Abstract
Background/Aim: This study aimed to evaluate the safety and recommended dose of nab-paclitaxel in combination with carboplatin and thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: Nab-paclitaxel was administered weekly with escalating doses, combined with carboplatin area under the curve (AUC) 2 and concurrent standard thoracic radiotherapy. Escalating doses of nab-paclitaxel were as follows: level 0, 30 mg/m2; level 1, 35 mg/m2; level 2, 40 mg/m2; level 3, 45 mg/m2. Results: Twelve patients were enrolled and received the treatment according to the protocol; seven patients (58%) had squamous cell carcinoma and all cases had stage III disease. At level 1, none of the three patients experienced dose limiting toxicity (DLT). At level 2, one of the first three patients experienced a fatal DLT of bronchopulmonary hemorrhage. None of the three more additional patients experienced DLT. At level 3, two of the three patients experienced a DLT of grade 3 febrile neutropenia and grade 4 neutropenia, respectively. Consolidation chemotherapy was provided to 10 of 12 patients. Radiation pneumonitis developed in five of 12 patients (42%). Eight patients (66.7%) showed partial response, and four (33.3%) showed stable disease. For the above reasons, level 2 (40 mg/m2) was considered the recommended dose in this study. Conclusion: Concurrent chemoradiotherapy with weekly nab-paclitaxel (40 mg/m2) and carboplatin (AUC 2) is a feasible and well-tolerated regimen in patients with previously untreated locally advanced NSCLC. A phase II trial with this regimen is warranted.
Lung cancer is a leading cause of death worldwide, especially in Japan where more than 75,000 patients die from the disease annually (1). The majority of lung cancers are histologically grouped as non-small cell lung cancer (NSCLC) (approximately 85%). As half of patients newly diagnosed with NSCLC are in stage III or higher, curative cases with surgical indications are a minority (2). Concurrent chemoradiation therapy (CCRT) is the standard treatment for locally advanced lung cancer (2). Many regimens are used in combination with radiation therapy; for example, carboplatin (CBDCA) plus paclitaxel (PTX), cisplatin (CDDP) plus vinorelbine (VNR), and other combinations, are often used (3). Each regimen has its advantages and disadvantages. PTX is often used in combination with CBDCA, and weekly administration is easy to adjust during the course of treatment depending on adverse events. However, there are known problems with PTX. Numbness as a side effect sometimes occurs, premedication using antihistamines and steroids for hypersensitivity to an additive, such as Cremophor EL® (polyoxyethylene castor oil) is necessary, and addition of ethanol makes use of PTX by patients with alcohol hypersensitivity difficult. To overcome these problems, nanoparticle-albumin binding (nab)-PTX without Cremophor EL® and ethanol has been developed (4). A previous phase III study revealed that weekly nab-PTX plus carboplatin showed longer survival and less neuropathy than PTX with carboplatin in patients with untreated NSCLC (5). As PTX is not biologically identical to nab-PTX, it is unclear whether nab-PTX can simply replace PTX for chemoradiation therapy, and what the optimal dose of nab-PTX is. Therefore, we conducted a phase I study to determine the effectiveness and appropriate dose of nab-PTX as part of a regimen for chemoradiation therapy.
Patients and Methods
Eligibility criteria. Eligibility criteria included the following: chemotherapy-naïve, histologically or cytologically confirmed NSCLC that was surgically unresectable and eligible for radiation chemotherapy, age ≥20 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, and adequate organ functions [absolute neutrophil count ≥1,500/μl, platelet count ≥100,000/μl, ALT and AST ≤5× upper limit of normal (ULN), total bilirubin ≤1.5× ULN, serum creatinine ≤1.5 mg/dl, SpO2 ≥90% (while breathing ambient air)]. Exclusion criteria included the following: no measurable lesions, uncontrolled infection, serious concomitant systemic disorders, active interstitial pneumonia, pneumoconiosis, active radiation pneumonitis, and active drug-induced lung injuries, pregnant or breast feeding, not practicing proper contraception, psychosis or psychiatric symptoms making participating in the study difficult, other active malignancies, a life expectancy less than 3 months, or any contraindication to CBDCA, nab-PTX, or irradiation. Informed consent was obtained from eligible patients before enrollment. This study was approved by the institutional review board of Kochi Medical School at Kochi University (number 25-67), and was registered with the University Hospital Medical Information Network (UMIN) in Japan (number UMINR000015432).
