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ORIGINAL ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 266-271

Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy


Department of Pulmonology, Kameda Medical Center, Chiba, Japan

Date of Web Publication26-Jul-2012

Correspondence Address:
Nobuhiro Asai
929 Higashi-cho, Kamogawa, Chiba
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.98983

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 > Abstract 

Background: While more elderly patients are being diagnosed with lung cancer every year, no anti-lung cancer therapy designed specifically for the elderly has been established yet. This is the first retrospective study to examine the efficacy and safety of amurubicin (AMR) for elderly patients with refractory relapsed small cell lung cancer (SCLC) as second or third-line chemotherapy.
Materials and Methods: Thirty-six patients were eligible for analyzing the frequency of hematologic and non-hematologic toxicities and effectiveness of AMR for refractory relapsed SCLC in both elderly (≥70 years) and non-elderly (<70 years) groups.
Results: Among these patients as third-line chemotherapy, the response rate and the disease control rate of refractory relapsed cases were 44.4 and 55.6%, respectively. The median of progression-free survival time was 3.0 months and the median of overall survival time was 5.1 months. There were no significant differences in the frequency of the grade 3-5 hematologic or non-hematologic toxicity between the elderly (≥70 years) and non-elderly (<70 years) patients or second and third-line chemotherapies.
Conclusions: AMR could be one of the effective tools in the treatment of elderly patients with refractory relapsed SCLC as third-line chemotherapy, and the recommended dose is 30 mg/m 2 for three consecutive days.

Keywords: Amurubicin, elderly, refractory relapsed small cell lung cancer, third-line chemotherapy


How to cite this article:
Asai N, Ohkuni Y, Matsunuma R, Nakashima K, Iwasaki T, Kaneko N. Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy. J Can Res Ther 2012;8:266-71

How to cite this URL:
Asai N, Ohkuni Y, Matsunuma R, Nakashima K, Iwasaki T, Kaneko N. Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy. J Can Res Ther [serial online] 2012 [cited 2019 Sep 17];8:266-71. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/266/98983


 > Introduction Top


Lung cancer remains the leading cause of cancer deaths, and approximately 13% of all patients with lung cancer are diagnosed as having small-cell lung cancer (SCLC). [1] Despite being highly sensitive to first-line chemotherapy and radiotherapy treatments, most SCLC patients experience relapse within two years and die from systemic metastasis. Median survival time (MST) of 9.4-12.8 months and two-year survival of 5.2-19.5% are disappointing. [2],[3] Additionally, elderly patients with SCLC commonly cannot undergo anti-tumor therapy because of poor general health condition.

Previously treated SCLC patients can be divided into two groups: refractory cases are those who failed first-line chemotherapy or responded but progressed within 60 days from the end of chemotherapy; sensitive cases are defined as those who responded to first-line chemotherapy and relapsed after a treatment-free interval of at least 60 days. Sensitive cases are more likely to respond to second-line chemotherapy than refractory cases. [4] The standard treatment for relapsed SCLC is not yet established. In addition, 80% of elderly patients (≥70 years) with lung cancer generally have complications, such as chronic obstructive pulmonary disease, heart disease, cerebrovascular disease, malnutrition, osteoporosis and dementia. [5] Elderly patients are less tolerant to chemotherapy and radiotherapy than non-elderly patients (< 70 years). We can presume that the tolerance dose in elderly patients for cancer treatment would be lower. In an aging society, therapy for lung cancer in elderly patients needs to be established.

Few reports suggest that third-line chemotherapy for SCLC was effective with acceptable toxicities, [6],[7] but the standard treatment for SCLC as third-line chemotherapy is not established yet. Therefore, it is common that physicians have difficulty in treating SCLC after failure of second-line chemotherapy. We retrospectively attempted to analyze all the patients with refractory relapse SCLC who received AMR monotherapy as second or third-line chemotherapy for the purpose of evaluating the efficacy and safety and determining the recommended dose of AMR. Our report is the first to focus on the efficacy and safety of low dose AMR monotherapy in the treatment of refractory relapse SCLC for elderly patients as third-line chemotherapy.


 > Materials and Methods Top


We retrospectively reviewed all patients with refractory relapsed SCLC after one or two previous regimens (at least one platinum-containing regimen) who received AMR. Thirty-six patients were eligible for analyzing the frequency of hematologic and non-hematologic toxicities and effectiveness of AMR for refractory relapsed SCLC in both elderly (≥70 years) and non-elderly (<70 years) groups. All of these patients had histological or cytological confirmation of SCLC and had previously received chemotherapy.

