• No results found

Randomized Phase II Study of Maintenance Irinotecan Therapy Versus Observation Following Induction Chemotherapy with Irinotecan and Cisplatin in Extensive Disease Small Cell Lung Cancer

N/A
N/A
Protected

Academic year: 2021

Share "Randomized Phase II Study of Maintenance Irinotecan Therapy Versus Observation Following Induction Chemotherapy with Irinotecan and Cisplatin in Extensive Disease Small Cell Lung Cancer"

Copied!
7
0
0

Loading.... (view fulltext now)

Full text

(1)

Randomized Phase II Study of Maintenance Irinotecan

Therapy Versus Observation Following Induction

Chemotherapy with Irinotecan and Cisplatin in Extensive

Disease Small Cell Lung Cancer

Ji-Youn Han, MD, Heung Tae Kim, MD, Kun Young Lim, MD, Sung Jin Yoon, RN, Dae Ho Lee, MD,

and Jin Soo Lee, MD

Introduction: To determine whether irinotecan maintenance

ther-apy in extensive disease-small cell lung cancer can improve survival of patients who responded to irinotecan plus cisplatin (IP) induction therapy.

Methods: A total of 120 chemo-naive patients with adequate organ

functions and Eastern Cooperative Oncology Group performance status of 0 to 2 were enrolled from March 2003 through April 2006. After IP induction therapy, with either schedule A (I: 60 mg/m2

intravenously (IV) on days 1, 8, and 15; P: 30 mg/m2

IV on days 1 and 8, every 4 weeks for six cycles) or schedule B (I: 60 mg/m2

and P: 30 mg/m2

IV on days 1, and 8, every 3 weeks for eight cycles), responding patients were randomized to either maintenance with irinotecan 100 mg/m2

IV on days 1, 8, and 15, every 4 weeks up to six cycles, or observation.

Results: Overall, 100 (83%) of 120 patients achieved objective tumor

responses (12 complete responses, 88 partial responses) after IP induc-tion therapy. Of those patients who remained in remission upon com-pletion of planned cycles of induction therapy, 45 were randomized to maintenance (n⫽ 21) or observation (n ⫽ 24). Median progression-free survival (PFS) and overall survival (OS) for all patients were 7.2 and 14.0 months, respectively. For the maintenance arm, median PFS and OS were 12.0 and 17.6 months, respectively. For the observation arm, median PFS and OS were 9.9 and 20.5 months, respectively, which was not significantly different from the maintenance arm.

Conclusions: IP chemotherapy is very useful for the treatment of

small cell lung cancer. However, maintenance irinotecan therapy did not seem to further affect the clinical outcome of patients who had responded to IP induction therapy.

Key Words: Maintenance chemotherapy, SCLC, irinotecan.

(J Thorac Oncol. 2008;3: 1039 –1045)

S

mall cell lung cancer (SCLC) accounts for 13 to 15% of all lung cancer and more than 60 to 70% of patients present with extensive disease (ED).1 Although etoposide

plus cisplatin (EP) regimen has been the mainstay of ED-SCLC treatment, median survival is about 9 months, with 5 to 10% surviving 2 years and only 1% of patients achieving a long-term disease-free survival.2 To improve this outcome

further, various attempts have been made, which included dose intensification with stem cell supports,3,4 maintenance

chemotherapy,5–19and also searches for a better

chemother-apy regimen.20

Irinotecan has been demonstrated to have significant ac-tivity against SCLC and a phase II trial conducted by the West Japan Thoracic Oncology Group showed irinotecan plus cispla-tin (IP) regimen had promising results. For previously untreated patients with ED-SCLC, the objective response rate was 86% with complete response (CR) rate of 26%.21 A subsequent

randomized phase III from the Japanese Cooperative Oncology Group reported a statistically superior benefit of IP combination over the standard EP chemotherapy. The median survival and 2-year survival rates on IP and EP arms were 12.8 months versus 9.4 months and 19.5% versus 5.2%, respectively.22 From a

separate randomized phase III trial, however, Hanna et al.23

reported no significant difference between IP and EP in response rate and survival in 331 patients enrolled from the United States, Australia, and Canada. On the other hand, Hermes et al. reported in 2007 a randomized phase III study of irinotecan plus carbo-platin versus etoposide plus carbocarbo-platin in 220 Norwegian and Swedish patients with ED-SCLC. Similar to the Japanese Co-operative Oncology Group data, they found a statistically sig-nificant difference in overall survival (OS) in favor of the irinotecan-containing regimen. Moreover, significantly more CRs were observed with irinotecan plus carboplatin therapy.24

