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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 89-95

Combined nimotuzumab with chemoradiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma: A retrospective study


1 Department of Radiation Oncology, Zhejiang Cancer Hospital (Zhejiang Cancer Research Institute); Department of Medical Oncology, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus); Department of Radiation Therapy, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, People's Republic of China
2 Department of Radiation Oncology, Zhejiang Cancer Hospital (Zhejiang Cancer Research Institute); Department of Radiation Therapy, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, People's Republic of China
3 Department of Medical Oncology, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus); Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People's Republic of China

Date of Web Publication7-Oct-2016

Correspondence Address:
Xiao Zheng
Department of Radiation Oncology, Zhejiang Cancer Hospital (Zhejiang Cancer Research Institute), 38 Guang Ji Road, Hangzhou 310022, Zhejiang
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191612

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 > Abstract 


Aims: To observe the efficacy and toxicities of combined nimotuzumab with chemoradiotherapy as the first-line treatment to advanced esophageal squamous cell carcinoma (ESCC).
Methods: The clinical data of 43 patients with local advanced or metastatic ESCC treated with nimotuzumab combined with chemoradiotherapy in our hospital were included in this retrospective study. The overall response, adverse events, overall survival (OS), and progressive-free survival (PFS) were analyzed.
Results: At 1 month after the treatment, objective response rate (complete response [CR] + partial response [PR]) was 65.12%, and disease control rate (CR + PR + stable disease [SD]) was 86.05%, with one patient (2.33%) showing CR, 27 (62.79%) patients with PR, 9 (20.93%) with SD, and 6 (13.95%) with progressive disease, respectively. The median OS was 15.5 months, and the median PFS was 8.83 months. Multivariate analysis showed that the patients with more cycles (>6 times) of nimotuzumab treatment had better PFS and OS than those with fewer cycles (≤6 times). Patients received high-dose radiation (>55 Gy) had a better PFS than those patients received low-dose radiation (≤55 Gy). Three patients suffered severe esophageal fistula, and three patients showed superficial skin erosion.
Conclusions: Chemoradiotherapy in combination with more than 6 weekly doses of nimotuzumab (>1400 mg) had a survival benefit to the patients with advanced ESCC. High-dose radiation therapy for primary tumor has been confirmed to improve PFS in these patients. Patients treated with nimotuzumab showed no increased risk of adverse events.

Keywords: Chemoradiotherapy, esophageal squamous cell carcinoma, nimotuzumab


How to cite this article:
Lai X, Gu Q, Zheng X, Liu G, Feng W, Lin X, Mao W. Combined nimotuzumab with chemoradiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma: A retrospective study. J Can Res Ther 2016;12:89-95

How to cite this URL:
Lai X, Gu Q, Zheng X, Liu G, Feng W, Lin X, Mao W. Combined nimotuzumab with chemoradiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma: A retrospective study. J Can Res Ther [serial online] 2016 [cited 2018 Aug 16];12:89-95. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/89/191612

Xiaojing Lai and Qing Gu contributed equally to this work.





 > Introduction Top


North-central China is one of the highest risk areas located in the “esophageal cancer belt,” 90% of cases are esophageal squamous cell carcinoma (ESCC).[1] Currently, concurrent chemoradiotherapy is a definitive treatment option for locally advanced and metastatic ESCC. Although surgery and chemoradiotherapy were found to improve local control, progressive-free survival (PFS), and overall survival (OS) in ESCC patients, the rates of treatment failure after therapy were still high. Improvements to the treatment strategy are, therefore, urgently needed.[2] This paper describes the clinical characteristics, prognosis, and adverse events of combined nimotuzumab with chemoradiotherapy in the 43 patients with locally advanced and metastatic ESCC.


