Efficacy of Taxane-Based Regimens in a First-line Setting for Recurrent and / or Metastatic Chinese Patients with Esophageal Cancer

Esophageal cancer is the eighth most common cancer with a dismal prognosis, which cause the sixth cancerrelated mortality worldwide (IARC, 2012). More than two-thirds of patients would be initially diagnosed as unresectable or metastatic disease (Thallinger, et al., 2011). Even patients with resectable disease have a high rate of recurrence with the expected median survival being only 24 months, and 5-year survival rate lower than 30% (Thallinger, et al., 2011; Mirinezhad, et al., 2014). The combination chemotherapy of 5-fluorouracil and cisplatin (PF) is the mainstay of palliative treatment for advanced or recurrent cancer (Nakajima, et al., 2013), however, their poor outcomes require urgently new researches been conducted. Taxanes, including paclitaxel (PTX) and docetaxel (DTX), have been demonstrated to be effective in advanced and recurrent esophageal cancer as monotherapy (Ajani, et al., 1994; Einzig, et al., 1996). Combinations with taxanes treatment, no matter two or three drugs regiment, including the combination of platinum,


Introduction
Esophageal cancer is the eighth most common cancer with a dismal prognosis, which cause the sixth cancerrelated mortality worldwide (IARC, 2012).More than two-thirds of patients would be initially diagnosed as unresectable or metastatic disease (Thallinger, et al., 2011).Even patients with resectable disease have a high rate of recurrence with the expected median survival being only 24 months, and 5-year survival rate lower than 30% (Thallinger, et al., 2011;Mirinezhad, et al., 2014).The combination chemotherapy of 5-fluorouracil and cisplatin (PF) is the mainstay of palliative treatment for advanced or recurrent cancer (Nakajima, et al., 2013), however, their poor outcomes require urgently new researches been conducted.
Taxanes, including paclitaxel (PTX) and docetaxel (DTX), have been demonstrated to be effective in advanced and recurrent esophageal cancer as monotherapy (Ajani, et al., 1994;Einzig, et al., 1996).Combinations with taxanes treatment, no matter two or three drugs regiment, including the combination of platinum,
The nanoparticle albumin-bound paclitaxel (Nab-PTX), a solvent excipients free formulation of paclitaxel, was developed to gain more therapeutic benefits of paclitaxel but eliminate the toxicities associated with Cremophor (Sparreboom, et al., 2005).Several studies elucidated the superiority of Nab-PTX in pharmacokinetics (Al-Hajeili, et al., 2014), particularly the intratumoral accumulation, absorption, binding to the endothelial cells, and transportation were higher compared with paclitaxel as well as better tolerance in breast cancer, lung cancer, ovarian cancer, pancreatic cancer (Desai, et al., 2006;Desai, et al., 2008;Von Hoff, et al., 2013).However, rare effort to study nab-PTX efficacy was focused on metastatic and/or recurrent esophageal cancer (Shi, et al., 2013).
China possesses the highest morbidity and mortality rates in the world (Lu, et al., 2014), and presents distinct characteristics with majority squamous cell cancer (SCC) and midportion location (Jie. and Kang., 2011;Zhao, et al., 2012), which differ from esophageal cancer patients in the western countries where has the rising incidence of adenocarcinoma of the lower esophagus with escalating rates of obesity, gastroesophageal reflux disease, and Barrett's esophagus (Vizcaino, et al., 2002;Dubecz, et al., 2014).To our knowledge, taxanes-based regimens were not fully studied in Chinese esophageal cancer (Huang, et al., 2004;Zhang, et al., 2007;Wang, et al., 2010;Zhang, et al., 2010;Wu, et al., 2012;Ji, et al., 2013), especially Nab-PTX (Shi, et al., 2013), even this new medicine was seldom reported in East Asian countries as Japan and South Korea.This retrospective study was conducted to evaluate the efficacy of taxanes-based regimens in Chinese patients with recurrent and/or metastatic esophageal cancer, compare the efficacy of TP with TPF regimen, and Nab-PTX based regimen with traditional taxanes including PTX and DTX-based regimen separately.

