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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References

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 (= 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 (= 0.024). The PFS for patients with EGFR-expressing tumor was longer compared with the PFS of patients with negative EGFR (= 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 (< 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.[1] 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.[2] Surgery is traditionally considered the best treatment for esophageal cancer, but surgical resection is possible in just 15–20% of all cases.[3] 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,[9] 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.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References

Study population

Patients newly diagnosed with stage II to stage IVa ESCC who were either not able to undergo surgery or who chose not to undergo surgery were included in the present study. Additional inclusion criteria were as follows: age of 18 years or older; the Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; and adequate bone marrow, hepatic and renal functions, defined as hemoglobin ≥100 g/L, WBC ≥3.8 × 109/L, absolute neutrophil count (ANC) ≥1.5 × 109/L, platelets ≥100 × 109/L, ALT or AST <2.5 times the upper normal limit, bilirubin ≤1.5 times the upper normal limit, and serum creatinine ≤1.5 g/L. The eligible patients had no other previous or concurrent malignancy, and no prior chest irradiation or systemic chemotherapy.

All tumors were staged according to the 2009 TNM (tumor, node, metastasis) classification,[14] and clinical staging was based on the results of endoscopy, barium swallow, endoscopic ultrasound (EUS), computed tomography (CT) or PET/CT scanning. In addition, the EGFR status of the tumors was detected.

The study followed the Declaration of Helsinki and was approved by the institutional review board of Zhengzhou University Affiliated Tumor Hospital. Written informed consent was obtained from the patients or their families prior to entering the study.

Chemotherapy

Cetuximab (Erbitux; Merck KGaA, Darmstadt, Germany) was administered at a dose of 400 mg/m2 (day 1 of week 1), followed by 250 mg/m2 weekly (weeks 2–8). Chemotherapy concurrent with radiation therapy was initiated on the day of the second infusion of cetuximab. The chemotherapy regimen consisted of paclitaxel (45 mg/m2) and cisplatin (20 mg/m2), repeated weekly for a total of 7 weeks. Dexamethasone 20 mg, diphenhydramine 50 mg and ranitidine 50 mg were administered intravenously for 30 min before chemotherapy administration. Patients underwent electrocardiogram monitoring for 5 h at the beginning of treatment.

Radiotherapy

Information from the barium swallow, the endoscopic examination and the CT scan was studied in detail before delineation of target tumor volume selected to receive radiation. The clinical target volume (CTV) encompassed the gross target volume (GTV) and the region draining the lymphatics based on the primary esophageal tumor location, which was defined as follows: the superior and inferior borders were 40 mm beyond GTV, and the lateral, anterior and posterior borders were 7 mm beyond GTV. The planning target volume (PTV) was created using an isotropic 3-D expansion of the CTV to 7 mm.

Radiation therapy was delivered using a high-energy linear accelerator (≥6 MV), and patients were treated with radiation therapy 5 days per week at a daily dose of 1.8 Gy/day, with the total dose of 59.4 Gy. Intensity-modulated radiation treatment planning was performed to ensure that an adequate dose was delivered to the target and that the total radiation dose was limited in normal tissues. The goal of the radiation therapeutic regimen was to achieve a dose volume constraint of V20 < 35% for the lungs, V30 < 40% for the heart, and a maximal dose of 45 Gy to the spinal cord. Liver dose was limited to V30 < 30% and a mean liver dose <20 Gy.

Toxicity assessment and treatment modifications

Toxicity assessment was performed weekly throughout all phases of the treatment program. Acute chemotherapy toxicity was graded based on the NCI common toxicity criteria (CTC). The cetuximab dose was not reduced for hematological toxicity, but the dose was decreased by 50 mg/m2 if other grade 4 toxicities were reported. A suspension of chemotherapy dosing was required if patients developed grades 3 or 4 toxicities, and the chemotherapy resumed when the toxicity improved to grade 2 or less. The paclitaxel and cisplatin doses were not reduced.

The Radiation Therapy Oncology Group (RTOG) morbidity scoring criteria was used to classify acute and late radiation toxicity. Patients' radiotherapy was postponed when grade 4 hematological toxicity or grades 3 or 4 toxicities related to radiation (skin and gastrointestinal reactions) developed. The radiation therapy resumed when serious adverse events resolved, with no reduction in prescribed radiation dose.

A patient was withdrawn from the study if the therapeutic regimen was delayed for either haematological or non-haematological toxicity for more than 2 weeks.

