that obtained with intravenous dosing in patients with SCLC [8]. Improved response rate, duration of response and survival have been seen in patients with SCLC with prolonged administration of intravenous etoposide when compared with a larger single dose, demonstrating the schedule dependency of this agent [9]. We and others have tested more prolonged courses of daily oral etoposide. A HOG phase II trial of daily oral etoposide in SCLC illustrated activity, especially in patients with no prior exposure to etoposide and in patients with a sensitive relapse. However, unlike testicular cancer, responses were not seen in patients who progressed during EP [10]. Therefore, earlier treatment with daily oral etoposide prior to progression might improve therapeutic results in patients with extensive SCLC. The primary endpoint of this phase III study was to determine whether the addition of 3 months of oral etoposide to non-progressing patients with extensive SCLC treated with four cycles of induction VIP improves progression-free survival (PFS) or overall survival. The secondary endpoint was to evaluate the toxicity of oral etoposide maintenance therapy after induction VIP.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pre-treatment studies included history and physical exam with assessment of KPS, posterioranterior and lateral chest X-ray and routine blood tests, including complete blood cell (CBC) counts with platelets and a chemistry panel, which included electrolytes, blood urea nitrogen and creatinine. All patients had a computed tomography (CT) scan of the abdomen and head (and chest if needed for measurements). Bone scans were optional and bone marrow aspirate and biopsy were not routinely performed in the absence of abnormalities in the peripheral blood smear. During induction treatment with VIP, blood counts and chest X-rays were performed with each course of chemotherapy. Urinalysis was evaluated prior to the start of each treatment course of VIP as well as on days 24 of therapy. At the end of the fourth and final course of VIP, all baseline abnormal studies were repeated to determine whether the patient had achieved any response to therapy.
All patients were treated with VIP induction consisting of etoposide 75 mg/m2 i.v. days 14, cisplatin 20 mg/m2 i.v. days 14 and ifosfamide 1.2 g/m2 i.v. days 14 with Mesna (Figure 1). Granulocyte colony-stimulating factor (G-CSF) at 5 µg/kg subcutaneously was administered on days 615 or until post-nadir WBC count was 10 000/mm3. Courses were repeated every 3 weeks for a total of four cycles unless the patient demonstrated disease progression or undue toxicity. A complete response (CR) was defined as complete disappearance of all objective evidence of disease for at least 1 month. A partial response (PR) was defined as a decrease of
50% in the sum of the products of diameters of measurable lesions for at least 1 month. Stable disease (SD) was defined as a decrease of <50% or increase of <25% with no new lesions during the study. Progression (PD) was defined as an increase of
25% in the sum of the products of diameters of measurable lesions or appearance of new lesions during the study period. Toxicity was assessed before each cycle of chemotherapy using the World Health Organization grade scale.
|
Statistical analysis
Patients were randomized to one of two treatment arms (etoposide or observation) following VIP induction in equal proportions using a stratified permuted block randomization. Patients were stratified according to KPS (80100 versus 5070) at baseline and at randomization and response (SD versus PR versus CR). The primary endpoints of the study were overall survival and PFS. The secondary endpoint was evaluation of the toxicity to daily oral etoposide following VIP chemotherapy. Based on a median survival of 9 months with VIP in a prior HOG study [4], the current study originally planned to accrue 168 randomized patients (with 158 deaths) for an 80% power to detect a 50% increase in median survival (from 9 to 13.5 months) by the log-rank test with a one-sided level of 0.05. The results of the paper were reported using a two-sided level of 0.05 since this is usually used for sample size and calculations. With a two-sided level of 0.05 the study would have required 202 patients with 191 deaths to detect a 50% difference in survival between the two groups with an 80% power. With the observed number of deaths reported in our study (139), the 5% two-sided level log-rank test has only 66% power to detect a 50% increase in overall survival. The study did not accrue the necessary number of patients to meet this criteria. The monitoring for treatment differences was performed using the OBrienFleming type group sequential boundaries [11]. Demographical characteristics were calculated for the overall group, the two arms and the non-randomized group. Univariate (unadjusted) analyses were undertaken first using the standard log-rank test. Characteristics, including KPS, gender, age and response to induction therapy, were compared in a multivariate analysis. Student t-tests were used to test continuous variables and 2 tests were used to test categorical variables. Survival time and PFS were defined from the date on which the study began until date of death (or date last seen) or date of progression, respectively. Survival curves were constructed using the KaplanMeier product limit method [12]. The Coxs proportional hazards regression model was used to determine the significance of treatment effect, adjusting for induction-phase response status, KPS, age and gender on survival and PFS [13]. The entire analysis was also re-run for the two KPS groups (5070 and 80100) at baseline and at randomization, separately.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The minimal follow-up time is 2 years for all patients. Patient characteristics at the time of randomization are depicted in Table 2. For the randomization, there was no significant difference between the two arms in terms of gender (P = 0.1715), KPS (P = 0.6815) or race (P = 0.2448). There was a significant difference in age as the observation group was older than the maintenance group (62.1 ± 8.9 for observation, 58.9 ± 8.5 for oral VP-16) (P = 0.0242). Overall, 45 patients had only one site of disease, 74 patients had two sites of disease and 114 patients had three or more sites of disease. No significant difference between the two treatment arms was observed with respect to number of sites of disease. The most frequent sites of metastasis at diagnosis were liver (n = 78), bone (n = 41), brain (n = 32) and adrenal gland (n = 26). The most frequent sites of relapse were the chest (n = 75), brain (n = 52), liver (n = 35) and bone (n = 22).
