【Mirror distance】The first shock strikes | a new era of immune combination, breaking the pattern of tumor treatment in the digestive system and escorting the lives of esophageal cancer patients

The burden of digestive tumor diseases in China is serious, and its morbidity and mortality rate are rising^[1,2], which seriously threatens the lives and health
of Chinese residents.
With the advent and popularization of molecular diagnosis and innovative therapies, the treatment of digestive tumors has made great progress, but there are still unmet needs and problems
that need to be solved urgently.
In order to further promote the development of cancer diagnosis and treatment in China's digestive system, Professor Huang Jing of the Cancer Hospital of the Chinese Academy of Medical Sciences was specially invited as the guest of honor, and joined hands with a number of clinical experts to jointly create the "Mirror Distance" academic interview column
.
In this issue, Professor Huang Jing and two discussion guests, Professor Zhang Jingdong of the Department of Gastroenterology of Liaoning Provincial Cancer Hospital and Professor Zhang Ming of the Department of Integrative Traditional Chinese and Western Medicine of Shanghai Chest Hospital, conducted academic exchanges around the hot topics of clinical diagnosis and treatment of esophageal cancer, with a view to providing reference for China's clinical practice and bringing the gospel
to more patients.

Review the overall development history and prospect of the current situation of esophageal cancer diagnosis and treatment

Professor Huang Jing

Cancer Hospital, Chinese Academy of Medical Sciences

As we all know, the number of new cases of esophageal cancer in China each year accounts for more than
half of the world.
Compared with European and American countries, esophageal cancer in China has great differences in etiology, pathological type, high incidence and other aspects, and is a malignant tumor
with "Chinese characteristics".
Therefore, to solve the problem of esophageal cancer in China, we should achieve "according to human conditions, according to local conditions", the following two professors are asked to take stock of the current diagnosis and treatment status of esophageal cancer in China and the key research data in the field.

Professor Zhang Jingdong

Liaoning Provincial Cancer Hospital

Most patients with esophageal cancer in China have a late stage of tumor when they are diagnosed, and many patients are not suitable for radical treatment
such as surgical resection.
First of all, from the perspective of national strategy, promote the "threshold forward" of tumor prevention and treatment, and detect early esophageal cancer patients as soon as possible through early diagnosis and early treatment and early screening strategies, so that patients can better obtain better survival benefits
through comprehensive treatment methods such as surgery, radiotherapy and chemotherapy.
In the prevention and treatment of early cancer screening, there is still a lot of work to be carried out in the
future.
Secondly, from a surgical point of view, esophageal cancer is a tumor with "Chinese characteristics", and the development of its surgical style is relatively slow, but with the progress of drug treatment, the choice of drugs in the perioperative stage is becoming more and more abundant, which further improves the survival benefit of
patients with esophageal cancer.
In addition, the application of radiotherapy techniques such as TOMO has improved local lesion control and strengthened other organ protection
.
From the perspective of drugs, the advent of drugs such as targeted and immunotherapy has broken the bottleneck of chemotherapy efficacy and brought earth-shaking changes to
the field of esophageal cancer.

Professor Zhang Ming

Shanghai Chest Hospital

In recent years, great progress
has been made in the early diagnosis, screening and treatment of esophageal cancer in China.
Screening for people at high risk of esophageal cancer can effectively reduce the incidence and mortality of esophageal cancer, but at present, China still lacks guidelines
for esophageal cancer screening and early diagnosis and treatment based on evidence-based medical evidence.
Therefore, the National Cancer Center has established an expert group for the formulation of guidelines for Chinese esophageal cancer screening and early diagnosis and early treatment, united with multidisciplinary experts, and based on the principles and methods recommended by the World Health Organization, formulated the "Chinese Esophageal Cancer Screening and Early Diagnosis and Early Treatment Guidelines (2022, Beijing)", which has laid a good foundation
for the standardized development of esophageal cancer screening and early diagnosis and early treatment in China.
In terms of drug therapy, targeted and immunotherapy have rewritten the treatment model
for esophageal cancer.
At present, immunotherapy has become the mainstream of esophageal cancer research, and the dosing regimen has moved from monotherapy to multimodal therapy
.
In the case of advanced esophageal cancer treatment, immunotherapy combined with chemotherapy has become the first-line standard treatment option
.
At present, five studies (such as the Checkmate-648 study) have supported the first-line treatment of advanced esophageal cancer with chemotherapy combined with PD-1 inhibitors, laying the foundation for the role and status
of immunocombined chemotherapy in the first-line treatment of esophageal cancer.
However, an analysis of the results of five studies found that not all patients were able to benefit from long-term survival from
first-line immunotherapy combined with chemotherapy.
How to enable more patients to obtain long-term survival benefits from immunotherapy is a problem that should be closely watched and urgently solved in the
future.

