Abstract
Aim: The present study aimed to evaluate the effectiveness and safety of weekly paclitaxel (PTX) combined with carboplatin (CBDCA) plus bevacizumab (BEV), followed by maintenance BEV in patients with advanced NSCLC. Patients and Methods: Patients with unresectable stage IIIB and IV NSCLC (n=43) were treated with CBDCA (AUC 6, day 1), BEV (15 mg/kg, day 1), and PTX (70 mg/m2, days 1, 8, 15) intravenously every 4 weeks, for 3 to 6 cycles, followed by maintenance BEV (15 mg/kg) every 3 weeks. Results: The objective response rate and disease control rate were 67.4% and 90.7%, respectively. The median progression-free survival was 7.6 months. The median overall survival was 17.7 months. Common adverse events were tolerable bone marrow suppression, fatigue, hypertension, and nasal bleeding. Conclusion: Weekly administration of PTX combined with CBDCA plus BEV therapy was effective, and well-tolerated by advanced NSCLC patients.
Lung cancer is the leading cause of cancer-related mortality worldwide, with an annual death toll of at least 72,000 persons in Japan (1) and 158,000 in the United States (2). The majority of lung cancers are histologically grouped as non-small cell lung cancer (NSCLC) (approximately 85%), with many NSCLC patients presenting with advanced disease at initial diagnosis (3). In the last decade, platinum-based chemotherapies combined with third-generation drugs such as platinum doublets have been established as the standard first-line regimen for NSCLC (4). Combination treatment consisting of carboplatin (CBDCA) plus paclitaxel (PTX) is one of the most widely used regimens, in which both agents are administered once every 3 weeks (4, 5). The most common toxicities associated with the CBDCA/PTX regimen are neuropathy, arthralgia, myalgia and bone marrow suppression (4, 5). To improve the tolerability of this regimen, alterations by lowering the dose of PTX (175 to 200 mg/m2, normally 225 mg/m2) (6) or by dividing administration of PTX into 3 fractions (70-100 mg/m2, on day 1, 8, 15, weekly for 3 of 3-4 weeks) (7-9) have been studied in clinical trials. These trials demonstrated that weekly administration of PTX showed similar efficacy but less neuropathy and arthralgia when compared to standard tri-weekly administration. Similar studies in Japanese patients have been reported (10-12), showing similar efficacy and less toxicity, and increased benefit for elderly patients (11-13). Bevacizumab (BEV) is a molecular targeted monoclonal antibody that inhibits angiogenesis, and has become a key agent in current chemotherapeutic regimens (14). Addition of BEV to standard CBDCA/PTX results in significant improvement of overall survival (OS) (15). Therefore, combination of weekly PTX and CBDCA and BEV may be efficacious and less toxic. However, the effects of this regimen have not been fully studied. Therefore, we conducted a phase II clinical trial to determine if weekly administration of PTX with CBDCA and BEV is beneficial.
Patients and Methods
Eligibility criteria. Eligibility criteria included the following: chemotherapy-naïve, histologically- or cytologically-confirmed non-squamous NSCLC that was surgically unresectable or relapsed stage IIIB or IV (UICC 7th edition), age ≥20 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, and adequate organ functions, including absolute neutrophil count ≥1,500/μL, platelet count ≥100,000/μL, hemoglobin ≥9.0 g/dL, ALT and AST ≤2.5 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN, serum creatinine ≤1.2 mg/dL, SpO2 ≥90% (while breathing ambient air), prothrombin time-international normalized ratio <1.5, and proteinuria ≤1+ or ≤2 g/24 h. Exclusion criteria included the following: no measurable lesions, uncontrolled infection, serious concomitant systemic disorders, massive pleural effusion, untreated current brain metastasis, active interstitial pneumonia, other active malignancies, a life expectancy less than 3 months, or any contraindication to CBDCA, PTX, or BEV. Informed consent was obtained from eligible patients before enrollment. This study was approved by the institutional review board of the Kochi Medical School at Kochi University (number 22-9), and was registered with University Hospital Medical Information Network (UMIN) in Japan (number UMIN000003674).
Study design and treatment modifications. This was a multi-center, non-randomized, prospective phase II study performed in the Kochi prefecture in Japan. Treatment consisted of induction therapy and maintenance. Patients received CBDCA (AUC 6 min·mg/mL) on day 1, BEV (15 mg/kg) on day 1, and PTX (70 mg/m2) on days 1, 8, and 15 (i.e. weekly for 3 of 4 weeks) intravenously every 4 weeks, for 3 to 6 cycles, followed by maintenance BEV (15 mg/kg) every 3 weeks until disease progression or intolerable toxicity occurred. The attending physician decided the induction cycle number, taking into consideration the treatment efficacy and/or adverse events. Dose of CBDCA was determined by the Calvert's formula, with estimated glomerular filtration rate methods (16). Pre-medication with antihistamine agent, H2 blocker, steroid, and anti-emetic was administered, as directed by the chemotherapy information. One-step dose reduction (CBDCA, from AUC 6 to AUC 5; PTX, from 70 mg/m2 to 60 mg/m2) was permitted, according to treatment-related toxicities. For example, when grade 4 neutropenia or thrombocytopenia occurred, treatment was withheld until symptoms improved to grade 1 severity or less, and CBDCA and PTX were resumed with dose reduction; however, BEV was not reduced and was resumed with the same dose. Dose reduction more than that indicated above was not allowed. Therapy initiation was delayed no more than 3 weeks. When either grade 3 hemoptysis or any grade of any arterial thrombosis and/or perforation of the digestive tract occurred, chemotherapy was permanently discontinued. Choice of second-line chemotherapy regimen was determined by the attending physician. The primary end-point was the objective response rate (ORR). In addition, the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety were evaluated.
