- Email: [email protected]
Irinotecan in Patients With Relapsed Small-cell Lung Cancer
Original Study
Comparison of Amrubicin and Weekly Cisplatin/Etoposide/Irinotecan in Patients With Relapsed Small-cell Lung Cancer Hitomi Sumiyoshi Okuma,1,2 Hidehito Horinouchi,1 Shinsuke Kitahara,1 Tetsuhiko Asao,1 Kuniko Sunami,1 Yasushi Goto,1 Shintaro Kanda,1 Yutaka Fujiwara,1 Hiroshi Nokihara,1 Noboru Yamamoto,1 Yuichiro Ohe1 Abstract Limited evidence is available for relapsed small-cell lung cancer (SCLC). Five hundred eighty consecutive patients with relapsed SCLC treated at our institute were analyzed. Multivariate analysis identified sensitive relapse and amrubicin treatment as independent favorable prognostic factors for survival. Amrubicin showed a favorable trend compared with cisplatin/etoposide/irinotecan in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Background: Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients. Patients and Methods: Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients’ characteristics and treatments to explore factors associated with the survival outcomes were reviewed. Results: A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P ¼ .007) and AMR as second-line treatment (vs. PEI) (P ¼ .005) as independent favorable prognostic factors for survival. Conclusion: AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted. Clinical Lung Cancer, Vol. -, No. -, 1-7 ª 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Amrubicin, Salvage chemotherapy, Second-line chemotherapy, Small cell lung cancer, Weekly cisplatin plus etoposide plus irinotecan
Introduction Lung cancer is the most common cause of cancer death worldwide.1 Small-cell lung cancer (SCLC) accounts for 15% to 18% of all cases of lung cancer.2-4 Over 60% of patients with SCLC present 1
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan Department of Medical Oncology, Graduate School of Medicine, Chiba University Hospital, Chiba, Japan 2
with extensive disease at diagnosis.3 First-line treatments for SCLC include a combination of cisplatin or carboplatin and etoposide or irinotecan, with a reported 2-year survival of approximately 40% in patients with limited disease, but only 5% to 10% in those with Address for correspondence: Hidehito Horinouchi, MD, Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo, Tokyo 104-0045, Japan E-mail contact: [email protected]
Submitted: May 28, 2016; Revised: Sep 5, 2016; Accepted: Sep 6, 2016
1525-7304/ª 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.cllc.2016.09.005
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Second-Line AMR or PEI for Relapsed SCLC extensive disease.5-8 Despite their relatively good response to chemotherapy and radiotherapy, the majority of patients with SCLC eventually show disease progression. Therefore, second-line therapy is often required, but the prognosis at relapse is still very poor.9 Response to second-line chemotherapy is reportedly correlated with the response to first-line therapy, the interval between the completion of initial chemotherapy, and the diagnosis of disease progression.10 Patients who respond to first-line chemotherapy and show a progression-free interval of over 90 days are most often regarded as showing sensitive relapse, as opposed to those showing a progression-free interval of less than 90 days, who are labeled as having refractory relapse.11-13 The importance of second-line therapy for SCLC was first proven by the pivotal phase III trial comparing best supportive care and topotecan.14 Up until today, many studies of second-line treatment have been conducted.12,13,15,16 In patients with sensitive relapse, the reported overall response rate (ORR) is in the range of 22% to 24%, and the reported median overall survival (OS) is in the range of 5 to 9 months12,13,15,16; on the other hand, in those with refractory relapse, the reported ORR is in the range of 6% to 12%, and the reported median OS is in the range of 3 to 5 months.11,14,16,17 Topotecan is still recognized as the standard choice worldwide for relapsed SCLC, but its survival benefit is limited. Amrubicin (AMR) is a third-generation anthracycline and potent topoisomerase II inhibitor that received approval in Japan in 2002, and whose efficacy as monotherapy has been shown in several phase II trials.18-22 These trials showed an ORR in the range of 36% to 53%, and a median OS in the range of 6 to 14 months. However, randomized phase III trials conducted in Western countries have failed to show its superiority over topotecan.16 Therefore, the use of AMR is limited throughout the world. Recently, the efficacy of a combination regimen consisting of weekly cisplatin plus etoposide plus irinotecan (PEI) has been demonstrated in patients with relapsed SCLC. In a randomized controlled trial, the median OS was 18.2 months and the ORR was 84%, both superior to those for topotecan.23 From the many randomized trials conducted for relapsed SCLC, topoisomerase (TOPO) inhibitors appear to be the key drugs for treating SCLC24; however, the choice of the best regimen needs further study. The objective of the present study was to retrospectively analyze the outcomes of the second-line treatments employed for relapsed SCLC over a 14-year period at our institution. In our analysis, AMR was compared with PEI, because PEI is another choice of secondline regimen alongside topotecan monotherapy after it showed its efficacy in a phase III trial, and no comparison of AMR and PEI has been conducted yet.
Patients and Methods Data Acquisition
2
-
Data of consecutive patients with SCLC receiving chemotherapy at the National Cancer Center Hospital between 2000 and 2014 were analyzed. The patients’ clinical characteristics and treatments were collected from the medical records. Extracted clinical data included the demographic characteristics (gender, age, date of diagnosis, and smoking history), known baseline prognostic factors (Eastern Cooperative Oncology Group performance status [PS], stage), first- and second-line treatment
Clinical Lung Cancer Month 2016
details (regimen, start, and last day of administration), and clinical outcomes (response to treatment documented by each physician, date of relapse, and date of last follow-up or death). Patients who showed disease progression or relapsed within 90 days of completion of the first-line treatment were classified as having refractory relapse, whereas the remainder were classified as having sensitive relapse. AMR was administered at the dose of 40 mg/m2 for 3 consecutive days, every 21 days, and PEI consisted of cisplatin (25 mg/m2) weekly for 10 weeks, etoposide (60 mg/m2) for 3 days on weeks 1, 3, 5, 7, and 9, and irinotecan (90 mg/m2) on weeks 2, 4, 6, 8, and 10, with granulocyte colony-stimulating factor support. This retrospective study was conducted with the approval of the Ethics Committee of the National Cancer Hospital (#2014-178), and in accordance with the Declaration of Helsinki.
Statistical Analysis Response rate was measured by each attending physician based on radiographic images or clinical symptoms using the Response Evaluation Criteria In Solid Tumors (RECIST) guideline (version depending on the year of treatment).25 OS was calculated from date of initiation of the second-line therapy to the date of death. The progression-free survival (PFS) was calculated from the date of initiation of the second-line therapy to the date of first radiographic or clinical documentation of progression or death. The KaplanMeier point-estimate survival analysis was used to evaluate the median PFS and OS. Log-rank statistics was used to compare the survival between groups. A Cox proportional hazards regression model was applied using variables thought to potentially influence the survival: gender, age, PS, smoking history, disease stage, firstline treatment, and second-line treatment. All analyses were performed using STATA, version 11 (StataCorp, College Station, TX).