Patients
The patients eligibility were 1) with histological and/ or pathological diagnoses as esophageal cancer; 2) with radiography and/or pathological evidences that patients had advanced (stage IV) or recurrent/metastatic disease; 3) Patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 with sufficient bone marrow, liver and renal function; 4) received taxane-based chemotherapy in first-line setting at Sun Yat-sen University Cancer Center from January 2009 to December 2013; 5) with complete follow-up data.Patients were excluded if the chemotherapy had been administered as neoadjuvant chemotherapy with radical treatment intent, and if all the lesions were covered by the radiotherapy, palliative surgery or intervention therapy after first line chemotherapy.Written informed consent for chemotherapy was obtained from all patients.

Treatment plan
Patients in PTX/ DTX group were premedicated intravenously (i.v.) 30min before therapy with dexamethasone 10 mg, cimetidine 400 mg (or a comparable histamine H2 receptor blocker) and diphenhydramine hydrochloride 40mg.All patients received 5-HT receptor antagonist before taxanes.PTX and DTX were administered i.v. at a starting dose of 170 mg/m 2 and 60-75mg/m 2 over 1h once every 3 weeks separately.Nab-paclitaxel was administered i.v. at a starting dose of 260 mg/m 2 over 30min each 3 week-period.Twelve patients received molecular targeted agents as cetuximab, nimotuzumab and endostatin (Table 1).In general, chemotherapy was delayed until recovery for a Grade 2 myelosuppression or any significant persisting nonhematologic toxicity.For grade 3-4 myelosuppression, G-CSF or thrombopoietin was administered and the dose of taxanes was adjusted on individual basis.Treatment was discontinued if the tumor progressed, severe toxicity occurred or at the patient's request.

Statistical analysis
Response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) in patients with measurable lesions.Progression-free survival (PFS) was measured from the initiation of taxanes to the progression, or death without evidence of progression.Overall survival (OS) was measured from the first day of diagnosed with advanced or recurrence to the day of death or to the final day of the follow-up period.Median PFS and median OS were estimated by the Kaplan-Meier method.
The distributions of the baseline characteristics of the patients were assessed by the χ 2 test.Statistical analyses were performed using SPSS software (version 18.0; IBM Corporation, Armonk, NY, USA).All tests were twosided, and p<0.05 was considered statistically significant.

Results
A total of 102 patients were enrolled in this retrospective study.Sixteen were administered Nab-PTX based chemotherapy and 86 received PTX or DTX based chemotherapy.Patients in Nab-PTX group consist of single agent regimen (3 patients) and combination with cisplatin or carboplatin (13 patients).Patients in PTX/DTX group comprise two subgroups: two-drug combination of PTX/DTX and platinum (TP) and triplet regimen TPF with addition of continuous infusion of 5-fluorouracil (5-Fu) or capecitabine (an oral fluoropyrimidine).

Patient characteristics
Clinico-pathological characteristics of patients are exhibited in Table 1.Among all the patients, 87 were male (85.3%).Median age was 59 (range 35-79).The lower esophageal location of the primary tumor was a majority (33.3% in total, 31.3% in Nab-PTX group, 34.4% in TP group, and 46.7% in TPF group), albeit the subsite unbalanced among three groups.Sixty-three (61.8%) patients had relapsed after prior treatment and the remaining 39 were newly diagnosed with metastases.The followed radiotherapy, palliative surgery/interventional therapy were performed more in Nab-PTX group than Efficacy of Taxane-Based Regimens in a First-line Setting for Recurrent and/or Metastatic Chinese Patients with Esophageal Cancer in PTX/DTX group.The three groups were similar in terms of other parameters including age, gender, ECOG performance status, histological type and target sites before first line treatment.

The efficacy of taxanes-based regimens
In the whole group, patients had received 1 cycle to 9 cycles (median 3 cycles) first line chemotherapy.The objective response rate (ORR) among patients with measurable disease was 20.6% in the whole group, and the disease control rate (CR + PR + SD, DCR) was 67.6% (Table 2).Response could not be evaluated in 19 patients for the following reasons: discontinuation before treatment evaluation due to toxicity in 2 patients and refusal by other patients.The median OS was 10.5 months (95% CI 10.1-16.4), and the median PFS was 6.04 months (95% CI 5.09-7.91).