AMR was initially administered at a dose of 40 mg/m 2 as second-line chemotherapy, and at a dose of 30 mg/m 2 as third-line chemotherapy on day 1-3 every 3 weeks. If grade 4 neutropenia, grade 3 febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or worse non-hematologic toxicities were observed, the dosages of AMR were modulated at a reduction of 20%. In addition, the initial dose of AMR was reduced by 20% if severe hematologic toxicities had been observed before.

Patient characteristics (age, gender, histology, stage, and PS), treatment response, adverse effects, previous chemotherapy regimens, the number of chemotherapy cycles, and the dose were analyzed.

Patients were evaluated for determining the stage of their disease before and one month after chemotherapy, whether or not their disease progressed or recurred by medical history and physical examination, chest radiography, computed tomography of the chest and abdomen, and other staging procedures such as magnetic resonance imaging of the head or positron emission tomography. Treatment response was evaluated according to the response evaluation criteria in solid tumors (RECIST). The severity of all adverse events that were related to AMR administration was assessed based on the common terminology criteria for adverse events (CTCAE, version 4.0). One or two-year survival times were measured from the diagnosis date of SCLC. Progression-free survival (PFS) was calculated from the start of AMR to obvious evidence of tumor progression. Overall survival time (OS) was calculated from the start of AMR until death or last follow-up evaluation. Fisher's exact test was used to estimate the treatment response and the correlation among different variables for both elderly and non-elderly groups. Survival curves were estimated using the Kaplan-Meier method. For all analyses, P < 0.05 was considered statistically significant.


 > Results Top


Patient Characteristics

From January 2006 to February 2009 at our institute, a total of 36 patients were treated with AMR alone. The patient's characteristics are shown in [Table 1]. Among them, thirty-two patients were males and four patients were females, and the median age was 66.5 years (range 47-80 years). Eighteen of the thirty-six patients (50%) were more than 70 years old. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status and eight patients had a PS of 0, twenty-eight patients had a PS of 1, and PS of 2-4 was not recorded. At the beginning of the treatment, all patients had extensive disease. The number of prior regimens was as follows: one, n =18; two, n =18. All patients had been treated with some form of cisplatin or carboplatin-based combination chemotherapy alone. Previous chemotherapy regimens are also shown in [Table 1]. The most common previous chemotherapy regimen was carboplatin plus etoposide.
Table 1: Baseline patient and disease characteristics

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Treatment response and number of treatment cycles of AMR as second or third-line chemotherapy

The median number of treatment cycles was three (range 1-10). Response of each age group is listed in [Table 2]. As for the response of thirty-six patients, one (2.8%) achieved a complete response (CR), twelve (33.3%) had a partial response (PR), eleven (30.6%) showed a stable disease (SD), and twelve (33.3%) had a progressive disease (PD). Thus, effective response rate (RR) and disease control rate (DCR) were seen in 36.1 and 66.7%, respectively. The median progression-free survival time (PFS) was 2.9 months [Figure 1]. Median survival time (MST) was 5.1 months [Figure 2]. One or two-year survival rates were 76.1and 28.3%, respectively [Figure 2].
Table 2:

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Figure 1: Progression-free survival (PFS) from the start of AMR monotherapy for all patients. Median PFS was 2.9 months

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Figure 2: Overall survival time (OS) from the start of AMR monotherapy for all patients. Median survival time (MST) was 5.1 months, and 76.1 and 28.3% of patients remained alive at 1 year and 2 years respectively

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Among the ten patients in the elderly group, the median number of treatment cycles was two (range 1-5). No CR was found. Four patients achieved a PR (40%), one patient had a SD (10%), and five patients showed a PD (50%). Thus, RR and DCR in elderly group were seen in 40 and 50% respectively [Table 2]a.

