Irinotecan monotherapy as third- or further-line treatment for patients with small cell lung cancer
Zenta Seto1, Naoki Takata1, Nozomu Murayama1, Kotaro Tokui1, Seisuke Okazawa1, Kenta Kambara1, Shingo Imanishi1, Toshiro Miwa1, Ryuji Hayashi2 , Shoko Matsui1 and Minehiko Inomata1
Abstract
1–6
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Background: Small cell lung cancer (SCLC) is a very aggressive cancer and recurrence is inevitable. Treatment of recurrent disease is important for improving the prognosis of patients with SCLC.
Methods: We conducted a retrospective observational study to investigate the efficacy and safety of irinotecan monotherapy as third- or further-line treatment in patients with SCLC.
Results: Data of 15 patients who had received irinotecan monotherapy as third- or further-line treatment between 2004 and 2019 were analyzed. The median progression-free survival duration (95% confidence interval) from the initiation of treatment with irinotecan was 2.7 (1.4–3.8) months, and the median overall survival duration (95% confidence interval) from the initiation of irinotecan treatment was 10.0 (3.9–12.9) months. Partial response, stable disease or non–complete response/non–progressive disease, and progressive disease were observed in 1, 6, and 8 patients, respectively. Adverse events ⩾ grade 3 in severity were observed in 2/2 (100%) patients who were homozygous for UGT1A1 mutation, 2/3 (66.7%) patients who were heterozygous for UGT1A1 mutation, 4/6 (66.7%) patients who had wild-type UGT1A1, and 2/4 (50.0%) patients in whom the UGT1A1 mutation status was unknown.
Conclusion: Our results suggest that irinotecan monotherapy can be a useful alternative treatment option in the third- line setting for patients with SCLC.
Keywords
Irinotecan, small cell lung cancer, third-line treatment
Date received: 21 March 2020; revised: 17 September 2020; accepted: 28 October 2020
Introduction
Small cell lung cancer (SCLC) is a highly aggressive can- cer, and despite its high sensitivity to first-line chemother- apy, recurrence is inevitable, especially in extensive disease.1,2 It is important to establish effective chemother- apy for recurrent disease to improve prognosis.
CAV therapy (cyclophosphamide, doxorubicin, and vin- cristine) was demonstrated to have modest activity following failure of platinum-based chemotherapy.3 Topotecan and amrubicin are the most studied agents for the treatment of recurrent SCLC. Topotecan was demonstrated to be associ- ated with survival benefit compared to supportive care4 and as effective as CAV therapy.5 In a phase III study conducted to
compare amrubicin and topotecan, almost equivalent overall survival (OS) was obtained in both the treatment arms.6
About 20% to 30% of patients with SCLC become can- didates for third-line treatment,7–10 and there is insufficient
1First Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
2Department of Medical Oncology, Toyama University Hospital, Toyama, Japan
Corresponding author:
Minehiko Inomata, MD, PhD, First Department of Internal Medicine, Toyama University Hospital, Sugitani 2630, Toyama City, Toyama, 930-0194, Japan.
Email: [email protected]
evidence for third-line treatment of SCLC. Previous stud- ies have reported the efficacy of several cytotoxic agents in the third-line setting, including of paclitaxel,11,12 ifosfa- mide,12 amrubicin,13 and albumin-bound paclitaxel.14 Immune checkpoint inhibitors including nivolumab15 and pembrolizumab16 were demonstrated to show durable response in a subset of patients with SCLC.
Irinotecan, an inhibitor of DNA topoisomerase I, has been reported as a potentially active agent for patients with recurrent SCLC. A previous phase II trial and other obser- vational studies of irinotecan have reported a median pro- gression-free survival duration (PFS) of 2–4 months and an OS duration of 4–6 months in patients with recurrent SCLC17–19 treated with irinotecan in the second-line set- ting. Zhao et al.20 compared the efficiency of second-line chemotherapy and reported that patients treated with CPT- 11 achieved good median PFS and OS.20 Furthermore, a phase 2 study showed promising efficacy of a combination therapy of irinotecan and carfilzomib, a proteasome inhibi- tor, in patients with SCLC who progressed after 1 plati- num-based chemotherapy.21
There have been no studies conducted to evaluate the efficacy and safety of irinotecan in patients who develop resistance to treatment with amrubicin or topotecan. Therefore, we retrospectively evaluated the therapeutic outcomes of patients with SCLC treated with irinotecan, in order to investigate the efficacy of irinotecan as third- or further-line treatment for patients with SCLC showing resistance to treatment with amrubicin and/or topotecan.
Patients and Methods
Patient selection
The medical records of patients with SCLC were reviewed and the data were retrospectively analyzed. The inclusion criteria were as follows: 1) cytologically or histologically confirmed SCLC; 2) irinotecan monotherapy as third- or further-line treatment between 2004 and 2019 after patients became resistant to treatment with platinum-based chemo- therapy, amrubicin, and/or topotecan.
The study was conducted with the approval of the ethics committee of the University of Toyama (approval R2019034), and information about the study was disclosed prior to the enrollment of patients, according to the Ethical Guidelines for Medical and Health Research Involving Human Subjects, Ministry of Health, Labour and Welfare, Japan.