Pre-study and treatment assessment. Chest radiography, blood chemistry, and complete blood counts were performed at least every 4 weeks. Computed tomography for the assessment of target or non-target lesions was performed every 4 weeks during induction therapy, and every 4 to 8 weeks during maintenance therapy. The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (17) was used to evaluate responses. Complete responses (CR) and partial responses (PR) were determined by 2 assessments no less than 4 weeks apart. A response designation of stable disease (SD) required tumor stabilization for at least 6 weeks. All toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0.
Statistical analysis. The primary end-point of the study was the objective response rate (ORR). Secondary end-points were the disease control rate (DCR), progression-free survival (PFS), OS, and safety. PFS was defined as the time from the date of entry until the date of first radiographic evidence of tumor progression or death due to any cause. OS was defined as the time from the date of enrollment until the date of death of any cause or last known follow-up date. The sample size was calculated using the Fisher's exact test. According to previous phase II clinical trials of CBDCA plus weekly PTX in Japan, response rates range from 45% to 55% (11, 12). On the basis of a 1-sided calculation (α=0.05, 1–β=0.8) with a null proportion of 40% and an alternative proportion of 60%, the minimum sample number was assumed to be 39. Consequently, 43 patients were required to allow for patient dropouts. The 95% confidence interval (CI) for ORR and DCR was determined using the Clopper-Pearson method. The time-to-event variables were calculated using the Kaplan-Meier method. Statistical significance was evaluated using the log-rank test. A p-value <0.05 was considered significant. The best response and OS were estimated using logistic regression and Cox proportional hazards regression methods, respectively.
Results
Patients' characteristics. From February 2011 to October 2013, a total of 43 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 68 years (range=35-80 years); 79.1% of patients were younger than 75 years, and 74.4% of patients were males. Twenty patients had a PS of 0, 23 had a PS of 1. Five patients (11.6%) were stage IIIB, 37 (86%) were stage IV, and 1 had postoperative relapsed disease. Thirty-nine patients (90.6%) had an adenocarcinoma, 2 (4.7%) had a non-small cell carcinoma, and 2 (4.7%) had a large cell carcinoma. Five patients (11.6%) had EGFR gene mutations, 30 patients had wild-type EGFR, and 8 patients had unknown status.
Treatment delivery. A total of 178 cycles of induction treatment were administered (median=4; range=1-6) (Table II). A total of 199 cycles of maintenance BEV were administered (median=2; range=0-37). One patient received a total of 37 cycles of BEV. In 20 patients (46.5%), doses were reduced or skipped because of toxicity or social reasons. Thirty-six out of 43 patients (83.7%) completed 3 or more courses of induction chemotherapy. The remaining 7 patients did not complete 3 courses of therapy for the following reasons: 5 patients had adverse events, 1 patient refused treatment, and 1 patient had progressive disease. The most frequent reason for discontinuation of therapy was disease progression (20 patients, 46.5%); the next reason was adverse events (16 patients, 37.2%); other reasons (7 patients, 16.3%) included patients' opinion, slow recovery, and subsequently identified EGFR mutation. Twenty-nine patients (67.4%) received second-line chemotherapy or more, while 10 patients did not. Four patients were still receiving maintenance BEV therapy at the time of study evaluation.
Patients' characteristics.
Efficacy. Out of the 43 patients enrolled, CR was not achieved by any patient. PR was observed in 29 patients (67.4%), yielding an overall response rate of 67.4% (95%CI=53.4-81.4) (Table II). SD in 10 patients was observed, whereas 2 patients progressed, and 2 patients were not evaluable (NE). The disease control rate was 90.7% (95%CI=82.0-99.4). In a sub-group of 9 elderly patients (≥75 years), 6 had a PR, 1 had SD, 1 had PD, and 1 was NE. Responses in the elderly subgroup were similar to younger patients. A survival analysis was performed at the end of November 2014. The median PFS was 7.6 months (95% CI=5.5-9.5) (Figure 1A) and the median survival time (MST) was 17.7 months (95% CI=11.6–28.6) (Figure 1B). OS was compared between the following groups: younger patients (<75 years) vs. older patients (≥75 years) (p=0.491), male vs. female (p=0.169), and EGFR wild type vs. mutated (p=0.174). As expected, no significant differences were detected.