These findings suggest that irinotecan plus platinum agent che-motherapy can improve the survival of ED-SCLC.

Regarding the role of maintenance chemotherapy in SCLC, there have been about 14 randomized phase III trials since 1980.6 –19 Although its role remains unresolved until

recently and quite controversial, at least five studies had found better progression-free survival (PFS) with mainte-nance chemotherapy12,15,16,18,19and three trials demonstrated

Research Institute and Hospital, National Cancer Center, Goyang, Korea. Disclosure: The authors declare that no conflict of interest exists for any of

the authors.

Address for correspondence: Jin Soo Lee, MD, Lung Cancer Branch, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi 411-769, Korea. E-mail: jslee@ncc.re.kr

Copyright © 2008 by the International Association for the Study of Lung Cancer

(2)

statistically significant advantage for OS with maintenance chemotherapy when only the patients who achieved objective responses to induction chemotherapy were included.6,8,14

Given the documented contribution of irinotecan in the treatment of SCLC, we postulated that irinotecan maintenance therapy might improve the outcome of ED-SCLC patients who achieved objective responses after IP induction therapy. There-fore, we conducted a randomized phase II trial to examine whether the irinotecan maintenance therapy would improve the survival of ED-SCLC patients who responded to IP induction chemotherapy.

PATIENTS AND METHODS

Eligibility criteria were as follows: (1) histologically con-firmed SCLC; (2) extensive-stage disease; (3) Eastern Cooper-ative Oncology Group performance status (PS) of 0 to 2; (4) ageⱖ18 years old; (5) adequate function of bone marrow (white blood cell count ⱖ4000/mm3 and platelet count ⱖ100,000/mm3), liver (bilirubin level ⱕ1.5 mg/dl, AST, and

ALTⱕ2 ⫻ the upper limit of normal), and kidney (creatinine levelⱕ1.5 mg/dl); (6) at least one bidimensionally measurable disease; (7) absence of active infection; (8) no prior chemother-apy or radiotherchemother-apy; (9) no history of myocardial infarction in the last 6 months, no congestive heart failure or significant arrhythmia; (10) no second primary cancer, except skin cancer. Patients with CNS metastasis were eligible as long as neurologic symptoms were controlled by corticosteroid.

All patients signed informed consent. The study was approved by the institutional review board of our institution

and was conducted in compliance with institutional review board regulations.

Treatment

Treatment was given in the outpatient setting, the schema of which is shown in Figure 1. The first 40 patients were treated with irinotecan 60 mg/m2intravenously (IV) on

days 1, 8, and 15, and cisplatin 30 mg/m2IV on days 1 and 8 of a 28-day cycles (schedule A). Because of frequent omission of day 15 irinotecan and delay in the next cycle of chemotherapy, next 80 patients were treated with irinotecan 60 mg/m2and cisplatin 30 mg/m2IV on days 1 and 8 of a 21-day cycle (schedule B). Patients received IP indu chemo-therapy up to maximum six (schedule A) or eight cycles (schedule B) for a total of 24 weeks unless there were disease progression or undue toxicity. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Response assessment was performed every three cycles or whenever clinically indicated according to the World Health Organization criteria.

