Esophageal cancer ranks 8th in the world in terms of incidence and 6th in terms of mortality, with approximately 400,000 new patients worldwide each year (HomsMYV, v.d. GaastA, SiersemaPD, et al. 2008). Esophageal cancer is predominantly squamous cancer in China and adenocarcinoma in developed western countries. The incidence of esophageal cancer in China is the 4th highest among tumors, and the main reasons for its treatment failure are distant metastases, uncontrolled local tumors and recurrence. As a systemic treatment, chemotherapy is an important part of comprehensive treatment for esophageal cancer. From the 1980s to the present, chemotherapy regimens for esophageal cancer have mostly used the combination of cisplatin and 5-fluorouracil, with an efficiency of 40% to 58% in neoadjuvant chemotherapy (GebskiV, BurmeisterB, SmithersBM, et al. 2007) and 25% to 35% in palliative chemotherapy (EnzingerPC. IlsonDH, KelsenDP.1999). In the past 5 years, studies have continued to explore the efficacy of next-generation chemotherapeutic agents in the treatment of esophageal cancer, mainly focusing on palliative chemotherapy for advanced esophageal cancer.
Previous palliative chemotherapy for esophageal cancer mostly used the combination chemotherapy regimen of cisplatin (Cisplain, DDP) and 5-fluorouracil (5-FU), with an efficiency of 25%-35% and a median survival time of 6-9 months, with the main side effects of mucositis and bone marrow suppression, but there is still no evidence-based medical evidence that palliative chemotherapy can prolong the survival of patients with advanced In 2006, Homs et al. (HomsMYV, v.d. GaastA, SiersemaPD, et al. 2006) published a Meta-analysis of chemotherapy for advanced esophageal cancer, collecting seven randomized controlled clinical trials (n = 1284), which showed that palliative chemotherapy based on DDP combined with 5-FU did not prolong the survival of advanced survival in esophageal cancer. Recent studies have mostly treated advanced esophageal cancer with a regimen of next-generation chemotherapeutic agents in combination with DDP or 5-FU.
1.Capecitabine (Xeloda, capecitabine)
Capecitabine is an oral fluorouracil drug that is rapidly absorbed in the gastrointestinal tract as a prodrug and is metabolized in the liver and tumor tissue to 5-FU, which has antitumor activity. a phase II clinical trial conducted by Lee et al. (LeeJ, ImYH, ChoEY. 2008) used Xeloda 1250mg/m2p.o.bidd1 to d14 and DDP 60mg/ m2i.v.d.d1 every 21 d (XP) regimen as first-line chemotherapy for 45 patients with advanced esophageal squamous carcinoma, with an efficiency of 57.8%, 26 cases in partial remission (Partialresponse, PR), no patients achieving complete remission (Completeresponse, CR), and progression-free survival ( Mediantimetoprogression (TTP) of 4.7 months (95% CI, 2.5-7.0), median survivaltime (MST) of 11.2 months (95% CI, 8.5-13.9), and common side effects were anorexia (18/191, 9.4%) and neutropenia (33/191). granulocytopenia (33/191, 17.3%), and the incidence of hand-foot syndrome was only 3.1% (6/191), with easily controlled toxicity. Another study conducted by Lee et al. (LeeSS, KimSB, ParkSI, et al. 2007) used 2 courses of XP (Xeloda 1000mg/m2p.o.bidd1 to d14 and DDP 60mg/m2i.v.d.d1 every 21d) followed by 54Gy of radiotherapy in 48 patients with stage M1a + concurrent single-week regimen XP (800 mg/m2p.o.bidd1 to d5 and DDP 30 mg/m2i.v.d.d1) for a total of 5 courses, with a TTP of 8.4 months (95% CI, 5.5 to 11.3) and an MST of 13.8 months (95% CI, 10.4 to 17.3) for patients with stage M1a esophageal squamous carcinoma. Xeloda administration is convenient, has little mucosal side effects, and the efficacy appears to be superior to 5-FU in the current small sample trial, pending further validation in phase III clinical trials.