Clinical information
The following patient data were obtained from the medical records: age, sex, Performance Status (PS), body mass index (BMI), serum lactate dehydrogenase (LDH) level at the initiation of irinotecan monotherapy, treatment history, UGT1A1 polymorphism genotype, and adverse events.
The disease stage at diagnosis was classified as limited disease or extensive disease. The type of recurrence after the first-line treatment was classified as sensitive relapse or refractory relapse, depending on whether it occurred within 3 months or later than 3 months after the last day of administration of first-line treatment. Tumor response was determined according to the Response Evaluation Criteria in Solid Tumors, version 1.1, based on computed tomogra- phy findings.
Statistical analysis
Survival curves were drawn using the Kaplan-Meier method to analyze PFS and OS. PFS was calculated as the time from the initiation of treatment with irinotecan to the date of death or detection of PD, and censored on the date of the last visit of the patients before they were confirmed to have progressive disease. OS was calculated from the initiation of treatment with irinotecan to the date of death and censored on the date of the last visit of the patients before they died. Statistical analysis was performed using the JMP 14.2.0 statistical software package (SAS Institute, Cary, NC).
Results
A total of 15 patients with SCLC received irinotecan mon- otherapy between 2004 and 2019. Irinotecan was adminis- tered at the dose of 100 mg/m2 on day 1, day 8, and day 15 of every 4-week cycle; the attending physician adjusted the treatment dose and schedule according to his or her clinical judgment.
Table 1 shows patient characteristics. All the patients were men and the median age was 68 years. Nine (60%) had limited disease at initial diagnosis. Twelve (80%) patients had a PS of 0–1 at the initiation of treatment with irinotecan. Ten (66.7%) patients had received irinotecan monotherapy as third-line treatment and 5 (33.3%) patients had received the drug as fourth- or further-line treatment.
Table 2 shows treatment history of the 15 patients. Seven patients (46.7%) were treated with chemoradiother- apy as first-line treatment. Median (range) PFS from the first-line treatment in patients treated with chemoradio- therapy and chemotherapy was 7.6 (6.1–30.2) months and 5.9 (4.3–7.1) months, respectively.
Figure 1 shows Kaplan-Meier curves for PFS and OS. The median (95% confidence interval [CI]) PFS and OS from the initiation of treatment with irinotecan monother- apy was 2.7 (1.4–3.8) months and 10.0 (3.9–12.9) months, respectively. The PFS rate at 3 and 6 months was 46.7% and 6.7%, respectively. The OS rate at 6 and 12 months was 66.7% and 37.0%, respectively. Partial response, sta- ble disease or non–complete response/non–progressive disease, and progressive disease were observed in 1, 6, and 8 patients, respectively.
Table 3 shows adverse events. Adverse events were observed in all patients; adverse events ⩾ grade 3 in sever- ity were observed in 10 of the 15 (66.7%) patients. The most common adverse events were diarrhea and leukopenia. UGT1A1 gene polymorphism was evaluated in 11 (73.3%) patients. Homozygosity and heterozygosity for UGT1A1 mutation were detected in 2 and 3 patients, respectively. Adverse events ⩾ grade 3 in severity were observed in 2/2
(100%) patients who were homozygous for UGT1A1 muta- tion, 2/3 (66.7%) patients who were heterozygous for UGT1A1 mutation, 4/6 (66.7%) patients who had wild-type UGT1A1, and 2/4 (50.0%) patients in whom the UGT1A1 mutation status was unknown (P = 0.880, Fisher exact test). One of the patients who was homozygous for UGT1A1 mutation experienced grade 3 anorexia and grade 4 leukope- nia and neutropenia, and the other patient experienced grade 3 diarrhea, grade 4 anorexia, grade 3 leukopenia, grade 3 neutropenia, and grade 3 anemia (Table 4).
Table 1. Patient characteristics (n = 15).
Characteristics Values
Discussion
Age, ya M/F Stageb
LD
ED
Type of relapse Sensitive Refractory
PS
0–1 ⩾2
LDH, IU/L BMI
PFS (prior treatment), mo
<3 ⩾3
Treatment line
3rd ⩾4th
68 (53–76) 15 (100)/0
9 (60.0)
6(40.0) 8 (53.3)
7(46.7) 12 (80.0)
3 (20.0)
267 (140–711) 23.5 (14.6–33.8)
6 (40.0)
9(60.0)
10(66.7) 5 (33.3)
The median PFS (95% CI) of our patients who received irinotecan monotherapy was 2.7 (1.4 to 3.8) months, which appeared to be consistent with the reported PFS in patients with SCLC who received third-line treatment with other cytotoxic agents.11–14 The median OS in the patients treated with irinotecan was 10 months, longer as compared with previous reports.