Approximately 3 to 4 weeks after the last course of induction IP chemotherapy, responding patients were ran-domized to receive either irinotecan maintenance or observa-tion alone. Stratificaobserva-tion factors were response to inducobserva-tion chemotherapy [CR versus partial response (PR)] and number of metastasis site (0 –1 versus 2 or more). Previously a phase I study reported that the recommended dose of single-agent irinotecan was 100 to 125 mg/m2once a week.25

Addition-ally, Masuda used irinotecan 100 mg/m2every week to treat

Induction chemotherapy ) 0 8 = n ( B e l u d e h c S ) 0 4 = n ( A e l u d e h c S

Irinotecan (60 mg/m2) IV on day 1, 8, & 15

Cisplatin (30 mg/m2) IV on day 1 & 8

Every 4 weeks X 6 cycles

or Irinotecan (60 mg/m

2IV on day 1 & 8

Cisplatin (30 mg/m2) IV on day 1 & 8

Every 3 weeks X 8 cycles

CR or PR (n=100) Treatment failure (SD or PD/death ) (n=20) Off study (n=75) Observation (n=24) or Maintenance (n=21) Irinotecan (100 mg/m2) IV on day 1, 8, & 15 Every 4 week X 6 cycles Randomization (n=45) Stratified by; • CR v PR • No of metastasis 0 or 1 v 2 or more Non-randomization (n=55) • PD after 1stevaluation • Toxicity • Patients’refusal

FIGURE 1. Study scheme. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

(3)

16 patients with refractory or relapsed SCLC, and 7 of 15 evaluable patients responded to irinotecan.26Based on these

data, patients received irinotecan 100 mg/m2IV on days 1, 8,

and 15, every 4 weeks up to six cycles as the maintenance therapy. Follow-up consisted of physical examination, blood cell counts, and chest radiographs every cycle and chest CT every three cycles. The same follow-up was applied to both arms when treatment was terminated. Choice of subsequent treatment for progression was left to the discretion of the investigator.

Statistical Analysis

Patients were randomized to one of two treatment arms (maintenance or observation) following irinotecan/cisplatin in-duction in equal proportions using a stratified permuted block randomization. Patients were stratified according to response to induction chemotherapy (CR versus PR) and number of metas-tasis site (0 or 1 versus 2 or more). The primary endpoint of the study was PFS. The secondary end point was evaluation of the toxicity to maintenance irinotecan following irinotecan/cisplatin induction chemotherapy and OS. This trial was designed to detect an increase in median PFS from 7 to 12 months in responding patients receiving maintenance chemotherapy (␣ ⫽ 0.05, ␤ ⫽ 0.02, one-tailed test) and required accrual of 50 assessable patients for each arm. Assuming the objective re-sponse rate of 85%, we initially planned accrue a total of 120 patients. 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 con-structed using the Kaplan–Meier product limit method.

RESULTS Patients

From March 2003 through April 2006, 120 patients were entered in this trial. Patients’ characteristics are listed in Table 1. Out of 100 responding patients (CR or PR), 63 patients main-tained objective tumor responses after a total of six or eight cycles of IP induction therapy. The other 37 initially responding patients became not eligible for randomization because of dis-ease progression during induction therapy. Among 63 patients maintaining tumor responses, 45 patients were randomized to either maintenance irinotecan single therapy or observation. The other 18 patients were not randomized for the following reasons: 14 patients’ refusal due to either declined PS or toxicities, and 4 due to follow-up loss. Twenty-one patients were randomized to irinotecan maintenance arm and 24 were to observation arm. Patient characteristics at the time of randomization are also depicted in Table 1.

Treatment Delivery

The median number of induction IP chemotherapy cycles delivered was six (range, 1– 8). By treatment schedule, 80% (32/40) of patients completed six cycles of IP chemotherapy in schedule A. In schedule B, 38% (30/80) of patients completed eight cycles and 63% (50/80) of patients received more than six cycles of IP chemotherapy. The reasons for treatment discontin-uation were disease progression (5% for schedule A, 34% for

schedule B), toxicity (5% for schedule A, 23% for schedule B), and follow-up loss (10% for schedule A, 6% for schedule B).

The median number of maintenance irinotecan single chemotherapy cycles delivered was three (range, 1– 6). Only 5 of 21 (24%) of patients completed all six cycles. The remaining patients did not complete maintenance irinotecan therapy because of PD (nine), pneumonia (two), poor PS (two), prolonged thrombocytopenia (one), acute myocardial infarction (one), and patient’s refusal (one).