Tegeo (S-1) is also an oral fluorouracil analog, consisting of a complex of tegafur (FT), gimeprazine (CDHP), and octreotide (Oxo). In Japan, S-1 has been approved for the treatment of advanced gastric cancer, colorectal cancer, non-small cell lung cancer, and head and neck cancer. Several studies have shown that S-1 is a broad-spectrum and safe anti-cancer drug. Three case reports (SeikeJ, YoshidaT, HondaJ, et al. 2006; KanamoriN, FujiiM, TakahashiT, et al. 2007; SeikeJ, MatsuokaH, YuasaY, et al. 2008) reported that patients with advanced esophageal cancer using an S-1-containing combination chemotherapy regimen after achieving CR, but data from phase II clinical trials or retrospective studies with small samples are still not reported and remain to be investigated.
2.Paclitaxel drugs
Paclitaxel can promote the polymerization and stabilization of microtubules, block mitosis, and inhibit tumor growth, which has broad-spectrum anti-tumor effects, as well as certain radiosensitizing effects, and the toxic side effects are easily tolerated. DDP (paclitaxel 175 mg/m2i.v.d.d1 and DDP 40 mg/m2i.v.d.d2 to d3 every 21 d) as a first-line regimen for advanced esophageal squamous carcinoma in a phase II clinical trial (n=30) with a median number of 3 courses, and the results showed an effective rate of 59.3%, CR in 5 cases (18.5%), PR in 11 cases (40.7%), and TTP of The study by Zhang et al. (ZhangXD, ShenL, LiJ, et al. 2007) also used paclitaxel + DDP (paclitaxel 175 mg/m2i.v.d.d1 and DDP75mg/m2i.v.d.d1 every 21 d) as a first-line regimen for advanced esophageal squamous carcinoma in a clinical trial (n=47), receiving a total of 2 to 6 courses of chemotherapy with a chemotherapy efficiency of 42.6%, followed by non-randomization into two groups, 21 cases in the radiotherapy group and 26 cases in the non-radiotherapy group, which showed a TTP of 5 months and an MST of 11 months in the non-radiotherapy group and The study by Cho et al. (ChoSH, ChungIJ, SongSY, et al. 2005) used paclitaxel + DDP (paclitaxel 90 mg/m2i.v.d.d1 and DDP 50 mg/m2i.v.d.d1 every 14 d) as a second-line regimen to treat 32 patients with advanced esophageal squamous carcinoma. The effectiveness rate was 41% with an MST of 7 months, 1-year survival rate of 28.1% and 2-year survival rate of 7.1%. Several small sample studies have used the doxorubicin + nedaplatin (OsakaY, TakagiY, HoshinoS, et?al. 2006; KanaiM, MatsumotoS, NishimuraT, et?al. 2007; FujitaY, HiramatsuM, KawaiM, et?al. 2008) regimen for second-line treatment of advanced esophageal squamous carcinoma with an MST of 7 to 11.4 months. The effect of paclitaxel is more certain, and phase III clinical trials are available.
3.Vincristine (vinorelbine, NVB)
Conroy et al. (ConroyT, EtiennePL. 2002) treated 71 patients with advanced metastatic esophageal squamous carcinoma with NVB + DDP (NVB25mg/m2i.v.d.d1,d8 and DDP180mg/m2i.v.d8). m2i.v.d.d1 every 21 d) regimen with an efficiency of 33.8%, a TTP of 3.6 months and an MST of 6.8 months, and a major toxic reaction of neutropenia. The combination of vincristine and paclitaxel has also shown some efficacy in advanced esophageal cancer. airoldi et al. (AiroldiM, CortesinaG, GiordanoC, etal. 2003) reported on 20 patients with advanced esophageal squamous carcinoma treated with NVB + doxorubicin regimen (NVB 20mg/m2i.v.d.d1, doxorubicin 80 mg/m2i.v.d.d1 every 21 d) chemotherapy for a maximum of 6 courses with an efficiency of 60% and an MST of 10.5 months. The efficacy needs to be further studied.