Results Patient Characteristics and Treatment Outcomes Between 2000 and 2014, 580 patients with SCLC received firstline chemotherapy or chemoradiotherapy. Among the 512 patients that developed relapse, 343 (59%) received second-line chemotherapy. Of the patients administered receiving second-line chemotherapy, 193 (56%) were diagnosed as having sensitive relapse and 148 (43%) as having refractory relapse. The selection of chemotherapy was left to the discretion of the attending physician. AMR was used most frequently in both groups, followed by PEI, and then irinotecan monotherapy. Of the patients, 31% received third-line treatment, and 11% received fourth- or later lines of treatment. Figure 1 shows the patient flow chart. The baseline characteristics of the patients who received AMR and PEI are shown in Table 1. The median duration of chemotherapy was 4 cycles and 6 weeks for AMR and PEI, respectively. The objective response rates (ORR) were 51% and 73%, respectively (Table 2). The median PFS was 4.5 months (95% confidence interval [CI], 4.1-5.2 months) in the AMR group and 4.2 months (95% CI, 3.6-4.9 months) in the PEI group (hazard ratio [HR], 1.40; 95% CI, 1.03-1.90) (Figure 2). The median OS was 10.0 months (95% CI, 8.6-11.7 months) in the AMR group and 10.8 months (95% CI, 8.0-13.8 months) in the PEI group (HR, 1.13; 95% CI, 0.82-1.56) (Figure 3). When the patients with sensitive relapse and refractory relapse were
Hitomi Sumiyoshi Okuma et al Figure 1 Patient Flow Diagram
First-line chemotherapy/chemoradiotherapy n=580 Second-line chemotherapy n=343 (59%) Refractory relapse n=148 (43%)
Sensive relapse n=193 (56%) Amrubicin Weekly cisplan/ etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=99 n=29 n=22 n=18 n=15 n=7 n=3
Amrubicin Weekly cisplan/ etoposide/irinotecan Irinotecan Planum doublet Paclitaxel Topotecan
n=89 n=27 n=20 n=5 n=4 n=3
No chemotherapy n=169 (29%)
No relapse n=68 (12%)
Unknown n=2 (0.5%) Planum doublet
n=2
Third-line chemotherapy n=179 (31%) Amrubicin Weekly cisplan/etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=47 n=23 n=49 n=13 n=15 n=25 n=7
Fourth-line chemotherapy n=65 (11%) Amrubicin Weekly cisplan/etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=7 n=8 n=14 n=6 n=21 n=5 n=4
analyzed separately, the median PFS was 5.3 months (95% CI, 4.46.4 months) in the sensitive relapse group treated with AMR, and 4.9 months (95% CI, 3.9-5.6 months) in the sensitive relapse group treated with PEI (HR, 1.40; 95% CI, 0.91-2.14) (See Supplemental Figure 1A in the online version). On the other hand, the median PFS was 4.1 months (95% CI, 3.0-4.6 months) in the refractory relapse group treated with AMR and 3.7 months (95% CI, 3.0-4.6 months) in the refractory relapse group treated with PEI (HR, 1.47; 95% CI, 0.92-2.34) (See Supplemental Figure 1B in the online version). The median OS was 14.2 months (95% CI, 9.8-15.7 months) in the sensitive relapse group treated with AMR and 14.8 months (95% CI, 10.2-17.9 months) in the sensitive relapse group treated with PEI group (HR, 0.96; 95% CI, 0.61-1.53) (See Supplemental Figure 2A in the online version). On the other hand, the median OS was 8.0 months (95% CI, 6.4-9.4 months) in the refractory relapse group treated with AMR and 8.0 months (95% CI, 4.5-11.1 months) in the refractory relapse group treated with PEI (HR, 1.31; 95% CI, 0.83-2.04) (See Supplemental Figure 2B in the online version).
Prognostic Factor Analysis Multivariate Cox regression analysis of the data from all 244 patients administered second-line AMR or PEI identified sensitivity to first-line chemotherapy (sensitive relapse over refractory relapse) and second-line chemotherapy regimen used (AMR over PEI) as independent predictors of the PFS (Table 3). The same analysis revealed sensitivity to first-line chemotherapy (sensitive relapse over refractory relapse) and age (younger than 66 years over 66 years and older) as additional significant factors. We conducted
the same analysis after dividing the patients into sensitive- and refractory relapse groups. Of the 128 patients of the sensitive relapse group that received second-line AMR or PEI, PS (0-1 over 2-3) and second-line chemotherapy (AMR over PEI) were identified as independent predictors of the PFS following first-line treatment (See Supplemental Table 1 in the online version). No significant predictive factor for OS was identified. On the other hand, in the 116 patients of refractory relapse treated with AMR or PEI, no significant prognostic factors were identified, although second-line treatment (See Supplemental Table 2 in the online version) was associated with a HR of 1.48 (95% CI, 0.84-2.62) favoring AMR.
Discussion In a large cohort of SCLC patients treated for disease relapse, we found that AMR and PEI were the most frequently used second-line therapies. Both treatments yielded survival outcomes worthy of notice, with a more favorable trend in the AMR-treated patients. Multivariate analysis identified second-line treatment with AMR as an independent favorable prognostic factor in terms of the PFS. This tendency was also seen in the patient group with sensitive relapse. Furthermore, in the refractory relapse group as well, a more favorable trend for the PFS was observed in the AMR as compared with the PEI treatment group. The median OS in the AMR treatment group was striking, in that it was substantially longer than that reported from phase III trials conducted abroad, where AMR is not considered as a second-line therapy because it failed to show a survival advantage in a randomized phase III trial, and also showed more toxicity.16
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Second-Line AMR or PEI for Relapsed SCLC Table 1 Patient Demographic and Clinical Characteristics AMR (n [ 188) n
PEI (n [ 56)
%
n
Others (n [ 99) %
n
%
Gender Female Male
45
24
9
16
18
18
143
76
47
84
81
82
Age, years Median (range)
65 (24-81)
66 (45-78)
68 (29-86)
Performance status 0
60
32
23
41
32
32
1
103
55
30
54
55
56
2
16
8.5
3
5.4
8
8
3
7
3.7
0
0
4
4
Unavailable
2
1.1
0
0
0
0
8
4.3
3
5.4
6
6
Smoking history Never-smoker Smoker
179
Unavailable
95
1
0.5
53
95
93
94
0
0
0
0
Stage LD
51
27
16
29
66
67
ED
134
71
38
68
33
33
0
0
Unavailable
3
1.6
2
3.6
First-line treatment Platinum þ ETP RT
94
50
33
59
58
59
Platinum þ IRI RT
69
37
14
25
14
14
Platinum þ IRI þ ETP RT
25
13
4
23
0
0
5
Sensitive
99
53
29
Refractory
89
47
27
Unavailable
0
0
0
Others
8
8
35
35
52
65
66
48
32
32
0
2
2
8.9
Relapse
Abbreviations: AMR ¼ Amrubicin; ED ¼ extensive disease; ETP ¼ etoposide; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; RT ¼ radiotherapy.
AMR is the world’s first anthracycline anti-cancer agent produced entirely through chemical synthesis26; it was first synthesized with the intent of developing an anti-tumor agent stronger than
doxorubicin (DXR). The active metabolite amrubicinol plays an important role in the antitumor effect of this drug, and the major mechanism of action of AMR is the stabilization of a cleavable
Table 2 Overall Response Rate AMR (n [ 188)
Median cycles/week (range)
PEI (n [ 56)
All
Sensitive Relapse (n [ 99)
Refractory Relapse (n [ 89)
All
Sensitive Relapse (n [ 29)
Refractory Relapse (n [ 27)
4 (1-27)
4 (1-27)
4 (1-17)
6 (1-10)
6 (1-10)
6 (1-10)
Response, n CR
7
5
2
4
3
1
PR
88
51
37
37
20
17
SD
57
30
28
9
4
5
PD
28
8
19
5
2
3
8
5
3
0
0
1
Objective response rate, %
51
57
44
73
79
67
Disease control rate, %
81
87
75
89
93
85
Unavailable
4
-
Abbreviations: AMR ¼ Amrubicin; CR ¼ complete response; PD ¼ progressive disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PR ¼ partial response; SD ¼ stable disease.
Clinical Lung Cancer Month 2016
Hitomi Sumiyoshi Okuma et al Figure 2 Progression-Free Survival of Patients Treated With AMR and PEI (n [ 244)
Table 3 Multivariate Cox Regression Analysis of PFS in Patients Treated With AMR and PEI (n [ 244) Factor
Progression-Free Survival (probability)
1.0
Median, months
0.9
Female
AMR 4.45 (95% CI, 4.12 to 5.24) PEI 4.18 (95% CI, 3.62 to 4.88)
0.8 0.7
No.
HR
Gender Male
(HR = 1.40; (95% CI, 1.03 to 1.90)
54 190
0.5 0.4 0.3
65 years
130
1
>65 years
114
1.02 1
ECOG PS
0.1
0-1
196
2-3
26
1.39
11
1
0
6
12
188 56
63 11
17 3
18 42 48 24 30 36 Time from second-line treatment (months)
54
60
1 1
1 1
No. at risk AMR PEI
Smoking history 9 2
4 1
4 1
3 1
3 1
3 1
Never-smoker Smoker
232
LD
67
Figure 3 Overall Survival of Patients Treated With AMR and PEI (n [ 244)
1.0
Median, months
Overall Survival (probability)
0.9
AMR PEI
9.95 (95% CI, 8.63 to 11.7) 10.8 (95% CI, 8.01 to 13.8) (HR = 1.13; (95% CI, 0.82 to 1.56)
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
6
12
188 56
127 41
63 23
18 24 30 36 48 42 Time from second-line treatment (months)
54
60
1 1
1 1
No. at risk AMR PEI
35 13
21 6
15 4
10 3
5 2
4 2
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/ irinotecan.