Toxicity

One hundred nineteen patients were included in evalu-ation of toxicity of induction IP chemotherapy. Overall, toxicity of induction therapy with IP was similar to our previous report.4 Myelosuppression was the most common

grade 3 or 4 toxicity and grade 3 diarrhea developed in 13 (12%) patients (Table 2). There were five treatment-related deaths (4%) that occurred after the first cycle of IP, three due to sepsis with neutropenia, and two due to pneumonia.

Maintenance with irinotecan was well tolerated. My-elosuppression was the most common grade 3 or 4 toxicity, with anemia reported in 28.6% of patients and granulocyto-penia in 28.6% of patients (Table 3). Nonhematologic toxic-ity was mild. There was no treatment-related death during maintenance irinotecan therapy.

Response

Of a total 120 patients, 12 patients (10%) achieved CR and 88 patients (73%) achieved a PR, for an overall response rate of 83%. Three patients (3%) maintained SD, and 17 TABLE 1. Patients’ Characteristics

Characteristics Total (nⴝ 120) n (%) Maintenance (nⴝ 21) n (%) Observation (nⴝ 24) n (%) Age, median (range) 63 (33–79) 63 (51–77) 63 (51–77) Sex Male 107 (89) 19 (91) 23 (96) Female 13 (11) 2 (9) 1 (4) ECOG PS 0 24 (20) 4 (19) 4 (17) 1 64 (53) 12 (57) 16 (66) 2 32 (27) 5 (24) 4 (17)

No. of metastatic sites

ⱕ1 68 (57) 16 (76) 18 (75) ⬎1 52 (43) 5 (24) 6 (25) Induction schedule Every 4 wk 40 (33) 11 (52) 13 (54) Every 3 wk 80 (67) 10 (48) 11 (56) Response to induction CR 12 (10) 4 (19) 6 (25) PR 88 (73) 17 (81) 18 (75) SD 3 (3) 0 0 PD 5 (4) 0 0 NA 12 (10) NA, nonassessable.

(4)

patients (14%) had treatment failure, which include 5 patients who developed PD during IP chemotherapy, 7 who stopped therapy due to toxicity or noncompliance, and 5 patients who died during the first cycle of IP chemotherapy.

Of the 21 patients randomized to maintenance irinote-can therapy, all were evaluable for response: 2 remain in CR, 7 remained in PR, whereas 12 had PD during the 6-month period of maintenance irinotecan therapy. In the observation

arm (n⫽ 24), 2 remained in CR, 3 remained in PR, whereas 19 had PD during the same 6-month period (Table 4).

Survival

After median follow-up of 39.1 month (range, 15.2– 52.7), 19 of 120 patients were known alive at the time of this report. Median OS for all patients was 14 months [95% confidence interval (CI), 12.5–15.7] with 1- and 2-year sur-TABLE 2. Maximal Hematologic and Nonhematologic Toxicity of Induction

Chemotherapy per Patient (n⫽ 119)

Grade by NCI-CTC Version 2.0

0 1 2 3 4 n (%) n (%) n (%) n (%) n (%) Hematologic toxicity Neutropenia 6 (5.0) 4 (3.4) 33 (27.7) 52 (43.7) 24 (20.2) Anemia 4 (3.4) 27 (22.7) 59 (49.6) 28 (23.5) 1 (0.8) Thrombocytopenia 49 (41.2) 43 (36.1) 17 (14.3) 9 (7.6) 1 (0.8) Nonhematologic toxicity

