Phase II Study of Consolidation Amrubicin After Concurrent Chemoradiotherapy in Patients With Limited-stage Small-cell Lung Cancer

Patients and Methods

Patient selection. Patients with histologically or cytologically confirmed LS-SCLC were eligible for the study. LS-SCLC was defined as disease confined to one hemithorax, including the ipsilateral hilar, bilateral mediastinal, and bilateral supraclavicular lymph node metastases. Pleural effusion of less than 1 cm by chest computed tomography (CT) was allowed, but patients with malignant pleural effusion were excluded. Each patient was required to meet the following criteria: No prior chemotherapy or radiotherapy, age 20-74 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, measurable lesions, adequate hematological function [white blood cell count (WBC) ≥3,000/mm³; platelets ≥100,000/mm³; hemoglobin ≥9.0 g/dl], and sufficient hepatic function [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤100 IU/l; total bilirubin ≤1.5 mg/dl] and renal function (creatinine ≤1.5 mg/dl). Patients with pericardial effusion, active concomitant malignancy, prior second primary cancer, active infection, severe heart disease, history of myocardial infarction in the previous 3 months, unstable angina, uncontrollable diabetes mellitus or hypertension, interstitial pneumonia or active lung fibrosis on chest radiograph, or psychiatric disease were excluded. This study was approved by the Institutional Review Board of each participating institution. Written informed consent was received from all patients (Clinical trial registration: UMIN000002352).

Treatment schedule. The study schema is shown in Figure 1. Induction treatment, consisting of etoposide at 100 mg/m² on days 1-3 and cisplatin at 60 mg/m² on day 1, was started within 7 days from registration. Etoposide was administered as a 1- to 2-h intravenous infusion, and cisplatin as a 1- to 2-h intravenous infusion with sufficient hydration. TRT was started on day 1 of the first cycle of etoposide-cisplatin and administered at a fraction dose of 1.5 Gy twice daily to a total dose of 45 Gy in 3 weeks. The second cycle of etoposide-cisplatin was given 4 weeks after the first cycle of etoposide-cisplatin, and an additional three cycles of etoposide-cisplatin was continued every 3 weeks unless the disease progressed or intolerable toxicities were observed. All the patients who were enrolled in the study were defined as the intention-to-treat (ITT) population.

After the induction treatment, patients were reassessed for the following criteria for the administration of consolidation amrubicin: completion of the defined induction treatment, no progressive disease [complete response (CR), partial response (PR), or stable disease (SD)] within 42 days from the start of the fourth cycle of etoposide-cisplatin, ECOG PS of 0-2, WBC ≥3,000/mm³, platelets ≥100,000/mm³, bilirubin ≤1.5 mg/dl, AST and ALT ≤100 IU/l, creatinine ≤2.0 mg/dl, fever <37.5°C, no active infection, radiation dermatitis or esophagitis of grade 2 or less, and no pulmonary infiltration beyond the irradiated field. All eligible patients received three cycles of amrubicin at 40 mg/m² on days 1-3 every three weeks (consolidation population). Amrubicin was administered as a 5-min intravenous injection. Prophylactic cranial irradiation (PCI) was optional for patients who achieved CR or near CR by the above treatment.

Thoracic radiotherapy. TRT was delivered from megavoltage equipment (6-10 MV) at a fraction dose of 1.5 Gy twice daily, with at least a 6-h interval between the fractions, to a total dose of 45 Gy in 30 fractions in 3 weeks. All patients underwent three-dimensional treatment-planning computed tomography within 7 days before the start of the treatment. The gross tumor volume (GTV) included the pretreatment primary GTV and metastatic lymph nodes of 1 cm or larger in the short axis diameter on computed tomographic images. The clinical target volume (CTV) was equal to the GTV and uninvolved mediastinal and ipsilateral hilar nodes. The other regions were not routinely included unless metastatic nodes were noted. The contralateral hilar lymph node was excluded from the CTV. The planning target volume (PTV) included the CTV plus sufficient margins (typically 0.5-1.0 cm laterally and 1.0-2.0 cm craniocaudally). The volume of the lung unaffected by cancer which would receive 20 Gy or more was kept to 35% or less. Heterogeneity corrections were applied to monitor unit calculations.

Evaluation of toxicity and dose modification. Toxicity was evaluated based on the National Cancer Institute-Common Terminology Criteria, version 4.0 (7). Blood tests and chest x-ray were required at least once a week during TRT, and at least once 2 weeks after the completion of TRT. If patients had WBC <1,000/mm³, neutrophils <500/mm³, platelets <25,000/mm³, or grade 3 non-hematological toxicities other than nausea, vomiting, fatigue, alopecia, and transient electrolyte disturbances, the doses of etoposide, cisplatin, and amrubicin were reduced by 20, 10, and 5 mg/m², respectively, in subsequent cycles. If the creatinine level was greater than 1.5 mg/dl during the etoposide-cisplatin treatment, the dose of cisplatin was reduced to 50 mg/m². The next cycle of etoposide-cisplatin was started when a patient had a WBC ≥3,000/mm³, platelets ≥100,000/mm³, bilirubin ≤2.0 mg/dl, AST and ALT ≤100 IU/l, creatinine ≤1.5 mg/dl, PS of 0-2, and fever <37.5°C. Amrubicin was started when a patient had a WBC ≥3,000/mm³, platelets ≥100,000/mm³, bilirubin ≤2.0 mg/dl, AST and ALT ≤100 IU/l, creatinine ≤2.0 mg/dl, PS of 0-2, and fever <37.5°C. If PS of 3 or 4, grade 2 pneumonitis or pulmonary infiltrates, or a fever of 38.0°C or higher developed, radiotherapy was withheld until recovery. If toxicities persisted and patients did not meet the above criteria for up to 14 days from the completion of the previous cycle of chemotherapy or from the termination of TRT, the study treatment was terminated. Use of granulocyte colony stimulating factor (G-CSF) agents was allowed at the discretion of the treating physician, but prophylactic use was permitted only during the consolidation phase.

Evaluation of tumor response. Tumor response was assessed after the completion of TRT, during 8 to 28 days from the start of the fourth cycle of etoposide-cisplatin, and after the last cycle of amrubicin. Post-treatment evaluation was performed every 2 months until death or progressive disease. The ORR was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (8).

Statistical analyses. The primary endpoint of the study was the 2-year PFS rate in the consolidation population. The secondary endpoints were the ORR, PFS, OS, and toxicities in the ITT and consolidation populations. The targeted sample size was 33 for the consolidation population, with a one-sided alpha of 0.1, a beta of 0.2, and expected and threshold 2-year PFS rates of 40% and 25%, respectively. Assuming the CCRT consisting of TRT and four cycles of etoposide-cisplatin to be completed by 85% of the patients, and a disease control rate of 95%, a total of 41 patients were required for the ITT population. If fewer than eight patients completed the three cycles of consolidation amrubicin among the first 17 patients, the study was to be terminated due to unfeasibility. The PFS and OS were estimated using the Kaplan-Meier method. The PFS was measured from the date of the first registration to disease progression, death from any cause, or the last follow-up. OS was measured from the date of the first registration to the date of death from any cause or the last follow-up. Patients who were lost to follow-up without events were censored at the last known date of follow-up. All patients who received at least one cycle of chemotherapy were considered assessable for response evaluation, and toxicity. All analyses were performed using JMP 14 software (SAS Institute, Cary, NC, USA).