From difficult steps to twists and turns, count the treatment of esophageal cancer

Esophageal cancer, which mainly includes esophageal adenocarcinoma (OAC) and esophageal squamous cell carcinoma (SCC), is the seventh most common cancer worldwide, causing about 450,000 deaths each year
.

Although previously considered a cancer with a poor prognosis, there has been encouraging progress in recent years
.

First, the High-Income Countries Cancer Survival Project (ICBP SURVMARK-2) reported the survival rates of esophageal cancer in two time periods 1995-1999 and 2011-2014, and the results showed that in seven high-income countries, OAC and SCC The 5-year survival rate roughly doubled, with patients under the age of 75 having the greatest impact
.

Second, in the era of combination therapy, the baseline 5-year survival rate for esophageal cancer is close to 50%, which has also doubled in 20 years
.

In addition, monitoring of Barrett's esophagus, gastroesophageal reflux disease, and cancer staging by raising cancer awareness increases the rate of early detection of mucosal and submucosal lesions and allows relatively low-risk endoscopic eradication therapy in selected patients ( EET), such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and radiofrequency ablation (RFA)
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Advances in surgical procedures, including standardization of the extent of surgical resection and lymphadenectomy, improvements in perioperative care, and a range of approaches including minimally invasive and robotic-assisted techniques, have created opportunities to improve patient survival
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With advances in genomics and molecular research, our understanding of esophageal carcinogenesis and tumor biology has grown, new treatments have emerged, and patient outcomes have improved
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However, despite advances in the diagnosis and treatment of esophageal cancer, several issues remain in daily multidisciplinary team discussions and decision-making, including the standard of endoscopic treatment, the choice of neoadjuvant therapy, the differences between SCC and OAC, the Whether patients with obvious complete clinical response to neoadjuvant therapy should consider non-surgical methods or surgical methods, as well as the role of immunotherapy and targeted therapy
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Endoscopic management of mucosal and submucosal cancers Esophagectomy was once the standard approach in patients with high-grade dysplasia (HGD) or mucosal invasion (T1a), in which lymph node metastases ( <2%) rarity supports a more targeted topical approach
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Therefore, EMR and ESD are superior to continuous monitoring or esophagectomy in the latest American Gastroenterology guidelines
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Current management recommends sparing esophagectomy for patients with T1b (submucosal invasion, in which lymph node metastasis occurs in about 20% of cases, and multifocal carcinoma or lesions not suitable for endoscopic resection)
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Therefore, the ability to distinguish mucosal (T1a) and submucosal (T1b) invasion would be valuable
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However, both endoscopic ultrasonography and CT-PET are limited by low sensitivity
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Endoscopy helps guide patients in choosing EMR and ESD
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Type III lesions, and to some extent Type IIc lesions, may be associated with more aggressive tumor growth
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Ulcerative lesions often reflect deeper disease that is less amenable to endoscopic treatment for technical reasons as well as for alternative malnutrition
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EET for OAC When endoscopic resection is considered technically feasible, EMR has become the norm for Western OAC (T1a-m1-3-sm1, early-stage tumors confined to the mucosa or the most superficial third of the mucosa) patients standard treatment
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ESD is also preferred in Japan
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ESD is increasingly being used for larger suspicious lesions where EMR treatment as a whole is not possible
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Criteria for curative resection included negative lateral and deep margins (R0), no lymphatic or vascular invasion (LVI), grade G1 or G2, well-differentiated or moderately well-differentiated, and no penetration outside the first submucosa (SM1).
Transparent, close to <500μm depth
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After biopsy of the tumor bed and biopsy of the entire high-risk segment (from 10 mm above the squamocolumnar junction to 5–10 mm distal to the Z-line of the esophagus) (mucosal biopsy samples taken from proximal to distal) approximately After 8 weeks, endoscopic resection should be performed
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RFA is often used in conjunction with endoscopic surgery, although photodynamic therapy, argon beam coagulation, or cryoablation may also ablate high-risk periepithelial cells
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With such interventions, relapse rates have been reported to range from 4.
5% to 14.
5%, with a median time to relapse of approximately 2 years
.