Infection (without neutropenia) 113 (95.0) 0 (0) 0 (0) 3 (2.5) 3 (2.5) Infection (with neutropenia) 116 (97.5) 0 (0) 0 (0) 1 (0.8) 2 (1.7) AST 87 (73.1) 29 (24.4) 1 (0.8) 1 (0.8) 1 (0.8) ALT 83 (69.7) 29 (24.4) 4 (3.4) 2 (1.7) 1 (0.8) Asthenia 2 (1.7) 29 (24.4) 85 (24.4) 3 (2.5) 0 (0.0) Alopecia 11 (9.2) 73 (61.3) 35 (2.94) 0 (0.0) 0 (0.0) Anorexia 0 (0.0) 40 (33.6) 74 (62.2) 5 (4.2) 0 (0.0) Nausea/vomiting 8 (6.7) 32 (26.9) 78 (65.6) 0 (0.0) 0 (0.0) Constipation 49 (41.2) 31 (26.1) 30 (26.1) 9 (7.6) 0 (0.0) Creatinine 82 (68.9) 35 (29.4) 1 (0.8) 1 (0.8) 0 (0.0) Diarrhea 21 (17.6) 49 (41.2) 35 (29.4) 14 (11.7) 0 (0.0) Mucositis 43 (36.1) 54 (45.4) 21 (17.6) 1 (0.8) 0 (0.0)

TABLE 3. Maximal Hematologic and Nonhematologic Toxicity of Maintenance Chemotherapy per Patient (n⫽ 21)

Grade by NCI-CTC Version 2.0

0 1 2 3 4 n (%) n (%) n (%) n (%) n (%) Hematologic toxicity Neutropenia 3 (14.3) 4 (19.0) 8 (38.1) 1 (4.8) 5 (23.8) Anemia 1 (4.8) 6 (28.6) 8 (38.1) 6 (28.6) 0 (0.0) Thrombocytopenia 8 (38.1) 10 (47.6) 3 (14.3) 0 (0.0) 0 (0.0) Nonhematologic toxicity

Infection (without neutropenia) 20 (95.2) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) Infection (with neutropenia) 20 (95.2) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) AST 18 (85.7) 2 (9.5) 1 (4.8) 0 (0.0) 0 (0.0) ALT 20 (95.2) 0 (0.0) 1 (4.8) 0 (0.0) 0 (0.0) Asthenia 1 (4.8) 8 (38.1) 12 (57.1) 0 (0.0) 0 (0.0) Alopecia 1 (4.8) 7 (33.3) 13 (61.9) 0 (0.0) 0 (0.0) Anorexia 1 (4.8) 6 (28.6) 14 (66.7) 0 (0.0) 0 (0.0) Nausea/vomiting 6 (28.6) 2 (9.5) 13 (61.9) 0 (0.0) 0 (0.0) Constipation 12 (57.1) 6 (28.6) 3 (14.3) 0 (0.0) 0 (0.0) Creatinine 11 (52.4) 10 (47.6) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhea 4 (19.0) 7 (33.3) 9 (42.9) 1 (4.8) 0 (0.0) Mucositis 15 (71.4) 5 (23.8) 1 (4.8) 0 (0.0) 0 (0.0)

(5)

vival rates were 59.2% (95% CI, 50.4 – 68.0) and 17.8% (95% CI, 10.4 –25.2), respectively, as shown in Table 5. Median PFS was 7.2 months (95% CI, 6.4 – 8.0) with 1- and 2-year PFS rates were 20.3% (95% CI, 13.0 –27.6) and 6.2% (95% CI, 1.5–10.9), respectively. Figures 2 and 3 show the pro-gression-free and OS curves for the patients who participated in the maintenance versus observation study.

Second-Line Therapy

Overall, 77 patients received salvage chemotherapy after PD, including 14 of 21 patients (66.7%) in the maintenance arm, and 19 of 24 patients (79.2%) in the observation arm. The most commonly used regimens were IP, AIV (adriamycin, ifosf-amide, and vincristine), CAV (cyclophosphifosf-amide, adriamycin, and vincristine), etoposide and cisplatin, paclitaxel and gemcit-abine, and others. Table 6 summarized the commonly used second-line treatments and their response rates.