Toxicities are shown in [Table 3]. The most frequent toxicity was myelosuppression: grade 3-4 leukopenia, neutropenia, and thrombopenia were seen in 30.8% (n=8), 38.5% (n=10), and 7.7% (n=2) respectively, while febrile neutropenia was 3.8% (n=1). No grade 3-4 non-hematologic toxicities were found. Only two patients (7.7%) received a granulocyte colony-stimulation factors (G-CSF) injection. There were no significant differences in the treatment response, hematologic or non-hematologic toxicities or the necessity of G-CSF between elderly and non-elderly groups.
Table 3: Toxicity by 36 patients during AMR alone

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Treatment response and toxicities of AMR alone as third-line chemotherapy

The treatment response of AMR alone as third-line chemotherapy was no CR (0%, n=0), 8 PR (44.4%, n=8), 2 SD (11.1%, n=2) and 8 PD (44.4%, n=8) and thus RR and DCR were seen in 44.4 and 55.6%, respectively. For the elderly with SCLC as third-line chemotherapy, neither CR nor SD were found and four PR (n=4, 44.4%) and five PD (n=5, 55.6%) were seen. Thus, RR was identical to DCR in this group and was 44.4% [Table 2]b.

The median progression-free survival time (PFS) and MST were 3.0 months [Figure 3], 5.1 months [Figure 4] respectively as third-line chemotherapy. Drug-related adverse events for all patients are shown in [Table 3]. There were no significant differences in the treatment response, hematologic or non-hematologic toxicities or the necessity of G-CSF both between second and third-line chemotherapy and between elderly and non-elderly groups as third-line chemotherapy as shown in [Table 4] and [Table 5].
Table 4: Comparison with the frequency of ×G3 toxicity during AMR alone between second and third-line
chemotherapy


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Table 5: Comparison with the frequency of toxicity between elderly and non-elderly during AMR alone as third-line chemotherapy

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Figure 3: PFS from the start of AMR monotherapy for the patients as third-line chemotherapy. Median PFS was 3.0 months

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Figure 4: OS from the start of AMR monotherapy for the patients as third-line chemotherapy. MST was 5.1 months

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 > Discussion Top


The treatment options for patients with relapsed SCLC are still limited. While most patients with SCLC experience tumor progression within two years after first-line chemotherapy, [1],[2],[3] it is very disappointing for physicians to have no established treatment for elderly patients with relapsed SCLC as second or third-line chemotherapy. In an aging society, more elderly patients with SCLC will be expected every year in future. Thus, a clinical study is needed to establish the standard treatment for the elderly with SCLC.

Topotecan is the only drug approved in United States for patients who have failed first-line chemotherapy treatment. [8],[9] No drug has been approved for patients who have failed second-line treatment. Also, there are quite a few patients who are too old to receive anti-tumor chemotherapy treatment. A review of 631 patients treated with intravenous topotecan in six studies of phase II-III showed a response rate of 20.4% in chemotherapy-sensitive relapse and 4.0% in chemotherapy-refractory relapse cases. These results are disappointing in terms of the risk-benefit balance. [4]

AMR is a fully synthetic 9-aminoanthracycline, converted in the body to amurubicinol by reduction of the 13-position ketone, possessing higher antitumor activity than the parent molecule. Although classified as anthracycline agents, amrubicin and amrubicinol exert cytotoxic effects as DNA topoisomerase II inhibitors, but not mainly as DNA intercalators. [10],[11],[12],[13],[14],[15],[16],[17] A Japanese phase II study with intravenous administration of single-agent AMR at 40 mg/m 2 for three consecutive days in previously treated SCLC patients was reported. The overall RRs were 52, 50% in sensitive and refractory relapse cases respectively. The MSTs were 11.6 months and 10.3 months in sensitive and refractory relapse cases respectively. [10] The phase II study also demonstrated AMR was superior to topotecan in terms of response rates and overall survival. On the other hand, G3-4 neutropenia, thrombopenia, anemia, FN were seen in 83, 20, 33 and 5% respectively. [4]

It has been reported that the hematologic toxicities are more severe in SCLC previously treated cases by using AMR compared to non-treated cases. [6],[18] However, our study showed that there were no statistical differences in the frequency of toxicities both between second and third-line chemotherapy, and between elderly and non-elderly as the above tables demonstrate. In addition, the frequency of ≥Grade 3 hematologic toxicities in this study were less compared with that of the phase II study previously demonstrated. [4] We suggest that low dose of AMR would be one of the tools for refractory relapsed SCLC as third-line chemotherapy regardless of previous treatment with acceptable toxicity.