Immunotherapy, breaking the dilemma of advanced esophageal cancer, significantly prolongs the survival of patients

Professor Huang Jing

Cancer Hospital, Chinese Academy of Medical Sciences

Immunotherapy has been very successful in the field of esophageal cancer, and it has gradually expanded from end-of-line treatment to the front line, breaking the dilemma of advanced esophageal cancer treatment, significantly prolonging the survival period of patients, and laying the foundation for the advent of
the immune era.
Next, I would like to ask the two professors to share the clinical advantages of immunotherapy and what changes have been brought to the clinical diagnosis and treatment of esophageal cancer since the launch of immunotherapy?

Professor Zhang Ming

Shanghai Chest Hospital

Chemotherapy-based medical therapy is the mainstay of treatment in patients with advanced esophageal cancer, but chemotherapy is generally ineffective and has a short remission time, so its efficacy in postoperative adjuvant therapy is limited
.
Different from the chemotherapy mechanism, immunotherapy mainly uses the body's immune-related cells to make the body's immune cells re-play their anti-tumor role, and then kill tumor cells
.
Although immunotherapy sometimes responds slowly, it lasts longer once it does
.
Some patients can get long-term survival and even cure from it
.
Long-term follow-up data show that immunotherapy can enable some patients with advanced lung cancer to achieve long-term survival
.

The Checkmate-648 study, for example, was a global randomized Phase 3 clinical study that included 970 patients with untreated and inoperable advanced or metastatic esophageal squamous cell carcinoma, including Chinese patients
.
Regardless of the patient's PD-L1 expression level, the patient was randomly assigned to the navuriumab plus chemotherapy group, the navuriumab plus pimumab group, or the chemotherapy alone group
.
The primary endpoints of the study included overall survival (OS) and progression-free survival (PFS) in tumor cell PD-L1 expression > 1% of patients assessed by the Independent Review Center, and secondary endpoints included OS and PFS
in the overall population 。 Among patients with PD-L1 expression > tumor cells, the median OS in the navuriumab combination chemotherapy group and the chemotherapy alone group was 15.
4 months and 9.
1 months, respectively, and the ORR was 53% and 20%, respectively.
Among the overall population, the median OS of navurizumab combined with chemotherapy and chemotherapy alone was 13.
2 months and 10.
7 months, respectively, and the ORR was 47% and 27%, respectively, which truly achieved long-term survival and high remission
.

Professor Huang Jing

Cancer Hospital, Chinese Academy of Medical Sciences

Currently, the topic focuses on the current status
of first-line treatment in patients with distant metastases and incurable surgical resection.
Next, Professor Zhang Jingdong was asked to introduce the key clinical research data
of locally advanced esophageal cancer.

Professor Zhang Jingdong

Liaoning Provincial Cancer Hospital

In the past, the options for postoperative treatment of locally advanced esophageal cancer were limited, and it remains to be answered
how to develop a postoperative treatment plan for patients who cannot achieve good remission through concurrent chemoradiotherapy.
Based on this problem, the researchers conducted a placebo-controlled study, the Checkmate-577 study, which showed that postoperative navulyuzumab treatment improved the patient's non-recurrence
.
In addition, for locally advanced esophageal cancer, whether it is radiotherapy or surgery to solve only the local problem, but there is a risk of local/remote recurrence in patients after surgery, so the solution to this problem is urgently needed clinically
.
The results of the Checkmate-577 study showed that postoperative non-PCR patients benefited well from immunotherapy
.
It should be noted that there are still many questions to be further explored in the future, such as the role of immunocombined chemotherapy in the postoperative adjuvant treatment of
esophageal cancer.