 > Methods Top


Patient characteristics

From February 2011 to February 2014, 43 patients (32 male and 11 females) with advanced ESCC treated in our hospital received nimotuzumab in combination with chemoradiotherapy whose clinical information was available. Mean age of these patients was 61-year-old (range 35–79). The main endpoints were clinical tumor response, PFS, OS, and side effects. The inclusion criteria were as follows: (1) All patients were histologically confirmed to have ESCC; (2) newly diagnosed Stage III/IV disease according to the seventh edition of tumor-node-metastasis classification for esophageal carcinoma (EC) (UICC, 2009); (3) with a Karnofsky performance status score ≥60; (4) metastatic disease limited to ≤3 sites; (5) no radiotherapy or chemotherapy contraindications; and (6) presumed ability to tolerate thoracic radiation therapy at doses ≥36 Gy; the exclusion criteria were: (1) Previously received thoracic surgery, radiotherapy, or chemotherapy; (2) with malignant pleural or pericardial effusion; and (3) have other malignant disease. The disease characteristics of these ESCC patients are listed in [Table 1].
Table 1: Baseline characteristics of the patients with ESCC

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Treatment schedule

High levels of expression of epidermal growth factor receptor (EGFR) in the range of 60–70% have been known in ESCC patients,[3] the EGFR status was not examined in all ESCC patients. A dosage of nimotuzumab: 200 mg/week was found to be the appropriate dose on the basis of nimotuzumab serum levels, the tumor response, and survival.[4],[5],[6] The patients received an intravenous drip loading dose of nimotuzumab 400 mg/time/week in the 1st week, and then nimotuzumab 200 mg/time/week in the following weeks. All patients were treated with chemoradiotherapy. Radiotherapy was administered at a daily dose of 1.8–2.2 Gy five times a week with 6 MV X-ray accelerators. The Gross Tumor Volume (GTV) was defined as the primary tumor and metastatic lymph nodes, the received dose of GTV was 4500–6600 cGy. The patients with Stage IV disease who treated with synchronous palliative chemoradiotherapy combination with nimotuzumab were included in this retrospective study. The V20 of total lung ≤27–30%, maximum point dose to the spinal cord ≤45 Gy, and the V40 of heart were required to be ≤40–50%. Combination of platinum and fluorouracil (FU) or other chemotherapy regimens were concurrently administered according to each patient's body surface area. All patients received at least two chemotherapy cycles and a thoracic radiation dose of at least 4500 cGy. Blood samples were tested for a routine laboratory analysis of the full blood count, white cells count, neutrophil leukocytes count, and blood platelet count before the administration of nimotuzumab combined with chemotherapy. The 5-hydroxytryptamine receptor antagonist was used to prevent gastrointestinal reactions. Generally, the granulocyte colony-stimulating factor should be used, while the number of white cells and neutrophil leukocytes decreased.

Follow-up

All patients were assessed clinical symptoms weekly during the treatment, and the acute and chronic toxicity was recorded in the medical records. The disease progression and recurrence were determined by means of imaging modalities including ultrasound, computed tomography (CT), magnetic resonance imaging, and positron emission tomography-CT. Follow-up was conducted at 1 month intervals in the first 1 year and at 3 months intervals thereafter.

Statistical analysis

OS was defined as the time from treatment initiation to the date of death from any cause. PFS was defined as the time from the initial treatment to the date of recurrence of cancer or death from any cause. The Kaplan–Meier method was used to estimate the OS and PFS data. The tumor stage, age, chemotherapy regimens, distant metastasis, the cycles of nimotuzumab treatment, and the received radiotherapy dosage of GTV were included in univariate analyses. The analyses of subgroups were based on various clinical characters of the patients, and the statistical differences in the survival of the subgroups were compared using the log-rank test. Multivariate analysis was performed to identify independent prognostic factors by Cox proportional hazards model. P < 0.05 was considered statistically significant. The statistical data were obtained using an SPSS software (version 19.0, IBM Corporation, Armonk, NY, USA).