|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Strategies employed to improve the results from standard chemotherapy include dose intensification using higher doses of drugs or more frequently dosed drugs aided by cytokine support, alternating non-cross-resistant regimens, consolidation therapy using different agents, addition of new drugs in multi-agent combinations and maintenance therapy. Previous studies evaluating the role of maintenance chemotherapy have failed to demonstrate consistently an advantage for this strategy. The results of this study indicate a prolongation in PFS in patients with KPS 80100 with the addition of 3 months of oral etoposide in non-progressing patients following four cycles of induction VIP. There is an indication of an improved survival with maintenance therapy, although survival results with VIP alone in our prior HOG trial [4] are similar to those in the maintenance arm in this trial. The current study was originally designed to detect a 50% improvement in survival with 80% power using a one-sided 5% test. However, we performed our analysis using a more standard two-sided 5% test, which resulted in the study being underpowered to find this difference. Furthermore, full patient accrual was not reached due to waning enthusiasm for the VIP induction during the study period.
At least two randomized trials have demonstrated a deleterious effect of maintenance therapy in patients with SCLC [19, 20]. Ettinger et al. [19] reported on a phase III prospective randomized trial which found that continuation of CAV improved time to progression but had no impact on overall survival. In the same study, the use of maintenance therapy in patients treated with a similar regimen suggested a prolonged survival in those patients not receiving maintenance therapy. A smaller trial for patients with limited disease SCLC showed an improvement in median survival of 5 months in patients receiving six versus 12 cycles of cyclophosphamide, vincristine and methotrexate in complete remitters [20]. In contrast, at least two randomized trials have demonstrated a possible benefit for a longer duration of therapy [21, 22] and two trials have demonstrated an improvement with the use of consolidation therapy [23, 24]. Cullen et al. [22] reported an improvement in median survival with 12 versus six cycles of CAV in 61 patients with extensive SCLC in CR. The Southeastern Cancer Study Group (SECSG) reported an improvement in PFS and overall survival in patients receiving consolidation VP who had responded to CAV induction [23]. The principle tested in this study, however, was the use of consolidation therapy, not maintenance therapy. The SECSG also evaluated patients with limited SCLC responding to induction CAV with or without radiation randomized to receive two additional courses of EP or observation. Once again, there was an improvement in median survival in those receiving consolidation [24].
