The incidence of esophageal cancer occupies the 8th place among all malignant tumors, and there are about 480,000 new cases worldwide each year. China is a high incidence area of esophageal cancer, with an average of 150,000 deaths per year, accounting for the 4th place of all malignant tumor deaths.
At present, the first choice of treatment for esophageal cancer is still surgery, with a 5-year survival rate of 90% after early surgery, but the majority of patients are in the middle and late stages when they are seen in hospitals, and only 20% of them are operable, with a 5-year survival rate of 20%-30% after surgery, and the overall survival rate of esophageal cancer has not improved significantly in the past 25 years. It is difficult to improve the efficacy of any single treatment modality significantly. Rational arrangement of comprehensive treatment procedures in a purposeful and planned manner has been widely appreciated.
1.Preoperative radiotherapy
If the cancer has invaded or adhered to the neighboring organs, it is not easy to be completely removed by surgery or cannot be removed, and there is a risk of cancer spreading and implantation. Preoperative radiotherapy can shrink the tumor, reduce the vitality of cancer cells, occlude the small blood vessels and lymphatic vessels around the tumor and fibrosis the surrounding tissues, improve the local resection rate and reduce the metastasis rate, and improve the survival rate. Liu Yanzhong divided 864 patients with stage III esophageal cancer into two groups. In the radiotherapy group, 526 cases were treated with preoperative radiotherapy and surgery, and 338 cases in the control group were treated with surgery alone.
The radical surgical resection rate and 1-year survival rate in the radiotherapy group were significantly higher than those in the control group (P<0.01), and the differences in postoperative complications and 5-year survival rate between the two groups were not statistically significant (P>0.05). The results suggest that preoperative radiotherapy for stage III esophageal cancer can improve the radical surgical resection rate, without increasing postoperative complications, and improve the near-term prognosis. In a study by Liu Quanxi, the observation group was given preoperative radiotherapy of 40 Gy and underwent radical resection of esophageal cancer with a small left chest incision after 2-3 weeks, while the control group underwent radical resection of esophageal cancer with a conventional incision. The results showed that the observation group could improve the recent survival rate and reduce postoperative complications.
2. Preoperative concurrent radiotherapy
So far, the effect of preoperative concurrent radiotherapy in the adjuvant treatment of esophageal cancer is more significant. Firstly, radiotherapy can take into account both local tumor and possible micro-metastases. Secondly, some chemotherapeutic drugs have the effect of radiotherapy sensitization, and their simultaneous use can reduce the dose of radiotherapy to reduce the adverse effects and improve the compliance and efficacy of treatment. The results of a phase III clinical trial by Stahl et al. showed that there was no difference in the surgical resection rate between the two groups compared with preoperative chemotherapy, but the preoperative radiotherapy group had a higher rate of complete pathological response (pCR) and lymphatic clearance. pCR) and negative lymph node clearance rates (15.6%:2.0% and 64.4%:37.7%, respectively), and the 3-year survival rate increased from 27.7% to 47.4% in the preoperative radiotherapy group. Another phase III clinical trial concluded that preoperative radiotherapy improved the median survival time and 5-year survival rate compared with surgery alone (4.48:1.79 and 39%:16%, respectively).
The results of several Meta-analyses in recent years also confirmed that preoperative concurrent radiotherapy + surgery significantly prolonged patients’ 1-, 2-, and 3-year survival rates, reduced local recurrence rates, and led to a decreased risk of death compared with surgical treatment alone, but did not reduce the incidence of post-surgical complications. Concomitant radiotherapy-naïve patients who received surgical salvage therapy improved median overall survival by 11.2 months compared with those who did not receive surgery; therefore, salvage surgery is an effective treatment option for concomitant chemoradiotherapy-naïve patients.
Prospective clinical studies at home and abroad have found a significant association between pCR and survival. pCR has become an important indicator for determining the prognosis of esophageal cancer. diaz et al. designed a clinical study in which 73 patients with esophageal cancer received preoperative cisplatin decafluorouracil + radiotherapy (50.4 Gy) with a clinical complete remission rate of 54%, 25 of whom received sequential surgical treatment with a pCR of 32%, and another The median survival time was 10. 33 months in 16 inoperable patients with one additional cycle of chemotherapy and 10 Gy radiotherapy, and the 2- and 5-year survival rates were 22% and 16%, and the factor that significantly influenced the survival time was the clinical complete remission rate. Therefore, further improvement of pCR in the comprehensive treatment of esophageal cancer is the key to the next clinical research.