 > Results Top


Efficacy

At 1 month after the treatment, one (2.33%) patient had attained complete response (CR) and 27 (62.79%) patients had achieved partial response (PR), whereas 9 (20.93%) and 6 (13.95%) patients showed stable disease (SD) and progressive disease (PD), respectively. Objective response rate (ORR = CR + PR) was 65.12%, and disease control rate (DCR = CR + PR + SD) was 86.05%. At the last follow-up, CR, PR, SD, and PD were observed in 8 (18.6%), 2 (4.65%), 0 (0%), and 33 (76.74%) patients, respectively. The ORR was 23.26% [Table 2] and the DCR was 23.26%. The median follow-up time was 16 months. The 1-year and 2-year OS rates were 67.44% and 27.91%, respectively. The median OS (mOS) was 15.5 months (95% confidence interval [CI]: 13.67–17.33 months) [Figure 1]a and [Table 3]. At the last follow-up, 31 (72.1%) patients had died: 12 (27.9%) of local recurrence, 16 (37.2%) of metastasis, and 3 (7.0%) of other causes. The 1-year and 2-year PFS rates were 30.23% and 9.3%, respectively. The median PFS (mPFS) was 8.83 months (95% CI: 5.208–12.452 months) [Figure 1]b and [Table 4]. Univariate analyses and multivariate analyses showed that gender, age, and tumor location were not the predictors of OS and PFS in patients with advanced ESCC.
Table 2: Clinical tumor response in 43 patients with ESCC

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Figure 1: Kaplan–Meier curves of (a) overall survival rate and (b) progress-free survival rate in 43 patients with local advanced and metastatic esophageal squamous cell carcinoma

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Table 3: Analysis for factors associated with overall survival in 43 patients with ESCC

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Table 4: Analysis for factors associated with disease-free survival in 43 patients with ESCC

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On univariate analysis, patients with more cycles (>6 times) of nimotuzumab treatment had better PFS (16.53 months vs. 3.77 months, P = 0.002) [Figure 2]b and [Table 4] and OS (15.87 months vs. 11.63 months, P = 0.036) [Figure 2]a and [Table 3] than those with fewer cycles (y6 times) of nimotuzumab treatment. Patients who had received the dosage of larger than 55 Gy had a better PFS than those patients received a dose ≤55 Gy (11.63 months vs. 3.7 months, P = 0.002) [Figure 3]b and [Table 4]. There was no difference in the OS between the higher dose radiotherapy group and lower dose radiotherapy group (17 months vs. 10 months, P = 0.058) [Figure 3]a and [Table 3]. The tumor stage, age, chemotherapy regimens, and distant metastasis had no statistically significant difference as predictive factors for OS or PFS [Table 3] and [Table 4]. The factors of age, chemotherapy regimens, distant metastasis, radiotherapy doses, and cycles of nimotuzumab treatment were entered into multivariate analysis. Cycles of nimotuzumab treatment (hazard ratio [HR]: 2.781; 95% CI: 1.163–6.649; P = 0.022) [Table 3] were identified as the independent predictive factor for OS. In the analysis of disease PFS, radiotherapy doses (HR: 2.905; 95% CI: 1.014–8.328; P = 0.047) [Table 4] and cycles of nimotuzumab treatment (HR: 2.828; 95% CI: 1.171–6.829; P = 0.021) [Table 4] were the statistically significant factors.
Figure 2: Kaplan–Meier curves for comparisons of (a) overall survival rate and (b) progress-free survival rate between the patients with more cycles (>6 times) and fewer cycles (≤6 times) of nimotuzumab treatment

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Figure 3: Kaplan–Meier curves for comparisons of (a) overall survival rate and (b) progress-free survival rate between the higher dose radiotherapy group (>55 Gy) and lower dose radiotherapy group (≤55 Gy)

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Adverse events

The main adverse events occurred during the treatment included esophagitis, arrest of bone marrow, dermatologic, gastrointestinal reaction, asthenia, and fever. The details of the adverse events by grade and incidence were showed in [Table 5]. None of these patients was found to be allergic to nimotuzumab. Nimotuzumab-related skin rash was not observed in these patients. Other toxicities included pulmonary infection (3/43), intestinal hemorrhage (1/43), lower extremity edema (1/43), and cachexia (1/43). Three patients suffered Grade IV esophagitis and treated by the application of palliative esophageal stent implantation due to severe esophageal fistula. Arrest of bone marrow was mainly Grade I–II, and could be cured by treated with granulocyte colony-stimulating factor. The dermatological was mainly located in the irradiated skin area and mostly presented as erythema and pigmentation. Three patients suffered superficial skin erosion were considered to be caused by the large dose of X-ray irradiation. Asthenia and fever are commonly seen in chemoradiotherapy and might be unrelated to nimotuzumab treatment.
Table 5: Common adverse events during treatment