At least eight randomized trials have demonstrated no benefit for the use of maintenance or consolidation therapy [2532]. In one study, non-progressing patients after five cycles of cyclophosphamide, doxorubicin and etoposide were randomized to seven additional cycles or no further therapy [26]. PFS was improved by 2 months in the maintenance arm without an improvement in overall survival. The European Lung Cancer Working Party failed to demonstrate a benefit for maintenance etoposide/vindesine for 12 cycles in patients receiving induction ifosfamide/etoposide and an anthracycline for six cycles [27]. A French trial failed to show a benefit for 12 versus six cycles of cyclophosphamide/doxorubicin/etoposide (with lomustine given with the first three cycles) in complete responders [25]. In another study, no survival advantage was seen with six additional cycles of cyclophosphamide, etoposide, methotrexate and vincristine, although there was a suggestion of a longer survival for patients receiving prolonged therapy who were in CR [28]. Spiro et al. [29] reported the results of a study of 610 patients who received four or eight cycles of cyclophosphamide, vin-cristine and etoposide with SCLC that demonstrated no improvement in response rates. Response to second-line therapy was superior in patients receiving only four cycles upfront. Inferior results were seen in patients receiving only four cycles of chemotherapy, but there was no difference between the groups if second-line chemotherapy was given to those patients receiving only four cycles upfront. The Medical Research Council Lung Cancer Working Party Study Group evaluated 458 patients with SCLC randomized to receive three or six courses of cyclophosphamide, etoposide, methotrexate and vincristine or six courses of etoposide and ifosfamide [30]. No survival advantage was seen with any of these three regimens. No improvement was demonstrated with CAV maintenance in patients receiving induction EP in another study [31]. Schiller et al. [32] demonstrated an improvement in PFS but failed to demonstrate any benefit in overall survival in patients who received four cycles of consolidation topotecan following four cycles of induction VP. Other trials have failed to demonstrate an improvement in survival using maintenance therapy when compared with historical controls [3338]. Only one non-randomized trial utilizing maintenance therapy suggested an improvement in survival when compared with historical controls [39]. A review of these randomized trials was recently reported by Sculier et al. [40].
Our study demonstrated an improvement in PFS, but not in overall survival, which is similar to the results of four other studies [26, 27, 29, 32]. Two of these studies included patients with limited disease [26, 27] and demonstrated improvements in PFS of 2 months with a median of 11 cycles of therapy [26] and 3 months with a median of 12 cycles of therapy [27]. These studies demonstrate that as many as 12 cycles of therapy with active agents failed to improve overall survival; therefore, the failure of 3 months of oral etoposide to provide a survival benefit in our study is not likely to be due to the duration of therapy. Two other trials that included only patients with extensive disease [29, 32] demonstrated an improvement in PFS of approximately 2 months in one study [29] and just over 1 month in the other [32], but failed to improve overall survival. The latter study was very similar in design to this study, but used a topoisomerase I inhibitor (topotecan) in maintenance instead of a topoisomerase II inhibitor (etoposide) and, in contrast to our study, was adequately powered to demonstrate whether a survival benefit existed.
While our previous HOG study demonstrated a modest survival advantage for VIP over EP, the VIP arm was associated with greater toxicity and inconvenience. Therefore, VIP is not routinely used at Indiana University or by the HOG to treat patients with SCLC. The value of oral maintenance etoposide remains unresolved unless a similar study with adequate power and a larger number of patients is repeated, using induction therapy with VIP or another regimen such as EP. Toxicity of oral etoposide was minimal in our study, and there was a statistically significant improvement in PFS and a suggestion of an improved overall survival with maintenance oral etoposide.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Mascaux C, Paesmans M, Berghmans T et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000; 30: 2336.[ISI][Medline]
3. Ettinger DS. Overview of ifosfamide in small cell lung cancer. Semin Oncol 1992; 19: 5967.[Medline]
4. Loehrer PJ, Ansari R, Gonin G et al. Cisplatin plus etoposide with and without ifosfamide in extensive small cell lung cancer: a Hoosier Oncology Group Study. J Clin Oncol 1995; 13: 25942599.[Abstract]
5. Miller J, Einhorn LH. Daily oral VP-16 in refractory germ cell tumors. Semin Oncol 1990; 17 (Suppl 2): 3639.[ISI][Medline]
6. Cooper M, Einhorn LH. Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 1995; 13: 11671169.[Abstract]
7. Stewart DJ, Nundy D, Maroun JA et al. Bioavailability, pharmacokinetics and clinical effects of an oral preparation of etoposide. Cancer Treat Rep 1985; 69: 269273.[ISI][Medline]
8. Cavalli F, Suntag RW, Jungi F et al. VP-16-213 monotherapy for remission induction of small cell lung cancer: a randomized trial using dosage schedule. Cancer Treat Rep 1978; 62: 473475.[ISI][Medline]
9. Slevin ML, Clark PI, Joel SP et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 1989; 7: 13331340.[Abstract]
10. Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer: a Hoosier Oncology Group Study. Semin Oncol 1990; 17: 3235.[ISI][Medline]
11. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 659663.[ISI]
12. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457481.[ISI]
13. Cox DR. Regression models and life-tables (with discussion). J Roy Stat Soc [Ser B] 1972; 34: 187220.[ISI]
14. Livingston RB, Moore TN, Heibrun L et al. Small-cell carcinoma of the lung: combined chemotherapy and radiation. A Southwest Oncology Group study. Ann Intern Med 1978; 88: 194199.[ISI][Medline]
15. Pujol J, Carestia L, Daures J. Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 2000; 83: 815.[Medline]
16. Roth B, Johnson D, Einhorn L et al. Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282291.[Abstract]
17.
