Endostatin and Oxaliplatin-Based Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma: Results of a Phase II Study.

LESSONS LEARNED: Definitive concurrent chemoradiotherapy based on oxaliplatin and endostatin was effective with the objective response rate exceeding 80%, and the treatment-related toxicities were acceptable.The treatment compliance of the current combination was much higher, without significant reduction in survival outcomes, than historical reports.
BACKGROUND: This phase II trial aimed at assessing the efficiency and safety of definitive concurrent chemoradiotherapy (dCRT) using oxaliplatin (OHP) and endostatin in patients with inoperable esophageal squamous cell carcinoma (ESCC).
METHODS: Radiotherapy was delivered with a daily fraction of 2.0 Gy to a total dose of 60.0 Gy over 6 weeks. Endostatin and OHP were both intravenously administered at doses of 7.5 mg/m2 daily for 2 weeks and 135 mg/m2 on day 1, respectively, every 3 weeks. The primary endpoint was the objective response rate (ORR).
RESULTS: The analysis included 37 patients. The median age was 63 years (range: 49-71 years), and all patients were stage III-IVA. Of these patients, 97.3% (36/37) completed the dCRT course with an ORR of 83.8%, including 10 (27.0%) patients with complete response and 21 (56.8%) patients with partial response. The median overall survival (OS) time was 18.5 months (95% confidence interval [CI]: 10.6-26.4) with a 2-year OS rate of 39.6% (95% CI: 0.202-0.590). The median progression-free survival (PFS) time was 11.5 months (95% CI: 7.6-15.4) with a 2-year PFS rate of 20.2% (95% CI: 0.049-0.355). Grade 3 toxicities included esophagitis (five patients) and leukocytopenia (three patients). Grade 4 leukopenia was observed in one patient. Late toxicity was infrequent, and no treatment-related death occurred. Posttreatment dysphagia scores were significantly improved when compared with baseline (p < .001).
CONCLUSION: dCRT based on OHP and endostatin resulted in high treatment compliance with manageable toxicities. This combination resulted in encouraging ORR without compromising survival outcomes. It should be validated in future clinical studies. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

Endostatin, a novel artificially synthesized antiangiogenesis drug, has been tested as a potential therapeutic strategy to overcome tumor resistance in many types of solid tumors, including non‐small cell lung cancer, colorectal cancer, bone soft tissue sarcoma, and metastatic malignant melanoma, in combination with different regimens of chemotherapy. However, it has been rarely tested in combination with chemoradiotherapy for patients with ESCC.

To our knowledge, this is the first study to evaluate oxaliplatin in combination with endostatin as first‐line treatment for inoperable ESCC.

The primary endpoint of this study was set to evaluate the efficiency of oxaliplatin and endostatin on the ORR of patients with ESCC. A Simon's optimal two‐stage design was required to accept the hypothesis that the true ORR was greater than 80% with 80% power and to reject the hypothesis that the ORR was less than 60% with a type I error of 0.05. After testing the combination on 13 patients with ESCC in the first stage, the trial would be terminated if 8 or fewer had an overall response. If the trial proceeded to the second stage, a total of 35 patients with ESCC would be enrolled. Considering some deviant cases, the preplanned accrual number was set to 37 patients.

Waterfall plot of responses to definitive concurrent chemoradiotherapy.

Based on our findings, the current treatment regimen was effective, with the primary endpoint (ORR) exceeding 80% for unresectable ESCC. Toxicities of this combination were quite acceptable, with only one patient recorded with grade 4 leukopenia; 97.3% of the patients completed treatment without changing treatment plan, with a median OS and PFS of 18.5 (95% CI: 10.6–26.4) and 11.5 (95% CI: 7.6–15.4) months, respectively. This treatment combination should be validated in future large sample clinical studies.

Trial Information

Esophageal cancer

Primary

None

Phase II

Single arm

Overall response rate

Toxicity

Overall survival

Progression‐free survival

Active and should be pursued further

Drug Information

Oxaliplatin

Eloxatin

Sanofi‐Aventis

Small molecule

Platinum compound

135 milligrams (mg) per squared meter (m2)

IV

Oxaliplatin 135 mg/m2 was administered as a 2 h intravenous infusion in 500 mL of 5% glucose on day 1 and day 22 during the treatment

Endostatin

Endostar

Simcere‐Medgenn Bio‐Pharmaceutical

Antibody

7.5 milligrams (mg) per squared meter (m2)

IV

Endostatin, 7.5 mg/m2 over 3 h infusion between days 1 and 14 and between days 22 and 35

Patient Characteristics

31

6

21 (56.8%) patients had clinical stage III; 16 (43.2%) patients with ESCC were diagnosed with clinical stage IVa

Median (range): 63

Median (range): 0

0 — 14

1 — 23

2 — 0

3 — 0

Unknown — 0

Detailed patient characteristics are presented in Table 1

Table 1.

Patients’ characteristics (n = 37)

Abbreviations: dCRT, definitive concurrent chemoradiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status.