DISCUSSION

Encouraged by a phase III trial results that had showed better survival outcome after IP chemotherapy when com-pared with EP, we previously reported promising activity of IP regimen for LD-SCLC and also for ED-SCLC.27,28In this

study, overall response rate was 83% with a CR rate of 10%. The median survival was 14 months (95% CI, 12.2–15.7) with 1- and 2-year survival rates of 59.2 and 17.8%. The median PFS was 7.2 months with 1- and 2-year PFS rates of

20.3 and 6.2%. These results are comparable with those of two studies of IP regimen for ED-SCLC, which have reported a median survival time of 13 and 12.8 months.21,22In

addi-tion, they are better than those of recent standard EP chemo-therapy. Two recent studies of EP regimen have reported a median survival of 8.9 and 10.2 months.22,23 Indeed, these

findings suggest that there was significant progress in the treatment of SCLC with the introduction of IP regimen. FIGURE 2. Kaplan–Meier plot for time to progression by randomization.

FIGURE 3. Kaplan–Meier plot for overall survival by ran-domization.

TABLE 5. Median Progression-Free and Overall Survival Times PFS (95% CI) OS (95% CI) Overall n⫽ 120 n⫽ 120 Median (mo) 7.2 (6.4–8.0) 14.0 (12.5–15.7) 1 yr (%) 20.3 (13.0–27.6) 59.2 (50.4–68.0) 2 yr (%) 6.2 (1.5–10.9) 17.8 (10.4–25.2) Randomization maintenance n⫽ 21 n⫽ 21 Median (mo) 12.0 (9.0–15.0) 17.6 (16.4–18.8) 1 yr (%) 47.6 (26.2–69.0) 85.7 (70.8–100) 2 yr (%) — 19.6 (0.6–38.6) Observation n⫽ 24 n⫽ 24 Median (month) 9.9 (8.5–11.3) 20.5 (12.5–28.5) 1 yr (%) 29.2 (11.0–47.4) 83.3 (68.4–98.2) 2 yr (%) — 33.7 (11.7–55.7)

PFS, progression-free survival; OS, overall survival.

TABLE 4. Responses During Maintenance Irinotecan Single Therapy Versus Observation

No. of Patients Maintenance (nⴝ 21) Observation (nⴝ 24) Maintained CR 2 2 Maintained PR 7 3

Achieved CR from induction PR 0 0

(6)

Nevertheless, irinotecan maintenance therapy for responding patients after six or eight cycles of induction IP chemotherapy did not further influence either PFS or OS in this study.

The role of maintenance chemotherapy in patients with SCLC has been debated for many years. So far, three ran-domized trials have shown a survival benefit of maintenance chemotherapy.6,8,14Interestingly, two of them used different

chemotherapy regimens, CAV regimen for induction therapy and EP regimen for maintenance therapy.8,14 These findings

suggest that addition of a noncross resistant regimen as mainte-nance therapy may improve the therapeutic efficacy. In addition, five trials have found improved PFS.12,15,16,18,19 Nevertheless,

most studies failed to detect a benefit for maintenance chemo-therapy.7,9 –11,13,14,17 Nevertheless, a recent meta-analysis on

maintenance therapy in SCLC revealed that maintenance ther-apy improved 1- and 2-year OS by 9% (from 30 to 39%) and 4% (from 10 to 14%), respectively. Similarly, 1- and 2-year PFS were also improved.29This finding suggests that some questions

about the role of maintenance chemotherapy in SCLC are still awaiting more definite answers. The emergence of novel tar-geted agents with different action mechanisms makes the ques-tions more interesting and has recently been proposed as possi-ble alternatives to maintenance chemotherapy. Interferons,30,31

metalloproteinase inhibitors,32 and thalidomide,33 have been

evaluated as maintenance therapy in SCLC, however, failed to prolong survival of patients with SCLC.

Our result regarding the role of maintenance irinotecan therapy in ED-SCLC patients deserves a word of caution since full patients accrual target was not reached. The opti-mum number of chemotherapy in ED-SCLC has not been clearly defined yet. General consensus is that there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.5Indeed, most randomized

trials of maintenance chemotherapy consisted of four to six cycles of induction chemotherapy.6 –19 In the current study,

initial 40 patients received six cycles of 4-week IP induction. Because of frequent omission of day 15 irinotecan and delay in the next cycle of chemotherapy, we changed the schedule as a 3-week cycle using the same doses of irinotecan and cisplatin on days 1 and 8. Instead we increased the number of induction therapy from six to eight cycles to match the whole duration of induction therapy. Because of the study design in