0.82-2.36
.22
0.77-3.83
.19
0.81-1.76
.37
0.73-1.46
.86
1.13-2.18
.007
1.16-2.34
.005
1
ED
172
1.19
ETP
127
1
IRI
83
First-line treatment
complex within the cancer cells via DNA topoisomerase II (Topo II). In studies using human tumor xenografts, AMR was demonstrated to exert a stronger antitumor effect than DXR against breast cancer (xenograft MX-1), small cell lung cancer (xenograft LX-1), and gastric cancer (xenografts SC-6, SC-9, and 4-1ST). In vivo research has demonstrated that AMR causes stronger myelosuppression than DXR, but that, however, recovery from the myelosuppressive effect of AMR is more rapid than that from the myelosuppressive effect of DXR.27 Cardiotoxicity is rarely encountered as compared with that for other anthracycline agents, and cumulative toxicities, such as renal failure associated with platinum agents, is not a concern. Therefore, AMR is a more feasible treatment option, in that it exerts less toxicity and requires fewer days of hospitalization. These findings suggest that AMR is a treatment that can be used for a long time without any substantive
.92
1.72
Stage Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/ irinotecan.
0.75-1.39
0.79
0.2
0.0
P .20
1
Age
0.6
95% CI 0.56-1.13
1.03
Sensitivity to first-line Sensitive-relapse
128
1
Refractory-relapse
116
1.57
AMR
188
1
PEI
56
Second-line treatment 1.65
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progression-free survival; PS ¼ performance status.
concern about cumulative toxicities, as compared with combination therapies based on platinum agents; therefore, AMR is one of the useful drugs that should be considered in the course of treatment in patients with SCLC. Patients with SCLC with sensitive relapse showed a better sensitivity to second-line treatment and a better prognosis as compared with those with refractory relapse. The ORR of 55% and median PFS of 5.3 months in the sensitive relapse group treated with AMR in the present study are similar to the outcomes reported from a phase II trial of an ORR of 67%, median PFS of 5.4 months, and median OS of 14.4 months in patients with SCLC with sensitive relapse assigned to the AMR treatment arm.28 In the phase III Amrubicin Clinical Trial-1 (ACT-1) trial, the ORR was 40.9%, the median PFS was 5.5 months, and the median OS was 9.2 months in the sensitive relapse subgroup of patients with SCLC treated with AMR.16 In the patients with SCLC with sensitive relapse treated with PEI in the present study, the ORR was 87% and the median PFS was 4.9 months. According to another randomized phase III trial of PEI in the secondline setting for patients with SCLC with sensitive relapse, the ORR was 84%, the median PFS was 5.7 months, and the median OS was 18.2 months.23 Interestingly, among the patients with sensitive relapse in the present study, a better survival was obtained in
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Second-Line AMR or PEI for Relapsed SCLC the AMR treatment group as compared with the PEI treatment group. With the present data and the historical trial of PEI showing a survival benefit over topotecan, we believe that the true benefit of AMR will become manifest in properly selected patients, for example, those with sensitive relapse. From the aspect of toxicity, there was 1 treatment-related death (1.8%) in the PEI treatment group and 2 treatment-related deaths (1.0%) in the AMR treatment group in this study. Historical data showed a higher adverse event occurrence rate in the PEI treatment group; the grade 3 to 4 adverse events in the PEI treatment group were neutropenia (83.3%), anemia (84.4%), thrombocytopenia (41.1%), diarrhea (7.8%), and febrile neutropenia (FN; 31.1%).23 On the other hand, the grade 3 to 4 adverse events in the AMR treatment group were neutropenia (41%), thrombocytopenia (21%), anemia (16%), infections (16%), febrile neutropenia (10%), and cardiac disorders (5%).16 Myelosuppression is critical, because refractory patients already have depressed bone marrow function. The 3-drug combination of PEI was originally designed as a weekly regimen to make it easier to modify the dosage and schedule.29,30 However, the frequency of febrile neutropenia of 31.1% despite granulocyte colony-stimulating factor support is high for patients receiving second-line treatment and is 2- to 3-fold higher as compared with that reported for monotherapy regimens. Furthermore, patients scheduled to receive PEI treatment need to be hospitalized, whereas AMR treatment can be administered on an outpatient basis. Therefore, AMR monotherapy is more feasible and is also associated with lower toxicity. The results also revealed exceptionally long-term survivors in the AMR treatment group. One of these patients received 27 cycles of treatment, and 6 received 16 to 18 cycles. Based on a study of longterm survival in 1714 consecutive SCLC patients, Lassen et al reported a 5-year survival rate of 3.5%31; they reported ED, PS > 2, presence of liver and/or bone marrow metastases, and elevated lactate dehydrogenase and/or alkaline phosphatase levels as negative prognostic factors. In our patient cohort, 6 patients (2.5%) survived for longer than 5 years, and indeed, all 6 patients had limited disease and a PS of 0 to 1. In addition, 5 of the patients received AMR as the second-line treatment, with 3 patients still, at the time of writing, under AMR treatment. AMR is a drug that could be administered over the long term, provided it shows efficacy, as it has very low toxicity. Some of the limitations of this study were that the database was from a single institute, and the study was retrospective in nature; the number of patients in the PEI arm was small; treatment was selected according to the physicians’ discretion and may have, therefore, been biased. Also, both treatment groups include patients treated in practice and those enrolled in an ongoing clinical trial at the time. Therefore, some patients’ tumor response evaluations were made by the treating physician, whereas others were evaluated according to each trial protocol, which may have contributed to the longer PFS compared with a cohort from a pure clinical trial. Furthermore, our results showed substantially longer median overall survival times as compared with reports from previous phase III trials of AMR or topotecan carried out abroad, which could be related to possible differences in the genetic background, medical care, study design, and/or drug exposure,32 and the higher frequency of use of
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post-relapse treatments including AMR, irinotecan, and topotecan in Japan. The similar median overall survival between AMR and PEI in our analysis may possibly have been due to post-relapse treatment or other factors; nonetheless, the long survival and simplicity of the regimen compared with PEI should be valued.
Conclusion Our results revealed that relapsed patients with SCLC receiving AMR as second-line therapy showed a longer median PFS as compared to those receiving PEI, with a similar median OS between the 2 treatment groups. A longer median PFS with AMR was also confirmed in patients diagnosed as having sensitive relapse. The 2 treatment groups showed different feasibility profiles. AMR is a highly active and well-tolerated treatment option that deserves to be recognized as a second-line treatment of choice as compared with topotecan and PEI, on the basis of the better survival and shorter hospitalization, respectively. Further investigation comparing AMR and PEI in selected patient groups is necessary.
Clinical Practice Points Despite their relatively good response to chemotherapy and
radiotherapy, the majority of patients with SCLC eventually show disease progression. The importance of second-line therapy for SCLC was first proven by the pivotal phase III trial comparing best supportive care and topotecan. Later, many studies of second-line treatment have been conducted, including AMR monotherapy and a combination regimen consisting of PEI. Both regimens have shown a survival benefit over topotecan in randomized trials in Japan. However, AMR failed to show its superiority over topotecan in a phase III trial; therefore, it is not a widely used drug around the world. The choice of the best regimen needs further study. No study has investigated the efficacy comparing AMR and PEI. In our analysis, AMR and PEI were the most used regiments at our institute. The following outcomes were obtained for AMR and PEI, respectively: ORR: 51% and 73%; median PFS: 4.5 and 4.2 months; and median OS: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P ¼ .007) and AMR as second-line treatment (vs. PEI) (P ¼ .005) as independent favorable prognostic factors for survival. AMR showed a more favorable outcome in terms of the feasibility and survival. Exceptionally long-term survivors were observed in patients treated with AMR. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted.
Acknowledgments The authors thank all the study participants who provided clinicopathological data for this analysis. The authors also thank Ms R. Torii for secretarial support in this study.
Disclosure The authors have stated that they have no conflicts of interest.