Adverse events. The adverse events are shown in Table III. In hematological toxicities, 20 patients (46.5%) had grade 3 or 4 neutropenia. Grade 3 thrombocytopenia and anemia were both observed in 2 patients (4.7%), respectively. All non-hematological toxicities were relatively mild. Although adverse events such as fatigue, appetite loss, hypertension, nasal bleeding, proteinuria, and alopecia were frequently observed, most of the cases were grade 1 or 2. Of note, only 1 patient had grade 3 neuropathy, and no patients had grade 4 neuropathy. Four patients (9.3%) had gastrointestinal bleeding (grade 1 or 3). One patient (2.3%) had a grade 3 interstitial pneumonia, and another developed a small intestinal perforation, which required non-urgent surgery.
Clinical response and treatment status.
Discussion
Tri-weekly CBDCA combined with PTX and BEV has become one of the standard chemotherapies for advanced non-squamous NSCLC (11). CBDCA and weekly PTX is an alternative administration to the tri-weekly regimen (7). Randomized studies have shown a reduction of toxicity, such as neuropathy and myalgia, with the weekly PTX regimen (9). In our phase II trial, we focused on fractionated administration of PTX combined with CBDCA and BEV in a 4-week cycle to elucidate efficacy and safety. Dosing and duration of treatment was chosen according to previous studies (10-13). As a result, we observed a remarkable ORR of 67.4%, DCR of 90.7%, PFS of 7.6 months, and MST of 17.7 months. The results were comparable to, or superior to, previous studies examining CBDCA and weekly PTX (8, 9), as well as Japanese studies (10-13). Meanwhile, maintenance therapy using BEV has recently become a key strategy for chemotherapy (15, 18). Our results were also comparable to previous studies examining standard CBDCA and PTX plus BEV (15). Our results suggest that addition of BEV plays an important role in this therapeutic combination resulting in the remarkable disease control rate. Although the median cycle of BEV was 2 in our study, it is noteworthy that 1 patient had received a total of 37 cycles of BEV without tumor progression. To our knowledge, only 1 study examining CBDCA and weekly PTX plus BEV has been reported (19), in which their study design was retrospective; additionally the patients had already been treated with some chemotherapy. Even so, the median PFS was 5.7 months and median OS was 14.5 months. Regardless of certain limitations, their results were comparable to those of our study. Taken together, these results suggest that combination of CBDCA and weekly PTX plus BEV is efficacious.
Progression-free (A) and overall (B) survival.
Summary of adverse events.
The toxicities commonly observed in this study were well-tolerated. The non-hematological toxicities including peripheral neuropathy were mostly mild to moderate and manageable. The incidence of grade 3 or 4 neuropathies in the study was apparently lower than that noted in patients treated with the conventional regimen. Our results suggest that dividing the administration of PTX reduces neuropathies, as previously reported (7-9). Since BEV is one of the molecular targeted inhibitors of angiogenesis, hemoptysis and/or other bleeding can be one of the underlying risks. Although events of grade 1 and 2 nasal bleeding were observed in 41.9% of patients, life-threatening hemorrhage was not noted in our study. Grade 1 and 3 gastrointestinal bleeding was observed in 9.3% of patients. Although it was manageable, its incidence was slightly higher than that reported by previous BEV studies (i.e. 0.9%-4.7%) (15, 18); this may be due to patients' characteristics and the small sample number in our study. Unfortunately, one patient developed manageable interstitial pneumonia and another patient developed intestinal perforation, which required for non-urgent operation. The incidence was low, but the possible risks are notable. By selecting appropriate indications of BEV, severe side effects become less frequent. Nine elderly patients (≥75 years) were included in the study; the severity and type of side effects did not correlate with patients' age. In our trial, 46.5% of patients required dose reduction and/or skipped administration. This indicates that it is easier to skip administration mid-course using the weekly PTX regimen than the tri-weekly regimen, resulting in quick management and less toxicity.
There may be certain disadvantages in this regimen, including the following: more hospital visits are required for the patient; cost of medical care of this regimen differs from the standard regimen. In addition, there exist some limitations to the study. This study was a single-arm trial with a relatively small sample size. Although most patients (69.8%) had wild-type EGFR, patients with the EGFR gene mutation (11.6%) were included in this study. Overall, our study revealed that this regimen is efficacious and well-tolerated, regardless of EGFR gene status.
In conclusion, weekly administration of PTX combined with CBDCA plus BEV therapy was effective, and well-tolerated by patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional regimen is warranted.
Acknowledgements
The Authors thank Drs. Mayuka Isaka, Naoki Shiota (Kochi University Hospital), Hiroyuki Kozai, Mayuri Nakano, Kozo Kagawa, Makoto Tobiume (NHO Kochi Hospital), Takeshi Nakajima (Kochi Medical Center) for their participation in enrolling patients and providing information for the study.
Footnotes
Conflicts of Interest
None declared.
- Received September 29, 2015.
- Revision received November 25, 2015.
- Accepted November 27, 2015.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