which randomization took place after six or eight cycles of induction therapy, many patients became not eligible for randomization because they went off study mainly due to disease progression during the initial six to eight cycles of induction therapy, especially among those patients treated on schedule B. It is interesting to note that 32 (80%) of 40 patients treated with schedule A received all six cycles of induction therapy, whereas only 30 (38%) of 80 patients treated with schedule B received all eight cycles of induction therapy. It was quite unexpected to see many patients in schedule B developed PD by the time of response re-evalu-ation after six cycles of IP chemotherapy. This was the major reason why we could not accrue the target sample size to examine the role of irinotecan maintenance therapy even though we completed the patient accrual as initially planned. Although our study did not demonstrate the survival benefit of irinotecan maintenance therapy over six or eight cycles of IP induction therapy, IP chemotherapy seems to be associated with better survival than old regimens in SCLC. Therefore, the value of irinotecan single or IP regimen as maintenance should be evaluated in larger number of patients with ade-quate power.

In summary, although IP chemotherapy showed signif-icant activity and favorable survival outcome in SCLC, main-taining irinotecan as a single therapy in patients with objec-tive tumor responses after six or eight cycles of IP chemotherapy failed to show any additional survival benefit.

ACKNOWLEDGMENTS

Supported in part by NCC grants NCC-0510140 and NCC-0510080.

REFERENCES

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics.

CA Cancer J Clin 2007;57:43– 66.

2. Ettinger D, Johnson B. Update: NCCN small cell and non-small cell lung cancer clinical practice guidelines. J Natl Compr Cancer Net 2005;3:S17–S21.

3. Woll PJ, Thatcher N, Lomax L, et al. Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients. J Clin Oncol 2001;19: 712–719.

4. Leyvraz S, Perey L, Rosti G, et al. Multiple courses of high-dose ifosfamide, carboplatin, and etoposide with peripheral-blood progenitor

TABLE 6. Second-Line Treatment

Overall (nⴝ 77) Randomization Nonrandomization (nⴝ 44) Maintenance (nⴝ 14) Observation (nⴝ 19) n RR (%) n RR (%) n RR (%) n RR (%) IP 25 8 (32.0) 1 0 15 5 (33.3) 9 3 (33.3) AIV 22 6 (27.3) 6 1 (16.7) 1 0 15 5 (33.3) CAV 13 5 (38.5) 3 2 (66.7) 1 0 9 3 (33.3) EP 8 3 (37.5) 1 1 (100) 1 0 6 2 (33.3) PG 6 4 (66.7) 2 2 (100) 1 0 3 2 (66.7) PC 1 0 1 0 0 0 0 0 VIP 2 0 0 0 0 0 2 0

RR, response rate; IP, irinotecan and cisplatin; AIV, adriamycin, ifosfamide, and vincristine; CAV, cyclophosphamide, adriamycin, and vincristine; EP, etoposide and cisplatin; PG, paclitaxel and gemcitabine; PC, paclitaxel and carboplatin; VIP, vincristine, ifosfamide, and cisplatin.

(7)

cells and filgrastim for small-cell lung cancer: a feasibility study by the European Group for Blood and Marrow Transplantation. J Clin Oncol 1999;17:3531–3539.

5. Sculier JP, Berghmans T, Castaigne C, et al. Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung Cancer 1998;19:141–151.

6. Maurer LH, Tulloh M, Weiss RB, et al. A 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.

7. Cullen M, Morgan D, Gregory W, et al. Maintenance chemotherapy for anaplastic small cell carcinoma of the bronchus: a randomised, con-trolled trial. Cancer Chemother Pharmacol 1986;17:157–160. 8. Einhorn LH, Crawford J, Birch R, Omura G, Johnson DH, Greco FA.

Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin

Oncol 1988;6:451– 456.

9. Bleehen NM, Fayers PM, Girling DJ, Stephens RJ. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 1989;59:584 –590.

10. 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.

11. 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.

12. Ettinger DS, Finkelstein DM, Abeloff MD, Ruckdeschel JC, Aisner SC, Eggleston JC. A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no mainte-nance 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.

