Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study
Introduction
Lung cancer is the leading cause of cancer-related deaths worldwide (1). Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is characterized by a rapid doubling time, a high growth fraction, and the early development of widespread metastases (2,3). Nearly 70% of patients with SCLC are diagnosed with extensive-stage SCLC (ES-SCLC), and systemic platinum-based chemotherapy has been the standard treatment for ES-SCLC for decades (4). Although first-line chemotherapy frequently results in high response rates, almost all patients with ES-SCLC experience early disease progression or recurrence, with less than 5% surviving for 2 years (4,5). Therefore, novel, effective treatments for ES-SCLC are warranted in daily clinical settings.
Recent trials have demonstrated that treatment with immune checkpoint inhibitors has greatly improved the prognosis of patients with non-SCLC (6-10). However, a phase 2 study of maintenance pembrolizumab and a phase 3 study of ipilimumab plus platinum-based chemotherapy did not show improved efficacy in the first-line treatment of ES-SCLC (5,11). In several recent phase 3 trials, the addition of immunotherapy to platinum and etoposide has resulted in significantly longer overall survival (OS) and progression-free survival (PFS) than chemotherapy alone (12,13). The main cytotoxic agents used for SCLC treatment are platinum plus topoisomerase inhibitors (e.g., etoposide, amrubicin, and irinotecan) (3,14).
Topoisomerase is an essential enzyme for DNA replication, and its inhibitors suppress tumor progression (15). Amrubicin is one of the second-line treatments for SCLC because it improved OS in patients with refractory disease in a phase 3 trial (16). Amrubicin and etoposide are type II topoisomerase inhibitors, and irinotecan is a type I topoisomerase inhibitor (15,17). However, it is unclear whether differences between their mechanisms of action affect the clinical outcomes of second-line amrubicin for relapsed ES-SCLC. Moreover, the impact of first-line immunochemotherapy on the efficacy of amrubicin monotherapy has not yet been elucidated. The present study aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors. We present the following article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-160/rc).
Methods
Patients
This study retrospectively assessed 320 patients with ES-SCLC who were refractory to first-line treatment with platinum-based chemotherapy or immunochemotherapy and received amrubicin monotherapy as second-line treatment at 22 institutions in Japan between April 2015 and November 2020. Eligible patients were aged >20 years, with histologically or cytologically confirmed SCLC and evaluable target lesions according to the Response Evaluation Criteria in Solid Tumors version 1.1. The following clinical data were extracted from retrospective medical records: age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), history of first-line treatment, overall response rate (ORR) following amrubicin monotherapy, Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, the PFS following amrubicin monotherapy, and the PFS of the first-line treatment. The relapse-free interval of the first-line treatment was also extracted and classified into sensitive or refractory relapse based on whether the period exceeded 90 days. OS was defined as the time from the first administration of platinum-based chemotherapy until any cause of death. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committees of the Kyoto Prefectural University of Medicine (No. ERB-C-1927-3) and all hospitals involved. However, the requirement for informed consent was waived because this was a retrospective study, and the official website was used as an opt-out method, which was approved by the Ethics Committee of each hospital.
Matching
Rigorous adjustment for significant differences in the baseline characteristics of patients with propensity score matching was performed using the following variables: age, sex, ECOG PS at first-line treatment initiation, and ECOG PS at amrubicin initiation. Nearest-neighbor matching was performed at a ratio of 1:1 without replacement. The caliper was set at 0.2.
Statistical analysis
PFS was analyzed using the Kaplan-Meier method and compared using the Peto-Peto-Wilcoxon test. PFS of amrubicin was defined as the time from the initiation of amrubicin to disease progression or death from any cause, while PFS of the first-line treatment was defined as the time from the initiation of the first-line treatment to disease progression. The data cut-off date was November 25, 2020. Variables related to PFS reported in previous studies and the most relevant factors identified in the results of univariable analyses were included in a multivariate Cox proportional hazards model. Hazard ratios estimated from the Cox analysis were reported with 95% confidence intervals (CIs). The pairwise deletion was used for missing data in some cases. All statistical analyses were performed using EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). P<0.05 was considered statistically significant.