Meta-analysis demonstrated that survival in patients with SCLC was better in Asian cohorts.22 Prognosis in Asian patients with SCLC might be relatively favorable. In addition, it is possible that patients with indolent tumors were eventually included in the study as good candidates for third-line treatment. BMI,8,23 plasma LDH level,8,24 and PFS or time to treatment failure after the previous regi- men8,9 have been reported as factors influencing the prog- nosis in patients with SCLC receiving third-line treatment. Although some patients had elevated serum LDH levels, the median age was relatively low, and a substantial num- ber of patients had a favorable PS and longer PFS after the previous treatment. Furthermore, the majority of patients
BMI: body mass index; ED: extensive disease; LD: limited disease; LDH: serum lactate dehydrogenase; PFS: progression-free survival; PS: Performance Status.
Values are median (range) or n (%).
aAt the initiation of treatment with irinotecan. bDisease stage at the initial diagnosis.
Table 2. Treatment history of the 15 patients.
were diagnosed with limited disease. Out of these 9 patients, 7 patients were treated with chemoradiotherapy and the PFS after the chemoradiotherapy was good. It is possible that these might have affected the good OS from the initiation of treatment with irinotecan.
1st line 2nd line CDDP+VP-16+RT 6
CBDCA+VP-16+RT 1
CDDP+VP-16 1 1
3rd line 4th line 5th line 6th line
CBDCA+VP-16 6 2
CDDP+CPT-11 1
AMR 12
3
2 2
CPT-11 10 4 1
TOP 2 7 2
nab-PTX 1 2
CBDCA+PTX 3 1
Total 15 15 15 12 10 3
AMR: amrubicin; CBDCA: carboplatin; CDDP: cisplatin; CPT-11: irinotecan; nab-PTX: nanoparticle albumin-bound paclitaxel; TOP: topotecan; RT: radiotherapy; VP-16: etoposide.
Figure 1. Progression-free survival (PFS) and overall survival (OS) from the initiation of treatment with irinotecan monotherapy. CI: confidence interval.
Table 3. Adverse events observed during treatment with irinotecan, n (%).
All grades ⩾ Grade 3
Diarrhea 11 (73.3) 2 (13.3)
Colitis 2 (13.3) 0
Constipation 2 (13.3) 0
Nausea 4 (26.7) 0
Anorexia 9 (60.0) 2 (13.3)
Dysgeusia 3 (20.0) 0
Fatigue 5 (33.3) 0
Hyponatremia 10 (66.7) 2 (13.3)
Hyperkalemia 5 (33.3) 0
Hypokalemia 2 (13.3) 0
Hypocalcemia 1 (6.7) 0
AST 4 (26.7) 0
ALT 5 (33.3) 0
γGTP 2 (13.3) 0
Leukopenia 11 (73.3) 6 (40.0)
Neutropenia 10 (66.7) 5 (33.3)
Anemia 10 (66.7) 3 (20.0)
Thrombocytopenia 9 (60.0) 0
ALT: serum alanine aminotransferase; AST: serum aspartate aminotransferase; γGTP: gamma-glutamyl transpeptidase.
Table 4. Adverse events ⩾ grade 3 in severity observed during treatment with irinotecan, classified according to the UGT1A1 polymorphism, n (%).
Homozygous Heterozygous Wild-type Unknown
Patients 2 3 6 4
Diarrhea 1 (50.0) 1 (33.3) 0 0
Anorexia 2 (100) 0 0 0
Hyponatremia 0 0 2 (33.3) 0
Leukopenia 2 (100) 1 (33.3) 1 (16.7) 2 (50.0)
Neutropenia 2 (100) 1 (33.3) 2 (33.3) 0
Anemia 1 (50.0) 1 (33.3) 1 (16.7) 0
Adverse events ⩾ grade 3 in severity were observed in 10 (66.7%) patients. While a meta-analysis reported the existence of a relationship between irinotecan toxicity and polymorphism of UGT1A1, the gene that encodes an enzyme that glucuronidates SN-38 (irinotecan),25 previous studies in patients with lung cancer have yielded inconsist- ent results.26–29 Because the dose of irinotecan differed among the studies, it is speculated that the relationship between irinotecan toxicity and UGT1A1 polymorphism may vary depending on the dose of irinotecan in patients with lung cancer. In the present study, although no statisti- cally significant relationship between UGT1A1 polymor- phism and adverse events was observed, both the patients who were homozygous for UGT1A1 mutation experienced severe adverse events such as anorexia or diarrhea. However, we could not arrive at any definitive conclusion because of the small sample size.
The most important limitation of the present study was the small sample size, which can potentially interfere with the results of the statistical analysis. In addition, a selec- tion bias was inevitable, since this was a retrospective study involving a single arm. It is difficult to rule out the possibility that the OS of 10 months could have resulted from patient selection bias, and we cannot definitively conclude that irinotecan monotherapy generally prolongs the survival in patients with SCLC showing disease pro- gression after second-line treatment.
In conclusion, the present study suggested that irinote- can monotherapy as third-line treatment yielded compara- ble treatment efficacy to previously reported efficacy of other cytotoxic agents as third-line treatment in patients with SCLC. Thus, irinotecan monotherapy can be a useful alternative treatment option for third-line chemotherapy in patients with SCLC.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs
Ryuji Hayashi https://orcid.org/0000-0002-4205-9540
Minehiko Inomata https://orcid.org/0000-0002-6846-187X
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