It is well known that AMR, as well as etoposide, is an inhibitor of DNA topoisomerase II. [15] No cross tolerance between AMR and etoposide has been reported yet. [19] In this study, all of the patients had previously received etoposide. We suggest that no cross tolerance between them was found as some clinicians described previously.

It is common that elderly patients are less in number who can receive cancer therapy when compared to non-elderly because 80% of elderly patients have complications such as chronic obstructive pulmonary disease (COPD), heart disease, cerebrovascular disease, osteoporosis and dementia. Therefore, elderly patients are considered to be in high risk range for the anti-cancer treatment. [11] Establishing an age to define elderly patients is still controversial. Previous clinical trials generally defined elderly as people who are more than seventy years, as in our study.

Siu, et al reported that age was not a risk factor in chemoradiotherapy for LD-SCLC. Although dose reduction or omission occurred more frequently in the elderly group, no significant differences were seen in the incidence of hematologic and non-hematologic toxicities, RR, OS between both elderly and non-elderly groups. Age was not considered to be a prognostic factor for SCLC by universal analysis. [20] Similar results have been reported [21],[22],[23],[24],[25],[26] and age over seventy years alone was not a risk factor for cancer. In this study, the dose of AMR was modulated depending on the medical condition, and previous adverse effects. As a result, chemotherapies were received safely with acceptable toxicities by dose reduction or omission. There was no significant difference in the frequency of hematologic or non-hematologic toxicities between both age groups. Age should not be a limiting factor for cancer treatment. We have to practice evidence-based individualized medicine.

Our study has several limitations. First, this was a retrospective analysis with a very small population. Retrospective studies may be less reliable in terms of the data collected, particularly for data such as physical examination. Second, although PFS and OS of 2 nd and 3 rd -line therapy patients were apparently similar, there might be an obscure but definite difference attributable to selection bias between the 2 nd -line and 3rd-line patients. Thus, a prospective study will be necessary and more cases are expected to be analyzed.

In conclusion, the standard therapy for elderly patients with SCLC is not yet established. AMR monotherapy could be one of the effective tools for elderly patients with refractory relapsed SCLC as second or third-line chemotherapy. We suggest that the recommended dose of AMR for elderly patients with refractory relapsed SCLC as third-line chemotherapy would be 30 mg/m 2 for three consecutive days. Further studies, especially prospective ones, are necessary.


 > Acknowledgement Top


We are grateful for the diligent and thorough critical reading of our manuscript by Mr. John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Mr. Matthew Larew, Administrative Intern at Kameda Medical Center (Japan).

 
 > References Top

1.Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, 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.  Back to cited text no. 1
[PUBMED]    
2.Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85-91.  Back to cited text no. 2
[PUBMED]    
3.El Maalouf G, Rodier JM, Faivre S, Raymond E. Could we expect to improve survival in small cell lung cancer. Lung Cancer 2007;57(suppl 2):S30-4.  Back to cited text no. 3
[PUBMED]    
4.von Pawel J, Ardizzoni A, Thatcher N. The relationship between treatment-free interval (TFI) and outcomes to therapy in patients with relapsed small cell lung cancer (SCLC): A review of 631 patients treated with iv topotecan in 6 studies. Lung Cancer 2003;41(S2):S235.  Back to cited text no. 4
    
5.Johnson DH. Small cell lung cancer in the elderly patient. Semin Oncol 1997;24:484-91.  Back to cited text no. 5
[PUBMED]    
6.Igawa S, Yamamoto N, Ueda S, Ono A, Nakamura Y, Tsuya A, et al. Evaluation of the Recommended Dose and Efficacy of Amrubicin as Second-and Third-Line Chemotherapy for Small Cell Lung Cancer. J Thorac Oncol 2007;2:741-4.  Back to cited text no. 6
[PUBMED]    
7.Park S, Ahn MJ, Ahn JS, Lee J, Hong YS, Park BB, et al. Combination chemotherapy with paclitaxel and ifosfamide as the third-line regimen in patients with heavily pretreated small cell lung cancer. Lung Cancer 2007;58:116-22.   Back to cited text no. 7
[PUBMED]    
8.von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan vscyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658-67.  Back to cited text no. 8
[PUBMED]    
9.Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, 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.  Back to cited text no. 9
[PUBMED]    
10.Onoda S, Masuda N, Seto T, Eguchi K, Takiguchi Y, Isobe H, et al. Phase II trial of amrubicin in patients with previously or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 2006;24:5448-53.  Back to cited text no. 10
[PUBMED]    
11.Ohe Y, Nakagawa K, Fujiwara Y, Sasaki Y, Minato K, Bungo M, et al. In vitro evaluation of the new anticancer agents KT6149, MX-2, SM5887, menogaril, and liblomycin using cisplatin- or adriamycin-resistant human cancer cell lines. Cancer Coooperative Group. Eur J Cancer 1989;49:4098-102.  Back to cited text no. 11
[PUBMED]    
12.Hanada M, Mizuno S, Fukushima A, Sasaki Y, Minato K, Bungo M, et al. A new anticancer agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn J Cancer Res 1998;89:1229-38.  Back to cited text no. 12
    
