Carboplatin in combination with etoposide for advanced small cell lung cancer complicated with idiopathic interstitial pneumonia: a single-arm phase II study

Abstract

Background

Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP.

Methods

Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21–28 days at a dose of area under the curve 4–6 on day 1 and etoposide at a dose of 80–100 mg/m² on days 1–3.

Results

Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0–9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5–85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7–6.8) months and 14.0 (95% CI: 7.6–27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41–76).

Conclusions

The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP.

Introduction

Small cell lung cancer (SCLC) is characterized by rapid progression and poor prognosis compared with non-small cell lung cancer (NSCLC). At the time of diagnosis, the majority of patients with SCLC have advanced disease. Thus, systemic chemotherapy is currently the standard of care for such patients. In 2020, the Japanese Ministry of Health, Labour and Welfare (JMHLW) approved the use of immune checkpoint inhibitors (ICI), namely anti-programed death ligand 1 (PD-L1) antibodies, in combination with carboplatin (CBDCA) and etoposide (ETP) for the treatment of SCLC. However, it has been reported that treatment with these agents induces interstitial lung disease (ILD) [1, 2]. Idiopathic interstitial pneumonia (IIP) is a common complication in patients with lung cancer [3]. Importantly, acute exacerbations (AEx) of IIP are the most serious side effects of chemotherapy among patients with lung cancer and IIP [4,5,6]. The safety and efficacy of ICI as a second-line treatment for NSCLC complicated with interstitial pneumonia (IP) has been evaluated in previous studies. The treatment resulted in early termination of the study due to a high incidence of AEx of IP [7, 8]. By focusing on a specific type of IP and severity, Fujimoto et al. reported tolerability and efficacy of ICI in a population of patients which did not include cases of honeycomb lung [9, 10]. Thus far, few studies have investigated the use of combination immunotherapy against SCLC complicated with IP. Therefore, the administration of ICI to patients with lung cancer complicated with IIP remains controversial. Nevertheless, in a previous phase II single-arm study, we reported that the combination of CBDCA with paclitaxel with/without bevacizumab was well tolerated in patients with NSCLC complicated with IIP [11, 12].

We have also conducted a feasibility study of carboplatin plus etoposide (CE) therapy for chemotherapy-naïve patients (N = 17) with advanced SCLC complicated with IIP who were ineligible for curative radiotherapy [13]. CE therapy was associated with an overall response rate of 88.2%; moreover, two AEx of IIP were observed. Currently, there is a lack of studies investigating the optimal treatment for SCLC complicated with IIP. Therefore, we conducted a single-arm phase II study to confirm the safety and efficacy of CE for patients with advanced SCLC complicated with IIP.

Patients and methods

Study design

This phase II study was performed at Nippon Medical School Hospital (Tokyo, Japan). Chemotherapy-naive patients with advanced SCLC complicated with IIP who met all the following inclusion criteria were enrolled: pathologically confirmed SCLC; clinical stage IIIA, IIIB, IV and postoperative recurrence who are ineligible for curative radiotherapy; stable IP confirmed through high-resolution computed tomography (HRCT); chemotherapy naïve; Eastern Cooperative Oncology Group performance status 0–2 and estimated life expectancy > 3 months; measurable lesions; and adequate bone marrow, hepatic, and renal functions as follows; WBC > 4000/mm3 or neutrophil > 2000/mm3, Hb > 9.0 g/dl, Plt > 100,000/mm3, Serum Bil < 1.5 mg/dl, AST, ALT < 100 U/L, Cre < 1.5 mg/dl, and PaO₂ > 60 mmHg or SpO₂ > 90%. The exclusion criteria were: presence of acute or sub-acute exacerbation of IP; presence of apparent collagen vascular disease; presence of unstable cardiovascular disease; presence of pleural effusion requiring drainage; and cases judged ineligible by the investigator. Here, stable IP is defined as that which has no acute or sub-acute exacerbation of IP judged by attending investigator. All enrolled patients provided written informed consent.

Diagnostic classification of IIP was performed according to the Guideline of Diagnosis and Treatment for Idiopathic Interstitial Pneumonia published by the JMHLW in 2004. Thus, we classified clinical IIP types into usual interstitial pneumonia (UIP) pattern and non-UIP pattern. The diagnosis of IPF was reached according to the American Thoracic Society/European Respiratory Society criteria, as previously described [13, 14]. In the absence of histological diagnosis, at least two board-certified pulmonologists reviewed the HRCT scan of the lungs. The UIP pattern typically includes basal predominant, subpleural reticular abnormality with traction bronchiectasis, honeycomb cyst, and absence of atypical features of IPF, such as peribronchovascular nodules, isolated cysts, or consolidation. The non-UIP pattern was characterized by the presence of basal predominant, non-specific pulmonary fibrosis and/or ground glass opacities, and other infiltrative shadows inconsistent with the UIP pattern, as previously described [11]. AEx of IIP was defined by the following criteria: exacerbation of dyspnea within 1 month; newly developed diffuse pulmonary opacities on chest CT and/or chest X-ray; decrease in arterial oxygen tension by > 10 mmHg under similar conditions; and absence of heart failure or lung infections [11].