Hitomi Sumiyoshi Okuma et al Supplemental Data Supplemental figures and tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.cllc. 2016.09.005.
References 1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61:212-36. 2. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006; 24:4539-44. 3. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005; 366:1385-96. 4. Witta SE, Kelly K. Chemotherapy for small cell lung cancer. In: Pass HI, Mitchell JB, Johnson DH, et al, eds. Lung Cancer: Principles and Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 5. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colonystimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 2005; 23:3752-9. 6. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985; 3:1471-7. 7. Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol 1999; 17:3540-5. 8. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346:85-91. 9. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: small-cell lung cancer, version 1.2016. Available at: https://www.nccn. org/professionals/physician_gls/pdf/sclc.pdf. Accessed: September 15, 2016. 10. Giaccone G, Donadio M, Bonardi G, Testore F, Calciati A. Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 1988; 6:1264-70. 11. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997; 15:2090-6. 12. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007; 25:2086-92. 13. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19:1743-9. 14. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed smallcell lung cancer. J Clin Oncol 2006; 24:5441-7.
15. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17:658-67. 16. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014; 32:4012-9. 17. Park SH, Cho EK, Kim Y, et al. Salvage treatment with topotecan in patients with irinotecan-refractory small cell lung cancer. Cancer Chemother Pharmacol 2008; 62: 1009-14. 18. Inoue A, Sugawara S, Yamazaki K, et al. Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 2008; 26: 5401-6. 19. Murakami H, Yamamoto N, Shibata T, et al. A single-arm confirmatory study of amrubicin therapy in patients with refractory small-cell lung cancer: Japan Clinical Oncology Group Study (JCOG0901). Lung Cancer 2014; 84:67-72. 20. Ettinger DS, Jotte R, Lorigan P, et al. Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer. J Clin Oncol 2010; 28:2598-603. 21. Jotte R, Conkling P, Reynolds C, et al. Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy. J Clin Oncol 2011; 29:287-93. 22. Asao T, Nokihara H, Yoh K, et al. Phase II study of amrubicin at a dose of 45 mg/ m2 in patients with previously treated small-cell lung cancer. Jpn J Clin Oncol 2015; 45:941-6. 23. Goto K, Ohe Y, Shibata T, et al. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, openlabel, randomised phase 3 trial. Lancet Oncol 2016; 17:1147-57. 24. Chhatriwala H, Jafri N, Salgia R. A review of topoisomerase inhibition in lung cancer. Cancer Biol Ther 2006; 5:1600-7. 25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 26. Ishizumi KON, Tanno N. Stereospecific total synthesis of 9-aminoanthracyclines: (þ)-9-amino-9-deoxydaunomycin and related compounds. J Org Chem 1987; 52: 4477-85. 27. Morisada S, Yanagi Y, Kashiwazaki Y, Fukui M. Toxicological aspects of a novel 9aminoanthracycline, SM-5887. Jpn J Cancer Res 1989; 80:77-82. 28. Maemondo M, Inoue A, Sugawara S, et al. 1471P: Final result of randomized phase 2 trial comparing amrubicin (A) with re-challenge of platinum doublet (P) in patients (PTS) with sensitive-relapsed small-cell lung cancer (SCLC): NJLCG0702. Ann Oncol 2014; 25(suppl 4):iv514. 29. Vasey PA, Kaye SB. Combined inhibition of topoisomerases I and IIeis this a worthwhile/feasible strategy? Br J Cancer 1997; 76:1395-7. 30. Sekine I, Nishiwaki Y, Kakinuma R, et al. Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507. Br J Cancer 2003; 88:808-13. 31. Lassen U, Osterlind K, Hansen M, Dombernowsky P, Bergman B, Hansen HH. Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18þ yearsean analysis of 1,714 consecutive patients. J Clin Oncol 1995; 13:1215-20. 32. Ettinger DS. Amrubicin for the treatment of small cell lung cancer: does effectiveness cross the Pacific? J Thorac Oncol 2007; 2:160-5.
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Second-Line AMR or PEI for Relapsed SCLC Supplemental Figure 1 Progression-Free Survival of Sensitive-Relapse (n [ 128) (A) and Refractory-Relapse (n [ 116) (B)
1.0
B
Median, months
0.9
5.34 (95% CI, 4.35 to 6.39) 4.88 (95% CI, 3.92 to 5.57) (HR = 1.40; (95% CI, 0.91 to 2.14)
AMR PEI
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
Median, months
0.9
AMR PEI
4.11 (95% CI, 2.99 to 4.61) 3.68 (95% CI, 2.96 to 4.57) (HR = 1.47; (95% CI, 0.92 to 2.34)
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0.0 0
No. at risk AMR PEI
1.0
Progression-free survival (probability)
Progression-free survival (probability)
A
99 29
6
39 8
12
18 24 30 36 42 48 Time from second-line treatment(months)
12 3
4 1
4 1
4 1
3 1
3 1
3 1
54
1 1
0
60
1 1
3
No. at risk AMR 89 PEI 27
6 9 12 Time from second-line treatment (months)
51 18
22 4
11 1
4 1
15
18
2 1
1 1
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/irinotecan.
Supplemental Figure 2 Overall Survival of Sensitive-Relapse (n [ 128) (A) and Refractory-Relapse (n [ 116) (B)
1.0
Overall survival (probability)
B
Median, months
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
-
0.8 0.7 0.6 0.5 0.4 0.3 0.2
0.0 0
6
12
99 29
73 26
44 16
24 18 30 36 42 48 Time from second-line treatment (months)
23 9
13 4
11 3
8 3
5 2
4 2
54
60
1 1
1 1
No. at risk AMR PEI
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/irinotecan.
7.e1
Median, months 7.99 (95% CI, 6.35 to 9.44) 7.96 (95% CI, 4.54 to 11.1) (HR = 1.31; (95% CI, 0.83 to 2.04) AMR PEI
0.1
0.0
No. at risk AMR PEI
1.0 0.9
14.2 (95% CI, 9.78 to 15.7) 14.8 (95% CI, 10.2 to 17.9) (HR = 0.96; (95% CI, 0.61 to 1.53) AMR PEI
Overall survival (probability)
A
Clinical Lung Cancer Month 2016
0
6
89 27
54 16
12 18 24 30 36 Time from second-line treatment (months)
20 8
13 5
9 3
5 2
3 1
42
48
1 1
1 1
Hitomi Sumiyoshi Okuma et al Supplemental Table 1 Multivariate Cox Regression Analysis of PFS in Patients With Sensitive Relapse (n [ 128) Factor
No.
HR
Gender
Supplemental Table 2 Multivariate Cox Regression Analysis of PFS in Patients With Refractory Relapse (n [ 116)
95% CI
P
Factor
0.51-1.34
.44
Gender
No.
HR
Female
30
1
Female
24
1
Male
98
0.82
Male
92
0.62
65 years
64
1
>65 years
52
1.30
Age
0.44-1.08
65 years
66
1
>65 years
62
0.67
ECOG PS
1.03-5.87
0-1
99
2-3
7
Smoker
122
ECOG PS 0-1
97
1
2.46
2-3
19
0.56
0.85-7.51 5
.04
Age
1
Smoking history Never-smoker
.11
.09
Smoking history
1
Never-smoker
2.53
Smoker
Stage
0.84-2.37
LD
53
1
ED
74
1.41
First-line treatment
0.77-2.17
.19
.33
6 110
Stage LD
14
1
ED
98
1.24
First-line treatment
1
ETP
64
1
IRI
47
1.30
IRI
36
0.76
AMR
99
1
AMR
89
1
PEI
29
1.74
PEI
27
1.48
.02
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progressionfree survival; PS ¼ performance status.
0.81-2.07
.27
0.27-1.13
.10
0.26-2.41
.68
0.64-2.40
.53
0.46-1.27
.30
0.84-2.62
.14
0.79
63
1.09-2.80
P .12
1
ETP Second-line treatment
95% CI 0.35-1.13
Second-line treatment
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progressionfree survival; PS ¼ performance status.