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 > Discussion Top


EC is the eighth most common human malignancies and the sixth most common cause of cancer death worldwide.[7] The two major histological subtypes of EC are ESCC and esophageal adenocarcinoma (EAC). Surgery is a curative treatment for EC, but only appropriate for 10–20% of the patient population. Unsuitability for surgery might be due to the advanced tumor stage, or because the patients have the comorbidities or poor performance status.[8] Definitive chemoradiation has now become standard treatment in patients with local advanced or metastatic ESCC.[9],[10] The classical chemotherapy regimen for ESCC was recognized to be the combination of FU and cisplatin. In recent years, due to the great efficacy and safety profile, taxane plus cisplatin has been widely used for ESCC treatment.[11]In vitro, Song et al. have reported that autophagic activation with nimotuzumab could enhance chemosensitivity and radiosensitivity of ESCC cells.[12] In a single-center prospective Phase II trial, Lu et al. have reported that nimotuzumab plus paclitaxel and cisplatin: Is an effective combination as the first-line chemotherapy for the patients with advanced ESCC, and the OS was 14.0 months (95% CI: 6.8–21.2 months).[13] The radiotherapy technology for EC has progressed from conventional radiotherapy to precise radiotherapy including intensity-modulated radiotherapy, image-guided radiotherapy, volumetric-modulated arc therapy, and helical tomotherapy.[14] Despite advances in pathogenesis, diagnosis, and multimodal therapies, the prognosis for patients with advanced ESCC remains poor. Therefore, new strategies to improve the outcome of patients with ESCC are needed to be further explored.

EGFR is a member of the ErbB receptor tyrosine kinase family and is overexpressed in up to 55% of esophagogastric cancers.[15] Generally, EGFR overexpression is observed at a higher rate of 50–70% in ESCC compared with EAC.[16] Overexpression of EGFR was significantly related to advanced disease, decreased survival, and a poor prognosis.[17],[18] Through ligand binding and stimulation, the cytoplasmic tyrosine kinase was activated, followed by the intracellular signal transduction cascades were initiated. The downstream signaling pathways for EGFR, such as the PI3K-AKT and RAS-MAPK pathways, were found to be involved in cell cycle arrest, cell apoptosis, cell proliferation, metastasis, and tumor angiogenesis.[19],[20],[21] It has been proven that many EGFR inhibitors, such as gefitinib, erlotinib, icotinib, and cetuximab, were effective and well tolerated in patients with head and neck, nonsmall cell lung, colon, and intestinal cancers.[22],[23],[24] Administration of EGFR inhibitors resulted in reduced cancer cells growth, decreased cancer metastasis, inhibition of tumor angiogenesis, and induction of cancer cells apoptosis.[25],[26],[27]

Nimotuzumab is a humanized anti-EGFR monoclonal antibody, it blocks EGFR activation and its downstream signaling through binding to the extracellular domain of the receptor and inhibiting EGF binding.[28]In vitro, nimotuzumab enhanced the lung cancer and breast cancer radiosensitivity through blocking the PI3K/AKT pathway to inhibit the radiation-induced activation of DNA-PKcs, and ultimately affected the DNA DSBs repair.[29] In another study, nimotuzumab increased ESCC radiosensitivity depending on the upregulation of IGFBP-3 through EGFR-dependent pathway.[30] Nimotuzumab combined with chemotherapy or radiotherapy has also been demonstrated to exhibit significant clinical efficacy against head and neck cancer, high-grade glioma, lung cancer, breast cancer, gastric cancer, and ESCC.[5],[11],[31] However, the efficacy, survival times, and side effects of combining nimotuzumab with the chemoradiation regimen for local advanced and metastatic ESCC, it is not clearly known.