Results
Patient characteristics
This study enrolled 320 patients with ES-SCLC who received amrubicin monotherapy as a second-line treatment (Figure 1). Among these, 59 (18%) patients received platinum plus irinotecan (irinotecan group), and the remaining 261 (82%) received platinum plus etoposide (etoposide group) as the first-line treatment. In the etoposide group, 23 patients received immunochemotherapy, including atezolizumab. The patient characteristics are shown in Table 1. Patients in the irinotecan group were significantly younger than those in the etoposide group (median: 67.0 vs. 71.0 years, P<0.001). The baseline PS was better in the irinotecan group than in the etoposide group, but there was no significant difference in PS at amrubicin initiation between the two groups.
Table 1
| Variables | Platinum plus etoposide, n=261 | Platinum plus irinotecan, n=59 | P value |
|---|---|---|---|
| Median age, years (range) | 71.0 (47.0–91.0) | 67.0 (50.0–83.0) | <0.001 |
| Age categorization, n (%) | <0.001 | ||
| <75 | 174 (66.7) | 55 (93.2) | |
| ≥75 | 87 (33.3) | 4 (6.8) | |
| Sex, n (%) | 0.18 | ||
| Male | 200 (76.6) | 40 (67.8) | |
| Female | 61 (23.4) | 19 (32.2) | |
| ECOG PS =0, 1, n (%) | |||
| At first-line initiation | 220 (84.3) | 56 (94.9) | 0.05 |
| At AMR initiation | 212 (81.2) | 51 (86.4) | 0.31 |
| Combined use of atezolizumab, n (%) | 23 (8.8) | 0 (0.0) | – |
ECOG PS, Eastern Cooperative Oncology Group performance status; AMR, amrubicin.
Clinical predictive factors related to the PFS following amrubicin monotherapy in the second-line setting
The ORR following amrubicin monotherapy was not significantly different between the irinotecan and etoposide groups (P=0.16; Table 2). The median PFS with amrubicin monotherapy was 2.6 months in all patients with ES-SCLC (Figure 2A). The PFS was longer in the irinotecan group than in the etoposide group (median: 3.2 vs. 2.5 months, P=0.034; Figure 2B). A propensity score matching analysis was performed to compare the topoisomerase inhibitors in the first-line treatment to minimize the impact of treatment allocation bias, as described in section 2.2. Clinicopathological features by regimens of first-line treatment after matching are shown in Table 3. A significant difference in the PFS following amrubicin monotherapy was observed between the irinotecan and etoposide groups in the propensity score matching analysis (median: 3.4 vs. 2.1 months, P=0.03; Figure 3).
Table 2
| Overall response rate for AMR treatment | Platinum plus etoposide, n=261 | Platinum plus irinotecan, n=59 | P value |
|---|---|---|---|
| Complete response, n (%) | 2 (0.8) | 1 (1.7) | 0.161 |
| Partial response, n (%) | 51 (19.5) | 17 (28.8) | |
| Stable disease, n (%) | 86 (33.0) | 23 (39.0) | |
| Progressive disease, n (%) | 72 (27.6) | 11 (18.6) | |
| Not evaluable, n (%) | 50 (19.2) | 7 (11.9) |
AMR, amrubicin.
Table 3
| Variables | Platinum plus etoposide, n=57 | Platinum plus irinotecan, n=57 | P value |
|---|---|---|---|
| Median age, years (range) | 68.0 (53.0–80.0) | 67.0 (50.0–83.0) | 0.025 |
| Age categorization, years, n (%) | 1 | ||
| <75 | 53 (93.0) | 53 (93.0) | |
| ≥75 | 4 (7.0) | 4 (7.0) | |
| Sex | 1 | ||
| Male | 38 (66.7) | 38 (66.7) | |
| Female | 19 (33.3) | 19 (33.3) | |
| ECOG PS =0, 1, n (%) | |||
| At first-line treatment initiation | 54 (94.7) | 54 (94.7) | 1 |
| At AMR initiation | 51 (89.5) | 51 (89.5) | 1 |
ECOG PS, Eastern Cooperative Oncology Group performance status; AMR, amrubicin.
