Clinical Investigation
Phase II Study of Concurrent Chemoradiation in Combination With Erlotinib for Locally Advanced Esophageal Carcinoma

Presented in part at the 44th American Society of Clinical Oncology Annual Meeting, May 30–June 3, 2008, Chicago, IL.
https://doi.org/10.1016/j.ijrobp.2009.10.012Get rights and content

Purpose

To investigate the feasibility and efficacy of concurrent chemoradiation in combination with erlotinib for locally advanced esophageal carcinoma.

Methods and Materials

Twenty-four patients with locally advanced esophageal carcinoma were treated with concurrent chemoradiotherapy. A daily fraction of 2.0 Gy was prescribed to a total dose of 60 Gy over 6 weeks. Concurrent paclitaxel (135 mg/m2, d1) and cisplatin (20 mg/m2, d1-3) were administered on Day 1 and Day 29 of the radiotherapy. Erlotinib, an oral epidermal growth factor receptor–tyrosine kinase inhibitor, was taken by every patient at the dose of 150 mg daily during the chemoradiotherapy.

Results

The median follow-up of the 24 patients was 18.6 months (range, 7.1–29.6 months). The 2-year overall survival, local-regional control, and relapse-free survival were 70.1% (95% CI, 50.4–90%), 87.5% (95% CI, 73.5–100%), and 57.4% (95% CI, 36.3–78.7%), respectively. During the chemoradiotheapy, the incidences of acute toxicities of Grade 3 or greater, such as leucopenia and thrombocytopenia, were 16.7 % (4/24) and 8.3% (2/24).

Conclusions

Application of concurrent chemoradiotherapy in combination with erlotinib for locally advanced esophageal carcinoma yielded satisfactory 2-year overall survival and local-regional control. The toxicities were well tolerated.

Introduction

Esophageal carcinoma is the sixth most common cause of cancer-related death, and 462,000 new cases were diagnosed during 2002 1, 2. However, the optimal treatment approach for esophageal carcinoma still needs to be elucidated. Surgery is the cornerstone in treatment for esophageal carcinoma. Data from two contemporary randomized studies indicated a median survival ranged from 13.6 to 16 months and 2-year survival of 34% to 37% 3, 4. In these two trials, nearly half of the patients could not achieve R0 resection. After resection alone, approximately 58% of patients experienced local-regional recurrence. It is unknown whether surgery after neoadjuvant chemoradiation is of benefit, although improvement in survival was reported in several series 5, 6.

Concurrent chemoradiation has been widely recognized as a viable option for locally advanced esophageal carcinoma. The Radiation Therapy Oncology Group (RTOG) 8501 trial showed that concurrent chemoradiation is superior to radiation alone as primary therapy (7). The combination of radiotherapy and concurrent chemotherapy with cisplatin and fluorouracil has led to a long-term survival rate of approximately 25%, an outcome similar to that associated with surgery alone. The patterns of failure observed after definitive chemoradiation showed that local-regional control is poor, with approximately 52% patients in the RTOG 8501 study experiencing local failure. Local-regional recurrence of cancer after surgery or radiotherapy alone remains a common problem.

The epidermal growth factor receptor (EGFR) is a member of the erb-B family of receptors with intrinsic tyrosine kinase activity. The EGFR is activated on binding of ligand to its extracellular domain, resulting in autophosphorylation and activation of downstream molecules, such as Ras, ErK, PI3K, and Akt. In tumorigenesis EGFR plays an important role in that it promotes growth of cells and is highly expressed in a variety of solid tumors, with overexpression observed in 29% to 90% of esophageal cancers, which may be correlated with poor prognosis and inferior response to therapy (8). Oral tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate for binding to the receptors of tyrosine kinase domain, inhibit the enzyme's ability to autophosphorylate, and block the receptor-dependent signaling cascade (9).

Early preclinical work showed that radiation-induced EGFR phosphorylation and tumor proliferation could be effectively blocked by the addition of an EGFR-signaling inhibitor (10). Further work in cell culture and xenograft models showed the capacity of EGFR inhibition to enhance radiation response in several tumor types (11). Bonner et al. demonstrated that radiotherapy plus cetuximab improved median and overall survival and significantly enhanced local tumor control in squamous-cell carcinoma of the head and neck (12). Dobelbower et al. reported safety and tolerability of erlotinib delivered at 150 mg/day with concurrent 5-FU, cisplatin, and thoracic radiation in a Phase I study of esophageal carcinoma (13).

Currently, preclinical and limited clinical data suggest that there may be significant potential for epidermal receptor inhibitors to enhance the effectiveness of radiation. The EGFR inhibitors are among the most promising molecular targeting agents in combination with radiotherapy. The potential advantage of EGFR-TKIs includes ease of administration and no issues with infusion reactions. The aim of our study was to evaluate the feasibility and efficacy of erlotinib added to concurrent chemoradiation in patients with locally advanced esophageal squamous cell carcinoma.

Section snippets

Patients

Twenty-four patients with squamous cell carcinoma of the esophagus between January 1, 2007, and October 31, 2008, were enrolled in this trial. All patients had pathologically confirmed esophageal squamous cell carcinoma. The 24 patients were staged according to the International Union Against Cancer (UICC, 2002)TNM stage criteria. Patients were clinically staged T1–4 Nx, M0–1a excluding patients with a tracheoesophageal fistula.

Pre-entry computed tomography (CT) of the thorax and abdomen with

Patient characteristics

Twenty-four patients were enrolled, with a median age of 61 years (range, 40–72 years) and median Karnofsky Performance Status of 90 (range, 80–90). One patient had T2, 17 had T3, and 6 had T4 disease diagnosed by EUS with reference of CT and MRI scans. Sixteen patients had N0, 8 had N1, and 8 had M1a. One patient's lesion was in cervical, 8 in upper, 12 in mid, and 3 in lower locations. Among these 24 patients, 7 had pretreatment weight loss of less than 10%, and 2 of more than 10% (Table 1).

Toxicities

Discussion

Radiotherapy or chemoradiotherapy, in combination with target therapy, had been tried in limited fashion. The introduction of targeted agents against the EGFR pathway has been shown to improve overall survival in locally advanced head and neck carcinomas. The results of the first randomized clinical Phase III trial on simultaneous fractionated irradiation and EGFR inhibition by the monoclonal antibody (mAb) cetuximab (Erbitux) were promising. The landmark study demonstrated the application of

Conclusion

Chemoradiotherapy in combination with erlotinib can be safely delivered in esophageal carcinoma. It has potential to enhance local control and to improve 2-year overall survival in esophageal carcinoma. The toxicities associated with therapy, although manageable, were significant.

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