3.Postoperative radiotherapy
The purpose of postoperative radiotherapy for radical esophageal cancer is to eliminate subclinical lesions in order to improve the survival rate. There are 2 types of postoperative radiotherapy: one is that the cancer tissue is not completely removed by surgery, and postoperative radiotherapy further destroys the residual cancer tissue. The other scenario is prophylactic radiotherapy after radical surgery. In a phase II clinical trial by Schreiber et al. that included 1046 patients with esophageal cancer, of whom 683 were treated with radiation alone and 363 with postoperative radiotherapy, the results showed that the number of lymph node metastases was one of the factors affecting the survival rate of patients with esophageal cancer according to the American Cancer Society ( The results showed that postoperative radiotherapy improved 3-year survival and disease-specific survival in patients with stage III or higher according to the Americanjoint Committee on Cancer (AJCC) staging, but there was no significant advantage for stage II patients. Currently, it is believed that postoperative prophylactic irradiation is beneficial for patients with palliative surgery, stage III patients and patients with positive lymph node metastases, and can improve survival rates.
4.Postoperative concurrent radiotherapy
Most clinical studies of postoperative adjuvant radiotherapy for esophageal cancer have not achieved satisfactory results, so it is combined with chemotherapy in order to become a better treatment option for postoperative patients and improve survival. bedenne et al. showed that compared with radical radiotherapy, postoperative radiotherapy has significantly improved local control rate. The Southwest Oncology Collaborative Group (INT) 0116 study demonstrated that postoperative adjuvant radiotherapy improved overall survival (P = 0.004) and tumor-free survival (P < 0.001), and concluded that the most ideal model of postoperative adjuvant treatment for stage N1 esophageal cancer is postoperative radiotherapy + chemotherapy.
Most patients with esophageal cancer have poor systemic conditions after surgery and find it difficult to tolerate radiotherapy and chemotherapy. Therefore, postoperative radiotherapy and chemotherapy should be implemented selectively according to the specific conditions of patients. Stage II and III esophageal cancer tolerates well to postoperative concurrent adjuvant radiotherapy, so it is recommended to perform postoperative concurrent radiotherapy.
5.Simultaneous radiotherapy
Concurrent radiotherapy alone is often used for patients with late clinical stage, hypopharynx, upper thoracic segment occupancy, organ function limitation and unwillingness to accept surgery for esophageal cancer. The aim is to utilize the complementary and synergistic effects of radiotherapy and chemotherapy to improve the local control rate and reduce distant metastases, thus improving survival. A Meta-analysis by Wong and Malthaner concluded that concurrent radiotherapy improved overall survival, tumor-free survival, and local control rates in patients with esophageal cancer compared with sequential radiotherapy.
The differences in overall survival and tumor-free survival rates for esophageal squamous carcinoma with radical radiotherapy compared with conventional surgical resection were not statistically significant, further confirming the place of radical radiotherapy in the treatment of esophageal squamous carcinoma. Some of these clinical studies even concluded that patients who underwent preoperative radiotherapy with significant clinical remission and good regression of tumor should be switched to radical radiotherapy instead of recommending sequential surgical treatment, because sequential surgery would instead increase the risk of treatment-related death, while sequential surgical salvage therapy could be chosen when the tumor is insensitive to radiotherapy.
Concurrent chemoradiotherapy for esophageal cancer has the advantages of preserving organs and improving patients’ quality of life, reducing the local recurrence rate and prolonging the survival period compared with radiotherapy alone.
6.Simultaneous chemoradiotherapy combined with new target drugs
In recent years, the combination of molecular targeted drugs with radiotherapy is a hot spot in tumor treatment. The commonly used molecular targeted drugs include anti-epidermal growth factor receptor (EGFR) drugs, tyrosine kinase inhibitors, anti-HER-2 monoclonal antibodies, vascular endothelial growth factor (VEGF), and endothelial growth factor (EGF). endothelial growth factor (VEGF) inhibitors, cyclooxygenase (COX) inhibitors, etc.