In our study, nimotuzumab combined with chemoradiotherapy was well tolerated in the 43 patients with advanced ESCC. At 1 month after the treatment, a CR was observed in 1 ESCC patient, which is similar to the findings of Liang et al. PR, SD, and PD were observed in 27 (62.79%), 9 (20.93%), and 6 (13.95%) patients, respectively. ORR was 65.12% and DCR was 86.05%. At the last follow-up, CR, PR, SD, and PD were observed in 8 (18.6%), 2 (4.65%), 0 (0%), and 33 (76.74%) patients, respectively. The ORR was 23.26% and the DCR was 23.26%. The 1-year and 2-year OS rates were 67.44% and 27.91%, respectively, and the corresponding PFS rates were 30.23% and 9.3%. The mOS was 15.5 months and the mPFS was 8.83 months. These results are more favorable than those reported for the advanced ESCC patients received chemoradiotherapy without EGFR targeted therapy. In a study reported by Mirinezhad et al., the mOS of patients treated with definitive chemoradiotherapy for locally advanced esophageal cancer was 13.9 months, with 1, 3, and 5 year survival rates of 55%, 18%, and 11%, respectively.[32] In the Radiation Therapy Oncology Group 85-01 trial, the 1-year survival rate of the locally advanced ESCC patients received chemoradiotherapy was 65.8%.[33]

The dose effect of nimotuzumab on OS and PFS was lack of research in previous clinical trials. In our study, univariate and multivariate analysis showed that 29 patients who received more cycles (>6 times) of nimotuzumab treatment (>1400 mg) had better PFS and OS than those with fewer cycles (≤6 times) of nimotuzumab treatment (≤1400 mg). These results indicated us that maintenance of nimotuzumab treatment might take the great benefit to the patients with advanced ESCC. Several articles published before were consistent with our findings; they reported that high-dose or maintained nimotuzumab treatment combined with radiotherapy with or without chemotherapy exhibited significant survival benefit in the patients with locally advanced rectal cancer or high-grade glioma.[34],[35] Ramos-Suzarte et al. reported that the patients with esophageal cancer who received six cycles of 200 mg weekly nimotuzumab have obtained improved survival.[4]. Liang et al. reported that the same regimen of nimotuzumab was effective in the patients with esophageal cancer who received nimotuzumab combined with radiotherapy.[5] More recently, Wang et al. have reported that the high-dose group (>1200 mg) had better survival than the low-dose group (r1200 mg) in esophageal cancer patients who underwent radiotherapy. The prevalent dose for nimotuzumab was 200 mg with six cycles without maintenance.[6] Furthermore, we had found that the patients who had received the dosage of larger than 55 Gy had a better PFS than those patients received a dose ≤55 Gy. However, there was no difference in the OS between these two groups. It indicated us that higher doses of radiation in GTV could improve local control and reduce the recurrence of ESCC, but not prolong the OS of advanced ESCC patients. In a retrospective analysis reported by Wang et al., nimotuzumab dose (1200 mg) and irradiation dose (60 Gy) were independent prognostic factors for OS of esophageal cancer patients.[6] Overall, compared with the patients in the previous retrospective analysis, our patients had worse survival. This can be associated with the advanced tumor stage and the poor performance status.

The main adverse events occurred during the treatment of nimotuzumab combined with chemoradiotherapy are key factors affecting the planned course of therapy. You et al. reported that nimotuzumab could be safety administered up to 800 mg with manageable toxicity.[36] Zhao et al. reported that nimotuzumab of 400 mg/week administered concurrently with chemoradiation was well tolerant in patients with locally advanced squamous cell carcinoma of esophagus.[37] A pilot study has reported that nimotuzumab combined with cisplatin and 5-FU in patients with advanced ESCC was safe and effective.[38] In our study, arrest of bone marrow gastrointestinal reaction, asthenia, and fever could be ameliorate by drug treatment and were well tolerated. Furthermore, three patients treated by the application of palliative esophageal stent implantation due to severe esophageal fistula. The cause of esophageal fistula was tumor invasion of the nearby airways. Three patients suffered superficial skin erosion were considered to be caused by the large dose of X-ray irradiation. Severe side effects often cause the interruption of treatment course and increase the risk of disease recurrence and treatment failure in patients with esophageal cancer. Therefore, management of adverse events during the treatment of advanced esophageal cancer was also crucial for the prognosis of the ESCC patients.


 > Conclusions Top


These results confirmed that a survival benefit was found in patients received maintained treatment of nimotuzumab. High-dose of radiation in a primary tumor could improve local control and reduce the recurrence of EC. Nimotuzumab showed no increased risk of adverse events in patients with locally advanced and metastatic ESCC. However, the adverse events occurred during the treatment of nimotuzumab combined with chemoradiotherapy regimens should be well managed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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