4.Camptothecin
The cytotoxic effect of camptothecin by inhibiting topoisomerase I was found to be synergistic with DDP. Lee et al. (LeeDH, KimHT, HanJY, et al. 2008) used Irinotecan + DDP (Irinotecan 65mg/m2i.v.d.d1,d8 and DDP 30mg/m2i.v.d8) to treat the disease. m2i.v.d.d1, d8 every 21 d) regimen to treat 32 patients with advanced esophageal squamous carcinoma with an effective rate of 31.3%, TTP of 4.4 months, MST of 9.6 months, 1-year survival rate of 27.4%, and 50% of patients with 3rd to 4th degree neutropenia.Irinotecan alone remains effective in patients with advanced disease who have failed DDP therapy. A phase II clinical study by Burkart et al. (BurkartC, BokemeyerC, KlumpB, et al. 2007) showed that in 14 patients with advanced esophageal squamous carcinoma who failed DDP therapy, they were treated with single-agent Irinotecan chemotherapy (Irinotecan 100 mg/m2i.v.d. d1, 8, 15, per 28d) with a TTP of 2 months (1 to 8 months) and an MST of 5 months (2 to 16 months).
5.Nedaplatin (NED)
NED is a new second-generation organic platinum-based anticancer drug, an analogue of DDP. a phase II clinical study by Xu et al. (XuRH, ShiYX, GuanZZ, etal. 2006), comparing the efficacy of NED+5-FU with PF regimen in advanced esophageal squamous carcinoma (n = 52), 30 in NF group and 22 in PF group, showed that the efficiency of NF group was higher than that of PF group ( 29.62% vs. 22.72%,P
6.Carboplatin
In a study by Jiang et al. (JiangY, QiuXH, YangYX, etal. 2006), carboplatin + formyltetrahydrofolate + 5-FU was used to treat 32 cases of advanced esophageal squamous carcinoma with an efficiency of 46.86% and an MST of 9 months, compared with the cisplatin regimen, the gastrointestinal response of this regimen was minimal, and its efficacy needs to be further investigated.
In conclusion, the efficacy of the new generation chemotherapeutic agents for advanced esophageal squamous carcinoma is not clear, Xeloda and paclitaxel have better efficacy with an effective rate close to 50% and MST about 10-11 months, NVB and irinotecan seem to have comparable efficacy with the traditional regimen, and the combination of NED and doxorubicin provides more options for second-line treatment of advanced esophageal squamous carcinoma. However, the current rationale is mostly from phase II clinical studies with small samples, and phase III clinical trials are urgently needed to clarify the efficacy of various drugs. In addition, oxaliplatin (L-OHP) and gemcitabine (GEM) have been shown to be effective in the palliative treatment of esophageal adenocarcinoma, but they have rarely been reported in the palliative treatment of esophageal squamous carcinoma, and their efficacy also needs to be studied.
Neoadjuvant chemotherapy
A preoperative combination chemotherapy regimen based on cisplatin and 5-Fu was applied in the 1980s, after which the combination of cisplatin and 5-Fu became the standard regimen for the treatment of esophageal cancer, with an efficiency of about 40%-58% (GebskiV, BurmeisterB, SmithersBM, etal. 2007). Preoperative chemotherapy is usually two to three courses, and the interval between preoperative chemotherapy and surgery is two to four weeks. Into the late 1990s, with the application of new generation chemotherapeutic drugs such as paclitaxel, doxorubicin, irinotecan, and nedaplatin, they also began to be used in neoadjuvant chemotherapy for esophageal cancer, and mostly combined with neoadjuvant radiotherapy for the co-treatment of esophageal cancer.
In a phase II clinical trial by Polee et al. (PoleeMB, TilanusHW, EskensFA, et al. 2003), a neoadjuvant chemotherapy regimen of paclitaxel + DDP (paclitaxel 180 mg/m2i.v.d.d1 and DDP 60 mg/m2i.v.d.d1 every 14 d) was used to treat 50 patients with esophageal cancer (47 squamous carcinoma and 3 adenocarcinoma). , 3 adenocarcinoma), 1 in stage IIA, 16 in stage IIB, 21 in stage III, and 12 with unknown stage, patients received 3 courses of chemotherapy, and those who were effective received another 3 courses of chemotherapy followed by surgery, and the results showed a chemotherapy efficiency of 59%, an MST of 20 months, a 1-year survival rate of 68%, and a 3-year survival rate of 30%. in 2007, Gebski et al. (GebskiV. BurmeisterB, SmithersBM, et al. 2007) Meta-analysis of 8 randomized controlled clinical trials of preoperative chemotherapy with surgery versus surgery alone (n = 1724) and 10 randomized studies (n = 1209) comparing the efficacy of neoadjuvant radiotherapy with surgery versus surgery alone was collected and the overall results showed that preoperative chemotherapy resulted in relative risk of death in patients with esophageal cancer by 10%, (HR 0.90; 95% CI 0.81 to 1.00; P = 0.05) and increased 2-year survival in patients with esophageal cancer by 7%, i.e., the number of patients who would need to receive chemotherapy to reduce death in one case (the inverse of the absolute value of risk reduction) was 15; preoperative radiotherapy also reduced the risk of death in patients with esophageal cancer ( HR0.81; 95% CI0.70-0.93; P?=0.002), which could reduce their relative risk of death by 19% and increase the 2-year survival rate of patients with esophageal cancer by 13%, i.e., the number of patients who would need to receive radiotherapy or chemotherapy to reduce death in one case was 8. This suggests that preoperative radiotherapy is more effective than preoperative chemotherapy. As a result, more studies are using new generation chemotherapeutic agents for neoadjuvant radiotherapy.