Murray N, Livingston R, Shephard F et al. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an intergroup study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999; 17: 23002308.
18. Noda K, Nishiwaki Y, Kawahara M et al. Randomized phase III study of irinotecan (CPT-11) and cisplatin versus etoposide and cisplatin in extensive-disease small-cell lung cancer: Japan Clinical Oncology Group Study (JCO9511). Proc Am Soc Clin Oncol 2000; 19: 483a (Abstr 1887).
19. Ettinger D, Finkelstein D, Abeloff M et al. A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 1990; 8: 230240.[Abstract]
20. Byrne MJ, van Hazel G, Trotter J et al. Maintenance chemotherapy in limited small cell lung cancer: a randomized controlled trial. Br J Cancer 1989; 60: 413418.[ISI][Medline]
21. Maurer L, Tulloh M, Weiss R et al. Comparison of combination chemotherapy-radiation therapy versus cyclophophamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer 1980; 45: 3039.[ISI][Medline]
22. Cullen M, Morgan D, Gregory W et al. Maintenance chemotherapy for anaplastic small cell carcinoma of the bronchi: a randomized, controlled trial. Cancer Chemother Pharmacol 1986; 17: 157160.[ISI][Medline]
23. Einhorn L, Crawford J, Birch R et al. Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 1988; 6: 451456.[Abstract]
24. Johnson D, Bass D, Einhorn L et al. Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group. J Clin Oncol 1993; 11: 12231229.[Abstract]
25. Lebeau B, Chastang CL, Allard P et al. Six vs. twelve cycles for complete responders to chemotherapy in small cell lung cancer: definitive results of a randomized clinical trial. Eur Respir J 1992; 5: 286290.[Abstract]
26. Giaccone G, Dalesio O, McVie G et al. Maintenance chemotherapy in small-cell lung cancer: long term results of a randomized trial. J Clin Oncol 1993; 11: 12301240.[Abstract]
27. Sculier JP, Paesmans M, Bureau G et al. Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. J Clin Oncol 1996; 14: 23372344.[Abstract]
28. 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: 584590.[ISI][Medline]
29. Spiro SG, Souhami RL, Geddes DM et al. Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1989; 59: 578583.[ISI][Medline]
30. Bleehen NM, Girling DJ, Machin D, Stephens RJ. A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 1993; 68: 11501156.[ISI][Medline]
31. Beith JM, Clarke SJ, Woods RL et al. Long term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung. Eur J Cancer 1996; 32A: 438443.
32.
Schiller J, Adak S, Cella D et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19: 21142122.
33. Einhorn L, Bond W, Hornback N et al. Long-term results in combined-modality treatment of small cell carcinoma of the lung. Semin Oncol 1978; 5: 309313.[ISI][Medline]
34. Tummarello D, Guioi F, Torresi V et al. Induction chemo-radiotherapy and maintenance alternating chemotherapy for small cell lung cancer. Acta Oncol 1990; 29: 417420.[ISI][Medline]
35. Warner-Efrati E, Sulkes A, Weshler Z et al. Chemotherapy induction, consolidation radiotherapy and maintenance alternating chemotherapy in small cell carcinoma of the lung. Isr J Med Sci 1988; 24: 593598.[ISI][Medline]
36. Ihde D, Mulshine J, Kramer B et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 1994; 12: 20222034.[Abstract]
37. Sculier J, Bureau G, Giner V et al. Induction chemotherapy with ifosfamide, etoposide, and anthracycline for small cell lung cancer: experience of the European Lung Cancer Working Party. Semin Oncol 1995; 22 (Suppl 2): 1822.
38. Joss R, Alberto P, Bleher E et al. Combined-modality treatment of small-cell lung cancer: randomized comparison of three induction chemotherapies followed by maintenance chemotherapy with or without radiotherapy to the chest. Ann Oncol 1994; 5: 921928.[Abstract]
39. Broder L, Sridhar K, Selawry O et al. A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification. Am J Clin Oncol 1994; 17: 527537.[ISI][Medline]
40. Sculier JP, Berghman T, Castaigne C et al. Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung Cancer 1998; 19: 141151.[ISI][Medline]