Nab-paclitaxel Monotherapy for Relapsed Small Cell Lung Cancer: Retrospective Analysis and Review
Abstract. Background/Aim: The utility of nanoparticle albumin-bound paclitaxel (nab-PTX) monotherapy in patients with relapsed small-cell lung cancer (SCLC) has not been fully evaluated. We aimed to investigate the efficacy and safety of nab-PTX monotherapy in relapsed SCLC patients, including heavily treated patients. Patients and Methods: We retrospectively analysed data from 17 patients with relapsed SCLC who were treated with weekly nab-PTX monotherapy at our hospital. We also reviewed past studies on nab-PTX monotherapy for relapsed SCLC. Results: The response rate, progression-free survival, and overall survival were 29.4%, 48 days (95%CI=33-89), and 134 days (95%CI=64-223), respectively. The most common adverse event of grade ≥3 was leukopenia (17.6%), followed by neutropenia, neuropathy, fatigue, and infections. Our results were consistent with previous studies. Conclusion: The efficacy of nab-PTX monotherapy for heavily treated relapsed SCLC patients might be moderate. Further studies to improve outcomes are warranted.
Small-cell lung cancer (SCLC) is one of the most aggressively growing cancers, and comprises approximately 15% of all lung cancer cases (1). Since SCLC is associated with high chemosensitivity, systemic chemotherapy is the main treatment for SCLC patients. However, most SCLC patients experience disease progression on or after the initial treatment and develop refractory disease (2, 3). Although past studies have shown the efficacy of topotecan and amrubicin monotherapy in the second-line setting, other treatment options have not been established (2-5). Several agents, such as irinotecan, paclitaxel (PTX), docetaxel, vinorelbine, nivolumab, and gemcitabine have been investigated as salvage therapies for relapsed SCLC (5-7). Particularly, PTX is one of the most frequently used agents as a salvage therapy for heavily treated relapsed SCLC patients in clinical practice in Japan.
Key Words: Small-cell lung cancer, relapsed, refractory, nab- paclitaxel, monotherapy.
Nanoparticle albumin-bound (nab)-PTX is a relatively novel cytotoxic anticancer drug developed to improve the therapeutic index of PTX and exhibits a more favourable safety profile compared to conventional solvent-based (sb)- PTX (8, 9). Although several reports presented nab-PTX monotherapy for SCLC (2, 3, 8, 10), the toxicity and efficacy of nab-PTX monotherapy for relapsed SCLC patients have not been fully evaluated. Therefore, we retrospectively assessed the utility of weekly nab-PTX monotherapy among relapsed SCLC patients treated at our hospital. We also reviewed past studies on nab-PTX monotherapy for relapsed SCLC.
Patients and Methods
Patients. In total, 17 patients with relapsed SCLC were treated with weekly nab-PTX monotherapy between October 2017 and September 2019 at Kainan Hospital. All patients had previously been treated with platinum-based doublet chemotherapy, had performance status (PS) 0-2 on the Eastern Cooperative Oncology Group scale, and histologically or cytologically proven SCLC. All patients had adequate bone marrow and organ function before nab- PTX therapy.
The patients were intravenously administered 75-100 mg/m2 nab- PTX each week for three consecutive weeks followed by a one-week break until radiographically confirmed disease progression, unacceptable toxicity, withdrawal, or death. The doses were decided at the discretion of the physician in charge, and subsequent doses of nab-PTX were modified based on haematological and non- haematological toxicities. Written informed consent for weekly nab- PTX monotherapy was obtained from all patients before nab-PTX treatment. Regarding this clinical study, informed consent was obtained in the form of an opt-out on the web site. This study is a retrospective observational study performed using the opt-out method of our hospital web site. Our retrospective analysis was approved by the ethics committee of Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives (No. 310624-01: approved on 24 June 2019). The data cut-off date was October 31, 2019.
Patient characteristics and response and toxicity evaluations. Patient characteristics such as age, sex, smoking status, comorbid pulmonary disease, and prior chemotherapy were retrospectively obtained from the medical records. The patients were evaluated to determine the stage, disease progression or relapse of their disease before starting treatment using chest X-ray, computed tomography (CT) of the chest and abdomen, and CT or magnetic resonance imaging (MRI) of the head. Limited disease (LD) was defined as follows: the cancer is only on one side of the chest, including the bilateral mediastinal and supraclavicular nodes, and can be treated with a single radiation field. Extensive disease (ED) was defined as the disease extending beyond LD. Sensitive relapse was defined as relapse at more than 90 days after completion of first-line chemotherapy. Refractory relapse was defined as relapse during or at less than 90 days after completion of first-line chemotherapy. Patients’ adverse events and responses were retrospectively assessed using the Common Terminology Criteria for Adverse Events (Version 5.0) and the Response Evaluation Criteria for Solid Tumors (Version 1.1).