Among neoadjuvant radiotherapy, paclitaxel has been studied more frequently. hsu et al. (HsuFM, LinCC, LeeJM, et al. 2008) retrospectively analyzed 127 patients with esophageal squamous carcinoma who received concurrent radiotherapy and compared the efficacy of paclitaxel + DDP (TP) and PF regimens. patients were all stage II-III, 44 received radical radiotherapy, 83 received neoadjuvant Lin et al. (LinCC, HsuCH, ChengJC, et al. 2007) used neoadjuvant radiotherapy with TP regimen for the treatment of intermediate to advanced esophageal cancer, enrolling In 2008, a phase III clinical trial of neoadjuvant radiotherapy (CROSS trial) was initiated in the Netherlands, in which paclitaxel + carboplatin was used as the chemotherapy regimen. It is expected to clarify the efficacy of neoadjuvant radiotherapy and surgery. The Center for Cancer Control of Sun Yat-sen University (Yang H, Fu JH, Hu T, et al. 2008) conducted a phase II clinical trial of preoperative radiotherapy and surgery for locally advanced esophageal cancer from January 2000 to December 2004. 42 consecutive patients with locally advanced squamous esophageal cancer in the thoracic segment who met the enrollment criteria were admitted. The preoperative radiotherapy regimen: 25 mg/m2 of norethindrone vincristine was administered intravenously on days 1, 8, 22 and 29, or 2.4 g/m2 of 5-FU was administered intravenously for 72 h on days 1 to 3 and 22 to 24, and 75 mg/m2 of DDP was administered intravenously on days 1 and 22. 2.0 Gy/d of conventional fractionated radiotherapy was administered 5 days a week for a total of 40 Gy during the same period. Four to six weeks after the end of radiotherapy, esophageal cancer resection was performed and the digestive tract was reconstructed. The clinical efficiency of preoperative radiotherapy was 83.3%. 40 cases received further surgery, with an R0 resection rate of 97.5% and a complete pathological remission rate of 23.8%. The 1-, 3- and 5-year survival rates for the whole group were 66.9%, 54.5% and 44.9%, respectively, with a median survival time of 43.4 months; the disease-free survival rates at 1, 3 and 5 years were 61.1%, 48.7% and 39.5%, respectively, with a median disease-free survival time of 32.7 months. Preoperative radiotherapy-induced myelosuppression, pulmonary toxicity, and esophageal toxicity were mostly of degree 1 to 2. There were no toxic side effects of preoperative radiotherapy leading to inoperability to operate or death. The postoperative pulmonary infection, severe arrhythmia, and perioperative mortality were 22.5%, 20%, and 5%, respectively. The results showed that preoperative radiotherapy and surgery can achieve high clinical efficiency and complete pathological remission rate, significantly reduce the stage of esophageal cancer, and are expected to improve the survival rate of localized mid- to late-stage esophageal cancer.