EGFR mutations

Frozen tumor sp amplification reactions were carried out following a nested polymerase chain reaction using isolated DNA as a template and using external and internal primers, as previously described.[15] Sequencing of polymerase chain reaction products was performed using the Applied Biosystems PRISM dye terminator cycle sequencing method with an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). We validated EGFR mutation detection using high-resolution melting analysis following the detailed analysis method described by Nomoto et al.[16] Human genomic DNA was used as a control sample with wild-type EGFR. Tumors were judged to have mutations when samples revealed left-shifted curves from those of the control samples.

Immunohistochemistry

Formalin-fixed, paraffin-embedded tissues (4 μm thick) were de-waxed in xylene, dehydrated in ethanol and then heated in a microwave oven (800 W) for 8 min to retrieve the antigens. Tissue sections were incubated with 3% hydrogen peroxide in methanol for 30 min to block endogenous peroxidase, and then washed with phosphate-buffered saline solution. The samples were incubated at 4°C overnight with anti-EGFR monoclonal antibody (dilution, 1:100; Santa Cruz Biotechnology, Santa Cruz, CA, USA). Subsequent steps were carried out according to the manufacturer's instructions. Diaminobenzidine (DAB) was used as the substrate to detect antigen-antibody binding, and the samples were counterstained with Mayer's haematoxylin. EGFR immunoreactivity was detected in normal epithelial cells of the esophagus and in squamous cell carcinoma tissues. For evaluation of EGFR expression, membranous and cytoplasmic staining of tumor cells was scored from 0 to 3 as follows: 0, no staining; 1, weak (approximately 10% cells with faint staining intensity); 2, moderate (at least 10% cells with moderate staining intensity); 3, strong (at least 10% cells with strong staining intensity). Moderate to strong immunostaining was judged as positive EGFR expression.

Evaluations of EGFR protein expression and gene mutations were performed independently by two pathologists without knowledge of the patients' clinical characteristics or other tumor biological features.

Follow up

Physical examination, barium swallow, cervical/thoracic/abdominal CT and endoscopy were performed 1 month after the completion of all the therapy. These tests were subsequently performed every 3 months for the first year and every 4 months thereafter for all patients in the study. A complete clinical response was defined as no tumor at the follow-up endoscopy with biopsy 4–6 weeks after completion of the treatment regimen.

Statistical analysis

The survival curves were constructed using the actuarial Kaplan–Meier method and differences between the curves were analyzed using the log-rank test. The PFS was assessed from the date of treatment to the first date of disease progression or death from any cause. Overall survival was calculated from the date of treatment until death from any cause or last follow up. The difference of response rates was tested using the Chi-squared method. All statistical analyses were performed using spss software (version 16.0.1; SPSS Inc., Chicago, IL, USA) and the correlation was significant at the 0.05 level (two-tailed).

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References

Patient characteristics

From January 2009 to August 2011, 31 patients were enrolled in the present study (Fig. 1). The median age was 63 years (range, 36–81 years). Twenty-one patients were male and 24 (77.4%) patients were aged between 55 and 70 years. Fourteen patients had stage II, nine had stage III and eight had stage IVa disease; 18 (58.1%) patients presented with node-positive disease according to clinical staging.

image

Figure 1. Patient disposition.

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Therapeutic efficacy

Of the 29 patients who were evaluable for a response, 20 (69.0%) had a clinical complete response (CR) and the remaining nine had a partial response (PR), resulting in an objective overall response rate (ORR = CR + PR) of 100%. We also assessed the correlations between tumor response and patient and tumor characteristics. Higher rates of CR were observed in patients with early stage disease, positive EGFR-expressing tumor and grade ≥2 cetuximab-induced rash. However, there was no significant difference in clinical tumor response with respect to other characteristics (sex, performance status and tumor location) (Table 1). An additional 2–4 cycles of triweekly chemotherapy of paclitaxel (135 mg/m2) plus cisplatin (75 mg/m2) was administered to eight patients who had a PR.

Table 1. Patient characteristics and correlation with response
CharacteristicCRPR P
No.%No.%
  1. AJCC, American Joint Committee on Cancer; CR, complete response; EGFR, epidermal growth factor receptor; PR, partial response.