EET for SCC Endoscopic therapy for SCC is less advanced
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Japan recommends the use of vascular irregularities, such as the loss of loop formation and the presence of dilated and tortuous vessels, as a guideline for predicting the depth of invasion
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When used in conjunction with conventional endoscopy, BLI magnification imaging has been shown to be superior in determining the depth of invasion; in addition, it has low inter-observer variability
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Endoscopic surgery for SCC is the most studied in Japan, therefore, most of the literature is related to ESD
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 Early lesions that can be resected include all lesions with a B1 vascular pattern (predicting infiltration of T1a superficial to muscular mucosa) and a B2 vascular pattern, suggestive of muscular mucosa or superficial Submucosa (SM1) extension, R0, G1/G2 grade, and LVI loss are good prognostic indicators, and in select cases, superficial invasion of the submucosa (≤200 μm) is acceptable
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Marginal involvement and adverse disease (eg, LVI) suggest additional treatment—esophagectomy or adjuvant chemoradiation
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Of the 176 patients initially with ESD, 87 had pT1a with LVI and the remaining patients had pT1b tumors and received adjuvant chemoradiotherapy, reporting a 3-year survival rate of 90%, so this approach can be used as esophagectomy effective alternative
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Optimal therapy for locally advanced esophageal cancer Preoperative chemoradiotherapy has become the standard treatment modality for patients with locally advanced resectable esophageal or borderline cancer, mainly based on the CROSS trial
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The study, which included 366 patients, 75% of whom had OAC, was originally published in 2012
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The results showed that for patients with locally advanced esophageal cancer, neoadjuvant chemoradiotherapy (paclitaxel, carboplatin, and 41.
4 Gy/23 fraction) was superior to surgery alone
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Median survival (OS) was 45 months for OAC patients and 81.
6 months for SCC patients compared to 24 months for the surgery group
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The 5-year OS rate for multimodal therapy (neoadjuvant therapy followed by radical surgical resection) was 47%, and there was no evidence of a significant increase in operative mortality
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Despite the outstanding outcomes, key questions remain, in particular whether this approach is superior to perioperative chemotherapy without radiation and whether definitive chemoradiation is an effective alternative to perioperative chemotherapy
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For the choice of preoperative neoadjuvant chemotherapy regimen for gastric cancer, the German FLOT-4 study attempted to compare the FLOT regimen [fluorouracil (5-FU), tetrahydrofolate, oxaliplatin, and docetaxel] with the ECF regimen (epirubicin The results showed that the median OS of the FLOT group was 50 months, and the pathological complete remission (pCR) rate was 16%, while the median OS of the control group was 35 months, and the pCR rate was 16%.
for only 6%
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Whether neoadjuvant chemoradiotherapy represented by the CROSS regimen is superior to optimal perioperative chemotherapy (FLOT) is the current major concern
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Previous studies, including the prematurely terminated Phase III POET RCT, the Phase II RCT (NeoRES-1), and the small Australian RCT have shown that use of a multimodal regimen failed to show any benefit compared with perioperative chemotherapy.
Survival advantage
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In the NeoRES-1 study, 3-year OS rates were 47% vs 49% for multimodal versus chemotherapy alone, P = 0.
77, despite higher pCR rates (28% vs 9%), pathological (ypN0) involvement The number of lymph nodes was lower (38% vs 65%, P = 0.
001), but perioperative mortality was increased
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At present, there are several phase III clinical studies comparing preoperative chemoradiotherapy with preoperative chemotherapy and perioperative chemotherapy
.

ESOPEC is a prospective, multicenter, phase III RCT study comparing the efficacy of CROSS neoadjuvant chemoradiotherapy and perioperative FLOT chemotherapy in patients with esophageal adenocarcinoma
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Neo-AEGIS is an open-label, multicenter phase III RCT study comparing the efficacy of CROSS neoadjuvant chemoradiotherapy and perioperative mMAGIC chemotherapy in patients with esophageal adenocarcinoma/esophagogastric junction cancer
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The TOPGEAR study is a randomized, multicenter, phase II/III clinical study evaluating neoadjuvant chemoradiotherapy versus ECF regimen neoadjuvant chemotherapy in resectable gastric/esophagogastric junction adenocarcinoma, through April 2017, phase II The results of the study showed that compared with the neoadjuvant chemotherapy group, the neoadjuvant chemoradiotherapy group had comparable adverse reactions and surgical complications, so the study is continuing to enroll patients in phase III
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Another multimodal strategy is to explore the optimal combination of radiotherapy and chemotherapy in neoadjuvant therapy
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In the NEOSCOPE study, 85 patients were randomly assigned to receive neoadjuvant oxaliplatin-capecitabine or carboplatin-paclitaxel combined with 45 Gy concurrent radiotherapy, and the pCR rate was higher in the carboplatin-paclitaxel group
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The PROTECT-1402 study compared FOLFOX combined with radiotherapy to the CROSS regimen
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The 2-year OS rate was 61.
8% (95%CI 55.
7-68.
5%), the median response time for responders was 40.
2 months, and the median response time for non-responders was 27.
4 months.
FOLFOX combined with radiotherapy was effective in responders best
.