Organ preservation, whether patients with locally advanced esophageal cancer surgery usher in a new dawn

Professor Huang Jing

Cancer Hospital, Chinese Academy of Medical Sciences

With the development and efficacy of pharmacotherapy, can esophageal organ function be preserved without surgery in patients who have achieved complete pathologic remission (pCR) through pharmacotherapy? On this topic, I would like to ask the two big coffee experts to combine the current situation of multidisciplinary cooperation in their own center to analyze the possibility of esophageal organ function retention, and how to achieve the "addition and subtraction" of treatment in different treatment modes, and whether "fish and bear paw" can be combined?

Professor Zhang Jingdong

Liaoning Provincial Cancer Hospital

Based on the anatomical location of the esophagus, surgical resection can have a huge impact on patients, so I personally believe that organ preservation should be considered in
the near future.
From the current evidence, preoperative three-agent chemotherapy and concurrent chemoradiotherapy can lead to pCR
in some patients.
At the same time, immunotherapy has brought good efficacy
to patients with advanced esophageal cancer.
Personally, I believe that by combining multiple treatment modes organically, it is expected to achieve the goal of preserving esophageal function and improving the quality of life of
patients.
It is important to note that treatment decisions to preserve organs must be based on clinical studies and adequate evaluation of the patient by the clinician
.

On the other hand, the choice of which type of patient to undergo surgery is still debatable
.
Because the esophagus is a cavity organ, it is still difficult
to assess whether a patient has achieved pCR status based solely on imaging results.
Whether new molecular detection methods, such as the detection of small residual lesions (MRD), can be applied to esophageal cancer in the future still need to be further explored
by researchers.
In addition, issues such as the setting of follow-up times are also worth considering
.
From personal experience, comprehensive treatment can enable some esophageal cancer patients to achieve the goal of organ retention in the future, but the questions of what treatment strategy to use and what evaluation plan to use remain to be answered
by researchers.

Professor Zhang Ming

Shanghai Chest Hospital

Tumor resection is considered an important treatment for patients with operable esophageal cancer, but in clinical practice, some patients cannot undergo surgical resection or surgery is difficult, especially in middle-aged and elderly people
with multiple comorbidities.
In addition, patients may have a longer postoperative recovery time, more surgical complications, and poor nutritional status, resulting in some patients undergoing surgical resection may not be able to recover to preoperative levels, and the prognosis is poor
.
Therefore, under the premise of effective drug treatment, trying to ensure organ function will help improve the prognosis
of some patients.

A randomized controlled study from Germany showed surgical benefit only in patients who did not achieve a complete clinical response (cCR) after chemoradiotherapy, with a 3-year survival rate improved by only 9%.

Thus, not all patients benefit from surgical resection
.
Therefore, clinicians should stratify patients to identify which patients can wait and observe after neoadjuvant therapy to preserve the esophagus and its function, and to use surgery as a means of
salvage.
When organ retention is the goal of treatment, it is also important
to accurately assess the patient's disease status after neoadjuvant therapy.
Some studies have suggested that single-point deep excavation biopsy has a higher
rate of discovery of residual tumors than traditional endoscopic biopsies.
Imaging studies also play an important role
in patient monitoring.
In addition, PET/CT, metabolic changes in tumor tissue, and liquid biopsy can all be used as tumor monitoring methods after neoadjuvant therapy, but these methods have high false-positive and false-negative rates
.

The preSANO study is a prospective, multicenter, diagnostic study of residual lesions after neoadjuvant chemoradiotherapy for esophageal cancer, which establishes models to evaluate the efficacy of neoadjuvant therapy in patients with esophageal cancer through a variety of means, including endoscopic biopsy, endoscopic ultrasonography, fine needle aspiration, and PET/CT examination
.
In order to maximize the detection of tumor cells that may be located under the mucosa, the study used single-point deep excavation biopsies at multiple points in time and multiple sites to sample early disease changes
.
The results of the study showed that the proportion of false-negative cases decreased from 31% of standard biopsies to 11%
of deep-excavation biopsies.
The esophageal cancer team at our hospital has also conducted the preSANO study and expects the results to be more instructive
in clinical practice.
In addition, our discipline has explored
the pattern of organ retention in cervical esophageal cancer under the concept of organ retention.
Although the project is still in its infancy, it is believed that it will play a greater role in esophageal function preservation as the rate of combination therapy cCR continues to increase, enabling more patients to achieve better survival benefits
.

