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- Patients and Methods
- Disclosure Statement
This study investigated cetuximab added to definitive concurrent chemoradiation for esophageal squamous cell carcinoma (ESCC). Previously untreated patients with stage II–IVa ESCC received cetuximab (400 mg/m2 per week in week 1, then 250 mg/m2 per week during weeks 2–8), paclitaxel (45 mg/m2 per week) and cisplatin (20 mg/m2 per week) in weeks 2–8 with 59.4 Gy radiotherapy. Epidermal growth factor receptor (EGFR) status in tumor specimens was assessed. Thirty-one patients were enrolled and evaluated for toxicity. Of the 29 patients assessable for a response, 20 (69.0%) had a clinical complete response (CR). Over a median follow up of 23.6 months, disease progression was observed in seven patients. The 1- and 2-year progression-free survival (PFS) rates were 85.5% and 75.1%, respectively. The PFS was shorter for patients with lymphatic metastatic disease than for those with locally confined tumor; the 1-year PFS rates were 78.7% and 92.3%, respectively (P = 0.038). Sixteen (55.2%) patients were immunohistochemically positive for EGFR. The patients with EGFR-expressing tumor had a CR rate of 75.0% compared with 61.5% in those with negative EGFR expression (P = 0.024). The PFS for patients with EGFR-expressing tumor was longer compared with the PFS of patients with negative EGFR (P = 0.133). The patients with prominent cetuximab-induced rash (≥grade 2) had a better CR rate and PFS than those with no or grade 1 rash (P < 0.05). The rates of grades 3/4 esophagitis, hematological and dermatological toxicities were 9.7%, 29.0% and 16.1%, respectively. The regimen of definitive chemoradiation plus cetuximab achieved good clinical response and has an acceptable safety profile in Chinese ESCC patients.
Esophageal cancer is among the top 10 most common cancers worldwide, and it has the fifth highest mortality rate among tumors at various sites within the body. The incidence of esophageal cancer has been increasing over the past three decades, and esophageal cancer remains the fourth leading cause of cancer death in China. Surgery is traditionally considered the best treatment for esophageal cancer, but surgical resection is possible in just 15–20% of all cases. Definitive chemoradiation is the standard treatment option for patients with esophageal cancer who are unsuitable for surgery either because of the presence of co-morbidity or because of the extent of disease. The US Intergroup RTOG 85-01 and other studies[4-8] enrolled predominantly patients with esophageal squamous cell carcinoma (ESCC). These studies have shown a remarkably consistent overall patient survival of 30–40% and a median survival of 14–18 months after treatment with definitive concurrent chemoradiation.
Although significant long-term results have been achieved using modern regimens of chemoradiation, the majority of ESCC patients will die of their disease, most commonly with local tumor progression or recurrence. Thus, improvements in local disease control might translate into an increase in long-term cures. Repopulation of clonogenic tumor cells during fractionated radiation treatment is known to be a principal mechanism of tumor radio-resistance. Research has indicated that the epidermal growth factor receptor (EGFR) can mediate radio-resistance in various solid human tumors, and result in tumor cell growth during fractionated radiotherapy. The monoclonal antibody, cetuximab, might overcome radiation-induced tumor cell growth stimulation in patients treated with chemoradiotherapy. Cetuximab has demonstrated synergistic activity with both radiotherapy and platinum-based chemotherapy in colorectal, non-small-cell lung and head and neck cancers.[10-13] However, the activity and safety of cetuximab in combination with concurrent chemoradiation in ESCC have not been well established.
We conducted this study of cetuximab, paclitaxel, cisplatin and concurrent radiation for treatment of ESCC patients. The primary end-points were tumor response and progression-free survival (PFS) in patients receiving cetuximab and definitive chemoradiation, treatment failure patterns and factors affecting treatment outcome were also investigated.
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- Patients and Methods
- Disclosure Statement
Surgery remains the main treatment for patients with potentially resectable esophageal cancer with no evidence of metastatic disease; however, the majority of patients are not eligible for surgery either because of the presence of co-morbidity or because of the extent of disease. Definitive chemoradiation (CRT) recommended by the RTOG 85-01 has now become standard practice in ESCC patients who are not surgical candidates, and the subsequent overall survival rate is comparable with those who underwent surgery. Following CRT, 45–58% of patients have local failure, which is mainly a result of persistent or recurrent diseases.[4-6, 17] Clinical studies have attempted to improve the clinical outcome by reducing the rate of local disease recurrence through integrating radiotherapy and chemotherapy in variable sequences in patients with ESCC, but a clear benefit has never been achieved.[7, 18]
The EGFR, ErbB-1, is the cell-surface receptor for members of the EGF family of extracellular protein ligands. EGFR is a member of the ErbB receptor tyrosine kinase family; EGF and transforming growth factor alpha (TGF-α) are natural ligands of EGFR. Through ligand stimulation, EGFR initiates one of the most important cellular growth-regulating pathways. Binding of a stimulatory ligand to the extracellular domain of EGFR results in activation of cytoplasmic tyrosine kinase and initiation of intracellular signal transduction cascades, thereby triggering cellular mechanisms that regulate cell growth, proliferation and differentiation. The EGFR signal transduction network plays an important role in multiple tumorigenic processes, contributing to cell cycle progression, angiogenesis, metastasis and protection of the cancer cell from apoptosis. The EGFR is constitutively expressed in a wide range of normal epithelial tissues, particularly in the basal layers of stratified epithelium and in squamous epithelium. Overexpression of EGFR, as wild type or with mutations, is seen in many human solid tumors. EGFR expression correlates with advanced disease, decreased survival and a poor prognosis.
