Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study

N. H. Hanna1,2,+, A. B. Sandler1, P. J. Loehrer Sr1,2,3, R. Ansari2,4, S. H. Jung5, K. Lane5 and L. H. Einhorn1,2,3

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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

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 1–4 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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Lung cancer is the leading cause of cancer death in both men and women in the USA with 157 000 projected deaths and an estimated 164 000 new cases diagnosed in the USA in 2000 [1]. Twenty to 25% of all lung cancers are small-cell type, with two-thirds of these patients presenting with extensive disease. Multiple chemotherapeutic trials have demonstrated response rates of 40% to 80% in extensive disease, including 10% to 20% complete responses (CR). The median survival for treated patients with extensive small-cell lung cancer (SCLC) is ~9 months with modern chemotherapy, with 5% to 10% surviving 2 years and only 1% of patients achieving a long-term disease-free survival. Etoposide and cisplatin (EP) is highly synergistic and used widely in patients with SCLC [2]. Strategies to improve on this have included the utilization of newer drugs. Ifosfamide has activity in previously untreated patients with SCLC. The Eastern Cooperative Oncology Group (ECOG) demonstrated a 45% response rate in 44 previously untreated patients with extensive disease [3]. Combination chemotherapy with etoposide (VP-16), ifosfamide and cisplatin (VIP) was originally developed as second- or third-line salvage therapy for patients with recurrent testicular cancer. The Hoosier Oncology Group (HOG) reported the results of a phase III trial in patients with extensive SCLC comparing EP with VIP, with a prolonged time to progression and a modest improvement in overall survival favoring the VIP arm [4].

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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients eligible for induction therapy with VIP had histological or cytological proof of extensive SCLC with a Karnofsky performance score (KPS) >=50, adequate bone marrow reserve [white blood cell (WBC) count >=4000/mm3 and platelet count >=100 000/mm3] and renal function (serum creatinine <2 mg/dl), and were able to take oral medications. Patients with limited disease (defined as disease confined to one hemithorax ± ipsilateral supraclavicular lymph node involvement), prior chemotherapy, congestive heart failure, pregnancy or a history of prior malignancies (except for cured basal or squamous cell skin cancers)—unless it had been >5 years since their prior disease with no evidence of recurrence—were ineligible. Patients with stable CNS metastasis were eligible and received concurrent whole-brain radiotherapy. The study was conducted by the HOG, a community-based co-operative group. The trial was approved by relevant institutional review boards before patient entry. Written, informed consent was obtained.

Pre-treatment studies included history and physical exam with assessment of KPS, posterior–anterior 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 2–4 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 1–4, cisplatin 20 mg/m2 i.v. days 1–4 and ifosfamide 1.2 g/m2 i.v. days 1–4 with Mesna (Figure 1). Granulocyte colony-stimulating factor (G-CSF) at 5 µg/kg subcutaneously was administered on days 6–15 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.



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Figure 1. Schema.

 
After completion of four cycles of VIP, patients with a CR, PR or SD were randomized to observation or oral etoposide (3–6 weeks after induction therapy was completed) at a dose of 50 mg/m2 daily for 21 consecutive days every 4 weeks for three courses (3 months). Oral etoposide is available in 50 mg capsules, so dosages were rounded to the nearest 25 mg (e.g. 75 mg/day translated to 50 mg alternating with 100 mg for the 21 days). To be eligible for randomization, patients must have received all four courses of VIP, had a KPS >=50, a WBC count >=4000/mm3 and a platelet count >=100 000/mm3 at the time of randomization. Following each cycle of oral etoposide, patients were re-evaluated for response. Non-progressing patients received their next cycle, while patients with PD were removed from the study. Weekly CBC counts were monitored and if the granulocyte count was <500/mm3 or the platelet count was <50 000/mm3, oral etoposide was held for 1 week. Upon recovery of the platelet count to >75 000/mm3 and the granulocyte count to >1500/mm3, the next cycle of oral etoposide was started with a 25% dose reduction. If granulocytes and platelets had not recovered after a 2-week delay, patients were removed from study, but followed for relapse and overall survival. Oral etoposide was reduced by 25% for any episode of granulocytopenic fever, thrombocytopenic bleeding or severe thrombocytopenia. Upon completion of therapy, all patients had re-evaluation of their disease monthly for the first 3 months, then every 2 months thereafter until progression or death.