Study treatment

Patients received CBDCA and ETP intravenously. CBDCA (area under the curve: 4–6) on day 1 and ETP (80–100 mg/m²) on days 1–3 every 3 or 4 weeks. Dosage selection was at the discretion of the attending investigators. Four to six cycles of treatment were administered, as deemed necessary by the investigators. Treatment was discontinued in the presence of following events: disease progression; development of unacceptable adverse events; patient refusal to receive further treatment; and decision by the investigator to terminate treatment. There was no plan for prophylactic use of granulocyte colony-stimulating factor (G-CSF); however, use of G-CSF after first-line treatment was allowed, depending on the decision of the investigator.

Statistical considerations

The primary endpoint of this study was safety, namely the rate of AEx of IIP related to CE. A few retrospective studies have investigated the risk of AEx caused by chemotherapies, reporting a rate of approximately 13–30% [15]. Based on these results, we set thresholds for incidence and expected incidence to 30% and 10%, respectively. Under the conditions of two-sided α = 0.05 and β = 0.2, it was calculated that 33 cases would be required. Considering the dropout rate, the estimated sample size was 35 cases. Patients diagnosed with collagen vascular disease-associated IP after enrollment were excluded from the analysis. The evaluation was conducted in compliance with the National Cancer Institute Common Toxicity Criteria Version 3.0 for safety, and the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines for antitumor activity. Based on previous findings [4], AEx occurring within 10 weeks following treatment termination was considered to be related to chemotherapy.

Results

Patient characteristics

Thirty-one patients were enrolled between December 2009 and December 2022. At the time of interim analysis, we did not observe AEx of IIP in this population. Therefore, we decided to terminate patient recruitment at this point. As shown in Table 1, 29 male and two female patients were enrolled. The median age was 72 years (range: 58–82 years). The Eastern Cooperative Oncology Group performance status was 0 and 1 for 12 and 19 patients, respectively. The majority of patients had Stage IV disease; five and eight patients had Stages IIIA and IIIB disease. One patient had experienced postoperative recurrence. Eleven and 20 patients showed UIP and non-UIP pattern, respectively, on HRCT. No patients developed lymphangitis carcinomatosa. All patients reported a smoking habit; 21 patients were current smokers at the time of diagnosis.

Table 1 Patient characteristics

Table 2 lists data obtained through pre-treatment laboratory tests and physical examinations. Test results were positive for C-reactive protein, lactate dehydrogenase, Krebs von den Lungen-6, and surfactant protein-D in the majority of patients. Vital capacity was relatively preserved at 91% and forced expiratory volume in 1 s (FEV1) was mildly reduced to 75.8%; 28% and 24% of patients showed reduced lung function, respectively. The percentage of diffusing capacity for carbon monoxide (%DLco) was decreased to 72%, and 68% of patients demonstrated reduced %DLCO. The median SpO₂ was 97%. Five patients were positive for anti-nuclear antibodies. Nevertheless, these patients did not have subjective symptoms of collagen vascular disease and did not meet the diagnostic criteria for collagen vascular disease.

Table 2 Pre-treatment laboratory data and physical examinations

Incidence of AEx of IIP

The primary endpoint was the incidence of AEx of IIP. There was no AEx observed in those 31 patients. The expected incidence rate was set at 10%. When calculating the probability of never experiencing an event, the p-value was 0.038. Following the period of study treatment, eventually four patients developed AEx of IIP; three of those cases were related to second or late line chemotherapy. All patients received corticosteroid therapy, and there was no occurrence of death from treatment related AEx of IIP.

Treatment efficacy

The objective response is shown in Table 3. A median of four cycles of treatment were delivered, and 27 patients received four to six cycles of CE therapy. Complete and partial responses were observed in 26 patients, and the objective response rate was 83.9% (95% confidence interval [CI]: 82.5–85.2). Three patients experienced progressive disease. One patient developed febrile neutropenia (FN) after administration of the first cycle, which led to death 3 weeks later. The median progression-free survival was 5.9 months (95% CI: 4.7–6.8) and the median overall survival was 14.0 months (95% CI: 7.6–27.6) (Fig. 1). The 1-year survival rate was 61% (95% CI 41–76).