Clinical Lung Cancer Month 2016
- 7.e2
Comparison of Amrubicin and Weekly Cisplatin/Etoposide/Irinotecan in Patients With Relapsed Small-cell Lung Cancer Hitomi Sumiyoshi Okuma,1,2 Hidehito Horinouchi,1 Shinsuke Kitahara,1 Tetsuhiko Asao,1 Kuniko Sunami,1 Yasushi Goto,1 Shintaro Kanda,1 Yutaka Fujiwara,1 Hiroshi Nokihara,1 Noboru Yamamoto,1 Yuichiro Ohe1 Abstract Limited evidence is available for relapsed small-cell lung cancer (SCLC). Five hundred eighty consecutive patients with relapsed SCLC treated at our institute were analyzed. Multivariate analysis identified sensitive relapse and amrubicin treatment as independent favorable prognostic factors for survival. Amrubicin showed a favorable trend compared with cisplatin/etoposide/irinotecan in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Background: Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients. Patients and Methods: Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients’ characteristics and treatments to explore factors associated with the survival outcomes were reviewed. Results: A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P ¼ .007) and AMR as second-line treatment (vs. PEI) (P ¼ .005) as independent favorable prognostic factors for survival. Conclusion: AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted. Clinical Lung Cancer, Vol. -, No. -, 1-7 ª 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Amrubicin, Salvage chemotherapy, Second-line chemotherapy, Small cell lung cancer, Weekly cisplatin plus etoposide plus irinotecan
Introduction Lung cancer is the most common cause of cancer death worldwide.1 Small-cell lung cancer (SCLC) accounts for 15% to 18% of all cases of lung cancer.2-4 Over 60% of patients with SCLC present 1
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan Department of Medical Oncology, Graduate School of Medicine, Chiba University Hospital, Chiba, Japan 2
with extensive disease at diagnosis.3 First-line treatments for SCLC include a combination of cisplatin or carboplatin and etoposide or irinotecan, with a reported 2-year survival of approximately 40% in patients with limited disease, but only 5% to 10% in those with Address for correspondence: Hidehito Horinouchi, MD, Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo, Tokyo 104-0045, Japan E-mail contact: [email protected]
Submitted: May 28, 2016; Revised: Sep 5, 2016; Accepted: Sep 6, 2016
1525-7304/ª 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.cllc.2016.09.005
Clinical Lung Cancer Month 2016
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Second-Line AMR or PEI for Relapsed SCLC extensive disease.5-8 Despite their relatively good response to chemotherapy and radiotherapy, the majority of patients with SCLC eventually show disease progression. Therefore, second-line therapy is often required, but the prognosis at relapse is still very poor.9 Response to second-line chemotherapy is reportedly correlated with the response to first-line therapy, the interval between the completion of initial chemotherapy, and the diagnosis of disease progression.10 Patients who respond to first-line chemotherapy and show a progression-free interval of over 90 days are most often regarded as showing sensitive relapse, as opposed to those showing a progression-free interval of less than 90 days, who are labeled as having refractory relapse.11-13 The importance of second-line therapy for SCLC was first proven by the pivotal phase III trial comparing best supportive care and topotecan.14 Up until today, many studies of second-line treatment have been conducted.12,13,15,16 In patients with sensitive relapse, the reported overall response rate (ORR) is in the range of 22% to 24%, and the reported median overall survival (OS) is in the range of 5 to 9 months12,13,15,16; on the other hand, in those with refractory relapse, the reported ORR is in the range of 6% to 12%, and the reported median OS is in the range of 3 to 5 months.11,14,16,17 Topotecan is still recognized as the standard choice worldwide for relapsed SCLC, but its survival benefit is limited. Amrubicin (AMR) is a third-generation anthracycline and potent topoisomerase II inhibitor that received approval in Japan in 2002, and whose efficacy as monotherapy has been shown in several phase II trials.18-22 These trials showed an ORR in the range of 36% to 53%, and a median OS in the range of 6 to 14 months. However, randomized phase III trials conducted in Western countries have failed to show its superiority over topotecan.16 Therefore, the use of AMR is limited throughout the world. Recently, the efficacy of a combination regimen consisting of weekly cisplatin plus etoposide plus irinotecan (PEI) has been demonstrated in patients with relapsed SCLC. In a randomized controlled trial, the median OS was 18.2 months and the ORR was 84%, both superior to those for topotecan.23 From the many randomized trials conducted for relapsed SCLC, topoisomerase (TOPO) inhibitors appear to be the key drugs for treating SCLC24; however, the choice of the best regimen needs further study. The objective of the present study was to retrospectively analyze the outcomes of the second-line treatments employed for relapsed SCLC over a 14-year period at our institution. In our analysis, AMR was compared with PEI, because PEI is another choice of secondline regimen alongside topotecan monotherapy after it showed its efficacy in a phase III trial, and no comparison of AMR and PEI has been conducted yet.
Patients and Methods Data Acquisition
2
-
Data of consecutive patients with SCLC receiving chemotherapy at the National Cancer Center Hospital between 2000 and 2014 were analyzed. The patients’ clinical characteristics and treatments were collected from the medical records. Extracted clinical data included the demographic characteristics (gender, age, date of diagnosis, and smoking history), known baseline prognostic factors (Eastern Cooperative Oncology Group performance status [PS], stage), first- and second-line treatment
Clinical Lung Cancer Month 2016
details (regimen, start, and last day of administration), and clinical outcomes (response to treatment documented by each physician, date of relapse, and date of last follow-up or death). Patients who showed disease progression or relapsed within 90 days of completion of the first-line treatment were classified as having refractory relapse, whereas the remainder were classified as having sensitive relapse. AMR was administered at the dose of 40 mg/m2 for 3 consecutive days, every 21 days, and PEI consisted of cisplatin (25 mg/m2) weekly for 10 weeks, etoposide (60 mg/m2) for 3 days on weeks 1, 3, 5, 7, and 9, and irinotecan (90 mg/m2) on weeks 2, 4, 6, 8, and 10, with granulocyte colony-stimulating factor support. This retrospective study was conducted with the approval of the Ethics Committee of the National Cancer Hospital (#2014-178), and in accordance with the Declaration of Helsinki.
Statistical Analysis Response rate was measured by each attending physician based on radiographic images or clinical symptoms using the Response Evaluation Criteria In Solid Tumors (RECIST) guideline (version depending on the year of treatment).25 OS was calculated from date of initiation of the second-line therapy to the date of death. The progression-free survival (PFS) was calculated from the date of initiation of the second-line therapy to the date of first radiographic or clinical documentation of progression or death. The KaplanMeier point-estimate survival analysis was used to evaluate the median PFS and OS. Log-rank statistics was used to compare the survival between groups. A Cox proportional hazards regression model was applied using variables thought to potentially influence the survival: gender, age, PS, smoking history, disease stage, firstline treatment, and second-line treatment. All analyses were performed using STATA, version 11 (StataCorp, College Station, TX).