Esophageal squamous cell carcinoma Although most esophageal cancer trials included patients with OAC and SCC, in the CROSS trial, the pCR rates for SCC and OAC after neoadjuvant chemoradiotherapy were 49% and 23%, respectively, suggesting the sensitivity of SCC to radiotherapy regimens Sex is higher
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Although the number of SCC patients treated is small (n = 41), its excellent response and survival rates have become benchmarks
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In a multicenter randomized controlled trial (NEOCRTE5010) including 451 patients with SCC, patients who received neoadjuvant chemoradiotherapy had a median survival of 100 months and a pCR rate of 43.
2% (P = 0.
025), which was significantly better than surgery alone
.

Due to the differences between the East and the West, in Japan, neoadjuvant chemotherapy + surgery is the standard treatment for patients with stage II-III esophageal squamous cell carcinoma, and chemoradiotherapy is mainly used for patients who refuse surgery or have contraindications to surgery
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The JCOG1109 study is a three-arm Phase III clinical trial started in 2012
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The purpose of this study is to confirm that for patients with cIB, II, III (except T4) esophageal squamous cell carcinoma, as neoadjuvant therapy, docetaxel + cisplatin + 5-FU (DCF) is superior to cisplatin + 5-FU, And cisplatin + 5-FU regimen concurrent radiotherapy (41.
4 Gy) is better than cisplatin + 5-FU
.

Instead, the debate in the West is mainly about neoadjuvant chemoradiotherapy plus surgery versus radical concurrent chemoradiotherapy, both considered equivalent in international guidelines and the Cochrane database of systematic reviews, based on two randomized controlled trials
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A German trial published in 2005 (n = 189) compared chemoradiotherapy (cisplatin, etoposide-40 Gy) in patients with cT3 and cT4 tumors, followed by surgery and continuous chemoradiation increased to 65 Gy, all patients received Initial induction chemotherapy with fluorouracil, leucovorin, etoposide, and cisplatin was given
.

Patients who underwent surgery had improved 2-year progression-free survival compared with patients who received neoadjuvant chemoradiation (64% vs 40%, P = 0.
003), but no improvement in overall survival and higher in-hospital mortality (11.
3%)
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A French randomized controlled trial (FFCD 9102) also showed that the addition of surgery did not significantly improve survival and that 3-month postoperative mortality was significantly increased
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However, an analysis of data from the (US) National Cancer Database 19,532 patients showed that, in a nonrandomized comparison, multimodality treatment with neoadjuvant chemoradiation plus surgery doubled survival compared with curative chemoradiation , in conjunction with the CROSS study and a range of related studies support the addition of surgery, especially in modern times when the risk of operative mortality is low
.

In Japan, although preoperative chemotherapy is more commonly used than neoadjuvant chemoradiotherapy plus surgery, a JCOG0909 trial used radical chemoradiotherapy as initial treatment with excellent results, and this regimen is currently used as an option for patients who are reluctant or unable to tolerate surgery.
patients preferred choice
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Because SCC is less common in Western patients, randomized controlled studies intended to include surgery as part of a control group have difficulty recruiting enough eligible patients
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Some patients with local recurrence may be candidates for salvage esophagectomy if definitive chemoradiotherapy is preferred based on guideline application, center preference, patient health status, or preference
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Encouragingly, in a large population-based study, there was no significant difference in median survival between patients who received neoadjuvant chemoradiotherapy plus surgery compared with those who underwent salvage esophagectomy for local recurrence (36 months vs 35.
5 months).
months, P = 0.
8)
.