13.Noda T, Watanabe T, Kohda A, Hosokawa S, Suzuki T. Chronic effects of a novel synthetic anthracycline derivative (SM-5887) on normal heart and doxorubicin-induced cardiomyopathy in beagle dogs. Invest New Drugs 1998;16:121-8.  Back to cited text no. 13
[PUBMED]    
14.Noguchi T, Ichii S, Morisada S, Yamaoka T, Yanagi Y. In vivo efficacy and tumorselective metabolism of amrubicin to its active metabolite. Jpn J Cancer Res 1998;89:1055-60.  Back to cited text no. 14
[PUBMED]    
15.Noguchi T, Ichii S, Morisada S, Yamaoka T, Yanagi Y. Tumor-selective distribution of an active metabolite of the 9-aminoanthracycline amrubicin. Jpn J Cancer Res 1998;89:1061-6.  Back to cited text no. 15
[PUBMED]    
16.Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T, Yanagi Y. Uptake and intracellular distribution of amrubicin, a novel 9-amino-anthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells. Jpn J Cancer Res 1990;90:685-90.  Back to cited text no. 16
    
17.Obana N, Imagawa S, Nakano Y, Yamamoto M, Noguchi T, Nagasawa T. Hematological aspects of a novel 9-amonanthracycline, amrubicin. Cancer Sci 2003;94:1104-6.  Back to cited text no. 17
    
18.Hasegawa Y, Takeda K, Kashii T, Kawano Y, Katayama H, Sumitani M, et al. Clinical Experiences of Amrubicin Hydrochloride Monotherapy in Previous Treated Patients With Small-Cell Lung Cancer. Jpn J Lung Cancer 2005;45:811-5.  Back to cited text no. 18
    
19.Shimokawa T, Shibuya M, Kitamura K, Hosomi Y, Hibino S, Ota T, et al. Retrospective analysis of efficacy and safety of amrubicin in refractory and relapsed small-cell lung cancer. Int J Clin Oncol 2009;14:63-9.  Back to cited text no. 19
[PUBMED]    
20.Siu LL, Shepherd FA, Murray N, Feld R, Pater J, Zee B. Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 1996;14:821-8.  Back to cited text no. 20
[PUBMED]    
21.Spiegelman D, Maurer H, Ware JH, Perry MC, Chahinian AP, Comis R, et al. Prognostic factors in small-cell carcinoma of the lung. J Clin Oncol 1989;7:344-54.  Back to cited text no. 21
    
22.Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcomes in small-cell lung cancer. An analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563-74.  Back to cited text no. 22
[PUBMED]    
23.Gronowitz JS, Bergstrom R, Nou E, Påhlman S, Brodin O, Nilsson S, et al. Clinical and serologic markers of stage and prognosis in small cell lung cancer - A multivariate analysis. Cancer 1990;66:722-32.  Back to cited text no. 23
    
24.Osterlind K, Hansen HH, Hansen M, Dombernowsky P, Andersen PK. Long-term disease-free survival in small-cell carcinoma of the lung: A study of clinical determinants. J Clin Oncol 1986;4:1307-13.  Back to cited text no. 24
[PUBMED]    
25.Sagman U, Maki E, Evans WK, Warr D, Shepherd FA, Sculier JP, et al. Small-cell carcinoma of the lung: Derivaton of a prognostic staging system. J Clin Oncol 1991;9:1639-49.  Back to cited text no. 25
[PUBMED]    
26.Wolf M, Holle R, Hans K, Drings P, Havemann K. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): The role of sex as a predictor for survival. Br J Cancer 1991;63:986-92.  Back to cited text no. 26
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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