Results Patient Characteristics and Treatment Outcomes Between 2000 and 2014, 580 patients with SCLC received firstline chemotherapy or chemoradiotherapy. Among the 512 patients that developed relapse, 343 (59%) received second-line chemotherapy. Of the patients administered receiving second-line chemotherapy, 193 (56%) were diagnosed as having sensitive relapse and 148 (43%) as having refractory relapse. The selection of chemotherapy was left to the discretion of the attending physician. AMR was used most frequently in both groups, followed by PEI, and then irinotecan monotherapy. Of the patients, 31% received third-line treatment, and 11% received fourth- or later lines of treatment. Figure 1 shows the patient flow chart. The baseline characteristics of the patients who received AMR and PEI are shown in Table 1. The median duration of chemotherapy was 4 cycles and 6 weeks for AMR and PEI, respectively. The objective response rates (ORR) were 51% and 73%, respectively (Table 2). The median PFS was 4.5 months (95% confidence interval [CI], 4.1-5.2 months) in the AMR group and 4.2 months (95% CI, 3.6-4.9 months) in the PEI group (hazard ratio [HR], 1.40; 95% CI, 1.03-1.90) (Figure 2). The median OS was 10.0 months (95% CI, 8.6-11.7 months) in the AMR group and 10.8 months (95% CI, 8.0-13.8 months) in the PEI group (HR, 1.13; 95% CI, 0.82-1.56) (Figure 3). When the patients with sensitive relapse and refractory relapse were
Hitomi Sumiyoshi Okuma et al Figure 1 Patient Flow Diagram
First-line chemotherapy/chemoradiotherapy n=580 Second-line chemotherapy n=343 (59%) Refractory relapse n=148 (43%)
Sensive relapse n=193 (56%) Amrubicin Weekly cisplan/ etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=99 n=29 n=22 n=18 n=15 n=7 n=3
Amrubicin Weekly cisplan/ etoposide/irinotecan Irinotecan Planum doublet Paclitaxel Topotecan
n=89 n=27 n=20 n=5 n=4 n=3
No chemotherapy n=169 (29%)
No relapse n=68 (12%)
Unknown n=2 (0.5%) Planum doublet
n=2
Third-line chemotherapy n=179 (31%) Amrubicin Weekly cisplan/etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=47 n=23 n=49 n=13 n=15 n=25 n=7
Fourth-line chemotherapy n=65 (11%) Amrubicin Weekly cisplan/etoposide/irinotecan Irinotecan Planum doublet Topotecan Paclitaxel Others
n=7 n=8 n=14 n=6 n=21 n=5 n=4
analyzed separately, the median PFS was 5.3 months (95% CI, 4.46.4 months) in the sensitive relapse group treated with AMR, and 4.9 months (95% CI, 3.9-5.6 months) in the sensitive relapse group treated with PEI (HR, 1.40; 95% CI, 0.91-2.14) (See Supplemental Figure 1A in the online version). On the other hand, the median PFS was 4.1 months (95% CI, 3.0-4.6 months) in the refractory relapse group treated with AMR and 3.7 months (95% CI, 3.0-4.6 months) in the refractory relapse group treated with PEI (HR, 1.47; 95% CI, 0.92-2.34) (See Supplemental Figure 1B in the online version). The median OS was 14.2 months (95% CI, 9.8-15.7 months) in the sensitive relapse group treated with AMR and 14.8 months (95% CI, 10.2-17.9 months) in the sensitive relapse group treated with PEI group (HR, 0.96; 95% CI, 0.61-1.53) (See Supplemental Figure 2A in the online version). On the other hand, the median OS was 8.0 months (95% CI, 6.4-9.4 months) in the refractory relapse group treated with AMR and 8.0 months (95% CI, 4.5-11.1 months) in the refractory relapse group treated with PEI (HR, 1.31; 95% CI, 0.83-2.04) (See Supplemental Figure 2B in the online version).
Prognostic Factor Analysis Multivariate Cox regression analysis of the data from all 244 patients administered second-line AMR or PEI identified sensitivity to first-line chemotherapy (sensitive relapse over refractory relapse) and second-line chemotherapy regimen used (AMR over PEI) as independent predictors of the PFS (Table 3). The same analysis revealed sensitivity to first-line chemotherapy (sensitive relapse over refractory relapse) and age (younger than 66 years over 66 years and older) as additional significant factors. We conducted
the same analysis after dividing the patients into sensitive- and refractory relapse groups. Of the 128 patients of the sensitive relapse group that received second-line AMR or PEI, PS (0-1 over 2-3) and second-line chemotherapy (AMR over PEI) were identified as independent predictors of the PFS following first-line treatment (See Supplemental Table 1 in the online version). No significant predictive factor for OS was identified. On the other hand, in the 116 patients of refractory relapse treated with AMR or PEI, no significant prognostic factors were identified, although second-line treatment (See Supplemental Table 2 in the online version) was associated with a HR of 1.48 (95% CI, 0.84-2.62) favoring AMR.
Discussion In a large cohort of SCLC patients treated for disease relapse, we found that AMR and PEI were the most frequently used second-line therapies. Both treatments yielded survival outcomes worthy of notice, with a more favorable trend in the AMR-treated patients. Multivariate analysis identified second-line treatment with AMR as an independent favorable prognostic factor in terms of the PFS. This tendency was also seen in the patient group with sensitive relapse. Furthermore, in the refractory relapse group as well, a more favorable trend for the PFS was observed in the AMR as compared with the PEI treatment group. The median OS in the AMR treatment group was striking, in that it was substantially longer than that reported from phase III trials conducted abroad, where AMR is not considered as a second-line therapy because it failed to show a survival advantage in a randomized phase III trial, and also showed more toxicity.16
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Second-Line AMR or PEI for Relapsed SCLC Table 1 Patient Demographic and Clinical Characteristics AMR (n [ 188) n
PEI (n [ 56)
%
n
Others (n [ 99) %
n
%
Gender Female Male
45
24
9
16
18
18
143
76
47
84
81
82
Age, years Median (range)
65 (24-81)
66 (45-78)
68 (29-86)
Performance status 0
60
32
23
41
32
32
1
103
55
30
54
55
56
2
16
8.5
3
5.4
8
8
3
7
3.7
0
0
4
4
Unavailable
2
1.1
0
0
0
0
8
4.3
3
5.4
6
6
Smoking history Never-smoker Smoker
179
Unavailable
95
1
0.5
53
95
93
94
0
0
0
0
Stage LD
51
27
16
29
66
67
ED
134
71
38
68
33
33
0
0
Unavailable
3
1.6
2
3.6
First-line treatment Platinum þ ETP RT
94
50
33
59
58
59
Platinum þ IRI RT
69
37
14
25
14
14
Platinum þ IRI þ ETP RT
25
13
4
23
0
0
5
Sensitive
99
53
29
Refractory
89
47
27
Unavailable
0
0
0
Others
8
8
35
35
52
65
66
48
32
32
0
2
2
8.9
Relapse
Abbreviations: AMR ¼ Amrubicin; ED ¼ extensive disease; ETP ¼ etoposide; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; RT ¼ radiotherapy.
AMR is the world’s first anthracycline anti-cancer agent produced entirely through chemical synthesis26; it was first synthesized with the intent of developing an anti-tumor agent stronger than
doxorubicin (DXR). The active metabolite amrubicinol plays an important role in the antitumor effect of this drug, and the major mechanism of action of AMR is the stabilization of a cleavable
Table 2 Overall Response Rate AMR (n [ 188)
Median cycles/week (range)
PEI (n [ 56)
All
Sensitive Relapse (n [ 99)
Refractory Relapse (n [ 89)
All
Sensitive Relapse (n [ 29)
Refractory Relapse (n [ 27)
4 (1-27)
4 (1-27)
4 (1-17)
6 (1-10)
6 (1-10)
6 (1-10)
Response, n CR
7
5
2
4
3
1
PR
88
51
37
37
20
17
SD
57
30
28
9
4
5
PD
28
8
19
5
2
3
8
5
3
0
0
1
Objective response rate, %
51
57
44
73
79
67
Disease control rate, %
81
87
75
89
93
85
Unavailable
4
-
Abbreviations: AMR ¼ Amrubicin; CR ¼ complete response; PD ¼ progressive disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PR ¼ partial response; SD ¼ stable disease.
Clinical Lung Cancer Month 2016
Hitomi Sumiyoshi Okuma et al Figure 2 Progression-Free Survival of Patients Treated With AMR and PEI (n [ 244)
Table 3 Multivariate Cox Regression Analysis of PFS in Patients Treated With AMR and PEI (n [ 244) Factor
Progression-Free Survival (probability)
1.0
Median, months
0.9
Female
AMR 4.45 (95% CI, 4.12 to 5.24) PEI 4.18 (95% CI, 3.62 to 4.88)
0.8 0.7
No.
HR
Gender Male
(HR = 1.40; (95% CI, 1.03 to 1.90)
54 190
0.5 0.4 0.3
65 years
130
1
>65 years
114
1.02 1
ECOG PS
0.1
0-1
196
2-3
26
1.39
11
1
0
6
12
188 56
63 11
17 3
18 42 48 24 30 36 Time from second-line treatment (months)
54
60
1 1
1 1
No. at risk AMR PEI
Smoking history 9 2
4 1
4 1
3 1
3 1
3 1
Never-smoker Smoker
232
LD
67
Figure 3 Overall Survival of Patients Treated With AMR and PEI (n [ 244)
1.0
Median, months
Overall Survival (probability)
0.9
AMR PEI
9.95 (95% CI, 8.63 to 11.7) 10.8 (95% CI, 8.01 to 13.8) (HR = 1.13; (95% CI, 0.82 to 1.56)
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
6
12
188 56
127 41
63 23
18 24 30 36 48 42 Time from second-line treatment (months)
54
60
1 1
1 1
No. at risk AMR PEI
35 13
21 6
15 4
10 3
5 2
4 2
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/ irinotecan.