Cetuximab (C225, Erbitux) is a human–mouse chimeric anti-EGFR that contains the human IgG1 constant region. Cetuximab blocks binding of EGF and TGF-α to EGFR and blocks phosphorylation and activation of EGFR tyrosine kinase. Cetuximab also stimulates EGFR internalization, effectively removing the receptor from the cell surface and thereby from interaction with the ligand. These events result in activation of immune functions through inhibition of cell growth, induction of apoptosis, decreased matrix metalloproteinase levels and inhibition of tumor angiogenesis.
Cetuximab, as a single agent or in combination with chemotherapy or radiotherapy, has demonstrated significant clinical efficacy against colorectal cancer and other solid tumors.[13, 23] Pathological analysis found that EGFR overexpression occurs in 29–92% of esophageal cancer patients and that it correlates with a poor prognosis.[24-26] However, it is not known whether a clear clinical benefit can be achieved from combining cetuximab with the chemoradiation regimen for esophageal cancer. The efficacy of concurrent chemoradiation plus cetuximab in ESCC has been evaluated in clinical trials. Safran et al. assessed cetuximab, paclitaxel and carboplatin in combination with 50.4 Gy radiation in 12 ESCC patients and found that this regimen had a 72% complete response rate. Recently, the final results of the Groupe d'Etude et de Recherche Clinique en Oncologie et Radiotherapie (GERCOR) phase II trial were released. The GERCOR study enrolled 79 patients with locally advanced cardia or esophageal cancer treated with the chemotherapy regimen FOLFOX (oxaliplatin, leukovolin and 5-fluorouracil) plus cetuximab and with radiotherapy at 50.4 Gy, and 53 patients with squamous cell carcinoma. After a median follow up of 19.4 months, an overall response rate was achieved in 77.2% of patients and the median PFS was 13.8 months.
Compared with a higher frequency of EGFR mutations detected in non-small-cell lung cancer (NSCLC), the EGFR kinase domain mutations were rarely detected in ESCC tumors.[29, 30] In the present study, EGFR mutations were detected in two of 16 patients with positive EGFR expression tumors. This suggests that EGFR overexpression is caused by increased EGFR gene copy number in just a fraction of esophageal tumors. However, patients with EGFR-expressing tumors experienced a significantly higher CR rate and demonstrated a trend towards improved time to progression while on treatment. The findings of the present study further suggest that analysis of EGFR expression using immunohistochemistry is an effective way to predict the efficacy of CRT plus cetuximab regimen in ESCC patients. Moreover, as high EGFR expression has been shown to be an adverse prognostic factor for esophageal cancer patients, it is conceivable that a higher CR and better PFS might be achieved if patients were selected on the basis of positive EGFR expression.
A radiation dose of 59.4 Gy was administered in the present study and the results revealed good local disease control. A CR was observed in 69.0% of ESCC patients, which is similar to the findings of Safran et al., but the 100% objective response rate observed in this study was significantly higher than in previous studies.[27, 28] In addition, no persistent tumor was found and only two patients developed local recurrence. It is reasonable to believe that delivering a prescribed dose of 59.4 Gy at 1.8 Gy/fraction is an appropriate radiation regimen for Chinese patients with esophageal cancer.
Radiation esophagitis is one of the most common acute toxicities during concurrent chemoradiation. The rate of grade 3/4 esophagitis in the present study was 9.7%, which is similar to previous studies with paclitaxel-based chemoradiation,[31, 32] and indicates that esophagitis was not increased with the addition of cetuximab to chemoradiation compared with these studies. There was also no increase in hematological toxicity; the observed rates of grades 3 and 4 hematological toxicities were 25.8% and 3.2%, respectively, in the present study, which is similar to previous observations.
Dermatological toxicities were increased with the addition of cetuximab. The most common cutaneous toxicity was a painful, pruritic acneiform rash on the face, which usually developed within the first to third week of cetuximab administration. The painful, pruritic acneiform rash was also observed on patients' neck and chest areas, but the rash on the neck and chest was less common and less severe than the rash observed on the face. The grades 2 and 3 dermatological toxicities occurred in 38.7% and 16.1% of patients, respectively, which is lower than the 25% incidence of grade 3/4 dermatological toxicity reported by Safran et al. Interestingly, we found that a 76.5% (13/17) CR rate was achieved in patients with prominent cetuximab-induced rash (grade 2 or above), while a CR rate was 58.3% (7/12) in patients with grade 1 rash or no rash. Patients with a prominent rash also displayed significantly better PFS than those with no or grade 1 rash. Studies showed that grade ≥2 rash strongly correlated with overall survival improvements in cetuximab-treated lung cancer and head/neck cancer patients.[33, 34] Rash development thus should be viewed as a positive event indicative of greater likelihood of clinical benefit from cetuximab treatment. Moreover, there was no increase in the severity of skin toxicities on the area within the radiation field in the present study. Applying warm and wet compresses with honeysuckle extract to the affected areas for 20 min three times a day could be very helpful in treating the rash.
In conclusion, this study demonstrates that definitive chemoradiotherapy plus cetuximab achieves a significant clinical response for Chinese patients with ESCC, and that cetuximab can be safely added to chemoradiation without an increase in the toxicity profiles. Randomized controlled trials are needed to further confirm the enhancement of antitumor activity using cetuximab in esophageal cancer patients who are treated with chemoradiation.