Statistical analysis. PFS and OS rates were analysed using the Kaplan–Meier method. PFS was measured from the start of nab- PTX therapy to the date of progressive disease, death, or last follow-up. OS was defined as the time between treatment initiation and death or last follow-up. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria) (11).
Selection of past studies regarding nab-PTX monotherapy for relapsed SCLC. We conducted a computer-based literature search for studies using MEDLINE (PubMed). In addition, we performed manual searches of references from relevant articles and complementary computer-based searches using ScienceDirect and ClinicalKey. The literature search of PubMed used the following terms: (paclitaxel) AND (small cell lung cancer) AND (refractory OR relapsed). Only papers written in English were included, and case reports were excluded. The date of the last search was December 31, 2019. Studies that met the following criteria were included: study subjects were refractory or relapsed SCLC patients, and the regimen of chemotherapy was nab-PTX monotherapy. The following information was extracted to the extent possible: first author’s name, year of publication, study location, study design, number of patients, number of prior regimens, response rate (RR), progression-free survival (PFS), overall survival (OS), severe (grade 3 or 4) neuropathy, and leukopenia/neutropenia.
Results
The clinical characteristics of the patients are shown in Table I. The median age of the patients was 71 years (range=50- 82 years), and our sample included 12 men and five women. No patients had poor PS (3 or 4), and all patients had previously been treated with platinum-based chemotherapy as a first-line chemotherapy. Fourteen patients (82.4%) had been treated with two or more lines of chemotherapy before receiving nab-PTX monotherapy. Four patients exhibited LD and 13 exhibited ED at the time of diagnosis. Three patients were classified as sensitive relapse and the remaining 13 as refractory relapse. Comorbid pulmonary disease was observed in seven patients, including interstitial lung disease (ILD) in six, chronic obstructive pulmonary disease (COPD) in five, and both ILD and COPD in four. Regarding the type of ILD, three out of six patients had radiation pneumonia and/or drug-induced pneumonia.
The chemotherapy delivery and treatment outcomes of nab- PTX monotherapy are shown in Table II. The median number of nab-PTX monotherapy cycles was two (range=1-6 cycles), and the nab-PTX dose was decreased in almost half of patients (75-89 mg/m2). There were five patients with a partial response (PR) and four with stable disease (SD); response rate (RR) and disease control rate (DCR) were 29.4% and 52.9%, respectively. The median PFS and OS were 48 days [95% confidence interval (CI)=33-89 days] and 134 days (95%CI=64-223 days), respectively (Figure 1a and b).
The toxicities of nab-PTX are summarized in Table III. Major adverse events of grade ≥3 were leukopenia (17.6%), neutropenia (11.8%), neuropathy (11.8%), fatigue (11.8%), and lung infection (11.8%). Of the 17 patients, only one developed a grade 4 event (lung infection). No other grade 4 adverse haematological or non-haematological events were observed, and no death related to nab-PTX monotherapy was observed. Other haematological and non-haematological toxicities were mild and easily manageable.
A total 190 potentially relevant articles were identified using PubMed, and 147 were excluded based on title review (Figure 2). The abstracts of the remaining 43 articles were reviewed, and seven articles were retrieved for further consideration. After reviewing seven articles, four articles were selected for data extraction. In addition, two additional studies were identified in the reference list of the candidate articles and an international conference abstract. Table IV shows the previous studies on nab-PTX monotherapy for relapsed SCLC (2, 3, 8, 10, 12, 13). Five of six studies were conducted in Japan and were retrospective analyses. The number of patients who were treated with nab-PTX monotherapy in the published original articles was less than 10 except our study. Two relatively large studies were presented as only conference abstracts (12, 13). The RR, PFS, and OS were 5.6-50%, 1.6-3.2 months, and 4.0- 6.7 months, respectively. Severe neuropathy and leukopenia/neutropenia (grade 3-4) were observed in 0-11.8% and 0-33.3% patients, respectively.