Discussion
Lack of standard second-line therapeutic regimen for patients with advanced and/or recurrent esophageal cancer (Thallinger, et al., 2011) was the reason for chosing the patients treated in the first line setting.In spite of the standard regimens recommended by NCCN guideline as combination of cisplatin and 5-Fu, TP and TPF regimens

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including PTX and DTX in the first line setting was settled by several studies (Petrasch, et al., 1998;Ajani, et al., 2005;Van Cutsem, et al., 2006), which had validated high clinical activities and survival advantages in metastatic or recurrent esophageal cancer, this superiority should not be extrapolated to Chinese patients for their different characteristics.In our study, the ORR of 20.6%, DCR of 67.6%, median OS of 10.5 months median PFS of 6.04 months in the whole group were observed.
In regard to the clinical activities, the addition of 5-Fu had been demonstrated a confirmed higher ORR than TP alone (37-43% vs 18-26%) (Ajani, et al., 2005;Roth, et al., 2007).The ORRs in our study were less impressive compared with the previous data (20.0%vs 19.7%).However, the DCR of 93.3% with TPF and 59.1% with TP, revealed that incorporation of 5-Fu produced a higher DCR than TP.Our study showed a tendency to higher ORR and DCR in patients with Nab-PTX than PTX/DTX based regimens (25% vs 19.8%, 81.3% vs 65.1%, respectively), although the differences were not statistically significant.The albumin-bound and nanoparticle technique of Nab-PTX allow higher dose application and cause less adverse events, which may contribute to the potential advantage.
Recently, an one-armed study illuminated the efficacy of Nab-PTX by evaluating the OS, PFS, and ORR in Chinese metastatic esophageal squamous cell cancer patients (Shi, et al., 2013), concluded with a longer median OS (15.5 months) and corresponding ORR and PFS compared with other traditional taxanes based regimens.However, the small patients' sample (33 patients) and subsequent treatments for most patients (87.9% patients receiving subsequent treatment after progression) may have contributed to better OS in the study (Shi, et al., 2013).In our project, albeit the differences in PFS or OS were not statistically significant for all regimens, the two endpoints tended to be better in Nab-PTX based and TPF than TP regimen.Firstly, the efficacy of Nab-PTX based regimen was akin to TPF.Though several studies had illuminated Nab-PTX with high efficacy and mild side effects in breast cancer (O'Shaughnessy, et al., 2013), nonsmall-cell lung cancer (Xing, et al., 2013) and pancreatic cancer (Zhang, et al., 2013), there is few influential evidence on esophageal cancer.In spite of lacking direct comparison of toxicity, more patients who received Nab-PTX were adminstered target agents compared with TPF in current study, suggesting better tolerance of Nab-PTX.However, the cost-effectivness of Nab-PTX should be taken into account in clinical practice.Secondly, addition of 5-Fu to TP regimen resulted in a trend of longer PFS and OS, which demands another well designed prospective study to confirm as well as the possible subsequent adverse events.Finally, we didn't separate PTX from DTX in the regimens, for there is no consensus in efficacy of these cognate agents for esophageal cancer yet.The efficacy of DTX was confirmed superior to PTX in breast cancer (Jones, et al., 2005), analogous in non-small-cell lung cancer (Esteban, et al., 2003), ovarian cancer (Hsu, et al., 2004) and gastric cancer (Park, et al., 2006).Mizota A et al. (Mizota, et al., 2011) compared PTX with DTX for advanced or recurrent esophageal cancer patients, no significantly different in terms of PFS and OS.Likewise, DTX had not obtained an advantage in second-line treatment (Fujita, et al., 2008).
Since this study was retrospective, non-randomized, small patients' sample, those limitations determined hard to compare the toxicity, quality of life, etc.More patients were included in the TPF group, the results might have been affected.
In conclusion, the three regimens of Nab-PTX based, TP and TPF are active and equal in first line setting of recurrent and/or metastatic esophageal cancer.TPF showed potential activity and, maybe, with more toxicities; Nab-PTX showed potential higher tolerance than TPF, but, less cost-effectiveness; so, the three regimens should become alternative treatments depend on patients' or doctors' consideration.

Figure 2 .
Figure 2. The OS of Nab-PTX Group and TP + TPF Group

Table 1 . Patient Characteristics
ORR was 25% among patients in  19.7% in TP group, and 20.0% in TPF group (p=0.93).The DCR was 81.3% in Nab-PTX group, 59.1% in TP The difference in number of patients who received radiotherapy between Nab-PTX group and TP group was statistically significant (p=0.007,Bonferroni correction would be to test each of the individual tests at a significance level of 0.017); Þ p=0.002; P* the P value of Nab-PTX and PTX+DTX group comparison; P** the P value of three-group comparison; † Ϋ p=0