In the univariate analysis, the PFS with amrubicin monotherapy was significantly longer in patients with good PS at amrubicin initiation [0, 1] than in those with poor PS [2, 3] [2.8 months (95% CI: 2.6–3.4 months) vs. 1.4 months (95% CI: 0.93–1.8 months), P<0.001; Table 4]. Thus, the multivariate analysis demonstrated that platinum plus etoposide at the first-line treatment and poor PS at amrubicin initiation were independent prognostic factors for prolonged PFS following amrubicin monotherapy (Table 5). In this study, PFS with amrubicin was evaluated in the aging of patients ≥70 and those ≥75 years. The results of ≥70 years old patients were similar to those of ≥75 years, compared with the younger patients (Figure S1).
Table 4
| Variables | No. of patients | Median PFS (95% CI) | P value |
|---|---|---|---|
| Age categorization, years | 0.210 | ||
| <75 | 229 | 2.6 (2.3–2.9) | |
| ≥75 | 91 | 2.6 (1.7–3.2) | |
| Sex | 0.647 | ||
| Male | 240 | 2.7 (2.3–3.1) | |
| Female | 80 | 2.5 (1.8–2.8) | |
| ECOG PS at first-line treatment initiation | 0.030 | ||
| 0, 1 | 276 | 2.7 (2.4–3.0) | |
| 2, 3 | 42 | 1.8 (1.2–2.7) | |
| ECOG PS at AMR initiation | <0.001 | ||
| 0, 1 | 263 | 2.8 (2.6–3.4) | |
| 2, 3 | 48 | 1.4 (0.93–1.8) | |
| First-line regimen | 0.030 | ||
| Platinum plus etoposide | 261 | 2.6 (1.9–2.8) | |
| Platinum plus irinotecan | 59 | 3.2 (2.6–3.8) | |
PFS, progression-free survival; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; AMR, amrubicin.
Table 5
| Variables | HR (95% CI) | P value |
|---|---|---|
| Age ≥75 years | 1.15 (0.78–1.68) | 0.490 |
| Female | 1.01 (0.75–1.35) | 0.960 |
| Poor ECOG PS at first-line initiation | 1.04 (0.71–1.53) | 0.840 |
| Poor ECOG PS at AMR initiation | 1.79 (1.26–2.54) | 0.001 |
| Use of platinum plus etoposide at the first-line treatment | 1.41 (1.00–1.98) | 0.048 |
PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; AMR, amrubicin.
Correlation between the PFS times following first-line treatment and amrubicin monotherapy in the second-line setting
The impact of first-line treatment on the clinical outcomes of amrubicin monotherapy in a second-line setting was evaluated. The irinotecan and etoposide groups were classified into two groups based on the median PFS following first-line treatment. The PFS following amrubicin monotherapy was significantly longer in the PFS ≥4.8 months group than in the PFS <4.8 months group (3.4 vs. 1.6 months, Peto-Peto-Wilcoxon test, P<0.001) in the etoposide group (Figure 4A). In contrast, there was no significant difference in the PFS following amrubicin monotherapy between the PFS ≥4.9 months group and the PFS <4.9 months group (2.9 vs. 3.5 months, Peto-Peto-Wilcoxon test, P=0.373) in the irinotecan group (Figure 4B). The subgroup analyses based on various clinicopathological factors are shown in Figure 5. Compared with chemotherapy with platinum and etoposide, the additional use of atezolizumab in the first-line treatment had no significant effect on the PFS following amrubicin monotherapy (Figure S2).
Correlation between the efficacies following first-line treatment and amrubicin monotherapy
The impact of the recurrence on the clinical outcomes of amrubicin monotherapy was evaluated by classifying both the irinotecan and etoposide groups into two groups based on the period from the last administration of the first-line treatment to recurrence. The PFS following amrubicin monotherapy was significantly longer in sensitive-relapsed patients than in refractory-relapsed patients (4.1 vs. 1.8 months, Peto-Peto-Wilcoxon test, P<0.001) in the etoposide group (Figure 6A). In contrast, no significant difference in the PFS following amrubicin monotherapy between sensitive-relapsed and refractory-relapsed patients (4.3 vs. 3.0 months, Peto-Peto-Wilcoxon test, P=0.19) in the irinotecan group (Figure 6B).