13. Lebeau B, Chastang CI, Allard P, et al. Six vs. twelve cycles for complete responders to chemotherapy in small cell lung cancer: defin-itive results of a randomized clinical trial. Eur Respir J 1992;5:286 –290. 14. Johnson DH, Bass D, Einhorn LH, 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;11:1223–1228.

15. Giaccone G, Dalesio O, McVie GJ, et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Co-operative Group. J Clin Oncol 1993;11:1230 –1240.

16. 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.

17. Beith JM, Clarke SJ, Woods RL, et al. Long-term follow-up of a randomized 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.

18. Schiller JH, 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.

19. Hanna NH, Sandier AB, Loehrer PJ Sr, et al. 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. Ann Oncol 2002; 13:95–102.

20. Ettinger DS. New drugs for chemotherapy-naive patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28:27–29.

21. Kudoh S, Fujiwara Y, Takada Y, et al. Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer: West Japan Lung Cancer Group. J Clin Oncol 1998;16: 1068 –1074.

22. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer: Japan Clinical Oncology Group. N Engl J Med 2002;346:85–91. 23. Hanna N, Bunn PA Jr, Langer C, et al. A randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer.

J Clin Oncol 2006;24:2038 –2043.

24. Hermes A, Bergman B, Bremnes R, et al. A randomized phase III trial of irinotecan plus carboplatin versus etoposide plus carboplatin in patients with small cell lung cancer, extensive disease (SCLC-ED): IRIS-Study. Proc Am Soc Clin Oncol 2007;24:624. Abstract 7523. 25. Negoro S, Fukuoka M, Masuda N, et al. Phase I study of weekly

intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 1991;83:1164 –1168.

26. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 1992; 10:1775–1780.

27. Han JY, Lee DH, Lee SY, et al. A phase II study of dose-intensified weekly concomitant administration of cisplatin and irinotecan in che-monaive patients with extensive-disease small-cell lung cancer. Med

Oncol 2005;220:281–290.

28. Han JY, Cho KH, Lee DH, et al. Phase II study of irinotecan plus cisplatin induction followed by concurrent twice-daily thoracic irradia-tion with etoposide plus cisplatin chemotherapy for limited-disease small-cell lung cancer. J Clin Oncol 2005;23:3488 –3494.

29. Bozcuk H, Artac M, Ozdogan M, et al. Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A meta-analysis of the published controlled trials. Cancer 2005;104:2650 –2657.

30. Jett JR, Maksymiuk AW, Su JQ, et al. Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer.

J Clin Oncol 1994;12:2321–2326.

31. Van Zandwijk N, Groen HJ, Postmus PE, et al. Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group. Eur J Cancer 1997;33:1759 –1766.

32. Shepherd FA, Giaccone G, Seymour L, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin

Oncol 2002;20:4434 – 4439.

33. Lee SM, Woll PJ, James LE, et al. A phase III randomized double blind,

References

Related documents

• QoS aware service and resource management schemes are designed and developed for admission control, offloading and resource allocation, to provide real-time analytics services

Abstract of master’s thesis Keywords PE collaboration, social innovation, cross-sector collaboration, SMEs, collaborative leadership, collective trust, knowledge sharing... III

A formula is obtained in this article for obtaining the analytical approximate solution of fifth order nonlinear differential systems, characterized by an oscillatory process, which

Third, the ambiguity premium is larger in men who purchase earthquake insurance, have never received insurance payment, and distrust insurance companies than each correspondents,

Given the pent-up demand for commercial space that existed at the start of the decade and given the various incentives for investment created by tax changes and financial

Mail alert: Service of London Stock Exchange that allows you to be updated on the latest changes of the italian market by subscribing to London Stock Exchange website. There

In this section we will check whether the game we study is supermodular (Milgrom and Roberts 1990), i.e., whether the agents’ strategies display the strategic complementarity

Note: The Figure shows average bribery mean effects depending on different values of the bribery dispersion for sales and labor productivity growth rates. -15 -10 -5 0 5 10 G rowt h