At present, the safety of neoadjuvant immunotherapy combined with chemotherapy is mostly controllable, but the pCR rate varies widely
between clinical studies.
This may be related to the combination of chemotherapy regimens, chemotherapy doses, and the sequence of chemotherapy combined with immunotherapy, which in turn affects the cCR rate
.
Therefore, future neoadjuvant immunologic combination chemotherapy regimens should be continuously optimized to increase cCR rates, providing greater possibilities
for esophagus preservation.
At the same time, it is expected that more randomized trials of standard surgery can be carried out at home and abroad through close monitoring, and it is believed that the era of organ preservation of esophageal cancer is no longer far away
with the assistance of multiple disciplines.

Complementing each other, the organic combination of traditional Chinese medicine and Western medicine jointly protects the survival prognosis of esophageal cancer patients

Professor Huang Jing

Cancer Hospital, Chinese Academy of Medical Sciences

Professor Zhang Ming is a young talent in the field of integrative oncology in China, and has unique insights in the anti-tumor treatment of integrative Chinese and Western medicine
.
Have you asked Professor Zhang Ming to talk about the treatment experience of tumors, especially esophageal cancer patients, from the perspective of integrated Chinese and Western medicine?

Professor Zhang Ming

Shanghai Chest Hospital

At present, many Chinese patients regard traditional Chinese medicine as one of the treatment methods for esophageal cancer, and many Chinese medicine practitioners have also conducted a large number of clinical research and observation, and have achieved certain experience and achievements in the early intervention of esophageal cancer, combined surgery and radiotherapy and chemotherapy, such as the study of radioactive oral mucositis caused by traditional Chinese medicine to improve radiotherapy was published in the authoritative journal of radiotherapy "American Society of Radiotherapy and Oncology (ASTRO)"
.
In addition, based on the clinical evidence of some traditional Chinese medicine preparations and monomers, traditional Chinese medicine is recommended
by the domestic clinical diagnosis and treatment guidelines for liver cancer.
It is believed that in the near future, with the continuous improvement of the research level of traditional Chinese medicine, more effective Chinese medicine programs, methods and clinical research results for esophageal cancer will emerge
.
In addition, Chinese medicine is mainly based on dialectical treatment in the clinic, but it is also necessary to absorb Western medicine treatment and organically combine
.
In clinical observation, some patients have improved their quality of life and prolonged survival
through the treatment of integrated traditional Chinese and Western medicine.

summary

Professor Huang Jing

10 years ago, the drug treatment of esophageal cancer was relatively less than that of other tumors (such as lung cancer, etc.
), but in the past 10 years, the drug treatment of advanced and locally advanced esophageal cancer has made great progress, and the treatment mode has also undergone a fundamental change
.
Since 2013, global oncology research has grown by a spurt, including an increase in esophageal cancer-related research, and it is expected that more patients can participate in clinical research and bring more hope
for treatment.
At the same time, it is also expected that the drug treatment and comprehensive treatment of esophageal cancer will make progress with the joint efforts of Chinese colleagues to provide a better treatment model for esophageal cancer patients in the
world.

Expert profile

Professor Huang Jing

• Deputy Director of the Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences

• Doctor of Medicine, doctoral supervisor

• Central Health Consultation Specialist

• Vice Chairman and Secretary General of the CSCO Esophageal Cancer Expert Committee

• Director of the Chinese Society of Clinical Oncology (CSCO).
  