OS analysis
At the date of data cut-off, the median follow-up was 13.6 months. No significant differences were observed between the OS of the irinotecan and etoposide groups (14.0 vs. 13.6 months, Peto-Peto-Wilcoxon test, P=0.35) (Figure 7).
Safety
Fifty patients in the irinotecan group and 241 in the etoposide group were evaluated for the safety of amrubicin monotherapy. Grade ≥3 CTCAEs were observed in 78% and 64.3% of patients in the irinotecan and etoposide groups, respectively (P=0.07). Grade ≥3 neutropenia was more frequently reported in the irinotecan group than in the etoposide group (78% vs. 57.9%, P=0.01). However, the incidence of febrile neutropenia was not of significance (P=1). Grade ≥3 pneumonitis were observed in both groups (4% vs. 7%, P=0.75). Discontinuation due to adverse events caused by pneumonitis and neutropenia occurred in both groups (10.5% vs. 13%, P=0.82) and treatment-related deaths were observed in 6 patients (2.5%) of the etoposide group (Table S1).
Discussion
The standard first-line treatment for ES-SCLC was platinum-based chemotherapy until immunochemotherapy was approved for clinical use (3,4). A previous clinical phase 3 trial showed that chemotherapy with cisplatin plus irinotecan resulted in a significantly longer OS than that with cisplatin plus etoposide (12.8 vs. 9.4 months) (18); however, other phase 3 trials failed to confirm this observation (19,20). Thus, based on several clinical trials for untreated patients with ES-SCLC, two cytotoxic combined regimens have existed as double standard therapies for first-line treatment in patients with ES-SCLC for decades. In this study, we focused on the aspects of the drug mechanism of action related to the clinical outcomes of amrubicin monotherapy in the second-line setting for ES-SCLC. Previous preclinical studies have reported that treatment with topoisomerase I inhibitors led to the downregulation of topoisomerase I activity and reciprocal enhancement of topoisomerase II activity using tumor cell lines, thereby resulting in high sensitivity to topoisomerase II inhibitors (21-23). Indeed, our current observations in 320 patients with ES-SCLC showed that, compared with etoposide (topoisomerase II inhibitor) treatment, first-line treatment with irinotecan (topoisomerase I inhibitor) was associated with prolonged PFS following amrubicin (topoisomerase II inhibitor) treatment. Murakami et al. reported that in 82 patients with chemotherapy-refractory SCLC, the efficacy of amrubicin was poorer in patients who were previously treated with etoposide, which is consistent with the results of our study (24). Interestingly, the PFS following amrubicin monotherapy was positively associated with the PFS following etoposide-containing chemotherapy in the first-line setting. Given that responders to the etoposide-containing regimen had better outcomes with amrubicin in the second-line setting, PFS might be a promising clinical factor in selecting responders to second-line amrubicin, although both are topoisomerase II inhibitors.
Recent clinical trials have demonstrated that immunochemotherapy has better patient outcomes than chemotherapy when used as first-line treatment for ES-SCLC (12,13). However, there is limited evidence to validate the sequence of first-line treatment and second-line amrubicin monotherapy for patients with ES-SCLC. Current observations showed that not only the sequential use of topoisomerase I followed by topoisomerase II inhibitors but also the sensitivity-based selection of topoisomerase I and II inhibitors could be predicted to improve the PFS following amrubicin therapy irrespective of its combination with immune checkpoint inhibitors. In contrast, chemotherapy of platinum plus irinotecan treatment could be a better option for ineligible patients for immune checkpoint inhibitors, such as autoimmune diseases with a high risk of severe immune-related adverse events. Further prospective investigations are needed to confirm our observations regarding the relationship between immunochemotherapy and second-line treatment.