6.1 ECFR monoclonal antibodies
The rate of positive expression in esophageal cancer is 50%-80%, and EGFR-targeted inhibitors can improve the radiosensitivity of tumor cells by blocking multiple EGFR-related signaling pathways. 57 cases of esophageal cancer were selected by Safran et al. and given cetuximab combined with paclitaxel and carboplatin chemotherapy and 50.4 Gy radiotherapy at the same time. 40 cases achieved complete remission without increasing treatment-related adverse effects. This suggests that cetuximab may have a sensitizing effect on radiotherapy.
6.2 Tyrosine kinase inhibitors
Ferry et al. reported 27 cases of advanced esophageal adenocarcinoma treated with gefitinib, 70% of which had received chemotherapy, and were treated with oral gefitinib 250 mg/d. As a result, 13% achieved partial remission and 29% achieved stabilization with a median time to progression of 1.9 months, and genetic analysis of tumor tissues after treatment revealed downregulation of genes related to cell proliferation and apoptosis pathways.
In a phase II trial by Rodriguez et al, patients received preoperative radiotherapy with cisplatin 20 mg/m2 on days 1-4, fluorouracil 1,000 mg/m2 on day 1, radiotherapy 30 Gy/20 f twice daily, surgery 4-6 weeks after radiotherapy, and then radiotherapy 6-8 weeks after surgery with the same protocol as preoperative, oral gefitinib preoperatively and postoperatively at the same time as radiotherapy ( In the experimental group, there was no increase in adverse effects other than mild rash and diarrhea, and there was a tendency for patients with diarrhea to have a favorable prognosis compared with the no gefitinib group. Another phase II clinical trial reported 22 cases of esophageal cancer treated with erlotinib (150 mg/d) monotherapy, with 2 cases of partial remission, 10 cases of stability and 10 cases of progression after 4 weeks, suggesting that the efficacy of erlotinib is certain.
6.3 Anti-HER-2 monoclonal antibody
The positive rate of high C-erbB2 expression was reported to be around 10%. In patients with HER-2-positive esophageal adenocarcinoma, Safran et al. added trastuzumab in combination with radiotherapy to a paclitaxel + cisplatin regimen with weekly cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 and concurrent radiotherapy 50.4 Gy for 6 weeks. No increase in adverse effects was seen, while efficacy increased.
6.4 VEGF inhibitors
VEGF is highly expressed in many malignant tissues and is closely related to biological behaviors such as invasive metastasis and poor prognosis. shah et al. selected 20 patients with advanced esophageal cancer who had lost their surgical indication and treated them with a combination of bevacizumab, irinotecan, and cisplatin, and achieved a disease control rate of 87%. In addition to bevacizumab, vascular endothelial inhibitor is also a multi-targeted angiogenesis inhibitor, which can specifically act on endothelial cells, especially those of microvessels, to inhibit their migration and induce apoptosis, thus inhibiting angiogenesis and tumor growth.
6.5 COX inhibitors
COX is an important rate-limiting enzyme in catalyzing the oxidative synthesis of prostaglandins from arachidonic acid, of which COX-2 has been shown to be significantly up-regulated in the expression of a variety of tumors, especially digestive system tumor tissues and corresponding tumor cell lines, and is seen as one of the early events in tumor formation. Among the COX-2 inhibitors, the most representative drug currently available is celecoxib. Clinical research organizations, including the Anderson Cancer Center Phase II clinical study, have shown that the combination of COX-2 inhibitors with chemoradiotherapy in the treatment of locally advanced esophageal cancer has initially shown a high safety profile and superior efficacy in the neoadjuvant and maintenance treatment of esophageal cancer.
The application of molecular targeted therapy has brought the possibility of prolonging the survival and improving the quality of survival for esophageal cancer patients. Esophageal cancer is a complex disease with many potential targets that can be blocked or inhibited. As the research progresses, the new generation of anti-tumor drugs targeting molecular targets will become the main research direction for esophageal cancer treatment by virtue of their specificity and targeting.
7.Conclusion
Esophageal cancer has a poor prognosis, and the rational formulation of individualized multidisciplinary comprehensive treatment plan can improve survival and enhance its quality of life. New treatments are needed to improve the survival and quality of life of advanced, recurrent or metastatic esophageal cancer. The continuous emergence of new anti-cancer drugs and the development and research of molecular targeted drugs and their clinical application make the prospect of comprehensive treatment of esophageal cancer more promising. The planned and rational combination of surgery, radiotherapy, chemotherapy, molecular targeted therapy and other therapeutic means to bring into play their respective potentials with complementary advantages and synergy is expected to bring a breakthrough in the treatment of esophageal cancer.