Study design and treatment modifications. This was a single-center, non-randomized, prospective phase I study performed at Kochi Medical School Hospital in Japan. We used a standard 3 + 3 dose escalation design. We aimed to evaluate the maximum tolerated dose (MTD) and decide the recommended dose (RD) of nab-PTX plus carboplatin combined with standard radiotherapy (2 Gy/day, 5 fractions/week, ≥30 fractions/course). Patients received CBDCA (fixed at AUC 2 min•mg/ml) and nab-PTX 30 to 45 mg/m2 intravenously on days 1, 8, 15, 22, 29, and 36 during 6 weeks of the radiotherapy (RT) period. We set the nab-PTX level 0 to 30 mg/m2, level 1 to 35 mg/m2, level 2 to 40 mg/m2, and level 3 to 45 mg/m2, and began the study with level 1. Treatment was postponed if the following criteria were not met on the day of administration of each course or on the day before administration: absolute neutrophil count ≥1,000/μl, platelet count ≥75,000/μl, total bilirubin ≤1.5 mg/dl, serum creatinine ≤1.5 mg/dl, and body temperature <38°C. Irradiation was postponed if an absolute neutrophil count ≤500/μl or febrile neutropenia occurred. Use of granulocyte-colony stimulating factor (G-CSF) was allowed only on non-irradiation days when either an absolute neutrophil count ≤500/μl or an absolute neutrophil count ≤1,00/μl with fever over 38°C was observed. The dose limiting toxicity (DLT) was defined as follows: grade 3 or higher non-hematologic toxicity, grade 4 hematologic toxicity, and febrile neutropenia of any grade. DLT was evaluated during the CCRT period. If DLT was not observed in any of the first three patients, the dose was escalated to the next level. If DLT occurred in one of three patients, three more additional patients were recruited at the same dose level. Subsequently, if DLT occurred in only one of six patients, the dose was escalated to the next level. If DLT occurred in two or more of six patients, dose escalation was discontinued, and three more patients were added to the previous level (maximum six patients). If DLT occurred in two or three of three patients, dose escalation was stopped and that dose was judged intolerable. Three more patients were then added to the previous level (maximum six patients). If DLT occurred in one of six patients, that dose was estimated as the MTD. The MTD was defined as the highest dose at which DLT was observed in zero or one of six patients. The RD was the highest dose not exceeding the MTD, and at least six patients needed to be treated at the RD.
Pre-study and treatment assessment. Thoracoabdominal computed tomography (CT) and brain magnetic resonance imaging were performed within four weeks of study initiation. Chest radiography, blood chemistry, and complete blood counts were performed at least every week. CT for the assessment of target or non-target lesions was performed every six weeks during the chemoradiotherapy, and every four to eight weeks during the optional consolidation therapy. Responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response (CR) and partial response (PR) were determined by two assessments no less than four weeks apart. A response designation of stable disease (SD) required tumor stabilization for at least six weeks. All toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.
Results
Patient characteristics. A total of 12 patients were enrolled. All patients were evaluated for efficacy and safety based on intention to treat. The baseline clinical characteristics of patients are summarized in Table I. The median patient age was 63.5 years (range=42-79 years); 75% of patients were younger than 75 years, and 66.7% of patients were male. Four patients (33.3%) had a PS of 0, and 8 (66.7%) had a PS of 1. None of the patients had a PS of 2 or higher. Seven patients (58.3%) were stage IIIA, and five patients (41.7%) were stage IIIB. Four patients (33.3%) had adenocarcinoma, seven (58.3%) had squamous cell carcinoma, and one (8.3%) had non-small cell carcinoma. Nine of the 12 patients (75%) had a history of smoking.