Table 3 Objective response

Fig. 1

A Progression-free survival (PFS) and B Overall survival (OS). Vertical bas indicate censored cases at the cutoff point. The median PFS, median survival time, and 1-year survival rate were 5.9 months, 14.0 months, and 61%, respectively

Adverse events

Table 4 lists treatment-related toxicities; Common Toxicity Criteria-AE grades ≥ 2 and ≥ 1 hematological and non-hematological adverse events were observed. Grades 3–4 neutropenia was observed in 23 patients (74.2%). Five patients (16.1%) developed FN, leading to death in one case (3.2%). Five patients (16.1%) developed grades 3–4 thrombocytopenia. One patient (3.2%) had grade 4 hyponatremia; this might have been a symptom of syndrome of inappropriate antidiuretic hormone secretion due to SCLC. Regarding non-hematological adverse events, two patients (6.5%) developed grade 2 pneumonitis during the study treatment period, however these patients did not fulfill the definition of AEx of IIP. Except for these cases, severe non-hematological adverse events were not observed. However, low-grade constipation, diarrhea, anorexia, fatigue, and hiccoughs were recorded.

Table 4 Treatment related adverse events

Four patients (12.9%) terminated protocol treatment due to severe adverse events, poor performance status, and progressive disease. Dose reduction was required in 14 patients (45.2%) due to the occurrence of adverse events. However, most non-hematological adverse events were of low grade and well tolerated.

Second-line treatment

Fourteen of the 31 patients received second-line treatment. The regimen included CE rechallenge (n = 6), CBDCA plus paclitaxel (n = 7), and CBDCA, paclitaxel, and bevacizumab (n = 1); four, four, and one patients achieved response (partial or complete response), respectively. Most patients who received CE had sensitive relapse: progression was observed after > 3 months since the last administration; and those who received CBDCA plus paclitaxel had refractory relapse: tumor progression was observed within 3 months after the last administration of CE. Four patients developed AEx of IIP after the study observation period; three of those cases were considered related to chemotherapy. Two patients received CBDCA plus paclitaxel, and one patient received CBDCA plus paclitaxel and bevacizumab. All patients received corticosteroids, and there were no deaths directly linked to AEx of IIP.

Discussion

This is the first prospective phase II study investigating the safety and efficacy of a specific cytotoxic chemotherapy regimen for the treatment of patients with SCLC complicated with IIP. The benefit of cytotoxic chemotherapy is greater for SCLC than NSCLC. Thus, the present results strongly support that patients with SCLC complicated with IIP should receive CE therapy as a first-line treatment.

AEx of IIP was not observed during the study period, indicating that the rate of AEx with CE is < 10%. Nonetheless, four patients (13%) eventually developed AEx related or not related to second or late line chemotherapy (three and one patients, respectively). As previously reported, 7.6% of patients with IIP without cancer develop AEx of IIP within 1-year of follow-up [16]. The rate of AEx was slightly higher in our study population. However, considering the progression-free survival of 5.9 months and overall survival of 14 months, there is a great benefit for patients with advanced stage SCLC complicated with IIP. These results were consistent with those of recent international phase III studies [17, 18], as well as the findings of the Japan Clinical Oncology Group 9511 trial of cisplatin plus ETP [19].

Hematological toxicities were observed which is similar to recent studies. Five patients developed FN. Among 5 patients, 1 received CBDCA AUC 6 and 100 mg/m2 of etoposide, 3 received AUC 5 and 100 mg/m2, and 1 received AUC5 and 80 mg/m2, respectively. The patient who developed grade 5 FN received AUC 5 and 100 mg/m2. These adverse events are considered tolerable but should be noted.

One patient developed diffuse ground-glass attenuation with severe respiratory failure after second line chemotherapy. Although we initially suspected AEx of IIP, the final diagnosis was pneumocystis pneumonia with high levels of β-D-glucan in serum.

We have previously reported that one patient out of 17 developed AEx associated with CE therapy, however no patients developed AEx in this study, with similar response and adverse events [13]. In the previous study, dosage of carboplatin and etoposide were fixed to AUC 6 and 100 mg, respectively. This indicates that adjusting dosage and schedule according to each patient by attending investigator was crucial.

Platinum plus ETP therapy has been a standard treatment for patients with advanced stage SCLC for a long period of time. Following approval by the JMHLW in 2018, the standard of care shifted to platinum plus ETP in combination with PD-L1 blockade agents. Nevertheless, the treatment of patients complicated with IIP using ICI is challenging. The present results encourage the use of CE as first-line treatment for such patients.

This study has several limitations. Firstly, this was a single-arm, single-institution study involving a limited number of patients. The diagnosis of IIP mostly depended on HRCT without histopathological examination. Since patients with SCLC complicated with IIP tended to develop severe symptoms at the time of diagnosis, the number of patients who met the inclusion criteria of this study was low; therefore, the recruitment period was prolonged. Moreover, the safety and efficacy of CE in patients with SCLC complicated with IIP who were not eligible for inclusion in this study remain unclear. In the past decade, supportive care for chemotherapy (e.g., antiemetic agents, G-CSF, ghrelin receptor agonists, etc.) has rapidly evolved. Enrolment of the first and last patients in this study was conducted in 2009 and 2022, respectively. These facts may have affected the safety and efficacy of this treatment regimen.

In conclusion, CE therapy used in this prospective phase II study was as safe and effective in patients with advanced SCLC complicated with IIP. Hence, CE may be the optimal regimen for first-line treatment in this population.