• Vice Chairman of the Oncology Rehabilitation Branch of the Chinese Society of Gerontology and Geriatrics

• Vice Chairman of the Colorectal Oncology Professional Committee of Beijing Medical Doctor Association

• Member of the Standing Committee of the Esophageal Cancer Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Colorectal Oncology Professional Committee of the Chinese Medical Doctor Association

• Vice Chairman of the Internal Medicine Treatment Committee of the Colorectal Oncology Professional Committee of the Chinese Medical Doctor Association

• Deputy head of the Gastric Cancer Group of the Cancer Prevention and Treatment Expert Committee of the Cross-Strait Medical and Health Exchange Association

• Director of Beijing Heathco Clinical Oncology Research Foundation

• Member of Beijing Chaoyang District Youth Federation

• He is the editorial board member of the Chinese Electronic Journal of Colorectal Diseases, the editorial board member of the Journal of Cancer Progression, and the deputy editor of the Chinese Journal of Biochemical Drugs

Expert profile

Professor Zhang Jingdong

• Chief physician and doctoral supervisor

• Director of the Second Ward of the Department of Gastroenterology, Liaoning Provincial Cancer Hospital

• Vice Chairman of Chemotherapy Committee of China Medical Education Association

• Member of the Colorectal Cancer Oncology Professional Committee of the Chinese Medical Doctor Association for the first term of the Colorectal Cancer Liver Metastasis and Multidisciplinary Diagnosis and Treatment (MDT) Professional Committee

• Member of the Standing Committee of the Precision Medicine and MDT Professional Committee of the Chinese Association of Research Hospitals

• Member of the MDT Committee of the Surgeon Branch of the Chinese Medical Doctor Association

• Member of the Standing Committee of the Abdominal Tumor Professional Committee of the Chinese Medical Education Association

• Vice Chairman of the Special Committee of Digestive Tumors of Beijing Cancer Prevention and Control Research Association

• Member of the Standing Committee of the CSCO Colorectal Cancer Expert Committee

• Member of the CSCO Antineoplastic Drug Safety Committee

• Member of the CSCO Clinical Research Expert Committee

• Chairman of the Chemotherapy Committee of Liaoning Anti-Cancer Association

• Vice Chairman of Oncology Branch of Liaoning Medical Association

• Vice Chairman of the Tumor Prevention and Control Professional Committee of Liaoning Preventive Medicine Association

• Chief physician, professor, doctoral supervisor

• Director of the Second Ward of the Department of Gastroenterology, Liaoning Provincial Cancer Hospital

Expert profile

Professor Zhang Ming

• Director of the Department of Integrative Traditional Chinese and Western Medicine of Shanghai Chest Hospital

• Ph.
  D.
  , Chief Physician, Master Supervisor

• Visiting Scholar, University of Maryland, USA

• Standing Director of the Cancer Palliative Care Research Committee of the World Federation of Traditional Chinese Medicine

• Standing Director of the Expert Committee on Traditional Chinese Medicine Work in the General Hospital of the World Federation of Chinese Medicine

• Young member of the Oncology Committee of the Chinese Association of Integrative Traditional and Western Medicine

• Member of the Standing Committee of the Oncology Branch of the Chinese Association for Ethnic Medicine

• Vice Chairman of the Oncology Committee of Shanghai Association of Traditional Chinese Medicine

• Secretary General of Traditional Medicine Professional Committee of Shanghai Anti-Cancer Association

• Vice Chairman of Tumor Branch of Shanghai Traditional Medicine Engineering Association

• He is a member of the Standing Committee of the Association for the Promotion of Integrated Traditional Chinese and Western Medicine in the General Hospital of Shanghai Association of Integrative Traditional Chinese and Western Medicine

• Standing Director of Youth Council of Shanghai Anti-Cancer Association

• He is a member of the Traditional Chinese Medicine Working Committee of Shanghai Association of Integrative Traditional Chinese and Western Medicine

• He has long been engaged in clinical and basic research on the prevention and treatment of malignant tumors by traditional Chinese medicine and integrated traditional Chinese and western medicine
  .
  

• As the person in charge, he has undertaken 14 national, provincial, ministerial and bureau-level projects, published more than 30 papers, edited 2 monographs, participated in the editing of 2 monographs, and participated in the compilation of
  7 books.
  

• Reviewer of Chinese Journal of
  Oncology, Shanghai Journal of Traditional Chinese Medicine, etc.
  

• As the main completer, he won the second prize of the Outstanding Scientific Research Achievement Award (Science and Technology) of Colleges and Universities, the third prize of the Science and Technology Progress Award of the Chinese Association of Traditional Chinese Medicine, the third prize of the Shanghai Science and Technology Progress Award, and the third prize of the Shanghai Medical Science and Technology Award
  .