Esophageal squamous cell carcinoma, 37

Primary Assessment Method

New Assessment

Total Patient Population

37

37

37

37

RECIST 1.1

n = 10 (27.0%)

n = 21 (56.8%)

n = 5 (13.5%)

n = 1 (2.7%)

n = 0 (0%)

11.5 months, CI: 7.6–15.4

18.5 months, CI: 10.6–26.4

Adverse Events

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

The present study was designed to evaluate the efficacy and toxicity of oxaliplatin (OHP)‐based definitive concurrent chemoradiotherapy (dCRT) combined with endostatin for patients with esophageal squamous cell carcinoma (ESCC). Our results demonstrated that the current combination was effective, with the primary endpoint (objective response rate, ORR) exceeding 80.0%; the treatment‐related toxicities were quite acceptable with only one patient recorded with grade 4 leukocytopenia. Additionally, compliance with this treatment regimen was much higher than historical reports in the setting of double‐regimen dCRT without markedly sacrificing survival outcomes.

Unsatisfactory treatment outcomes had driven physicians to further explore potential treatment combinations to improve the dismal situation for the management of ESCC. According to the landmark results of the RTOG 85‐01 trial, the combination of cisplatin and fluorouracil (5‐FU) resulted in substantial toxicity with all cycles of chemotherapy, and the combination could only be administered as planned in 33 of 61 (54%) patients with esophageal cancer (EC) [3]. In another trial, RTOG 0436 [4], patients with EC were randomly assigned to receive concurrent cisplatin and paclitaxel with or without weekly cetuximab in combination with radiotherapy. Results indicated that the grade 3 or higher hematologic toxic effects were 45% in the dCRT plus cetuximab group and 44% in the dCRT group. The 2‐ and 3‐year overall survival (OS) rates for the dCRT plus cetuximab group were 45% and 34% versus 44% and 28% for the dCRT group (hazard ratio, 0.90; 95% confidence interval, 0.70–1.16; p = .47). Moreover, 109 (69%) patients treated in the dCRT plus cetuximab group and 127 (75%) in the dCRT group received chemotherapy per protocol, with dose modifications were recorded in 87 (55%) and 85 (50%) in each group, respectively. This trial failed to demonstrate any survival improvement for patients with locally advanced EC treated with dCRT plus targeted therapy. Insignificant results were also seen in the SCOPE‐1 trial, which evaluated the addition of cetuximab to 5‐FU and cisplatin‐based chemoradiation treatment scheme [5]. As for bevacizumab, another vascular endothelial growth factor inhibitor, a former phase II trial had indicated that the addition of bevacizumab and erlotinib to neoadjuvant chemoradiation also did not demonstrate any survival benefit or improved pathologic complete response rate over similar regimens without targeted therapies [6]. Thus, the rationale of combining doublets chemotherapy with targeted inhibitors for unselected patients with EC seems impracticable in a series of prospective studies. To date, few studies have evaluated the efficacy of single‐agent chemoradiotherapy for non‐age‐selected EC patients. In a phase II study evaluating the feasibility and efficiency of dCRT with single‐agent chemotherapy of S‐1, 93.3% (28/30) patients with EC completed the full course of radiotherapy with no grade 4 toxicity or treatment‐related death. Survival analysis demonstrated that the median progression‐free survival (PFS) and OS time was 19 and 24 months, respectively [7]. This treatment combination showed favorable efficacy with acceptable toxicity in elderly patients with EC. But the suitability of single‐agent dCRT for non‐age‐selected patients with EC still remains uncertain at the current stage.

As a potent radio‐sensitizing drug that could overcome resistance to cisplatin, OHP had also been assessed for the management of EC with different combinations in a series of studies. In the PRODIGE5/ACCORD17 trial [8], 133 patients with EC were assigned to receive FOLFOX regimen; results showed that combined chemoradiotherapy was delivered as planned in 93% patients in the FOLFOX group. Although survival analysis indicated no significant difference between the FOLFOX group and the 5‐FU and cisplatin group, the FOLFOX regimen was associated with a marginally significant reduction of treatment‐related death compared with the 5‐FU and cisplatin regimen (1 vs. 6; p = .066). The authors concluded that although dCRT with FOLFOX did not increase PFS and OS compared with dCRT based on 5‐FU and cisplatin, the FOLFOX regimen might be a more convenient treatment option for patients with unresectable EC. Previously, we also reported a phase II clinical trial evaluating the efficiency and safety of dCRT based on OHP and paclitaxel for patients with EC [2]. Our results indicated that 26 (76.5%) of 34 patients finished dCRT on schedule with a median OS of 23.7 months. Toxic effects were acceptable, with grade 3 and 4 leukocytopenia recorded in eight (23.5%) and five (14.7%) patients, respectively.

Regarding improvement in the dysphagia score, which was another important indicator of functional status for patients with EC, our results indicated that 24 (64.9%) patients experienced improvement of dysphagia score after dCRT by at least one grade when compared with baseline. This result was consistent with the findings of Ueda et al. [9]. In their report, the dysphagia score was improved after dCRT in 36 (72%) patients with metastatic esophageal cancer and did not change between before and after treatment in 14 (28%) patients. Because dysphagia score has been confirmed as having a substantial impact on the quality of life, we might consider that this treatment could also bring improved quality of life for patients with ESCC.

In conclusion, this pilot study demonstrated that the combination of OHP and endostatin in the setting of dCRT could be safely delivered in patients with unresectable ESCC. Patients with ESCC highly complied with this treatment regimen, and the toxicities associated with therapy were quite manageable. No significant reduction in survival was noted. It should be validated in future large sample clinical studies.

Kaplan‐Meier curves of OS and PFS.

Abbreviations: OS, overall survival; PFS, progression‐free survival.

Distribution of dysphagia score at baseline and after dCRT.

Abbreviation: dCRT, definitive concurrent chemoradiotherapy.