Patient characteristics.
Treatment delivery. At level 1, none of the three patients experienced DLT, therefore the study progressed to the next level. At level 2, one patient of the first three patients developed bronchopulmonary hemorrhage. The patient had squamous cell carcinoma with occasional hemoptysis before the start of treatment. Although his hemoptysis was thought to be from the tumor, he died of hemoptysis during the treatment protocol, suggesting a severe adverse event and DLT. However, this was not considered to be directly related to the therapy. Three more patients were subsequently treated at level 2. None of the three additional patients exhibited any DLT, thus the study progressed to the next level. At level 3, two of three patients experienced DLT of grade 3 febrile neutropenia and grade 4 neutropenia, respectively. Consequently, no more patients were added. For the above reasons, level 2 (40 mg/m2) was considered the MTD and RD in this study. Median radiation dose was 60 Gy; one patient prematurely terminated at 40 Gy and one patient received 66 Gy. After the protocol-related treatment, consolidation chemotherapy was provided to 10 of 12 patients (83.3%).
Efficacy. Out of 12 patients, CR was not achieved in any patients. PR was observed in eight patients (66.7%; 2 in level 1, 5 in level 2, 1 in level 3), and SD was observed in four patients (33.3%; 1 in level 1, 1 in level 2, 2 in level 4). PD (progressive disease) was not observed in any patients in this study. The overall response rate was 66.7%. Although survival was not an additional endpoint, median overall survival was 34.1 months.
Adverse events. The adverse events are summarized in Table II. Regarding hematological toxicities, three patients in level 2 (25.0%) had grade 3 neutropenia, one patient in level 3 (8.3%) showed grade 4 neutropenia, and one patient in level 3 (8.3%) developed febrile neutropenia, suggesting DLT in level 3. Grade 3 thrombocytopenia was observed in one patient in level 2 (8.3%), whereas grade 3 or 4 anemia was not seen. Regarding non-hematological toxicities, one patient in level 2 (8.3%) showed grade 3 increases in ALT and AST, two patients (16.7%, 1 in level 1 and 1 in level 2) showed grade 3 lung infections. One patient in level 2 developed DLT of grade 5 bronchopulmonary hemorrhage, as described above. Radiation pneumonitis developed in 5 of 12 patients (42%), including the non-testing period, but resolved in all five of the patients. None of the patients developed severe pneumonitis.
Adverse events.
Discussion
In this phase I study, we evaluated weekly nab-PTX plus carboplatin with thoracic RT for patients with locally advanced NSCLC. The RD of nab-PTX in our study was concluded to be 40 mg/m2 and the overall response rate (ORR) was 66.7%. These results are similar to those from previous studies. To date, several studies on weekly nab-PTX plus carboplatin with thoracic RT have been reported, including three phase I, one phase I/II, two phase II, and one phase III studies. In these studies, the RD of nab-PTX ranged from 40 to 80 mg/m2. Lammers et al. first reported the efficacy and toxicity of this regimen in 10 patients in 2015 (6). They showed that none of the patients experienced DLT at 40 mg/m2 of weekly nab-PTX, but two patients experienced DLT at 60 mg/m2. They concluded that weekly nab-PTX (40 mg/m2) plus carboplatin (AUC 2) with RT was well-tolerated, with an ORR of 90% (6). Based on the results of a phase I study in 14 patients, Kaira et al. reported that 80 mg/m2 was considered the MTD and was defined as the RD, with an ORR of 71.4% (7). Kawano et al. conducted a phase I/II study and showed that 50 mg/m2 of nab-PTX was recommended in combination with carboplatin at AUC 2 for CCRT in the phase I part (8). They showed an ORR of 76.8%, a median progression-free survival (PFS) of 11.8 months, and feasible toxicities in the phase II part. These studies, including our study, indicated that doses ranging from 40 to 80 mg/m2 of nab-PTX may be recommended and effective in combination with carboplatin in chemoradiation therapy.