Adjuvant chemotherapy
In 2008, a Meta-analysis conducted by Zhang et al. (JZhang, H-QChen, Y-WZhang, et al. 2008) collected six randomized controlled clinical trials (n = 1001) of surgery with postoperative adjuvant chemotherapy versus surgery alone and showed that postoperative adjuvant chemotherapy failed to prolong the survival of patients with esophageal cancer, and further stratified analysis showed that in a trend toward prolonged survival in patients presenting with regional lymph node metastases (OR 0.763; 95% CI 0.538-1.083; P>0.05). The authors also reported the results of a retrospective study of adjuvant chemotherapy for esophageal cancer, in which a total of 270 patients with esophageal cancer were enrolled in the trial, 90 in the chemotherapy group and 180 in the no-chemotherapy group, with a mean age of 53.81 years (34-68 years) in the chemotherapy group and 56.06 years (30-77 years) in the no-chemotherapy group, with only 4.4% of patients with adenocarcinoma in both groups, and approximately 74% of patients in both groups undergoing three-field esophageal cancer In both groups, only 4.4% were adenocarcinoma patients, and approximately 74% of patients underwent lymph node dissection for esophageal cancer in three fields. The chemotherapy regimen was cisplatin (25 mg?m-2?d-1, days 1 to 3) + fluorouracil (375 mg?m-2?d-1, days 1 to 5) + folinic acid (135 mg?m-2?d-1, days 1 to 5) in 3-week cycles, administered within 7 weeks after surgery, and 4 to 6 cycles of chemotherapy were planned. The results of their study showed that postoperative adjuvant chemotherapy failed to prolong the survival of patients with esophageal cancer but prolonged the survival of patients with stage IVA, with 1- and 3-year survival rates of 75% and 25%, respectively, for the 26 patients with stage IVA in the unchemothered group and 100% for the 22 patients with stage IVA in the chemotherapy group (P=0.01).
The results of a previous Meta-analysis by Malthaner et al. (MalthanerRA, WongRK, RumbleRB, et al. 2004) also showed that postoperative adjuvant chemotherapy failed to improve the prognosis of patients with esophageal cancer. Therefore, there are very few clinical trials investigating the role of next-generation chemotherapeutic agents in adjuvant chemotherapy for esophageal squamous carcinoma. However, most of the previous clinical trials were based on DDP + 5-FU chemotherapy regimens, and the new chemotherapeutic agents are better than the traditional regimens in terms of efficiency, side effects, and ease of use. Therefore, we believe that the use of new chemotherapeutic agents for postoperative adjuvant chemotherapy for intermediate and advanced esophageal squamous carcinoma is a future research direction.
In conclusion, the development of chemotherapy for esophageal cancer is slow, and there are no clear conclusions and standard protocols in the fields of palliative chemotherapy, neoadjuvant chemotherapy and adjuvant chemotherapy. The main reasons are: most of the patients in western developed countries are esophageal adenocarcinoma, and there are only a few patients with esophageal squamous carcinoma in their clinical studies, so the conclusions drawn are difficult to be applied to the treatment of esophageal squamous carcinoma; although China is a country with a high prevalence of esophageal squamous carcinoma, there is a lack of strict prospective randomized controlled clinical trials. In contrast to other tumors, such as breast cancer and lung cancer, the research on chemotherapy and molecular targeted drugs has developed very rapidly, and the current research hotspots have focused on three aspects: from general pathological typing to specific pathological typing, for example, lung cancer used to be divided into small cell lung cancer and non-small cell lung cancer, but now chemotherapy should take into account adenocarcinoma, large cell carcinoma or squamous carcinoma; from phenotype (Phynotype) to genotype ( For example, in the application of gefitinib for non-small cell lung cancer, only the expression of EGFR was considered in the past, but now the mutation of EGFR 19, 20 and 21 should be considered; from whether the gene is expressed to how much it is expressed, for example, in the application of Herceptin for breast cancer, not only the expression of CerBb-2 but also its overexpression should be considered.
Translational research in molecular biology has greatly promoted the development of tumor therapy and provided the possibility of individualized tumor treatment. Some of our doctors think that chemotherapy for esophageal cancer is ineffective and has no future for research, but in fact, the median survival of advanced lung cancer treatment at the end of last century was only 8 months, which is also very poor. At present, the development of tumor drug therapy is very clear. As a country with high incidence of esophageal squamous carcinoma, we cannot sit back and wait for the research progress of developed countries, and we cannot copy the research results of other countries due to the genetic differences of different human races, we should carry out our own clinical trials, and in the process, we should pay attention to the translational research of molecular biology to find the molecular markers related to the treatment of esophageal squamous carcinoma, and be in the world esophageal cancer academic field, this undertaking is imperative to achieve the status it deserves.