Perioperative outcomes were also similar, with no difference in perioperative mortality
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Proton beam therapy (PBT) is emerging as an alternative to standard radiotherapy, although trial data are currently lacking
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PBT has the potential to reduce off-target side effects while maintaining the dose distribution of the primary tumor
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Early research suggests that it may be effective in OAC and SCC
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Advanced esophageal cancer targeting and immunotherapy Advances in cancer genomics, molecular biology and immunology are revolutionizing cancer treatment
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In the field of esophageal cancer, it is mainly manifested in metastatic or advanced incurable disease
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The multicenter phase III ToGA study of targeted therapy compared trastuzumab combined with chemotherapy versus chemotherapy alone as first-line therapy in patients with advanced HER2+ gastroesophageal junction cancer and gastric cancer
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The results of the study showed that chemotherapy combined with trastuzumab can improve the objective response rate (ORR), and the median progression-free survival (PFS) and median OS were significantly prolonged
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Based on this study, trastuzumab has been approved for treatment-naïve patients with HER-2-positive metastatic gastroesophageal junction cancer and gastric cancer
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The REGARD and RAINBOW studies have demonstrated that ramucirumab is currently the only targeted drug that has demonstrated efficacy as a single agent or in combination with paclitaxel in the second-line treatment of advanced gastric cancer and gastroesophageal junction adenocarcinoma
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The PETRARCA study compared perioperative trastuzumab combined with pertuzumab and chemotherapy in patients with Her2-positive esophagogastric adenocarcinoma, and compared the efficacy of FLOT chemotherapy.
The results showed that the combination of trastuzumab and pertuzumab Perioperative FLOT regimen in the treatment of HER2-positive patients with resectable esophagogastric adenocarcinoma can significantly improve the pCR and lymph node negative rates
.

Immunotherapy In recent years, immunotherapy has not only made brilliant achievements in the field of advanced esophageal cancer treatment, but also rewritten the treatment mode of esophageal cancer
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The KEYNOTE-590 study is the first global multi-center phase III clinical trial to explore the efficacy of immunotherapy combined with chemotherapy in the first-line treatment of advanced esophageal cancer
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Compared with chemotherapy alone, the PD-1 inhibitor pembrolizumab in combination with chemotherapy showed a survival benefit in patients with OAC or SCC, especially in patients with a combined positive score (CPS) ≥10
.

The CheckMate-649 study demonstrated that nivolumab combined with chemotherapy in patients with metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma can significantly improve OS and PFS, especially in patients with CPS ≥ 5
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The CheckMate-648 study is a phase III clinical trial evaluating the efficacy of first-line double immunotherapy or immunocombination chemotherapy compared with chemotherapy alone in advanced esophageal squamous cell carcinoma
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Both combination regimens achieved statistically significant overall survival benefits in PD-L1-positive patients and in all randomized populations
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The optimal biomarkers for immune checkpoint inhibitors have not been identified, and in addition to PD-L1 overexpression, microsatellite instability (MSI), high mutational burden, and DNA mismatch repair deficiency may also predict durable responses
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Will immunotherapy have more prominent advantages in adjuvant and neoadjuvant treatment of esophageal cancer? A series of studies are also underway
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CheckMate-577 is a phase III, randomized, multicenter, double-blind clinical study to evaluate the use of esophageal cancer and gastroesophageal junction cancer in patients with esophageal cancer and gastroesophageal junction cancer who have not achieved pathological complete response after neoadjuvant chemoradiotherapy after surgery.
The efficacy of monoclonal antibody as adjuvant therapy
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With at least 6.
2 months of follow-up, adjuvant nivolumab doubled the median DFS of patients to 22.
4 months and reduced the risk of disease recurrence or death by 31%, the first adjuvant immunotherapy in patients with esophageal cancer It has been shown to bring significant clinical benefit
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The CheckMate -577 study provides new high-level evidence for adjuvant therapy for locally advanced esophageal cancer, supporting adjuvant immunotherapy after neoadjuvant chemoradiotherapy, which is a major advance in the field of adjuvant therapy for esophageal cancer
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Whether this regimen is effective in neoadjuvant therapy remains to be explored, and whether adjuvant therapy complements the effect of optimal perioperative chemotherapy regimens (such as FLOT) also requires further evaluation
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SUMMARY Advances in endoscopic techniques, cancer staging, and surgery offer real hope for further early detection and cure of esophageal cancer
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The treatment of advanced esophageal cancer used to be difficult.
With the deepening of research, from chemotherapy to targeted therapy to immunotherapy, the treatment concept of advanced esophageal cancer has undergone tremendous changes
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Challenges still exist, we have enough confidence to move forward to challenges and unknowns
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Reference: Bolger JC, Donohoe CL, Lowery M, et al.
Advances in the curative management of oesophageal cancer[J].
British Journal of Cancer, 2021: 1-12.