On the contrary, a phase II study reported that nab-PTX plus carboplatin is not recommended for chemoradiation therapy in terms of adverse events. Hasegawa et al. conducted a phase II study of 40 mg/m2 of nab-PTX plus carboplatin (AUC 2) and thoracic RT (60 Gy/30 Fr) for patients with locally advanced NSCLC (9). In their report, treatment-related death occurred in two of 10 patients (20%); one patient died of radiation pneumonitis and the other died of heart failure. In that study, their ORR was 40.0% and median PFS was 6.7 months, showing poor results compared to other studies. While a therapy-related mortality of 20% is high, a total number of 10 patients is too small for any definitive judgments regarding this regimen. More cases are needed for further assessment of this regimen. In the present study, one patient died of hemoptysis, but this was due to the underlying cancer and not directly related to the therapy. Overall, the regimen was well tolerated and effective in the present study compared to other studies.
Similar studies, targeting only squamous cell carcinoma, on elderly patients, and on administration of nab-PTX every two weeks, have also been reported. Wu et al. reported a phase II study focusing on squamous cell carcinoma, showing an ORR of 75%. In their study, a dose of 60 mg/m2 of nab-PTX was used and only eight patients were enrolled due to slow recruitment. Among the eight patients, 75% experienced radiation esophagitis, and 50% experienced grade 2 or higher radiation pneumonitis (10). Focusing on elderly patients, Omori et al. reported a phase I study of this regimen. They showed that 30 mg/m2 of nab-PTX is recommended for elderly patients and that this regimen is tolerable and effective for elderly, with an ORR of 76.5% (11). Biweekly administrational has also been reported (12). Tanaka et al. showed biweekly administration of carboplatin (AUC 4) and nab-PTX (100 mg/m2) combined with thoracic RT (60 Gy/30 Fr) was feasible and effective, with an ORR of 96.4% and a median PFS of 18.2 months.
Recently, the phase III PACIFIC trial was conducted to evaluate the efficacy of one-year administration of durvalumab for patients with locally advanced NSCLC after CCRT, showing improved PFS compared with placebo (hazard ratio, 0.52; p<0.001) (13). Results of the PACIFIC trial have made durvalumab one of the standard therapies for locally advanced NSCLC. However, the PACIFIC trial did not specify a chemotherapy regimen, and it remains unknown which regimen should be used in combination with durvalumab. Our data and previous data suggest that weekly nab-PTX plus carboplatin is a hopeful candidate for CCRT. A randomized phase III trial has been started in Japan (14) and results are expected soon.
A major limitation of the present phase I study is the low number of enrolled patients. With only 12 patients, the study cohort is too small to allow appropriate conclusions to be drawn regarding the ORR, survival, and adverse events. However, the ORR was as high as 66.7%, which is comparable to the ORR for conventional treatment.
In conclusion, CCRT with weekly nab-paclitaxel (40 mg/m2) and carboplatin (AUC 2) is a feasible and well-tolerated regimen in patients with previously untreated locally advanced NSCLC. A phase II trial with this regimen is warranted.
Acknowledgements
The Authors appreciate all of the patients and their families participated in this study.
Footnotes
Authors’ Contributions
Study design and analysis: Kubota T and Sakai M; Patients enrollment and treatment: Kubota T, Sakai M, Anabuki K, Takamatsu K, and Mukaida K; Radiation therapy: Kobayashi K; Manuscript writing: Kubota T; Review: Yamagami T, and Yokoyama A.
Conflicts of Interest
No Authors have any financial or personal relationship with any person or organization that could inappropriately influence this study.
- Received August 28, 2023.
- Revision received September 21, 2023.
- Accepted September 22, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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