0.82-2.36
.22
0.77-3.83
.19
0.81-1.76
.37
0.73-1.46
.86
1.13-2.18
.007
1.16-2.34
.005
1
ED
172
1.19
ETP
127
1
IRI
83
First-line treatment
complex within the cancer cells via DNA topoisomerase II (Topo II). In studies using human tumor xenografts, AMR was demonstrated to exert a stronger antitumor effect than DXR against breast cancer (xenograft MX-1), small cell lung cancer (xenograft LX-1), and gastric cancer (xenografts SC-6, SC-9, and 4-1ST). In vivo research has demonstrated that AMR causes stronger myelosuppression than DXR, but that, however, recovery from the myelosuppressive effect of AMR is more rapid than that from the myelosuppressive effect of DXR.27 Cardiotoxicity is rarely encountered as compared with that for other anthracycline agents, and cumulative toxicities, such as renal failure associated with platinum agents, is not a concern. Therefore, AMR is a more feasible treatment option, in that it exerts less toxicity and requires fewer days of hospitalization. These findings suggest that AMR is a treatment that can be used for a long time without any substantive
.92
1.72
Stage Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/ irinotecan.
0.75-1.39
0.79
0.2
0.0
P .20
1
Age
0.6
95% CI 0.56-1.13
1.03
Sensitivity to first-line Sensitive-relapse
128
1
Refractory-relapse
116
1.57
AMR
188
1
PEI
56
Second-line treatment 1.65
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progression-free survival; PS ¼ performance status.
concern about cumulative toxicities, as compared with combination therapies based on platinum agents; therefore, AMR is one of the useful drugs that should be considered in the course of treatment in patients with SCLC. Patients with SCLC with sensitive relapse showed a better sensitivity to second-line treatment and a better prognosis as compared with those with refractory relapse. The ORR of 55% and median PFS of 5.3 months in the sensitive relapse group treated with AMR in the present study are similar to the outcomes reported from a phase II trial of an ORR of 67%, median PFS of 5.4 months, and median OS of 14.4 months in patients with SCLC with sensitive relapse assigned to the AMR treatment arm.28 In the phase III Amrubicin Clinical Trial-1 (ACT-1) trial, the ORR was 40.9%, the median PFS was 5.5 months, and the median OS was 9.2 months in the sensitive relapse subgroup of patients with SCLC treated with AMR.16 In the patients with SCLC with sensitive relapse treated with PEI in the present study, the ORR was 87% and the median PFS was 4.9 months. According to another randomized phase III trial of PEI in the secondline setting for patients with SCLC with sensitive relapse, the ORR was 84%, the median PFS was 5.7 months, and the median OS was 18.2 months.23 Interestingly, among the patients with sensitive relapse in the present study, a better survival was obtained in
Clinical Lung Cancer Month 2016
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Second-Line AMR or PEI for Relapsed SCLC the AMR treatment group as compared with the PEI treatment group. With the present data and the historical trial of PEI showing a survival benefit over topotecan, we believe that the true benefit of AMR will become manifest in properly selected patients, for example, those with sensitive relapse. From the aspect of toxicity, there was 1 treatment-related death (1.8%) in the PEI treatment group and 2 treatment-related deaths (1.0%) in the AMR treatment group in this study. Historical data showed a higher adverse event occurrence rate in the PEI treatment group; the grade 3 to 4 adverse events in the PEI treatment group were neutropenia (83.3%), anemia (84.4%), thrombocytopenia (41.1%), diarrhea (7.8%), and febrile neutropenia (FN; 31.1%).23 On the other hand, the grade 3 to 4 adverse events in the AMR treatment group were neutropenia (41%), thrombocytopenia (21%), anemia (16%), infections (16%), febrile neutropenia (10%), and cardiac disorders (5%).16 Myelosuppression is critical, because refractory patients already have depressed bone marrow function. The 3-drug combination of PEI was originally designed as a weekly regimen to make it easier to modify the dosage and schedule.29,30 However, the frequency of febrile neutropenia of 31.1% despite granulocyte colony-stimulating factor support is high for patients receiving second-line treatment and is 2- to 3-fold higher as compared with that reported for monotherapy regimens. Furthermore, patients scheduled to receive PEI treatment need to be hospitalized, whereas AMR treatment can be administered on an outpatient basis. Therefore, AMR monotherapy is more feasible and is also associated with lower toxicity. The results also revealed exceptionally long-term survivors in the AMR treatment group. One of these patients received 27 cycles of treatment, and 6 received 16 to 18 cycles. Based on a study of longterm survival in 1714 consecutive SCLC patients, Lassen et al reported a 5-year survival rate of 3.5%31; they reported ED, PS > 2, presence of liver and/or bone marrow metastases, and elevated lactate dehydrogenase and/or alkaline phosphatase levels as negative prognostic factors. In our patient cohort, 6 patients (2.5%) survived for longer than 5 years, and indeed, all 6 patients had limited disease and a PS of 0 to 1. In addition, 5 of the patients received AMR as the second-line treatment, with 3 patients still, at the time of writing, under AMR treatment. AMR is a drug that could be administered over the long term, provided it shows efficacy, as it has very low toxicity. Some of the limitations of this study were that the database was from a single institute, and the study was retrospective in nature; the number of patients in the PEI arm was small; treatment was selected according to the physicians’ discretion and may have, therefore, been biased. Also, both treatment groups include patients treated in practice and those enrolled in an ongoing clinical trial at the time. Therefore, some patients’ tumor response evaluations were made by the treating physician, whereas others were evaluated according to each trial protocol, which may have contributed to the longer PFS compared with a cohort from a pure clinical trial. Furthermore, our results showed substantially longer median overall survival times as compared with reports from previous phase III trials of AMR or topotecan carried out abroad, which could be related to possible differences in the genetic background, medical care, study design, and/or drug exposure,32 and the higher frequency of use of
6
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Clinical Lung Cancer Month 2016
post-relapse treatments including AMR, irinotecan, and topotecan in Japan. The similar median overall survival between AMR and PEI in our analysis may possibly have been due to post-relapse treatment or other factors; nonetheless, the long survival and simplicity of the regimen compared with PEI should be valued.
Conclusion Our results revealed that relapsed patients with SCLC receiving AMR as second-line therapy showed a longer median PFS as compared to those receiving PEI, with a similar median OS between the 2 treatment groups. A longer median PFS with AMR was also confirmed in patients diagnosed as having sensitive relapse. The 2 treatment groups showed different feasibility profiles. AMR is a highly active and well-tolerated treatment option that deserves to be recognized as a second-line treatment of choice as compared with topotecan and PEI, on the basis of the better survival and shorter hospitalization, respectively. Further investigation comparing AMR and PEI in selected patient groups is necessary.
Clinical Practice Points Despite their relatively good response to chemotherapy and
radiotherapy, the majority of patients with SCLC eventually show disease progression. The importance of second-line therapy for SCLC was first proven by the pivotal phase III trial comparing best supportive care and topotecan. Later, many studies of second-line treatment have been conducted, including AMR monotherapy and a combination regimen consisting of PEI. Both regimens have shown a survival benefit over topotecan in randomized trials in Japan. However, AMR failed to show its superiority over topotecan in a phase III trial; therefore, it is not a widely used drug around the world. The choice of the best regimen needs further study. No study has investigated the efficacy comparing AMR and PEI. In our analysis, AMR and PEI were the most used regiments at our institute. The following outcomes were obtained for AMR and PEI, respectively: ORR: 51% and 73%; median PFS: 4.5 and 4.2 months; and median OS: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P ¼ .007) and AMR as second-line treatment (vs. PEI) (P ¼ .005) as independent favorable prognostic factors for survival. AMR showed a more favorable outcome in terms of the feasibility and survival. Exceptionally long-term survivors were observed in patients treated with AMR. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted.
Acknowledgments The authors thank all the study participants who provided clinicopathological data for this analysis. The authors also thank Ms R. Torii for secretarial support in this study.
Disclosure The authors have stated that they have no conflicts of interest.
Hitomi Sumiyoshi Okuma et al Supplemental Data Supplemental figures and tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.cllc. 2016.09.005.