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 (80–100 versus 50–70) 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 O’Brien–Fleming 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 {chi}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 Kaplan–Meier product limit method [12]. The Cox’s 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 (50–70 and 80–100) at baseline and at randomization, separately.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From September 1993 through June 1998, 233 patients were entered in the trial. Patient populations for VIP induction are listed in Table 1. Two hundred and twenty-eight of 233 patients were eligible (two patients were ineligible due to mixed histology and three due to limited disease) and evaluable for survival analysis. Two hundred and twenty-five of 228 eligible patients were evaluable for response to VIP (three were inevaluable: two patients were never treated and one patient was inevaluable for unknown reasons). Two hundred and thirty-one treated patients were evaluable for toxicity data to VIP.


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Table 1. Patient population for VIP
 
One hundred and forty-four of 166 non-progressing patients were randomized to maintenance oral etoposide or observation following VIP. Twenty-two patients were eligible based on response criteria but not randomized for the following reasons: 12 patients were ineligible due to poor KPS or induction toxicities, three patients refused randomization, two patients had protocol violations during induction therapy, one patient had PD initially reported as SD, one patient was lost to follow-up, one patient had unassessable disease, one patient did not finish four cycles of VIP and one patient was not entered for unknown reasons. Seventy-two patients were randomized to oral etoposide and 72 to observation.

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).


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Table 2. Patient characteristics at randomization
 
Toxicity
Toxicity to induction therapy with VIP was similar to our previous report [4]. Grade 3/4 toxicities to maintenance oral etoposide are listed in Table 3. Maintenance oral etoposide was well tolerated. Myelosuppression was the most frequent grade 3/4 toxicity, with anemia seen in 20% of patients, granulocytopenia in 42% of patients, including 4% with neutropenic fevers, and 20% with thrombocytopenia. Nonhematological toxicity was mild. Persistent alopecia during oral etoposide was observed. There were no treatment-related mortalities with oral etoposide. Compliance with oral etoposide was good, with 64% of patients completing all three cycles. The remaining patients did not complete oral etoposide due to PD or hematological toxicity.


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Table 3. Grade 3/4 toxicities to maintenance oral etoposide (n = 72)
 
Response and survival
For 225 patients who were evaluable for response to VIP, 28 patients achieved a CR (12.4%), and 116 patients achieved a PR (51.5%) for an overall response rate of 63.9%. Twenty-two patients maintained SD (9.7%), and 59 patients were treatment failures (26.2%), with 26 patients developing PD during VIP, 12 patients stopping therapy early due to toxicity or non-compliance and 21 patient deaths during VIP. Of the patients randomized to maintenance oral etoposide (n = 72), 72 were evaluable for response: 10 maintained a CR, 29 maintained a PR, six maintained SD, three patients achieved a CR who had a PR with induction therapy, and 24 had PD during the 3-month period of oral etoposide. In the observation arm (n = 72) 72 were evaluable for response over the same 3-month period: seven patients maintained a CR, 23 maintained a PR, four maintained SD, one patient had a PR subsequently defined as a CR and 37 patients had PD, as depicted in Table 4.


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Table 4. Responses during oral etoposide versus observation
 
There was a statistically significant improvement in median PFS favoring the maintenance arm over the observation arm (8.2 versus 6.5 months, P = 0.0018, as illustrated in Figure 2). Seventy-one and 67 patients eventually progressed on the observation and maintenance arm, respectively. The median survival for all patients was 9.8 months with 1-, 2- and 3-year survival of 36.4%, 8.8% and 4.4%, respectively, as shown in Table 5. There was a trend towards 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 favoring the maintenance arm over the observation arm, as illustrated in Figure 3 (P = 0.0704). Overall, nine of the 144 randomized patients remain alive (n = 7 for maintenance arm, n = 2 for observation arm).



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Figure 2. PFS analysis comparing observation versus treatment (oral etoposide).

 

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Table 5. Overall survival analysis
 


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Figure 3. Overall survival comparing observation versus treatment (oral etoposide).

 
All patients with a KPS of 50–70 (n = 62) before entry on to the study died, while 156 of 166 patients with a KPS 80–100 died. The median survival for all patients with a baseline KPS 50–70 was 6.66 months, with 1- and 2-year survival being 21% and 3.2%, respectively. The median, and 1- and 2-year survival for patients with a baseline KPS 80–100 was 11 months, 42.2% and 10.8%, respectively. There was no statistically significant difference in median, 1-, 2- and 3-year survival in either KPS 50–70 (P = 0.8721) or 80–100 group (P = 0.0882) according to the randomization arms. There was also no difference in survival between the two arms when evaluating for the KPS values at randomization (P = 0.1868 for KPS 50–70 and P = 0.0998 for KPS 80–100), as shown in Table 6. There was no difference in PFS between the maintenance and observation arms with a baseline KPS 50–70 (median 6.30 versus 5.85 months) (P = 0.3738) or randomized KPS 50–70 (median 6.81 versus 5.69 months) (P = 0.0561), but patients with a baseline KPS 80–100 randomized to maintenance chemotherapy had a significant improvement in PFS of 8.83 versus 6.56 months in the observation arm (P = 0.0027), as did patients with a KPS 80–100 at randomization (8.33 versus 6.61 months) (P = 0.0060).