Gender
Male14706670.648
Female630333
Age (years)
Median62 65  
Range36–81 58–78 
Performance status
09454440.887
11155556
Tumor location
Cervical210  0.304
Upper thoracic630333
Middle/lower thoracic1260667
AJCC clinical stage
II11552220.000
III525333
IVa420444
EGFR expression
Negative8405560.024
Positive1260444
Rash grade
0–17355560.003
2–31365444

Over a median follow-up period of 23.6 months (range, 6.5–37.5 months), no death was noted in the present study. Disease progression was observed in seven patients: one patient developed tumor recurrence at the primary site; one had lung metastasis; one had liver metastasis; one developed regional lymph node recurrence; two developed non-regional lymph node metastases; and one patient presented with non-regional lymph nodes and bone metastases. The 1- and 2-year PFS rates were 85.5% and 75.1%, respectively (Fig. 2A).

image

Figure 2. (A) Progression-free survival for the evaluable patients enrolled in the present study (= 29). Kaplan–Meier curves for progression-free survival according to (B) treatment response, (C) epidermal growth factor receptor (EGFR) protein expression level and (D) rash grade.

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We then analyzed the clinical pathological factors affecting the PFS of ESCC patients after cetuximab combined with chemoradiation. A longer PFS was observed in patients who achieved CR compared with those who had a PR, although this difference did not reach statistical significance. The 1-year PFS rates were 89.4% and 76.2%, respectively, = 0.069 (Fig. 2B). The time to progression was shorter for patients with regional or non-regional lymph node metastases than for those without lymph node involvement; the 1-year PFS rates were 78.7% and 92.3%, respectively (= 0.038).

Expression of EGFR

We evaluated the presence of activating mutations in the EGFR gene exons 18–21 and also EGFR protein expression. Sixteen patients (55.2%) were positive for EGFR expression using immunohistochemical staining (Table 1) and only two (6.9%) displayed an EGFR gene mutation in exon 19. The patients with EGFR-expressing tumor had a CR rate of 75.0% compared with 61.5% in those with negative EGFR expression (= 0.024). The PFS for patients with EGFR-expressing tumors was longer compared with the PFS of patients with negative EGFR (1-year PFS rate, 87.1% vs 83.9%), but this was not significantly different (= 0.133) (Fig. 2C).

Treatment toxicity

Toxicity reactions were assessed in all 31 patients; 29 patients experienced at least one adverse event during the present study and two patients experienced grade 4 toxicity. Two patients withdrew from the study: one had gastrointestinal toxicity after the third week of chemotherapy and irradiation with 34.2 Gy, but the symptoms did not resolve over 2 weeks; and the other developed a tracheoesophageal fistula after 23 days of treatment, which was treated surgically. In the remaining 29 patients, three had their treatment interrupted <5 days because of toxicity reactions.

No deaths occurred due to toxic reactions, and no cardiac toxicities or hypersensitivity reactions to paclitaxel were reported. Prophylactic feeding tubes were not used. In general, the regimen was well tolerated. The most common toxicity noted with chemoradiation and cetuximab was rash (87.1%), and five (16.1%) patients had grade 3 cutaneous toxicity. The PFS was significantly better in patients who experienced an acneiform rash of at least grade 2 severity compared with those with no rash or grade 1 rash; the 1-year PFS rates were 93.8% and 74.1%, respectively (= 0.022) (Fig. 2D). The rates of grade 3 and 4 esophagitis were 6.5% and 3.2%, respectively. Other grade 3 non-hematological toxicities included anorexia (3.2%) and nausea (3.2%). Two patients (6.9%) experienced hypomagnesemia. Hematological toxicity included grade 3 and 4 neutropenia, 19.4% and 3.2%, respectively. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 3.2% of patients, respectively. Acute toxicities are listed in Table 2. Multiple toxicities in the same patient are scored as separate events.

Table 2. Toxicities to treatment regimen
 No. patients (= 31)All grades
Grade 2Grade 3Grade 4No.%
Non-hematological
Rash12502787.1
Esophagitis8212167.8
Fatigue200516.1
Anorexia310825.8
Constipation100412.9
Diarrhea10039.7
Nausea210722.6
Vomiting00039.7
Weight loss300825.8
Electrolyte imbalance
Hyponatremia00026.5
Hypomagnesemia200516.1
Hypokalemia10039.7
Hypocalcemia00013.2
Hematological
Neutropenia9612374.2
Anemia310929.0
Thrombocytopenia210825.8

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References

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.[19] 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.[20] EGFR expression correlates with advanced disease, decreased survival and a poor prognosis.[21]

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.[22] 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.[27] 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.[28]

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.[27] 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.

Disclosure Statement

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References

The authors have no potential conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure Statement
  7. References
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