Discussion
We present the results of the efficacy and safety of weekly nab-PTX monotherapy in relapsed SCLC patients. The RR, DCR, PFS, and OS in our study were 29.4%, 52.9%, 48 days (3, 6, 14-19), and we could not detect the clinical benefit of nab-PTX in peripheral neuropathy. This was perhaps because our study included two patients who had previously been treated with sb-PTX and/or 11 heavily treated patients who were treated with three or more previous regimens. Compared with sb-PTX, nab-PTX has advantages such as effective accumulation to the tumour, fewer allergies, short administration time, and glycaemic control (8, 9). Since nab- PTX is more expensive than sb-PTX, the cost-effectiveness of nab-PTX compared to that of sb-PTX should be further evaluated.
The effect of nab-PTX monotherapy for relapsed SCLC was clinically moderate, but it might be inadequate. Several studies have presented the efficacy and safety of combination therapy with carboplatin (CBDCA) and sb-PTX or nab-PTX for relapsed SCLC (2, 5, 10). Although combination with CBDCA could be more effective (ORR of 24-80%, OS of 3.3-8.7 months), the frequency of grade ≥3 leukopenia and neutropenia was higher in the combination therapy group (2, 5, 10). These adverse events are manageable, and combination with CBDCA should be recommended when the patient’s general condition is good. Recently, other combination therapies such as sb-PTX and new drugs, namely alisertib and pembrolizumab, have been reported (20, 21). As past preliminary studies suggest that prior treatment with PTX may induce programmed cell death ligand- 1 (PD-L1) expression on tumor cells, a combination therapy with immune checkpoint inhibitor (ICI) and PTX might be expected (20). In addition, nab-PTX does not require co- administration of glucocorticoids, which has a potential to attenuate immune responses and, therefore, may be beneficial for use as a chemotherapy with ICI (2).
Figure 1. Kaplan–Meier survival curves of progression-free (a) and overall (b) survival of the 17 patients treated with nab-paclitaxel monotherapy. The median progression-free survival (PFS) time was 48 days (95%CI=33-89), and the median overall survival (OS) time was 134 days (95%CI=64-223).
Amrubicin and topotecan monotherapy are standard therapies for relapsed SCLC patients. In addition, subgroup analysis of a randomized phase III trial showed that amrubicin is effective for refractory relapse SCLC patients (3, 4). However, topotecan-induced acute exacerbation (AE) occurred in 20.0-23.8% and amrubicin-induced AE occurred in 10-17.6% of SCLC patients with interstitial lung disease (ILD) (3, 22, 23). Therefore, standard chemotherapy for relapsed SCLC with ILD has not been established (3, 22). A retrospective study has suggested the PTX regimen as a treatment option for relapsed SCLC patients with ILD (22). In our analysis, six patients with ILD were treated with nab- PTX monotherapy, and one patient developed AE. Since one retrospective analysis reported that sb-PTX-induced AE occurred in 29.4% of SCLC patients with idiopathic interstitial pneumonias (3), the administration of PTX, including nab-PTX, in relapsed SCLC patients with ILD should be carefully considered.
Since nab-PTX administration schedule and/or dose setting were different in several studies, it is important to clarify the appropriate nab-PTX regimen. Furthermore, since five out of six studies on nab-PTX monotherapy for relapsed SCLC have been conducted in Japan, confirmatory studies might be required in several countries. Larger prospective trials should be conducted to reveal the clinical usability of nab-PTX monotherapy in relapsed SCLC patients. Regarding the literature review, we abstracted data from only English-based articles and fundamentally used only PubMed search results because of a lack of regular access to other databases. In addition, since two of six studies were presented as only conference abstracts, detailed information of the two studies could not be extracted. However, given the nature of studies for relapsed SCLC, we believe that our report provides several insights regarding the clinical availability of PTX in SCLC patients for oncologists and pulmonologists.
In conclusion, weekly nab-PTX monotherapy showed moderate activity with acceptable toxicities in relapsed SCLC patients. Our study results were nearly consistent with the results of past studies focusing on nab-PTX monotherapy in relapsed SCLC. However, the efficacy and benefit of nab-PTX monotherapy for heavily treated SCLC patients may be limited and inadequate. Further clinical studies, including those on combination therapy, are needed to evaluate the use of nab-PTX in relapsed SCLC patients.