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Table 6. Overall survival stratified by KPS at randomization
 
In the multivariate analyses on patients with a baseline KPS 50–70 and 80–100 adjusting for age, gender and response to induction therapy, maintenance oral etoposide offered an improvement in PFS in the KPS 80–100 group only (P = 0.0035, Cox’s hazard ratio 0.548). There was no improvement in overall survival in any KPS group. There was a significant improvement in survival favoring patients with a baseline KPS 80–100 versus 50–70 (P = 0.0021, Cox’s hazard ratio 0.511) and females versus males (P = 0.0426, Cox’s hazard ratio 0.692). There was a trend towards improved survival in responding patients versus SD patients (P = 0.0633, Cox’s hazard ratio 0.543 for CR versus SD, and P = 0.0750, Cox’s hazard ratio 0.609 for PR versus SD patients).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Median survival for patients with extensive SCLC has increased from 9 weeks to 9 months with modern chemotherapy regimens. Active agents include platinum compounds, topoisomerase I and II inhibitors, alkylators, vinca alkaloids, anthracyclines and taxanes. Combination chemotherapy has been standard treatment for extensive SCLC for over 25 years. Cyclophosphamide, doxorubicin (Adriamycin) and vincristine (CAV) was a common regimen in the period 1975–1985 [14]. Presently, the most commonly used regimen is cisplatin (or carboplatin) plus etoposide. Cisplatin-containing regimens have demonstrated survival benefits over regimens without this alkylating agent in two meta-analyses [2, 15]. There has been little improvement in the last two decades (unlike limited disease) in improving the median survivals of 8–10 months, and 1, 2 and 3 year survival of 35%, 10% and <5%, respectively, in patients with extensive SCLC. Roth et al. [16] reported no difference in survival with CAV versus EP compared with alternating the two regimens. Dose intensity of four of the most active drugs, cisplatin, vincristine, doxorubicin and etoposide, did not result in improved survival over CAV/EP in a study reported by Murray et al. [17]. Noda et al. [18] have recently reported the results of a phase III trial in Japan demonstrating a 4-month improvement in median survival favoring cisplatin/CPT-11 compared with EP.

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 80–100 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
 
This study was supported in part by an unrestricted educational grant from Bristol-Myers Squibb Oncology (Grant No. 03-628-95-01).


    Footnotes
 
+ Correspondence to: 535 Barnhill Drive Room 473, Indianapolis, IN 46202, USA. Tel: +1-317-274-3515; E-mail: nhanna@iupui.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Greenlee RT, Murray T, Buldea S et al. Cancer Statistics, 2000. CA Cancer J Clin 2000; 50: 12–13.

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: 23–36.[ISI][Medline]

3. Ettinger DS. Overview of ifosfamide in small cell lung cancer. Semin Oncol 1992; 19: 59–67.[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: 2594–2599.[Abstract]

5. Miller J, Einhorn LH. Daily oral VP-16 in refractory germ cell tumors. Semin Oncol 1990; 17 (Suppl 2): 36–39.[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: 1167–1169.[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: 269–273.[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: 473–475.[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: 1333–1340.[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: 32–35.[ISI][Medline]

11. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 659–663.[ISI]

12. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457–481.[ISI]

13. Cox DR. Regression models and life-tables (with discussion). J Roy Stat Soc [Ser B] 1972; 34: 187–220.[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: 194–199.[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: 8–15.[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: 282–291.[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: 2300–2308.[Abstract/Free Full Text]

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: 230–240.[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: 413–418.[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: 30–39.[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: 157–160.[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: 451–456.[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: 1223–1229.[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: 286–290.[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: 1230–1240.[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: 2337–2344.[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: 584–590.[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: 578–583.[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: 1150–1156.[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: 438–443.

32. Schiller J, Adak S, Cella D et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19: 2114–2122.[Abstract/Free Full Text]

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: 309–313.[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: 417–420.[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: 593–598.[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: 2022–2034.[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): 18–22.

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: 921–928.[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: 527–537.[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: 141–151.[ISI][Medline]





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