There are some limitations to our study. First, this was a retrospective study, and the first-line treatments differed depending on the institution, although we also used propensity score analysis. Second, while the results of phase 3 trials on cisplatin plus irinotecan regimens varied by country, all patients in this cohort were Japanese. However, our findings in real-world settings regarding the selection of topoisomerase inhibitors for ES-SCLC treatment are notable and could help improve ES-SCLC prognosis. Further investigations are required to address these issues.
Conclusions
The observations in this study suggest that patients previously treated with the topoisomerase I inhibitor irinotecan-containing regimen might have promising outcomes with amrubicin monotherapy by switching the target for topoisomerase inhibition. Further prospective studies are required to clarify the best sequence strategy for the first- and second-line treatments for ES-SCLC. Our results showed that different types of topoisomerase inhibitors could affect the PFS following second-line amrubicin monotherapy in patients with ES-SCLC.
Acknowledgments
We would like to thank the patients, their families, and all investigators involved in this study. This work was supported by Editage (www.editage.com) for English language editing.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-160/rc
Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-160/dss
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-160/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-160/coif). Tadaaki Yamada serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2023. Tadaaki Yamada received commercial research grants from Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical K.K., and Takeda Pharmaceutical Company Limited and personal fees from Eli Lilly. AO received personal fees from Chugai-Roche, AstraZeneca, Boehringer Ingelheim, and Bristol Myers Squibb. KT received research grants from Chugai-Roche and Ono Pharmaceutical and individual fees from AstraZeneca, Chugai-Roche, MSD-Merck, Eli Lilly Boehringer Ingelheim, and Daiichi Sankyo. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committees of the Kyoto Prefectural University of Medicine (No. ERB-C-1927-3) and all hospitals involved. However, the requirement for informed consent was waived because this was a retrospective study, and the official website was used as an opt-out method, which was approved by the Ethics Committee of each hospital.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Dómine M, Moran T, Isla D, et al. SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019). Clin Transl Oncol 2020;22:245-55. [Crossref] [PubMed]
- Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer 2015;121:664-72. [Crossref] [PubMed]
- Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2016;34:3740-8. [Crossref] [PubMed]
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
- Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:123-35. [Crossref] [PubMed]
- Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-50. [Crossref] [PubMed]
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
- Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65. [Crossref] [PubMed]
- Gadgeel SM, Pennell NA, Fidler MJ, et al. Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol 2018;13:1393-9. [Crossref] [PubMed]
- Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9. [Crossref] [PubMed]
- Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2021;22:51-65. [Crossref] [PubMed]
- Horita N, Yamamoto M, Sato T, et al. Amrubicin for relapsed small-cell lung cancer: a systematic review and meta-analysis of 803 patients. Sci Rep 2016;6:18999. [Crossref] [PubMed]
- Chhatriwala H, Jafri N, Salgia R. A review of topoisomerase inhibition in lung cancer. Cancer Biol Ther 2006;5:1600-7. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Kurata T, Okamoto I, Tamura K, et al. Amrubicin for non-small-cell lung cancer and small-cell lung cancer. Invest New Drugs 2007;25:499-504. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Kim DW, Kim HG, Kim JH, et al. Randomized Phase III Trial of Irinotecan Plus Cisplatin versus Etoposide Plus Cisplatin in Chemotherapy-Naïve Korean Patients with Extensive-Disease Small Cell Lung Cancer. Cancer Res Treat 2019;51:119-27. [Crossref] [PubMed]
- Zatloukal P, Cardenal F, Szczesna A, et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 2010;21:1810-6. [Crossref] [PubMed]
- Sugimoto Y, Tsukahara S, Oh-hara T, et al. Elevated expression of DNA topoisomerase II in camptothecin-resistant human tumor cell lines. Cancer Res 1990;50:7962-5. [PubMed]
- Gupta RS, Gupta R, Eng B, et al. Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I. Cancer Res 1988;48:6404-10. [PubMed]
- Tan KB, Mattern MR, Eng WK, et al. Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors. J Natl Cancer Inst 1989;81:1732-5. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