References 1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61:212-36. 2. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006; 24:4539-44. 3. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005; 366:1385-96. 4. Witta SE, Kelly K. Chemotherapy for small cell lung cancer. In: Pass HI, Mitchell JB, Johnson DH, et al, eds. Lung Cancer: Principles and Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 5. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colonystimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 2005; 23:3752-9. 6. Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985; 3:1471-7. 7. Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol 1999; 17:3540-5. 8. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346:85-91. 9. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: small-cell lung cancer, version 1.2016. Available at: https://www.nccn. org/professionals/physician_gls/pdf/sclc.pdf. Accessed: September 15, 2016. 10. Giaccone G, Donadio M, Bonardi G, Testore F, Calciati A. Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 1988; 6:1264-70. 11. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997; 15:2090-6. 12. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007; 25:2086-92. 13. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19:1743-9. 14. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed smallcell lung cancer. J Clin Oncol 2006; 24:5441-7.
15. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17:658-67. 16. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014; 32:4012-9. 17. Park SH, Cho EK, Kim Y, et al. Salvage treatment with topotecan in patients with irinotecan-refractory small cell lung cancer. Cancer Chemother Pharmacol 2008; 62: 1009-14. 18. Inoue A, Sugawara S, Yamazaki K, et al. Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 2008; 26: 5401-6. 19. Murakami H, Yamamoto N, Shibata T, et al. A single-arm confirmatory study of amrubicin therapy in patients with refractory small-cell lung cancer: Japan Clinical Oncology Group Study (JCOG0901). Lung Cancer 2014; 84:67-72. 20. Ettinger DS, Jotte R, Lorigan P, et al. Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer. J Clin Oncol 2010; 28:2598-603. 21. Jotte R, Conkling P, Reynolds C, et al. Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy. J Clin Oncol 2011; 29:287-93. 22. Asao T, Nokihara H, Yoh K, et al. Phase II study of amrubicin at a dose of 45 mg/ m2 in patients with previously treated small-cell lung cancer. Jpn J Clin Oncol 2015; 45:941-6. 23. Goto K, Ohe Y, Shibata T, et al. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, openlabel, randomised phase 3 trial. Lancet Oncol 2016; 17:1147-57. 24. Chhatriwala H, Jafri N, Salgia R. A review of topoisomerase inhibition in lung cancer. Cancer Biol Ther 2006; 5:1600-7. 25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 26. Ishizumi KON, Tanno N. Stereospecific total synthesis of 9-aminoanthracyclines: (þ)-9-amino-9-deoxydaunomycin and related compounds. J Org Chem 1987; 52: 4477-85. 27. Morisada S, Yanagi Y, Kashiwazaki Y, Fukui M. Toxicological aspects of a novel 9aminoanthracycline, SM-5887. Jpn J Cancer Res 1989; 80:77-82. 28. Maemondo M, Inoue A, Sugawara S, et al. 1471P: Final result of randomized phase 2 trial comparing amrubicin (A) with re-challenge of platinum doublet (P) in patients (PTS) with sensitive-relapsed small-cell lung cancer (SCLC): NJLCG0702. Ann Oncol 2014; 25(suppl 4):iv514. 29. Vasey PA, Kaye SB. Combined inhibition of topoisomerases I and IIeis this a worthwhile/feasible strategy? Br J Cancer 1997; 76:1395-7. 30. Sekine I, Nishiwaki Y, Kakinuma R, et al. Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507. Br J Cancer 2003; 88:808-13. 31. Lassen U, Osterlind K, Hansen M, Dombernowsky P, Bergman B, Hansen HH. Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18þ yearsean analysis of 1,714 consecutive patients. J Clin Oncol 1995; 13:1215-20. 32. Ettinger DS. Amrubicin for the treatment of small cell lung cancer: does effectiveness cross the Pacific? J Thorac Oncol 2007; 2:160-5.
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Second-Line AMR or PEI for Relapsed SCLC Supplemental Figure 1 Progression-Free Survival of Sensitive-Relapse (n [ 128) (A) and Refractory-Relapse (n [ 116) (B)
1.0
B
Median, months
0.9
5.34 (95% CI, 4.35 to 6.39) 4.88 (95% CI, 3.92 to 5.57) (HR = 1.40; (95% CI, 0.91 to 2.14)
AMR PEI
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
Median, months
0.9
AMR PEI
4.11 (95% CI, 2.99 to 4.61) 3.68 (95% CI, 2.96 to 4.57) (HR = 1.47; (95% CI, 0.92 to 2.34)
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0.0 0
No. at risk AMR PEI
1.0
Progression-free survival (probability)
Progression-free survival (probability)
A
99 29
6
39 8
12
18 24 30 36 42 48 Time from second-line treatment(months)
12 3
4 1
4 1
4 1
3 1
3 1
3 1
54
1 1
0
60
1 1
3
No. at risk AMR 89 PEI 27
6 9 12 Time from second-line treatment (months)
51 18
22 4
11 1
4 1
15
18
2 1
1 1
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/irinotecan.
Supplemental Figure 2 Overall Survival of Sensitive-Relapse (n [ 128) (A) and Refractory-Relapse (n [ 116) (B)
1.0
Overall survival (probability)
B
Median, months
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
-
0.8 0.7 0.6 0.5 0.4 0.3 0.2
0.0 0
6
12
99 29
73 26
44 16
24 18 30 36 42 48 Time from second-line treatment (months)
23 9
13 4
11 3
8 3
5 2
4 2
54
60
1 1
1 1
No. at risk AMR PEI
Abbreviations: AMR ¼ Amrubicin; HR ¼ hazard ratio; PEI ¼ weekly cisplatin/etoposide/irinotecan.
7.e1
Median, months 7.99 (95% CI, 6.35 to 9.44) 7.96 (95% CI, 4.54 to 11.1) (HR = 1.31; (95% CI, 0.83 to 2.04) AMR PEI
0.1
0.0
No. at risk AMR PEI
1.0 0.9
14.2 (95% CI, 9.78 to 15.7) 14.8 (95% CI, 10.2 to 17.9) (HR = 0.96; (95% CI, 0.61 to 1.53) AMR PEI
Overall survival (probability)
A
Clinical Lung Cancer Month 2016
0
6
89 27
54 16
12 18 24 30 36 Time from second-line treatment (months)
20 8
13 5
9 3
5 2
3 1
42
48
1 1
1 1
Hitomi Sumiyoshi Okuma et al Supplemental Table 1 Multivariate Cox Regression Analysis of PFS in Patients With Sensitive Relapse (n [ 128) Factor
No.
HR
Gender
Supplemental Table 2 Multivariate Cox Regression Analysis of PFS in Patients With Refractory Relapse (n [ 116)
95% CI
P
Factor
0.51-1.34
.44
Gender
No.
HR
Female
30
1
Female
24
1
Male
98
0.82
Male
92
0.62
65 years
64
1
>65 years
52
1.30
Age
0.44-1.08
65 years
66
1
>65 years
62
0.67
ECOG PS
1.03-5.87
0-1
99
2-3
7
Smoker
122
ECOG PS 0-1
97
1
2.46
2-3
19
0.56
0.85-7.51 5
.04
Age
1
Smoking history Never-smoker
.11
.09
Smoking history
1
Never-smoker
2.53
Smoker
Stage
0.84-2.37
LD
53
1
ED
74
1.41
First-line treatment
0.77-2.17
.19
.33
6 110
Stage LD
14
1
ED
98
1.24
First-line treatment
1
ETP
64
1
IRI
47
1.30
IRI
36
0.76
AMR
99
1
AMR
89
1
PEI
29
1.74
PEI
27
1.48
.02
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progressionfree survival; PS ¼ performance status.
0.81-2.07
.27
0.27-1.13
.10
0.26-2.41
.68
0.64-2.40
.53
0.46-1.27
.30
0.84-2.62
.14
0.79
63
1.09-2.80
P .12
1
ETP Second-line treatment
95% CI 0.35-1.13
Second-line treatment
Abbreviations: AMR ¼ Amrubicin; CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; ED ¼ extended disease; ETP ¼ etoposide; HR ¼ hazard ratio; IRI ¼ irinotecan; LD ¼ limited disease; PEI ¼ weekly cisplatin/etoposide/irinotecan; PFS ¼ progressionfree survival; PS ¼ performance status.
Clinical Lung Cancer Month 2016
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